EA041715B1 - METHODS FOR THE TREATMENT OF uterine fibroids and heavy menstrual bleeding - Google Patents

Description

Cross-references to related applications

The present patent application claims priority over U.S. Provisional Application No. 62/402034, filed September 30, 2016; U.S. Provisional Application No. 62/402055, filed September 30, 2016; U.S. Provisional Application No. 62/402150, filed September 30, 2016; U.S. Provisional Application No. 62/492839, filed May 1, 2017; and U.S. Provisional Application No. 62/528409, filed July 3, 2017, the contents of which are hereby incorporated by reference in their entirety.

Technical field

The present invention relates generally to methods of treating estrogen sensitive conditions, and more particularly relates to methods of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a subject in need thereof. The present disclosure also relates to methods for treating one or more side effects of the administration of a gonadotropin-releasing hormone (GnRH) antagonist.

State of the art

Hormone-sensitive diseases of the reproductive system, such as uterine fibroids, endometriosis, and adenomyosis, can have a significant impact on the quality of life of many women. Under these conditions, hormones such as estrogens and progesterone may influence the severity and/or frequency of symptoms.

For example, uterine fibroids are benign, estrogen-sensitive tumors (fibroids) that grow in the muscular wall of the uterus in about 25% of women of reproductive age. Most uterine fibroids are asymptomatic, but about 25% of women with uterine fibroids develop symptoms that require treatment. In addition to an individual's genetic predisposition, estrogens, progesterone, and human growth hormone may play important roles in regulating fibroid growth. Although uterine fibroids are benign tumors that are often asymptomatic, they can cause wasting symptoms such as abnormal uterine bleeding, heavy or painful periods, anemia, abdominal pain, back pain, increased abdominal girth and bloating, frequent urination or urinary retention, constipation or painful bowel movements, pregnancy loss, painful intercourse and, in some cases, infertility. Endometriosis is a gynecological disease in which cells of the uterine lining grow outside the uterine cavity, most commonly on the ovaries. Endometriosis is a chronic and usually progressive disease that occurs almost exclusively in women of reproductive age and can cause non-menstrual pelvic pain, dysmenorrhea, dyspareunia, and infertility. It is estimated to affect 10% of fertile women and 20 to 40% of infertile women. Endometriosis lesions outside the uterus exhibit a hormonal response pattern similar to that in the uterine mucosa. During the menstrual cycle, the lesions grow, differentiate, and enter the abdominal cavity, thereby causing a cascade of inflammation that can lead to non-menstrual pelvic pain, pain during menstruation, painful intercourse, and, in some cases, infertility. Adenomyosis is a condition other than endometriosis in which endometrial tissue is found in the myometrium (the muscular layer of the uterus). Among other symptoms, patients with adenomyosis may experience heavy menstrual bleeding (MPB) and chronic pain.

Non-surgical treatment for these conditions may include non-steroidal anti-inflammatory drugs, oral contraceptives, and GnRH agonists. Surgical interventions may include hysterectomy and myomectomy and may be used when non-surgical therapy fails to treat symptoms or no longer works.

Because these conditions are hormone sensitive, there is interest in treatments that involve regulation of one or more hormones such as estrogen or progesterone, for example using a GnRH agonist (GnRH receptor agonist) or GnRH antagonist (GnRH receptor antagonist). It is difficult enough to achieve a balance of estrogen and progesterone that alleviates one or more of the symptoms while avoiding the significant side effects of hormone suppression. For example, if estradiol levels fall below a certain threshold, loss of bone mineral density (BMD) may occur. Loss of bone mineral density over time can lead to serious negative consequences, such as an increased risk of bone fracture or osteoporosis. Suppression of progesterone without simultaneous suppression of estrogen can lead to endometrial hyperplasia, which is a risk factor for endometrial cancer. Conversely, estrogen- or progesterone-sensitive symptoms and disorders may be exacerbated if estrogen or progesterone levels exceed the upper therapeutic limit. Balancing such hormonal interactions is further complicated by the sensitivity of the conditions themselves, as not all hormone-responsive gynecological conditions are sensitive to the same levels of estrogen or progesterone. For example, certain conditions exhibit a hierarchy of estrogen sensitivity—fibroids (eg, uterine fibroids) are generally more estrogen sensitive than endometriosis (see R. L. Barbieri, Am. J. Obstet. Gynecol (1992), 166(2):740-745 ). In addition, some symptoms of one condition may be relieved more quickly by progesterone suppression, while others may

- 1 041715 ptomes of the same condition may respond more quickly to estrogen suppression. Thus, the development of a therapy that can be used to treat more than one condition or more than one symptom, or a combination thereof, is a challenge.

GnRH peptide agonists such as leuprolide acetate (sold by AbbVie Endocrine Inc. under the trademarks LUPRON and LUPANETA) are commonly used to treat benign sex hormone dependent gynecological diseases such as endometriosis and uterine fibroids. However, the suppressive effect of GnRH agonists on sex hormone secretion is usually preceded by a transient increase in gonadotropin secretion. This is followed by a decrease in sensitivity (desensitization) in the pituitary gland and a decrease in the secretion of the sex hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland. The initial rise in hormone levels caused by GnRH agonists can lead to a temporary worsening of symptoms, known as a clinical flare. This initial stimulatory (or flare) phase, in which LH and FSH are secreted in supraphysiological amounts, may be a problem in sex steroid dependent diseases. Temporary worsening of symptoms may include worsening BMI. The effectiveness of GnRH agonist therapy begins to appear approximately 3-4 weeks after the initial dose. In addition, the complete suppression of estrogen resulting from treatment with GnRH agonists can lead to unacceptable side effects, in particular accelerated loss of bone mineral density. GnRH agonists also cannot be administered orally because they are peptides. In addition, these agonists are only available as depot formulations and waning of effect may occur after several months.

In contrast, GnRH antagonists exhibit classical competitive blockade of GnRH receptors on the cell membrane of gonadotropic cells instead of down-regulation and desensitization. Inhibition of GnRH receptors reduces the release of gonadotropins, thereby reducing the production of estrogen and progesterone in women. Therefore, GnRH antagonists can have a rapid onset of action and achieve hormone suppression faster than GnRH agonists. Without any intrinsic agonist activity, the clinical flare associated with GnRH agonists can be completely avoided. In addition, the effects of GnRH antagonists may be reversible and lead to a rapid recovery of gonadal function after discontinuation. Therefore, GnRH antagonists may provide greater control for patients and their physicians regarding the elimination of any unwanted side effects of hormone suppression.

For each individual patient, the GnRH antagonist treatment strategy has been to balance either using a lower dose of the antagonist, such as a lower dose of elagolix, or a higher dose with the addition of reversal therapy, but still not the maximum suppressive dose, or approach adopted by Obseva (representing an individual titration for each patient). The body of many women shows an insufficient response to such procedures. Thus, current GnRH antagonist therapies result in significant variability in female body response caused by incomplete suppression of the GnRH antagonist. In many women, it is likely that the present methods and uses can avoid the causes of therapy variability caused by incomplete suppression of the GnRH antagonist, which would otherwise add another variability in addition to the variability caused by the dosage of hormones administered in combination. At highly suppressive doses, variability due to incomplete suppression can be minimized or eliminated, and variability can be due to hormone dosage alone.

There have been attempts to combine a hormone replacement drug with an active ingredient that suppresses sex hormone levels in order to mitigate the effect that the active ingredient has on loss of bone mineral density. However, current GnRH agonists are usually provided in a dosage form that is separate from the hormone replacement drug, such as an injection followed by either a capsule or tablet. This creates compliance issues for subjects who must remember to take not only the active ingredient product but also the hormone replacement drug in a separate dosage form. This raises serious safety concerns when chronically administered with a GnRH agonist or antagonist, as any adverse effects, such as loss of bone mineral density, due to non-compliance with the regimen, will be observed over a long period of time. For these and additional reasons, the U.S. Food and Drug Administration has to date not permitted the use of long-term GnRH agonist or antagonist regimens. As described above, GnRH agonist treatment typically has an initial flare period. The introduction of a hormone replacement drug that begins at the beginning of treatment with a GnRH agonist can further aggravate the symptoms of a hormonal flare. Delaying the administration of a hormone replacement drug until hormone levels are suppressed after a flare-up can still lead to vasomotor and other symptoms. Selective progesterone receptor modulators (SPRMs) are another class of compounds that can be used to modulate the effects of hormones. SMRPs are substances that

- 2 041715 which can have a mixed antagonistic and agonistic effect on progesterone receptors in a tissue-specific manner.

Achieving a balance of hormones, symptoms, and side effects when treating hormone-sensitive conditions such as uterine fibroids, endometriosis, or adenomyosis can be difficult, as discussed above. Simply combining any GnRH antagonist, GnRH agonist, or SPRM with a hormone replacement drug may not result in sufficient hormone suppression to adequately treat one or more symptoms, or may not maintain hormone levels high enough to avoid one or more detrimental side effects. In some cases, the plasma concentration of one or more hormones in a subject may change during each day, so that neither adequate treatment nor the prevention of certain side effects is achieved. In other cases, a change or imbalance over a longer period of time, such as over several months, may prevent long-term use of therapy, such as more than 3, 6, or 12 months. For example, some treatments are prescribed for intermittent use only, requiring the patient to stop treatment for a certain period of time to reduce the risk of detrimental side effects such as endometrial hyperplasia or loss of bone mineral density. Therapy using such therapies may also require additional monitoring for unwanted side effects, such as ultrasound, endometrial biopsy, and/or bone densitometry.

Thus, what is needed is a method for treating hormone-sensitive gynecological conditions such as uterine fibroids, endometriosis, or adenomyosis, or symptoms associated with such conditions, that effectively treats the condition or symptom while minimizing or avoiding one or more of the side effects that are commonly associated with GnRH antagonist, and helps ensure the correct dosage so that the GnRH antagonist can be safely used for long-term therapy and as an alternative to invasive surgical procedures. In addition, a non-peptide preparation is needed that can be administered orally, preferably once a day.

The essence of the invention

Instead of trying to achieve a target hormone range by administering specific doses of a GnRH antagonist to lower hormone levels, the present methods and uses can use a highly suppressive dose that, in combination with the hormonal drugs described herein, can consistently provide hormone levels in a range that is simultaneously effective for the treatment of symptoms of, for example, endometriosis, uterine fibroids, adenomyosis, etc., as described herein, while minimizing the side effects typically associated with GnRH antagonist treatment. Thus, when used in the methods and applications described herein, highly suppressive doses in combination with hormone administration can result in a narrower distribution of estradiol levels for many women who are effective for the symptoms of the conditions described herein, and at the same time they have one or more side effects of GnRH antagonist treatment are minimized.

In one aspect, provided herein is a combination preparation containing about 10 to about 60 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; from about 0.5 to about 2 mg of estradiol, or the equivalent amount of estradiol; and about 0.01 to about 5 mg progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding or pain associated with uterine fibroids, endometriosis or adenomyosis in a premenopausal woman.

In some embodiments, treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks. In certain embodiments, the progestin is norethisterone or a salt thereof in an amount of from about 0.1 to about 0.5 mg. In yet other embodiments, the combination preparation contains from about 20 to about 50 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In other embodiments, the combination preparation contains about 40 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1 ,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the combination preparation contains about 1 mg of estradiol or an equivalent amount of estradiol. In other embodiments, the progestin is norethisterone acetate (NETA) and the combination formulation contains about 0.5 mg of NETA.

In other embodiments, the combination formulation contains about 0.5 mg NETA, about 1 mg estradiol, and about 40 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or corresponding

- 3 041715 a total amount of its pharmaceutically acceptable salt.

In certain embodiments, the combination preparation is in a unit dosage form. In other embodiments, the combination preparation contains separate dosage forms that are administered together.

In yet other embodiments, prior to administration of the combination preparation, treatment further comprises oral administration once daily of about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of it pharmaceutically acceptable salt for at least 4 consecutive weeks and up to 24 consecutive weeks.

In some embodiments, the combination preparation is for use in the treatment of endometriosis. In other embodiments, the combination preparation is for use in the treatment of adenomyosis. In still other embodiments, the combination preparation is for use in the treatment of uterine fibroids.

In some embodiments, the combination preparation is for use in the treatment of heavy menstrual bleeding. In certain embodiments, heavy menstrual bleeding is associated with a non-cancerous etiology. In some embodiments, heavy menstrual bleeding is associated with one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

In some embodiments, the combination preparation is for the treatment of pain associated with uterine fibroids, endometriosis, or adenomyosis. In certain embodiments, the pain is associated with endometriosis. In some embodiments, the pain is chronic pain, dyspareunia, pain associated with defecation, or pain associated with urination.

In another aspect, provided herein is a combination formulation comprising about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, from about 0, 5 to about 2 mg of estradiol or an equivalent amount of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for maintaining bone mineral density in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administration of N-(4-(1 -(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d] pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

In one other aspect, provided herein is a combination formulation containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy- 3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; from about 0.5 to about 2 mg of estradiol, or the equivalent amount of estradiol; and about 0.01 to about 5 mg progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: hot flashes, night sweats and other vasomotor symptoms in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis or profuse menstrual bleeding, administration of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks.

In another aspect, provided herein is a combination formulation comprising about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, from about 0, 5 to about 2 mg of estradiol or an equivalent amount of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of maintaining one or both of the following: lipid profile or range of blood glucose levels in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, administration of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

- 4 041715

In some embodiments, the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

In other embodiments, one or more of the following in a premenopausal woman: the lipid profile or range of blood glucose levels does not change in a clinically significant manner after or during treatment compared to the lipid profile or range of blood glucose levels before treatment.

In a further aspect, provided herein is a combination preparation containing about 10 to about 60 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of treating one or both of vulvovaginal atrophy or vaginal dryness in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N -(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

In yet another aspect, provided herein is a combination preparation containing about 10 to about 60 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3 -pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use for the treatment of headaches in a premenopausal woman in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding, by administration of N-(4-(1 -( 2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine -6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks.

In certain embodiments, the headache is a migraine associated with the menstrual cycle.

In another aspect, provided herein is a combination formulation comprising about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of contraception in a premenopausal woman in need of it.

In some embodiments, the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

In some embodiments of any of the above aspects, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg. In certain embodiments, the combination preparation contains from about 20 to about 50 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2 ,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In yet other embodiments, the combined preparation contains about 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2, 4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the combination preparation is in a unit dosage form. In other embodiments, the combination preparation contains separate dosage forms that are administered together.

In some embodiments, the combination preparation contains about 1 mg of estradiol or an equivalent amount of estradiol. In other embodiments, the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

In certain embodiments, the combination formulation contains about 0.5 mg NETA, about 1 mg estradiol, and about 40 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

- 5 041715 or the corresponding amount of its pharmaceutically acceptable salt.

In some embodiments, prior to administering the combination preparation, the method further comprises administering orally once daily about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

In another aspect, provided herein is a combination formulation comprising about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for achieving amenorrhea in a premenopausal woman for at least 12 or at least 24 weeks. In some embodiments, the method comprises orally administering the combination preparation to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks.

In another aspect, provided herein is a combination formulation comprising about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for increasing fertility or preventing miscarriage in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-( 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering the combination drug orally to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks and stopping treatment for at least 4 weeks while the woman attempts or reattempts to conceive.

In yet another aspect, provided herein is a combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy- 3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in the treatment of anemia in a premenopausal woman. In one embodiment, the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks.

In some embodiments, a premenopausal woman has heavy menstrual bleeding. In certain embodiments, heavy menstrual bleeding is associated with a non-cancerous etiology.

In other embodiments, the premenopausal woman has one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or symptoms associated with one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

In some embodiments of any of the above aspects, administration of the combination preparation is once a day for at least 48 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks.

In some embodiments, the combination drug is suspended for conception and pregnancy. In some embodiments, administration is resumed after delivery.

In other embodiments, the combined preparation is administered prior to a meal. In some embodiments, the drug is taken at least 30 minutes before meals or on an empty stomach. In some embodiments, the combination preparation is administered at least 1 hour before a meal or at least 2 hours after a meal.

In some embodiments, the combination preparation is administered in one or more immediate release dosage forms.

In yet another aspect, provided herein is a combination preparation containing from about 65 to about 140 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy- 3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol, or an equivalent amount of estradiol, and about 0.5 to

- 6 041715 about 2.0 mg of norethisterone acetate or another progestin, for simultaneous or sequential use in the treatment of symptoms of uterine fibroids or endometriosis in a premenopausal woman.

In some embodiments, the treatment comprises administering the combination preparation to said woman once a day. In some embodiments, administration of the combination preparation suppresses the endometrium. In some embodiments, the combination preparation is in unit dosage form.

In another aspect, provided herein is a combination preparation containing about 65 to about 140 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol, or an equivalent amount of estradiol, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: hot flashes and other vasomotor symptoms and loss of bone mineral density in a premenopausal woman who continues to show one or more of the following symptoms: hot flashes and other vasomotor symptoms and loss of bone mineral density , orally administered once daily combinations of about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, about 1.0 mg of estradiol, and about 0.5 mg of norethisterone acetate, the treatment comprising administering the combined preparation to said premenopausal woman. In one embodiment, administration of the combination preparation suppresses endometrial tissue.

In one aspect, a method is provided for treating one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman in need thereof, the method comprising administering orally to the premenopausal woman once a day for at least 24 consecutive weeks of the combination, containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1 ,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (compound 1) or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin. In some embodiments, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg.

In some embodiments, a premenopausal woman is being treated for endometriosis. In other embodiments, a premenopausal woman is being treated for adenomyosis. In yet other embodiments, a premenopausal woman is being treated for uterine fibroids.

In another aspect, a method is provided for treating heavy menstrual bleeding in a premenopausal woman in need thereof, the method comprising administering orally to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing from about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In some embodiments, heavy menstrual bleeding is associated with a non-cancerous etiology. In certain embodiments, heavy menstrual bleeding is associated with one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

In another aspect, this document provides a method of treating pain associated with uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman in need thereof, the method comprising administering orally to the premenopausal woman in need thereof once daily for at least at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In some embodiments, the pain is associated with endometriosis. In some embodiments, the pain is chronic pain, dyspareunia, pain associated with defecation, or pain associated with urination.

In certain embodiments of the foregoing methods, upon cessation of treatment, said premenopausal woman will become pregnant or give birth. In some embodiments, prior to treatment, the premenopausal woman experienced one or more miscarriages, or an inability to conceive, or a combination of these conditions.

In one aspect, a method is provided for maintaining bone mineral density in a premenopausal woman in need thereof who is receiving treatment from one or more of the following:

- 7 041715 stations: uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding, administration of No. pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a woman in premenopausal women in need thereof, once daily for at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of Na(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl )-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin.

In another aspect, a method is provided for treating one or more of the following conditions: hot flashes, night sweats, or vasomotor symptoms other than hot flashes or night sweats in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids , endometriosis, adenomyosis, or heavy menstrual bleeding, by administration of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof , once daily for at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-( 6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or according to a total amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In yet another aspect, a method is provided for maintaining one or both of the lipid profile or range of blood glucose levels in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or profuse menstrual bleeding, administration of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2, 3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof once a day for at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of pharmaceutically acceptable salt; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; wherein one or more of the following in a premenopausal woman: the lipid profile or range of blood glucose levels does not change in a clinically significant manner after or during treatment compared to the lipid profile or range of blood glucose levels before treatment.

In another aspect, a method is provided for treating one or both of the following conditions: vulvovaginal atrophy or vaginal dryness in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof once a day for at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4 -dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In yet another aspect, there is also provided a method of treating headache in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4(1 - (2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine -6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof once daily for at least 24 consecutive weeks of a combination containing from about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2 ,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of pharmaceutically

- 8 041715 acceptable salt, from about 0.5 to about 2 mg of estradiol or the corresponding amount of the equivalent of estradiol and from about 0.01 to about 5 mg of progestin. In some embodiments, the headache is a migraine associated with the menstrual cycle.

In one aspect, a method of contraception is provided for a premenopausal woman in need thereof, the method comprising administering orally to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing about 10 to about 60 mg N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[ 2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In certain embodiments of any of the above methods, the progestin is norethisterone or a salt thereof in an amount of from about 0.1 mg to about 0.5 mg. In other embodiments, the combination contains about 20 to about 50 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the composition contains about 40 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1, 2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments of any of the methods above, the combination is in unit dosage form. In other embodiments of the methods presented above, the combination contains separate dosage forms that are administered together.

In other embodiments of any of the above methods, the combination contains about 1 mg of estradiol or the corresponding amount of estradiol equivalent.

In other embodiments of any of the above methods, the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

In certain embodiments of any of the above methods, the combination contains 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3 -(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof .

In some embodiments of any of the above methods, treatment results in one or both of contraceptive effects and amenorrhea during treatment.

In other embodiments of any of the above methods, after at least 4 consecutive weeks of administration of the combination, ovarian production of estrogen in a premenopausal woman is suppressed.

In still other embodiments of any of the above methods, after at least 4 consecutive weeks of administration of the combination, the serum estradiol concentration in a premenopausal woman is between 20 and 50 pg/ml between daily doses of the combination.

In certain embodiments of any of the above methods, after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone in a premenopausal woman is suppressed.

In still other embodiments of any of the above methods, after at least 4 consecutive weeks of administration of the combination, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/ml between daily doses of the combination.

In some embodiments of any of the above methods, for a premenopausal woman with uterine fibroids, one or both of the number and size of uterine fibroids are reduced during and/or after treatment compared to one or both of the number and size of uterine fibroids before treatment.

In some embodiments of any of the above methods, prior to administering the combination, the method further comprises orally administering once daily about 10 to about 60 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino) methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or the corresponding amount of its pharmaceutically acceptable salt for at least 4 consecutive weeks and up to 24 consecutive weeks.

In some embodiments of any of the above methods, during and/or after treatment, a premenopausal woman experiences improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, irregular menses, bleeding, inflammation, pain, fatigue, obstruction urinary frequency, urinary frequency, urinary incontinence, constipation, anxiety, sleep disturbances, quality of life, activities of daily living, female sexual dysfunction, and depression. In some embodiments, the pain is chronic pain. In other embodiments, the pain is dyspareunia. In other further embodiments, the pain is pain on defecation or pain on urination.

In one aspect, a method for achieving amenorrhea in a premenopausal woman in need of

- 9 041715 in this, for at least 12 or at least 24 weeks, and the method contains oral administration to a woman in premenopause in need of it, once a day for at least 12 or at least 24 consecutive weeks a combination containing about 10 to about 60 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In another aspect, a method is provided for preventing miscarriage in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1-(2, 6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl) phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising administering orally to a premenopausal woman once a day for at least 12 or at least 24 consecutive weeks of a combination containing from about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, from about 0.5 to about 2 mg of estradiol, or an appropriate amount of the equivalent alenta estradiol and about 0.01 to about 5 mg progestin; and stopping treatment for at least 4 weeks while the woman tries to conceive again.

In yet another aspect, a method is provided for increasing fertility in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1(2 ,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising administering orally to a premenopausal woman once a day for at least 12 or at least 24 consecutive weeks of a combination containing from about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount in the equivalent of estradiol and from about 0.01 to about 5 mg of progestin; and stopping treatment for at least 4 weeks while the premenopausal woman is trying to conceive. In some embodiments, upon cessation of treatment, said premenopausal woman will become pregnant or give birth.

In certain embodiments, prior to treatment, the premenopausal woman experienced one or more miscarriages, an inability to conceive, or a combination of these conditions.

In one aspect, a method of treating anemia in a premenopausal woman in need thereof is provided, the method comprising administering orally to the premenopausal woman once daily for at least 12 or at least 24 consecutive weeks of a combination comprising about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In certain embodiments, a premenopausal woman has heavy menstrual bleeding. In some embodiments, heavy menstrual bleeding is associated with a non-cancerous etiology.

In some embodiments of the method described above, a premenopausal woman has one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or symptoms associated with one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

In certain embodiments of any of the above methods, the combination is administered once a day for at least 48 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks.

In other embodiments of any of the above methods, administration of the combination is suspended for conception and pregnancy. In some embodiments, administration is resumed after delivery.

In some embodiments of any of the above methods, the combination is administered prior to a meal. In other embodiments of any of the above methods, the introduction is carried out at least 30 minutes before meals or on an empty stomach. In some embodiments of any of the above methods, the combination is administered at least 1 hour before a meal or at least 2 hours after a meal.

In certain embodiments of any of the above methods, the combination is administered in one or more immediate release dosage forms.

In other embodiments of any of the above methods, the woman's bone mineral density in

- 10 041715 premenopausal woman during and/or after treatment is within ±2% of the bone mineral density of a premenopausal woman before treatment.

In another aspect, this document also provides a method of treating a premenopausal woman with symptoms of uterine fibroids or endometriosis, the method comprising administering to said woman once daily a combination of about 65 to about 140 mg of N-(4-(1-(2,6 -difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl) phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol equivalent, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin, and wherein administration of the combination suppresses the endometrium. In some embodiments, the combination is effective in treating symptoms of uterine fibroids or endometriosis and reducing one or more side effects, including one or more of the following: hot flashes, night sweats, loss of bone mineral density, or vasomotor symptoms other than hot flashes or night sweats. In certain embodiments, the combination is in unit dosage form.

In yet another aspect, this document provides a method of treating a premenopausal woman who continues to experience one or more of the following: hot flashes, night sweats, vasomotor symptoms other than hot flashes or night sweats, or loss of bone mineral density when administered orally once a day. day of combination about 10 to about 60 mg N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, about 1.0 mg of estradiol and about 0.5 mg of norethisterone acetate wherein the method comprises administering to said premenopausal woman a combination of about 65 to about 140 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy -3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol equivalent, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin, and wherein administration of the combination inhibits endometrial tissue.

In one aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of one or more of the following conditions: uterine fibroids, endometriosis or adenomyosis in a premenopausal woman.

In another aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-Tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament for the treatment of heavy menstrual bleeding in a woman in premenopause.

In yet another aspect, this document provides the use of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of pain associated with uterine fibroids, endometriosis or adenomyosis, in a premenopausal woman. In some embodiments, the pain is chronic pain, dyspareunia, pain associated with defecation, or pain associated with urination.

In yet another aspect, this document provides the use of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament for maintaining bone mineral density in premenopausal women.

In another aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of one or more of the following conditions: hot flashes, night sweats and other vasomotor symptoms in a premenopausal woman.

In one aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for maintaining one or both of lipid profile or range of blood glucose levels in a premenopausal woman.

- 11 041715

In another aspect, this document provides the use of N(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1 ,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for the treatment of one or both of the following conditions : Vulvovaginal atrophy or vaginal dryness in a premenopausal woman.

In yet another additional aspect, this document provides the use of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament for the treatment of headaches in a woman in premenopause.

In one aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or estradiol equivalent and progestin for the manufacture of a contraceptive medicament for a premenopausal woman.

In some embodiments, the premenopausal woman was treated with N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding.

In another aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for achieving amenorrhea in a premenopausal woman .

In one aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament for the prevention of miscarriage in a premenopausal woman .

In yet another aspect, this document provides the use of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for increasing fertility in a woman in premenopause.

In another aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament for the treatment of anemia in a premenopausal woman .

In some embodiments of any of the above uses, the drug formulation contains about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

In one aspect, this document provides the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent of estradiol and norethisterone acetate or other progestin for the manufacture of a medicament for the treatment of symptoms uterine fibroids or endometriosis in a premenopausal woman. In some embodiments, the drug formulation contains about 65 to about 140 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2, 4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol; and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin.

In yet another aspect, this document provides the use of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or the equivalent of estradiol and norethisterone acetate or other progestin for the manufacture of a medicament for treatment premenopausal women who continue to use

- 12 041715 experience one or more of the following: hot flashes and other vasomotor symptoms or loss of bone mineral density when administered orally once a day a combination of about 10 to about 60 mg N(4-(1-(2,6-difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 1.0 mg of estradiol and about 0.5 mg of norethisterone acetate, wherein the drug formulation contains from about 65 to about 140 mg of N-(4-(1-(2, 6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl) phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol equivalent; and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin.

Other objects and advantages of the present disclosure will become apparent from the detailed description that follows.

Brief description of graphic materials

Embodiments of the present disclosure are described below in more detail with reference to the accompanying drawings, which show some, but not all, embodiments of the disclosure. The same numbers refer to the same elements throughout the document.

In FIG. 1 is an exemplary menstrual blood loss graphical evaluation table for estimating the amount of menstrual blood loss.

In FIG. 2 is an exemplary numerical rating scale (NRS) for measuring pain in uterine fibroids.

In FIG. 3A-C show questions from an exemplary Uterine Fibroid Symptom (UFS) and Health-Related Quality of Life (QOL) questionnaire used to analyze quality of life.

In FIG. 4 is a table of dose escalation schedules for cohorts 1-10 according to Example 4.

In FIG. 5A-C are tables of plasma pharmacokinetic (PK) parameters for cohorts 1-6 according to Example 4.

In FIG. 6A-C are tables of plasma PK parameters for cohort 7 according to example 4.

In FIG. 7A-F are tables of plasma PK parameters for cohorts 8-10 according to Example 4.

In FIG. 8 is a table of plasma and urine PK parameters for cohorts 1-6 according to Example 4.

In FIG. 9 is a table of plasma and urine PK parameters for cohort 7 according to example 4.

In FIG. 10 is a table of urine PK parameters for cohort 7 according to Example 4.

In FIG. 11 is a table of plasma and urine PK parameters for cohorts 8-10 on days 1 and 14 of the treatment period according to Example 4.

In FIG. 12 is a table of urinary PK parameters for cohorts 8-10 on Day 1 of the treatment period according to Example 4.

In FIG. 13 is a table of urinary PK parameters for cohorts 8-10 on day 14 of the treatment period according to Example 4.

In FIG. 14 shows a statistical analysis of the PK parameters of plasma after a meal and on an empty stomach in accordance with example 4.

In FIG. 15A and 15B are graphs of mean plasma concentrations versus time profiles after single doses of Compound 1 according to Example 4.

In FIG. 16 shows the statistical evaluation of the plasma concentrations of Compound 1 for the 810 cohorts according to Example 4.

In FIG. 17 is a graphical representation of mean trough concentrations in response to a 10 mg dose of Compound 1 relative to a day of treatment in the multiple escalating dose portion of Example 4.

In FIG. 18 is a graphical representation of mean trough concentrations in response to a 20 mg dose of Compound 1 relative to a day of treatment in the multiple escalating dose portion of Example 4.

In FIG. 19 is a graphical representation of mean trough concentrations in response to a 40 mg dose of Compound 1 relative to a day of treatment in the multiple escalating dose portion of Example 4.

In FIG. 20 shows a statistical analysis of connection time independence of 1 according to example 4.

In FIG. 21 is a graphical representation of the single dose normalized AUC( ₀ . _in f from the single incremental dose portion of Example 4.

- 13 041715

In FIG. 22 is a graphical representation of the individual dose normalized C _max from the single incremental dose portion of Example 4.

In FIG. 23 is a graphical representation of the individual dose normalized _Cmax from the multiple incremental dose portion of Example 4.

In FIG. 24 is a graphical representation of the single dose normalized AUC( ₀ - _tau ) from the multiple escalating dose portion of Example 4.

In FIG. 25A and 25B are graphs of mean plasma concentrations after several doses of Compound 1 according to Example 4.

In FIG. 26A and 26B are graphs of the mean plasma concentrations of Compound 1 under postprandial and fasting conditions according to Example 4.

In FIG. 27 is a linear scale plot of mean serum estradiol (E2) concentrations following single doses of Compound 1 according to Example 4.

In FIG. 28 is a linear scale plot of mean serum estradiol (E2) concentrations after multiple doses of Compound 1 according to Example 4.

In FIG. 29 is a linear scale plot of mean serum progesterone concentrations after multiple doses of Compound 1 according to Example 4.

In FIG. 30A-H are demographic and baseline tables according to Example 5A.

In FIG. 31 is a table showing the overall graphical assessment of menstrual blood loss (PBAC) at weeks 6-12 over a 12 week treatment period according to Example 5A.

In FIG. 32 is a table with an overall indicator of the graphical assessment of the amount of menstrual blood loss (PBAC) at weeks 6-12, showing changes from baseline over a treatment period of 12 weeks in accordance with example 5A.

In FIG. 33 is a table of the proportion of subjects with an overall menstrual blood loss graph score (PBAC) of less than 10 at weeks 6-12 compared to uterine volume at treatment initiation over a treatment period of 12 weeks according to Example 5A.

In FIG. 34 is a table of fibroid volumes over a 12 week treatment period according to Example 5A.

In FIG. 35 is a table of uterine volumes over a 12 week treatment period according to Example 5A.

In FIG. 36 is a graphical representation of plasma concentrations of unchanged Compound 1 over a 12 week treatment period in which Compound 1 was administered 30 minutes before meals, in accordance with Example 5A.

In FIG. 37 is a table of plasma concentrations of the unchanged compound 1 shown in FIG. 36.

In FIG. 38 graphically depicts plasma concentrations of unchanged Compound 1 over a 12 week treatment period according to Example 5A.

In FIG. 39 is a table of plasma concentrations of the unchanged Compound 1 shown in FIG. 38.

In FIG. 40 is a table of plasma concentrations of unchanged Compound 1 over a 12 week treatment period in which Compound 1 was not administered 30 minutes before a meal.

In FIG. 41 is a table of NRS scores measuring pain symptoms over a 12 week treatment period according to Example 5A.

In FIG. 42 is a table of UFS-QOL scores measuring symptom severity over a 12 week treatment period according to Example 5A.

In FIG. 43 is a table of UFS-QOL (Health Related Quality of Life (HRQL) scores) over a 12 week treatment period according to Example 5A.

In FIG. 44 is a table of UFS-QOL scores measuring the effect of uterine fibroids on a subject's level of anxiety over a 12 week treatment period in accordance with Example 5A.

In FIG. 45 is a table of UFS-QOL scores measuring subject activity over a 12 week treatment period in accordance with Example 5A.

In FIG. 46 is a table of UFS-QOL scores measuring a subject's energy/mood over a 12 week treatment period according to Example 5A.

In FIG. 47 is a table of UFS-QOL scores measuring a subject's level of control over a 12 week treatment period according to Example 5A.

In FIG. 48 is a table of UFS-QOL scores measuring subject self-awareness over a 12 week treatment period according to Example 5A.

In FIG. 49 is a table of UFS-QOL scores measuring a subject's sexual function over a 12 week treatment period according to Example 5A.

In FIG. 50 is a table of hemoglobin concentrations over a 12 week treatment period according to Example 5A.

In FIG. 51 is a table of hemoglobin concentrations in subjects taking concomitant

- 14 041715 iron preparations, for a treatment period of 12 weeks in accordance with example 5A.

In FIG. 52 is a table of hemoglobin concentrations in subjects not taking concomitant iron preparations over a 12 week treatment period according to Example 5A.

In FIG. 53 is a table of percentage hematocrit over a 12 week treatment period according to Example 5A.

In FIG. 54 is a table of serum iron concentrations over a 12 week treatment period according to Example 5A.

In FIG. 55 is a table of ferritin concentrations over a 12 week treatment period according to Example 5A.

In FIG. 56A-D are graphs depicting serum LH concentrations over a 12 week treatment period in accordance with Example 5A.

In FIG. 57 is a table of serum LH concentrations shown in FIG. 56A-D.

In FIG. 58A-D are graphs depicting serum FSH concentrations over a 12 week treatment period in accordance with Example 5A.

In FIG. 59 is a table of the serum FSH concentrations shown in FIG. 58A-D.

In FIG. 60A-D are graphs depicting serum E ₂ concentrations over a 12 week treatment period in accordance with Example 5A.

In FIG. 61 is a table of the serum estradiol (E ₂ ) concentrations shown in FIG. 60A-D.

In FIG. 62A-D are graphs depicting serum P concentrations over a 12 week treatment period in accordance with Example 5A.

In FIG. 63 is a table of the serum progesterone concentrations shown in FIG. 62A-D.

In FIG. 64 is a table showing the return of menstrual cycles after administration of placebo or one of the three formulations of Compound 1 (10, 20 and 40 mg) over a 12 week treatment period according to Example 5A.

In FIG. 65A-C show a portion of the questions included in the patient diary according to Example 6.

In FIG. 66A-B are questions from an illustrative work productivity and performance impairment (general health) questionnaire used to analyze quality of life.

In FIG. 67 is an exemplary patient overall impression of change questionnaire to determine the change in symptoms of uterine fibroids since the start of treatment.

In FIG. 68 summarizes the proportion of patients with a total graphical assessment of the amount of menstrual blood loss (PBAC) <10 for 6-12 weeks in accordance with example 5A.

In FIG. 69 shows median serum estradiol levels.

In FIG. 70 is a graphical representation of plasma concentrations of unchanged Compound 1 over a 24 week treatment period according to Example 8.

In FIG. 71 is a table of plasma concentrations of the unchanged compound 1 shown in FIG. 70.

In FIG. 72 is a graphical representation of the plasma concentrations of unchanged Compound 1 over a 24 week treatment period in which Compound 1 was administered 30 minutes before meals, in accordance with Example 8.

In FIG. 73 is a table of plasma concentrations of unchanged compound 1 shown in FIG. 72.

In FIG. 74 is a graphical representation of plasma concentrations of unchanged Compound 1 over a 24 week treatment period in which Compound 1 was not administered 30 minutes before a meal, according to Example 8.

In FIG. 75 is a table of plasma concentrations of unchanged compound 1 shown in FIG. 74.

In FIG. 76A-C is a table of demographic and baseline characteristics according to Example 8.

In FIG. 77 is a graphical representation of serum luteinizing hormone (LH) concentrations over a 24 week treatment period according to Example 8.

In FIG. 78A-B is a table of serum LH concentrations depicted in FIG. 77.

In FIG. 79 graphically depicts serum concentrations of follicle stimulating hormone (FSH) over a 24 week treatment period according to Example 8.

In FIG. 80A-B are a table of the serum FSH concentrations shown in FIG. 79.

In FIG. 81 is a graphical representation of serum concentrations of estradiol (E ₂ ) over a 24 week treatment period according to Example 8.

In FIG. 82A-B are a table of the serum estradiol (E ₂ ) concentrations shown in FIG. 81.

In FIG. 83 is a graphical representation of serum progesterone concentrations over a 24 week treatment period in accordance with Example 8.

In FIG. 84A-B is a table of serum progesterone concentrations depicted in

- 15 041715 fig. 83.

In FIG. 85 is a table of endometriosis biochemical marker (CA125) concentrations over a 24 week treatment period according to Example 8.

In FIG. 86 is a table of percent change from baseline in endometriosis biochemical marker (CA125) concentrations over a 24 week treatment period according to Example 8.

In FIG. 87 is a graphical representation of the average visual analogue scale (VAS) scores across visits for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 88 is a table of mean VAS scores across visits for pelvic pain depicted in FIG. 87.

In FIG. 89 is a graphical representation of the change from baseline in mean VAS across visits for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 90 is a table of changes from baseline to the average VAS across the visits depicted in FIG. 89.

In FIG. 91 is a table of changes from baseline to visit mean VAS (versus leuprolide acetate) for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 92 is a graphical representation of the mean visit-to-visit VAS for dyspareunia over a treatment period of 168 days according to Example 8.

In FIG. 93 is a table of mean VAS across visits for dyspareunia depicted in FIG. 92.

In FIG. 94 is a graphical representation of the change from baseline in mean VAS across visits for dyspareunia over a treatment period of 168 days according to Example 8.

In FIG. 95 is a table of changes from baseline to visit mean VAS for dyspareunia depicted in FIG. 94.

In FIG. 96 is a table of changes from baseline to visit mean VAS (versus leuprolide acetate) for dyspareunia over a treatment period of 168 days according to Example 8.

In FIG. 97 is a graphical representation of the mean visit-to-visit VAS for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 98 is a table of mean VAS scores across visits for dysmenorrhea depicted in FIG. 97.

In FIG. 99 is a graphical representation of the change from baseline in mean VAS across visits for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 100 is a table of changes from baseline to visit mean VAS for dysmenorrhea depicted in FIG. 99.

In FIG. 101 is a table of changes from baseline to visit mean VAS (versus leuprolide acetate) for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 102 is a table of mean Biberoglu & Behrman Modified Scores (M-B&B) for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 103 is a table of mean M-B&B scores for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 104 is a table of mean M-B&B scores for deep dyspareunia over a treatment period of 168 days according to Example 8.

In FIG. 105 is a table of changes from baseline to mean M-B&B for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 106 is a table of changes from baseline to mean M-B&B for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 107 is a table of changes from baseline to mean M-B&B for deep dyspareunia over a treatment period of 168 days according to Example 8.

In FIG. 108 is a table of changes from baseline to mean M-B&B scores (versus leuprolide acetate) for pelvic pain over a treatment period of 168 days according to Example 8.

In FIG. 109 is a table of changes from baseline to mean M-B&B (versus leuprolide acetate) for dysmenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 110 is a table of changes from baseline to mean M-B&B scores (versus leuprolide acetate) for profound dyspareunia over a treatment period of 168 days according to Example 8.

- 16 041715

In FIG. 111 is a table of Biberoglu & Behrman (B&B) visit mean scores for dysmenorrhea over a 24 week treatment period according to Example 8.

In FIG. 112 is a table of mean B&B scores by visit for dyspareunia over a 24 week treatment period according to Example 8.

In FIG. 113 is a table of mean B&B scores by visit for pelvic pain over a 24 week treatment period according to Example 8.

In FIG. 114 is a table of mean B&B visits for pelvic tenderness over a 24 week treatment period according to Example 8.

In FIG. 115 is a table of mean B&B scores across induration visits over a 24 week treatment period according to Example 8.

In FIG. 116 is a table of changes from baseline to mean B&B visits for dysmenorrhea over a 24 week treatment period according to Example 8.

In FIG. 117 is a table of changes from baseline to mean B&B visits for dyspareunia over a 24 week treatment period according to Example 8.

In FIG. 118 is a table of changes from baseline to mean B&B visits for pelvic pain over a 24 week treatment period according to Example 8.

In FIG. 119 is a table of changes from baseline to mean B&B visits for pelvic tenderness over a 24 week treatment period according to Example 8.

In FIG. 120 is a table of changes from baseline to mean B&B across induration visits over a 24 week treatment period according to Example 8.

In FIG. 121 is a table showing the ratio of days with pain medication over a treatment period of 168 days according to Example 8.

In FIG. 122 is a table of changes from baseline in the ratio of days with pain medication over a treatment period of 168 days according to Example 8.

In FIG. 123 is a table of changes from baseline in the ratio of days with pain medication (versus leuprolide acetate) over a treatment period of 168 days according to Example 8.

In FIG. 124 is a table of the mean number of bleedings over a treatment period of 168 days according to Example 8.

In FIG. 125 is a table of changes from baseline in mean bleeding over a treatment period of 168 days according to Example 8.

In FIG. 126 is a table of changes from baseline in mean bleeding (versus leuprolide acetate) over a treatment period of 168 days according to Example 8.

In FIG. 127A-B is a table of the number of subjects who achieved amenorrhea over a treatment period of 168 days according to Example 8.

In FIG. 128 is a table of the proportion of subjects who achieved amenorrhea (versus leuprolide acetate) over a treatment period of 168 days according to Example 8.

In FIG. 129 is a table of quality of life (QOL) statistics on endometriosis health status-30 (ENP-30, English: Endometriosis Health Profile-30) in relation to pain over a treatment period of 24 weeks in accordance with example 8.

In FIG. 130 is a table of statistics for quality of life (ENP-30) in relation to control and impotence over a treatment period of 24 weeks in accordance with example 8.

In FIG. 131 is a table of statistics for quality of life (ENP-30) in relation to emotional well-being over a treatment period of 24 weeks in accordance with example 8.

In FIG. 132 is a table of statistics for quality of life (ENP-30) in relation to social support for a treatment period of 24 weeks in accordance with example 8.

In FIG. 133 is a table of statistics for quality of life (EHP-30) in relation to self-perception over a treatment period of 24 weeks in accordance with example 8.

In FIG. 134 is a statistical table showing the change from baseline in quality of life (EHP-30) in pain over a 24 week treatment period according to Example 8.

In FIG. 135 is a statistical table showing the change from baseline in quality of life (EHP-30) in terms of control and impotence over a treatment period of 24 weeks according to Example 8.

In FIG. 136 is a statistical table of change from baseline in quality of life (EHP-30) in emotional well-being over a treatment period of 24 weeks according to Example 8.

In FIG. 137 is a table showing the statistics of change from baseline in quality of life (EHP-30) in relation to social support over a treatment period of 24 weeks according to Example 8.

- 17 041715

In FIG. 138 is a statistical table showing the change from baseline in quality of life (EHP-30) in self-reported over a 24 week treatment period according to Example 8.

In FIG. 139 is a statistical table showing the change from baseline in quality of life (EHP-30) (versus leuprolide acetate) in relation to pain over a 24 week treatment period according to Example 8.

In FIG. 140 is a statistical table of change from baseline in quality of life (EHP-30) (versus leuprolide acetate) in relation to control and impotence over a 24 week treatment period according to Example 8.

In FIG. 141 is a statistical table of change from baseline in quality of life (EHP-30) (versus leuprolide acetate) in emotional well-being over a 24 week treatment period according to Example 8.

In FIG. 142 is a statistical table of change from baseline in quality of life (EHP-30) (versus leuprolide acetate) in relation to social support over a 24 week treatment period according to Example 8.

In FIG. 143 is a statistical table showing the change from baseline in quality of life (EHP-30) (versus leuprolide acetate) in self-perception over a 24 week treatment period according to Example 8.

In FIG. 144 is an exemplary endometriosis pain questionnaire used for psychometric analyses.

In FIG. 145 is an exemplary M-B&B scoring scale used for dysmenorrhea, pelvic pain, and deep dyspareunia.

In FIG. 146A-C is an exemplary Endometriosis Symptom Scale (SEMS) used for psychometric analyses.

In FIG. 147A-M is an illustrative electronic Endometriosis Symptom Scale (SEMS) used for psychometric analyses.

In FIG. 148A-C is an illustrative form of mood states used for psychometric analyses.

In FIG. 149A-C is an illustrative basic clinical questionnaire used for psychometric analyses.

In FIG. 150A-B is an illustrative clinical summary questionnaire used for psychometric analyses.

In FIG. 151A-E is an exemplary Endometriosis Health Questionnaire (ENP-30) used to analyze quality of life.

In FIG. 152A (plot) and FIG. 152B (table) shows the mean VAS for total pelvic pain (mm) according to Example 8A.

In FIG. 153A and FIG. 153B (table) shows the mean VAS for dysmenorrhea (mm) according to Example 8A.

In FIG. 154A and FIG. 154B (table) shows the mean VAS for non-menstrual pelvic pain (mm) according to Example 8A.

In FIG. 155A and FIG. 155B (table) shows the mean VAS for dyspareunia (mm) according to Example 8A.

In FIG. 156A-B shows the change from baseline in mean VAS at the end of treatment (mm) according to Example 8A (Mean VAS and Modified (Patient) B&B). From left to right in each group, columns: placebo, 10 mg compound 1 (relugolix), 20 mg compound 1, 40 mg compound 1, leuprorelin.

In FIG. 157 reports that treatment with compound 1 for 12 weeks resulted in a significant dose-dependent reduction in total pelvic pain according to example 7. From left to right in each group, columns: placebo, 10 mg of compound 1 (relugolix), 20 mg of compound 1, 40 mg compound 1, leuprorelin.

In FIG. 158 shows the mean percent change from baseline in VAS for total pelvic pain at the end of the treatment period according to Example 7. From left to right in each group, columns: placebo, 10 mg Compound 1 (relugolix), 20 mg Compound 1, 40 mg compound 1, leuprorelin.

In FIG. 159 shows the mean percent change from baseline in VAS for total pelvic pain and dysmenorrhea at the end of the treatment period according to Example 7. From left to right in each group, columns: placebo, 10 mg compound 1 (relugolix), 20 mg compound 1, 40 mg compound 1, leuprorelin.

In FIG. 160 represents the change from baseline in the mean VAS score for total pelvic pain, non-menstrual pelvic pain, dysmenorrhea, and dyspareunia by visit according to Example 7. Diamond marker denotes placebo; a marker in the form of a light square indicates 10 mg of compound 1; the marker in the form of a triangle indicates 20 mg of compound 1;

- 18 041715 the marker in the form of a dark square indicates 40 mg of compound 1; and the circle marker represents leuprorelin.

In FIG. 161 shows the serum concentration (median) of the pharmacodynamic markers as determined in Example 7. The diamond-shaped marker denotes placebo; a marker in the form of a light square indicates 10 mg of compound 1; the marker in the form of a triangle indicates 20 mg of compound 1; the marker in the form of a dark square indicates 40 mg of compound 1; and the circle marker represents leuprorelin.

In FIG. 162 is a graph showing the onset/shift of endocrine effects following administration of Compound 1 as described in the study in Example 7.

In FIG. 163 shows estradiol levels in healthy female volunteers treated in the phase 1 study with Compound 1, with and without reverse hormone therapy.

In FIG. 164 is a graph depicting the mean and standard deviation (SD) of serum estradiol on the last day of treatment (week 6) - the top line is Compound 1 with reentry therapy and the bottom line is Compound 1 without reentry therapy.

In FIG. 165 is a graph depicting the mean and standard deviation (SD) of C-telopeptide and N-telopeptide (compound 1 on the left; compound 1 with reentry therapy on the right) of each weekly result.

In FIG. 166 is a graph showing the average number of hot flashes (of any severity) - the top line represents Compound 1; the lower line is connection 1 with reverse therapy.

In FIG. 167 is a table that summarizes some of the differences between compound 1 (relugolix) and the GnRH antagonist elagolix.

In FIG. 168 is a scatter plot of Compound 1 (relugolix) AUC024 versus C _avg concentration of estradiol (E2) at week 6 in the study described in Example 9.

In FIG. 169 is a scatter plot of C _avg of estradiol (E ₂ ) versus change from baseline for N-telopeptide (NTx) at week 6 of the study described in Example 9.

In FIG. 170 is a scatter plot of C _avg of estradiol (E ₂ ) versus change from baseline in C-telopeptide (CTx) at week 6 of the study described in Example 9.

In FIG. 171 is a plot of the ratio of menstrual bleeding (as reported by subject) to C _avg of estradiol (E ₂ ) at week 6 of the study described in Example 9.

In FIG. 172 is a graph showing the percentage of subjects with serum estradiol (E ₂ ) levels less than 10 pg/ml versus dose of Compound 1 (relugolix) in the study described in Example 5A.

In FIG. 173 is a graph depicting the serum levels of estradiol (E2) in individual subjects versus plasma concentration of Compound 1 in the study described in Example 5A.

In FIG. 174 is a graph showing the percentage of subjects with a menstrual blood loss graph score (PBAC) of 0 at weeks 6-12 and the mean change from baseline in bone mineral density at week 12 versus dose of Compound 1 in the study described in Example. 5A.

In FIG. 175 is a graph depicting Compound 1 (relugolix) AUCo-24 at week 3 versus baseline body mass index in the study described in Example 9.

In FIG. 176 is a graph of the proportion of subjects who responded to RVAC who achieved their primary endpoint in the study described in Example 10.

In FIG. 177 is a graph showing the proportion of responders who achieved secondary endpoint results in the study described in Example 10. Primary endpoint results are also included for context.

In FIG. 178A-C are plots of fibroid volume at the secondary endpoint, uterine volume at the secondary endpoint, and secondary hemoglobin for subjects in the study described in Example 10.

In FIG. 179 is a plot of bone mineral density over time in two different treatment groups in the study described in Example 10.

In FIG. 180A-E are eDiary entries for the studies described in Examples 13 and 14.

In FIG. 181 is a summary of the results of the cognitive survey in the study described in Example 18.

In FIG. 182 provides a summary of each of the concepts measured by the SEMS assessed in Example 18, along with the number of subjects who reported the relevance of that concept.

In FIG. 183A-C compares subjects' reported symptoms with patient reported outcomes (PRO) in the study described in Example 18.

- 19 041715

Detailed description of the invention

As discussed above, achieving a hormone balance that relieves one or more of the symptoms of conditions such as uterine fibroids, endometriosis, and/or adenomyosis while avoiding certain side effects of hormone suppression is challenging. Surprisingly, it has been found that, in some embodiments, the methods provided herein can treat uterine fibroids, endometriosis, or adenomyosis, or one or more of the symptoms associated with these conditions. It has also surprisingly been found that, in some embodiments, these methods may further include preventing or ameliorating one or more side effects of administering the GnRH antagonist, such as loss of bone mineral density or vasomotor symptoms. For example, instead of using a dose that simply lowers hormone levels, completely or almost completely suppressing hormones and then adding a certain amount of hormones, as described in this document, can lead to a narrower distribution of estradiol levels for a large number of women and can be simultaneously effective against the symptoms described herein while controlling the side effects commonly associated with GnRH antagonist treatment. In other words, compared to the balancing approach described above, the present methods and uses may surprisingly lead to the successful treatment of more women. Thus, for example, the uses and methods described herein may result in less loss of bone mineral density for a given level of efficacy (in terms of symptom control) or, alternatively, more efficacy in symptom control for a given amount of change in bone mineral density.

Disclosed herein are methods of using an orally active GnRH antagonist (K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea) (compound 1) or a pharmaceutically acceptable salt thereof for the treatment of uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding, infertility; pain associated with uterine fibroids, endometriosis or adenomyosis; anemia; or one or more symptoms of uterine fibroids, endometriosis, or adenomyosis; or to prevent miscarriage. Also disclosed are methods of contraception; maintaining bone density, a normal lipid profile, or a normal range of blood glucose levels; or treatment of one or more of the following conditions: hot flashes, night sweats, other vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, and headaches in a premenopausal woman treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding, with Compound 1 or a pharmaceutically acceptable salt thereof. Once daily oral administration of Compound 1 or a pharmaceutically acceptable salt to a subject can result in rapid suppression of estrogen and progesterone levels without an initial rise in hormone levels leading to worsening of symptoms, also known as a clinical or hormonal flare.

The term premenopausal woman may, for example, include a woman who has started menstruating but has not yet gone through menopause. The term premenopausal woman may include a woman who is experiencing perimenopause. Whether a woman is premenopausal can be determined by assessing the woman's medical history, for example by asking the woman questions. In a woman who has not had a period for a year or more, a serum FSH level greater than or equal to 30 mIU/mL may also indicate that the woman has reached menopause.

The methods provided herein include the co-administration of a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). As discussed above, suppression of estrogen and/or progesterone, for example by administering a GnRH agonist or GnRH antagonist, or altering the action of progesterone, for example by administering a SPRM, can lead to unwanted and side effects.

Estrogen suppression can lead to loss of bone mineral density and vasomotor side effects such as hot flashes or night sweats. Loss of bone mineral density can be a side effect that deserves special attention because the subject may not be aware of the loss of bone mineral density in the short term (for example, within weeks or months), but over time this can lead to significant health problems, such as increased risk of bone fracture and/or osteoporosis. This loss of bone mineral density can occur when estrogen levels fall below a certain threshold and can occur for short periods of time, such as for only a few hours per day if estrogen levels fall below a threshold. Thus, if estrogen levels are not maintained consistently throughout each day during treatment, the subject may lose bone mineral density for part of the day, which can lead to cumulative negative long-term health outcomes.

Similarly, suppressing progesterone without simultaneously suppressing estrogen can lead to detrimental side effects. Free estrogen in women can cause endometrial hyperplasia, which is a risk factor for endometrial cancer. Therapy that suppresses progesterone without simultaneous suppression of estrogen may lead to adverse effects when administered for

- 20 041715 for a long time, such as three months or more. Patients may be prescribed therapy cycles with breaks in between to reduce the risk of serious side effects such as endometrial hyperplasia. This type of discontinuous planning may be required for SPRM therapies that selectively modulate progesterone receptors.

Administration of a hormone replacement drug combination with Compound 1 or a pharmaceutically acceptable salt thereof, as described herein, may help maintain bone mineral density or treat one or more vasomotor symptoms (eg, hot flashes or night sweats) or other side effects of Compound 1 administration or its pharmaceutically acceptable salt. These other side effects may include, for example, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, and headache. Administration of a hormone replacement drug may also, in some embodiments, prevent or reduce one or more of the symptoms of free estrogen. The ability to mitigate the side effects of GnRH antagonist treatment while maintaining efficacy (eg, reducing heavy menstrual bleeding associated with uterine fibroids or adenomyosis, or pain associated with uterine fibroids, endometriosis or adenomyosis, etc.) may allow long-term use Compound 1 or a pharmaceutically acceptable salt thereof. In addition, such a safe and effective long-term treatment may provide an alternative to surgical treatment (eg, hysterectomy or myectomy) or other invasive procedures (eg, laparoscopy) commonly prescribed for some of the conditions described herein, such as uterine fibroids and endometriosis. Thus, women with these conditions may, in some embodiments, effectively manage their symptoms in the long term without sacrificing their reproductive potential.

There may also be an upper limit for estrogen and an upper limit for progesterone for certain conditions. The disorders described in this document and their symptoms are estrogen sensitive, such as endometriosis and uterine fibroids. These disorders can be exacerbated by hormones such as estrogen rising above the upper limit, even if the level is only above the limit for a short period of time, such as several hours a day. In some cases, this aggravation of the disorder may be unknown to the subject in the short term, but may lead to a symptom flare over time. Likewise, some symptoms of uterine fibroids are thought to have a greater response to progesterone than to estrogen, such as fibroma growth.

The dose of the hormone replacement drug and Compound 1 or a pharmaceutically acceptable salt thereof and their compatible administration in combination may be important to maintain the concentration of Compound 1 and estrogen within a treatment window where the level of Compound 1 is sufficient to suppress endogenous estrogen production, thus providing treatment for symptoms. and/or conditions while the level of estrogen provided by a hormone replacement drug (eg, a combination of estradiol or an estradiol and progestin equivalent) is sufficient to prevent one or more symptoms of a hypoestrogenic condition (eg, loss of bone mineral density, vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise or headache). As described above, falling outside of this treatment window during the day can result in one or more negative side effects such as loss of bone mineral density, vasomotor symptoms, or exacerbation of the symptom or condition being treated.

Simply combining any GnRH antagonist or GnRH agonist with a hormone replacement drug may not result in sufficient hormone suppression to adequately treat one or more symptoms, or may not maintain hormone levels high enough to avoid one or more detrimental side effects. In some cases, for other treatments, the plasma concentration of one or more hormones in a subject may vary during each day, so that neither adequate treatment nor the prevention of certain side effects is achieved. In other cases, for other treatments, a change or imbalance over a longer period of time, for example, over several months, may prevent long-term use of therapy, for example, for more than 3, 6 or 12 months. Surprisingly, it has been found that once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug can result in greater stability of plasma estrogen concentration than administration of other GnRH antagonists or GnRH agonists.

In FIG. 163 are two graphs showing the effect on serum estradiol levels of a single oral administration of Compound 1 or a combination of Compound 1 and a hormone replacement preparation containing estradiol and progestin norethisterone acetate (E ₂ /NETA) according to Example 9. The graph on the left shows the median trough concentration serum estradiol measured in a blood sample taken at the study visit prior to administration on that day. As shown in this graph, administration of Compound 1 once daily results in a serum estradiol concentration that is consistently below 10 pg/mL for several weeks. Subjects treated with estradiol and NETA (E ₂ /NETA) as reentrant therapy also had consistent trough serum estradiol levels as measured at each visit,

- 21 041715 but above the threshold of 20 pg/ml. As shown in the right graph, the median concentration of estradiol during the study visit at week 3 remained in the range of 20 to 50 pg/ml within 24 hours after administration of compound 1 and estradiol and NETA (E ₂ /NETA). Administration of Compound 1 without a hormone replacement drug resulted in serum estradiol levels below 10 pg/mL for the next 24 hours. Maintaining serum estradiol levels within this range of 20 to 50 pg/mL by administering Compound 1 and a hormone replacement drug such as estradiol or the equivalent of estradiol and a progestin, may provide relief from one or more symptoms of estrogen-sensitive conditions (eg, uterine fibroids, endometriosis, or adenomyosis) or heavy menstrual bleeding, as well as reduction of one or more GnRH antagonist side effects, such as loss of mineral bone density or vasomotor symptoms.

In contrast, other GnRH antagonists, such as elagolix, are less effective or ineffective at suppressing estrogen levels when administered once daily. In FIG. 167 summarizes some aspects of elagolix administration compared to Compound 1 (relugolix). In some studies, maximum estrogen suppression has been achieved with twice daily administration of 200 mg or more of elagolix, while other studies indicate that once daily administration of 200 mg of elagolix is less effective at suppressing E2 (estradiol) than 200 mg divided into for 7 injections throughout the day (see J. W. Ng, et al., Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Females (poster, 2016); J. Grundy, et al., Nature (2008), Vol 83: Supplement 1, S9). The IC50 of elagolix is 1.5 nM and the half-life of elagolix is 2.46.3 h (see Chen et al., J. Med. Chem. 2008, 51:7478-7485, compound 10b; Struthers et al., J Clin Endocrinol Metab Feb 2009 94 (2): 545-551 In contrast, Compound 1 can suppress E2 to below 10 pg/mL in most subjects when administered at 40 mg per day, has an IC50 of 0.12 nM , and has a half-life of 3742 hours.

Furthermore, it is surprising that uterine fibroids and endometriosis, which are both estrogen sensitive diseases, can in some embodiments be treated with the same dose of Compound 1 or a pharmaceutically acceptable salt thereof. Estrogen-dependent diseases do not have the same sensitivity to estrogen. These diseases are not all sensitive to the same levels of estrogen, but rather show a hierarchy of sensitivity. Fibroids (eg, uterine fibroids) are generally more estrogen sensitive than endometriosis and therefore the ability to treat endometriosis with the same dose of Compound 1 or a pharmaceutically acceptable salt thereof that can be effective in uterine fibroids is surprising. A discussion of estrogen sensitivity can be found in R. L. Barbieri, Am. J. Obstet. Gynecol (1992), 166(2): 740-745.

It is also surprising that, in some embodiments, the methods of the present invention can treat progesterone sensitive symptoms or conditions and estrogen sensitive symptoms or conditions. For certain conditions and/or symptoms, progesterone suppression may lead to greater improvement. For example, it is believed that fibroid tissue is progesterone responsive, and hence consistent progesterone suppression may reduce the size and/or number of fibroids in a subject with uterine fibroids (see S. E. Bulun, Uterine Fibroids, N. Engl. J. Med. (2013 ), 369:1344-1355) Compound 1 or a pharmaceutically acceptable salt thereof can also suppress endogenous progesterone production. A dose of Compound 1 or a pharmaceutically acceptable salt thereof, administered as described herein, may be sufficient to suppress endogenous progesterone production, such progesterone suppression may treat symptoms and/or conditions while estrogen and progestin levels provided a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin) may be sufficient to prevent one or more symptoms of a hypoestrogenic condition (eg, loss of bone mineral density, vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) and/or preventing symptoms associated with free estrogen. In addition, it may be desirable to suppress both progesterone and estrogen to treat, for example, multiple symptoms of a single condition. For example, it is thought that heavy menstrual bleeding associated with uterine fibroids may be related to estrogen levels, and thus suppression of both estrogen and progesterone results in greater symptom relief in some women with uterine fibroids.

As previously mentioned, the combination of any GnRH agonist or GnRH antagonist alone with a hormone replacement drug may not always provide effective treatment of a hormone-responsive condition and/or amelioration of the side effects of hormone suppression. GnRH agonists, which also result in estrogen suppression after the initial clinical flare period, may be co-administered with reverse hormone therapy. However, combining GnRH agonists for estrogen suppression with reversible hormone therapy has had mixed results. A review of data from a dozen clinical trials evaluating the treatment of uterine fibroids with GnRH agonists with hormone reversal therapy found that treatment outcomes and effects on bone mass, vasomotor symptoms, and quality of life varied significantly, with some data being inconclusive (see R.M. Moroni, et al., Cochrane Database of Systemic Reviews (2015), Issue 3, Article No:

- 22 041715

CD010854) Leuprolelin, a GnRH agonist, can be combined with hormone reversal therapy up to 6 months. The FDA (US Food and Drug Administration) has not approved an extension of the treatment period to 12 months.

Data related to the request to extend treatment to 12 months showed that 10 of 157 women had a decrease of more than 5.0% in one or more measurements of bone mineral density from baseline, and all but one of of these, this decrease occurred after the week 24 visit. In addition, the request did not include evidence that treatment for up to 1 year resulted in better suppression of endometriosis symptoms or prolongation of therapeutic effect after completion of therapy (see Medical Review(s). ) Part 1, Part 2, and Part 3 at www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-708S011_Lupron.cfm, accessed September 18, 2017).

Surprisingly, administration of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an estradiol equivalent and a progestin) can result in effective treatment of uterine fibroids and/or reduction, prevention, or improvement of one or more of the symptoms associated with a hypoestrogenic state (eg, loss of bone mineral density, vasomotor symptoms such as hot flashes or night sweats, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache), against the background of inconsistent results achieved by the administration of GnRH agonists. For example, in FIG. 165 are graphs showing the change from baseline in C-telopeptide and N-telopeptide at two time points during Compound 1 (relugolix) alone or with estradiol/norethisterone reentry therapy. C-telopeptide and N-telopeptide are biomarkers associated with bone metabolism. As shown in FIG. 165, the use of estradiol/norethisterone reentry therapy in combination with Compound 1 resulted in a significant reduction in change from baseline in both C-telopeptide and N-telopeptide as a result of treatment with Compound 1 alone. This indicates that administration of the combination Compound 1 and a hormone replacement drug resulted in less bone resorption than Compound 1 alone.

Compound 1, or a pharmaceutically acceptable salt thereof, has a faster onset of action than currently available GnRH agonists, and unlike available peptidic GnRH agonists that are administered either subcutaneously or intranasally, Compound 1 is a non-peptide formulation that can be administered orally and once a day. Compared to GnRH agonists such as leuprolide acetate, which is typically administered as a depot formulation, Compound 1 or a pharmaceutically acceptable salt thereof provides several advantages. Such benefits include, but are not limited to, oral administration, rapid onset of estrogen suppression, no clinical flare, and rapid return to baseline estrogen levels upon discontinuation of treatment. In contrast to treatments that use depot injections, treatment with an oral preparation containing Compound 1 or a pharmaceutically acceptable salt thereof administered once daily may allow for short-term leave where the subject can stop treatment for a period of time and later resume treatment without no side effects or with minimal side effects. For example, a more rapid return of hormone levels to baseline may be useful in treating a comorbid condition or in restoring fertility in women who wish to attempt and become pregnant. This contrast is shown in Fig. 162, which shows the serum concentration of estradiol in subjects after discontinuation of compound 1 (relugolix) or leuprolide (right graph) in the study described in example 7. As can be seen in the graph, four weeks after discontinuation of compound 1, the average concentration of estradiol in serum returned to levels similar to the control (placebo), while the average concentration of estradiol in serum in subjects who stopped taking leuprolide is only about one-fifth of the control. Thus, the treatment methods of this disclosure may provide a desirable fast on/off option for premenopausal women, allowing intermittent treatment as needed or desired.

Thus, provided herein are methods of treating uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman, comprising administering a once daily oral dosage form of a gonadotropin-releasing hormone (GnRH) antagonist Compound 1, or a pharmaceutically acceptable salt thereof, in combination with estradiol or estradiol equivalent and progestin for premenopausal women. This document also provides pharmaceutical compositions containing Compound 1 and a formulation containing estradiol or an estradiol equivalent and a progestin for use in the treatment of uterine fibroids, endometriosis, or adenomyosis. As discussed below, in some embodiments, the methods include administering to a premenopausal woman a combination of about 10 to about 60 mg of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, and a hormone replacement drug.

In certain embodiments, it may be desirable to first administer Compound 1 or a pharmaceutically acceptable salt thereof without reentrant therapy for a period of time prior to transitioning to combination administration. The combination may be administered, for example, as a fixed dose

- 23 041715 or in the form of two or more separate dosage forms that are administered together. This may be desirable, for example, in a woman with severe symptoms or multiple symptoms, or if one or more symptoms are to be relieved more quickly. Administration of Compound 1 or a pharmaceutically acceptable salt thereof without a hormone replacement drug may result in lower serum estradiol and/or serum progesterone levels more rapidly than administration of the combination, and therefore may more rapidly relieve one or more of the symptoms of an estrogen sensitive condition or to progesterone.

In addition, provided herein are methods of treatment and pharmaceutical compositions for use in the treatment of one or more symptoms or conditions selected from the group consisting of the following conditions: heavy menstrual bleeding, infertility, female sexual dysfunction (e.g., decreased libido, decreased arousal, or decreased sexual activity), gender transition, spotting, sex hormone-induced cancers, use of analgesic compounds (eg, reduced use of analgesic compounds), amenorrhea, fertility (eg, maintenance of fertility), anemia (associated with heavy menstrual bleeding or independent of heavy menstrual bleeding), pain (eg, dyspareunia, chronic pain, pain with bowel movements, or pain with urination), inflammation, irregular menstruation, symptoms related to the size and/or volume of uterine fibroids, miscarriage, depression, chronic fatigue, anxiety, and sleep disturbance. In some embodiments, one or more of these symptoms or conditions are associated with uterine fibroids, endometriosis, or adenomyosis. In other embodiments, one or more of these symptoms or conditions are not associated with uterine fibroids, endometriosis, or adenomyosis. In certain embodiments, one or more of these symptoms or conditions occur in a premenopausal woman who has not been diagnosed with uterine fibroids, has not been diagnosed with endometriosis, or has not been diagnosed with adenomyosis, or any combination of the above.

The methods provided herein may allow a premenopausal woman to become pregnant, pregnant, or give birth after cessation of treatment. The ability to become pregnant, be pregnant, or give birth after stopping treatment, as described in this document, may be an advantage over other methods. As discussed above, many treatments for uterine fibroids, endometriosis, or adenomyosis, or symptoms associated with these conditions (eg, heavy menstrual bleeding or pain associated with one or more of these conditions), both in the short and long term, include surgery (such as a hysterectomy) to rule out pregnancy. In contrast, the methods described herein, such as methods for the treatment of endometriosis, uterine fibroids, adenomyosis; heavy menstrual bleeding or pain associated with uterine fibroids, endometriosis, or adenomyosis for an extended period of time, such as at least 24 consecutive weeks, may allow sufficient control of the condition or symptom to avoid surgery and allow premenopausal women to become pregnant, be pregnant or give birth after stopping treatment. In certain embodiments, the premenopausal woman has experienced one or more miscarriages, or an inability to conceive, or a combination thereof prior to treatment as described herein.

In addition, provided herein are methods for reducing one or more side effects associated with the administration of a GnRH antagonist, such as Compound 1, wherein the side effect is selected from the group consisting of loss of bone mineral density, hot flashes, night sweats, vasomotor symptoms other than hot flashes or night sweats, vulvovaginal atrophy, vaginal dryness, fatigue, malaise and headache. In addition, this document provides methods for maintaining a lipid profile or maintaining a normal range of glucose levels in a subject who has been administered a GnRH antagonist such as Compound 1 or a pharmaceutically acceptable salt thereof. Such methods may include administering Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation to a premenopausal woman. In some embodiments, the subject has been diagnosed with uterine fibroids, endometriosis, or adenomyosis. In other embodiments, the menopausal woman has not been diagnosed with uterine fibroids, endometriosis, or adenomyosis.

As noted above, the methods and uses described herein can, for a number of women, increase response rates with respect to experienced symptoms of the conditions described herein and narrow the distribution (narrow the range) of estradiol levels while maintaining bone health.

Throughout this disclosure, the amounts of Compound 1 disclosed refer to the amount of the free form of Compound 1 present in the formulation. As used herein, the term appropriate amount refers to the amount of pharmaceutically acceptable salt of compound 1 required to obtain the amount of the free form of compound 1 specified in the formulation or method. One of ordinary skill in the art will understand how to calculate the appropriate amount of the salt of the compound, such as the corresponding amount of the pharmaceutically acceptable salt of Compound 1, given the difference in molecular weight between the free form of the compound and

- 24 041715 salt form. For example, about 40 mg of compound 1 would correspond to about 42.3 mg of the hydrochloride salt of compound 1.

Physiologically acceptable, pharmaceutically acceptable, or pharmacologically acceptable compounds and compositions may include materials that are not biologically or otherwise undesirable. For example, the material can be administered to an individual without causing any essentially undesirable biological effects, or without adverse interaction with any of the components of the composition in which it is contained.

As used herein, treatment or therapy for a condition, such as a specified disease or disorder, may include treating one or more symptoms of the condition and/or preventing the occurrence of the condition. Treatment may include relief of one or more symptoms (e.g., pain) or prevention of one or more symptoms, such as preventing new fibroids or shrinking existing fibroids, preventing new endometriomas or endometriosis lesions, or reducing the number or inflammation of existing lesions. Pain relief may include, for example, reduction of pelvic pain (including dysmenorrhea), non-menstrual pelvic pain, or dyspareunia.

Combination formulations are also provided for use in any of the methods described herein. In some embodiments, the implementation of the combination drug is intended for simultaneous or sequential use. In some embodiments, the combination preparation comprises Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In some embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Also contemplated is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment according to any of the methods described herein. Also contemplated is the use of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment according to any of the methods described herein. In some embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin.

I. Connection 1.

Compound 1 is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridαzinyl)-2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea. Compound 1 is represented by the chemical structure below:

Compound 1 and pharmaceutical compositions, including Compound 1, can be prepared by the methods described in US Pat. No. 7,300,935, US Pat. No. 8,058,280, US Pat. the disclosure of which is incorporated herein by reference in their entirety. Compound 1 may also be referred to herein as relugolix.

The salts of compound 1 used in this disclosure are preferably physiologically acceptable acid addition salts. Such salts include, for example, salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like) and salts with organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like).

Compound 1 is an orally active non-peptide compound. Compound 1 is believed to antagonize GnRH via GnRH receptors that are present in anterior pituitary basophils (secretory cells) and inhibit GnRH-stimulated secretion of luteinizing hormone and follicle-stimulating hormone from these cells. As a result, the drug reduces the concentration of hormones in the blood, including estradiol and progesterone. Because Compound 1 is a GnRH antagonist, it is considered to be non-flare and has a faster onset of action than GnRH agonists. Unlike known GnRH agonists, Compound 1 is not a peptide drug. Although GnRH agonists are administered intramuscularly, subcutaneously, or intranasally, Compound 1 can be administered orally, allowing daily administration and maintenance.

- 25 041715 Maintaining a stable plasma level of a GnRH antagonist. In addition, Compound 1 has been shown to have higher affinity for human GnRH receptors than leuprolide acetate (a peptide agonist) and cetrorelix (a peptide antagonist).

Unlike GnRH agonists such as leuprolide acetate, Compound 1 is not a depot or slow release formulation and hormone levels return to baseline more quickly upon discontinuation of Compound 1 treatment, which may provide greater control for patients and their physicians. Thus, unlike treatments that use depot injections, the treatments described in this disclosure may include short breaks where subjects can stop treatment for a period of time and then resume treatment without any side effects. For example, a faster return of hormone levels to baseline may be useful in treating comorbidities and in restoring fertility in women who wish to attempt pregnancy. In addition, as a GnRH antagonist, Compound 1 has a rapid onset of action. Thus, the treatment methods of this disclosure may provide the desired fast on/off option for subjects, allowing intermittent treatment as needed or desired.

In some embodiments, the immediate release version of Compound 1 has a half-life (T _1/2 ), sometimes referred to as mean plasma half-life, of about 37 hours to about 42 hours. In fact, the T _1/2 for the immediate release version of Compound 1 has been found to reach about 61 h.

In some embodiments, the methods provided herein do not include administering Compound 1, or a pharmaceutically acceptable salt thereof, within 6 hours of administration of a P-glycoprotein (P-gp) inhibitor, CYP3 A inducer, or P-gp inducer, or any of them. combinations. P-gp mediates the export of drugs from specific cells, such as cells located in the small intestine, the blood-brain barrier, hepatocytes, and the renal proximal tube. P-gp can be affected by P-gp inducers or inhibitors that reduce P-gp mediated uptake or efflux or increase P-gp activity, respectively. CYP3A is a subfamily of monooxygenases that may be involved in drug metabolism. P-gp or CYP3A inducers may include carbamazepine, rifampin, St. John's wort, bosentan, efavirenz, mitotane, modafinil, or nafcillin. P-gp inhibitors may include amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, eliglustat, erythromycin, felodipine, itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quercetin, quinidine, reserpine, ranolazine, saquinavir, telaprevir, tipranavir, ticagrelor, tacrolimus and verapamil. A discussion of the P-gp transport system can be found in J.D. Wesslery, et al. JACC (2013) 61(25): 2495-502. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours prior to administration of a P-gp inhibitor, CYP3A inducer, or inducer P-gp or any combination thereof. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours after administration of a P-gp inhibitor, CYP3A inducer, or inducer P-gp or any combination thereof. In some embodiments, for example, when treatment is initiated that includes administering Compound 1 or a pharmaceutically acceptable salt thereof, Compound 1 or a pharmaceutically acceptable salt thereof is administered at least 16 hours, at least 20 hours, or at least 24 hours. h prior to administration of a P-gp inhibitor, CYP3A inducer, or P-gp inducer, or any combination thereof. In other embodiments, for example, when treatment is initiated that includes administering Compound 1 or a pharmaceutically acceptable salt thereof, Compound 1 or a pharmaceutically acceptable salt thereof is administered at least 16 hours later, at least 20 hours later, or at least 24 hours later. h after administration of a P-gp inhibitor, CYP3A inducer, or P-gp inducer, or any combination thereof.

P. Hormone replacement drug.

As described above, provided herein are methods of treating or preventing a condition or symptom as described herein, comprising administering to a premenopausal woman in need thereof a combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In some embodiments, the hormone replacement drug contains estradiol or an estradiol equivalent, or a progestin, or a combination thereof.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose that suppresses estrogen production, such as a dose that results in sustained suppression of estrogen over a 24 hour period. In some embodiments, the dose suppresses estradiol production to a serum level of less than 20 pg/mL or less than 10 pg/mL. In some embodiments, co-administration of a hormone replacement drug with Compound 1 or a pharmaceutically acceptable salt thereof may prevent, reduce, or otherwise alleviate symptoms associated with a hypoestrogenic condition, such as loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, dryness vagina, fatigue, malaise or headache. In some embodiments, one or no

- 26 041715 how many vasomotor symptoms are selected from hot flashes and night sweats.

The hormone replacement drug may contain a progestin. A progestin may, for example, refer to a compound that has a biological activity similar to progesterone. Examples of progestins that can be used in the methods and compositions provided herein include norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestrone acetate, promegestone and dienogest. In some embodiments, the progestin is norethisterone acetate.

The hormone replacement drug may contain estradiol or an estradiol equivalent. The equivalent of estradiol can be, for example, a compound whose biological activity is similar to that of estradiol (17-β-estradiol). Examples of estradiol equivalents include equine conjugated estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol, tibolone and stilbestrol.

III. Myoma of the uterus.

Uterine fibroids are benign, estrogen-sensitive tumors (fibroids) that grow in the muscular wall of the uterus in about 25% of women of reproductive age. The most common symptom of uterine fibroids is UMC with periods of increased duration (10 to 14 days instead of the usual 5 to 7 days) and increased volume (300 to 500 ml per menstrual cycle compared to less than 80 ml for a normal menstrual cycle). Specifically, UMC is thought to be caused by a combination of increased uterine surface area, weak uterine contraction due to fibroids, and increased circulation, blood stasis, or impaired hemostasis due to endometrial hypertrophy in close proximity to the fibroids. Constant BMC can cause iron deficiency anemia and associated fatigue and loss of energy. Therefore, OMC is the main factor that worsens the quality of life of patients with uterine myoma. Other symptoms that may occur in addition to or independent of UMC include pressure or pain in the abdomen and pelvis due to large fibroids, lower back pain, frequent urination or urinary tract obstruction, constipation, and pregnancy loss.

This document provides a method for treating uterine fibroids in a premenopausal woman in need thereof, comprising administering orally to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an estradiol equivalent and progestin). Also provided is a method for treating uterine myoma-related heavy menstrual bleeding in a premenopausal woman, comprising administering to the premenopausal woman once a day a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Further provided is a method for treating pain associated with uterine fibroids in a premenopausal woman in need thereof, comprising administering to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Additionally, a method for treating a premenopausal woman with symptoms of uterine fibroids is provided, comprising administering to the premenopausal woman once a day a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. The combination may be administered, for example, either as a fixed dose or as two or more separate dosage forms that are administered together. Additionally, combination preparations are provided for use in any of these methods. In some embodiments, the implementation of the combination drug is for simultaneous or sequential use. In certain embodiments, the combination preparation comprises Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In certain embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Further provided is the use of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment in accordance with any of these methods. In some embodiments, the implementation of the hormone replacement drug contains estradiol or an estradiol equivalent and a progestin.

In some embodiments of the methods for treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptomatic uterine fibroids provided herein, the premenopausal woman experiences relief of one or more symptoms during treatment or after treatment. One or more symptoms may be selected from the group consisting of anemia, heavy menstrual bleeding, irregular menstruation, bleeding, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, urinary incontinence, constipation, restlessness, sleep disturbance, quality of life, daily activities, female sexual dysfunction and depression. The pain may be, for example, back pain, pelvic pain, uterine pain, chronic pain, pain with bowel movements, pain with urination or dyspareunia, or any combination thereof. So about

- 27 041715 times, provided herein are methods of treating one or more symptoms associated with uterine fibroids in a premenopausal woman in need thereof, comprising administering to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof, and hormone replacement drug.

Daily activities may, for example, include one or more activities that people usually do every day without requiring help. These activities may include: eating, bathing, dressing, using the toilet, moving around (walking), and being able to regulate urination and defecation.

Anemia may, for example, include a medical condition in which the red blood cell count or hemoglobin is below normal. For men, anemia is usually defined as a blood hemoglobin level of less than 13.5 g/100 ml, and for women, as a blood hemoglobin level of less than 12.0 g/100 ml.

Anxiety may, for example, include a feeling of unease, nervousness, or a premonition of trouble, and may be associated with an inevitable event or an event with an uncertain outcome.

Chronic pain may, for example, include ongoing or recurring pain lasting beyond the course of an acute illness or injury or for more than 3-6 months. Chronic pain can negatively affect a person's well-being.

Constipation may, for example, include the occurrence of three or fewer bowel movements per week and may include bowel movements associated with hard, dry stools, a feeling of incomplete bowel movement, or the need to strain to pass a bowel movement, or any combination thereof.

Depression may, for example, include major depressive disorder or major depression and be a major mood disorder. Its symptoms can affect how the subject feels, thinks, and performs daily activities such as sleeping, eating, or working. In some embodiments, symptoms must be present for at least two weeks to be diagnosed with depression. A person who experiences one or more of the following signs and symptoms most of the day, almost every day, for at least two weeks, may suffer from depression: a persistent sad, anxious, or empty mood; feelings of hopelessness or pessimism; irritability; feelings of guilt, worthlessness, or helplessness; loss of interest or pleasure in hobbies and activities; decreased energy or fatigue; slowing down of movements or speech; feeling restless or having trouble sitting still; difficulty concentrating, remembering, or making decisions; difficulty sleeping, waking up early or oversleeping; changes in appetite and/or weight; thoughts of death or suicide or suicide attempts; chronic pain or acute pain, headaches, cramps or digestive problems without a clear physical cause and/or that do not improve even with treatment. Not everyone who is depressed may experience every symptom. Some people experience only a few symptoms, while others may experience many. Several persistent symptoms in addition to low mood may be required for a diagnosis of major depression, but people with only a few but debilitating symptoms may benefit from treatment for their subsyndromal depression. The severity and frequency of symptoms, as well as their duration, will vary depending on the individual and his or her particular illness. Symptoms may also vary depending on the stage of the disease.

Fatigue may, for example, include a feeling of tiredness, other than weakness, that comes on gradually.

Female sexual dysfunction may, for example, include persistent intermittent problems with sexual response, desire, orgasm, or pain associated with sexual activity that upsets the woman and/or strains her relationship with her partner. Female sexual dysfunction can be measured using one or more questionnaires that evaluate parameters of sexual function such as desire, libido, and arousal.

Dyspareunia may, for example, involve painful intercourse due to medical or psychological reasons. The pain may be mainly on the outer surface of the genitals or deeper in the pelvis with deep pressure on the cervix. It may affect a small part of the vulva or vagina, or be felt all over.

Heavy menstrual bleeding (HMB) may, for example, include any of the following: bleeding that lasts more than 7 days; bleeding that completely soaks one or more tampons or pads every hour for hours on end having to wear more than one pad at a time to control your period the need to change pads or tampons during the night or menstruation with blood clots that are 25 mm in diameter or larger. Heavy menstrual bleeding can refer to periods with increased duration (10 to 14 days instead of the usual 5 to 7 days) and increased volume (300 to 500 ml per menstrual cycle compared to less than 80 ml for a normal menstrual cycle). Heavy menstrual bleeding can interfere with daily activities. Using the alkaline hematin method, the amount of blood collected in women's products can be determined. Heavy menstrual bleeding may include loss of >80 ml of blood over a period of time, which

- 28 041715 is evaluated by the method of alkaline hematin. Heavy menstrual bleeding may also include a global graphical assessment of menstrual blood loss of at least 100 points.

Tides may also be referred to as hot flashes.

Urinary incontinence may, for example, include involuntary urination.

Inflammation may, for example, include the biological process by which leukocytes in the body and substances that leukocytes produce participate in a defensive response against one or more foreign organisms such as bacteria and/or viruses. The inflammatory response can be caused by disease states in the absence of infection, or by harmful pathogens such as damaged cells or an irritant. Sometimes inflammation can cause damage to the body while trying to protect it.

Irregular periods may, for example, include periods that occur more frequently than every 21 days; periods that occur less frequently than every 35 days; or menstruation that lasts more than 8 days. Missed, early, or late periods can also be signs of an irregular cycle, particularly if one or more of the signs occur frequently, and the time between periods and duration varies significantly from month to month.

Pain may, for example, include physical suffering or discomfort resulting from illness or injury.

Quality of life (QOL) may, for example, include a subject's overall well-being related to their health and happiness. A subject's quality of life can be measured using one or more instruments that capture an individual's perception of how one or more diseases, syndromes, or symptoms affect various areas of their lives, such as their ability to carry out daily activities.

A sleep disorder may, for example, include one or more conditions that affect a subject's sleep. These may include insomnia, inability to fall asleep and/or stay asleep; hypersomnia, excessive sleepiness, or sleep disturbances that are associated with difficulty breathing during sleep. Certain conditions, syndromes, or symptoms described in this document may cause sleep disturbances such as uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain.

Bleeding may, for example, include light bleeding from the vagina. The bleeding may be just a few spots, or it may be a very light flow of blood. Bleeding can occur between periods just before or just after normal periods. While bleeding may be similar to menstruation, bleeding is much milder and often short-lived. In most cases, bleeding stops after a few hours or days.

Urinary tract obstruction may, for example, include partial or complete blockage of the flow of urine from the body.

Frequent urination may, for example, include the need to urinate many times during the day, at night (nocturia), or both. Urination may occur in normal or less than normal volumes.

In some embodiments, the methods for treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or women with symptoms of uterine fibroids provided herein result in a decrease in the number of uterine fibroids, a decrease in the size of one or more fibroids uterus, or preventing the growth of uterine fibroids, or any combination thereof during and/or after treatment. The size and/or number of uterine fibroids can be assessed, for example, by transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging, computed tomography, or laparoscopy. In some embodiments, the methods of treating a premenopausal woman with symptoms of uterine fibroids provided herein suppress the woman's endometrium. Endometrial suppression may include, for example, an endometrial thickness on transvaginal ultrasound that is less than or equal to 4 mm; or endometrial biopsy showing endometrial atrophy or weak secretory features; or a hard-to-obtain pattern, consistent with atrophy.

In some embodiments, the method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids results in one or both of contraception and amenorrhea during treatment. Amenorrhea may, for example, refer to the absence of a period, such as one or more missed periods. A woman who has missed at least three menstrual cycles in a row may have amenorrhea, as can a girl who has not menstruated by age 15. Contraception may, for example, refer to one or more methods used to prevent pregnancy. These may include barrier methods to prevent sperm from entering the egg by physical blocking to prevent contact, such as condoms, a diaphragm, or spermicide. Hormonal methods of contraception may include only

- 29 041715 progestin contraceptives or combined hormonal contraceptives containing progestin and estrogen. Hormonal methods of contraception work by suppressing the secretion of gonadotropins, preventing ovulation and changing the consistency of the mucus located in the cervix, which makes it difficult for sperm to pass. Contraception may additionally include intrauterine devices, which are implants that are placed inside the uterus and act as a barrier method to impede the passage of sperm and also affect the endometrium to prevent implantation of a fertilized egg. Some intrauterine devices may additionally contain hormones.

Administration of the combination, as in the method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids, can result in suppression of ovarian estrogen production in premenopausal women. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. Suppression of ovarian estrogen production can be demonstrated by blood levels of estrogen that are in the postmenopausal range, such as estradiol levels <20 pg/ml, in a subject administered Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug. Suppression of ovarian estrogen production in a subject co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation containing estradiol or an estradiol equivalent can be demonstrated by blood estradiol levels of 20 to 50 pg/mL. In some embodiments, for example, in women who are administered a higher dose of a hormone replacement drug (containing, for example, up to 5 mg of estradiol or estradiol equivalent), suppression of ovarian estrogen production in a woman who is co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug, can be demonstrated by blood levels of estradiol between 55 and 150 pg/mL. Suppression of ovarian estrogen production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, the method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids, may cause the serum concentration of estradiol in a premenopausal woman to be in a certain range. In some embodiments, administration of the combination results in the serum concentration of estradiol in a premenopausal woman ranging from about 20 to about 50 pg/mL between daily doses of the combination. In some embodiments, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

Administration of the combination described herein in a method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids may result in suppression of ovarian progesterone production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian progesterone production in a premenopausal woman is suppressed. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone is suppressed in a premenopausal woman. Suppression of ovarian progesterone production can be demonstrated, for example, by blood progesterone levels that are in the postmenopausal range, for example, by progesterone levels <2 ng/ml, in a woman who has not received progesterone. Suppression of ovarian progesterone production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, the method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids may cause the serum progesterone concentration in a premenopausal woman to be in a certain range. . In some embodiments, administration of the combination results in a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL, less than about 4 ng/mL, less than about 3 ng/mL, less than about 2 ng /ml or

- 30 041715 less than about 1 ng/ml between daily doses of the combination. In certain embodiments, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

In some embodiments of any of the above methods, administration of the combination results in any combination of suppression of ovarian estrogen production in a premenopausal woman, suppression of ovarian progesterone production in a premenopausal woman, or a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL between daily doses. combinations as described above.

In some embodiments, the combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug is administered orally for at least 24 consecutive weeks. In certain embodiments, the combination contains from about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination contains about 20 to about 50 mg, about 30 to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

The hormone replacement drug may contain estradiol or an estradiol equivalent, a progestin, or any combination thereof. In certain embodiments, the implementation of the hormone replacement drug contains estradiol or the equivalent of estradiol. In other embodiments, the implementation of the hormone replacement drug contains a progestin. The progestin may be, for example, norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestrone acetate, promegestone or dienogest. Estradiol equivalents can be, for example, conjugated equine estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol , tibolone or stilbestrol. In certain embodiments, the hormone replacement preparation contains both estradiol or an estradiol equivalent and a progestin. The progestin may be, for example, norethisterone or a salt thereof.

In some embodiments of any of the methods described above, the hormone replacement preparation contains from about 0.01 to about 5 mg of progestin. For example, in some embodiments, the hormone replacement drug contains about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg , about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3, 75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg progestin. In some embodiments, the hormone replacement preparation contains from about 0.1 to about 0.5 mg of progestin, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0 .5 mg progestin. In some embodiments, the progestin is a norethisterone salt, such as norethisterone acetate. In certain embodiments, the implementation of the hormone replacement drug contains about 0.5 mg of norethisterone acetate. In other embodiments, the combination contains about 0.625 to about 5 mg of nomegestrol acetate, or about 0.05 to about 0.5 mg of levonorgestrel, or about 0.5 to about 5 mg of dienogest.

In some embodiments, the implementation of the hormone replacement drug contains from about 0.5 to about 2 mg of estradiol or the corresponding amount of estradiol equivalent. For example, in some embodiments, the hormone replacement drug contains about 0.5 to about 1 mg, about 0.5 to about 1.5 mg, about 1 to about 1.5 mg, about 1 to about 2 mg , about 1.5 to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of estradiol, or the equivalent amount of estradiol.

In one embodiment, the hormone replacement preparation contains about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin. In some embodiments, the implementation of the hormone replacement drug contains about 1 mg of estradiol or the corresponding amount of estradiol equivalent. In a particular embodiment, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg. In one embodiment, the progestin is norethisterone acetate (NETA). In certain embodiments, the combination contains about 0.5 mg of NETA.

In one embodiment, the combination contains about 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 10 to about 60 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 40 mg

- 31 041715 compound 1 or the corresponding amount of its pharmaceutically acceptable salt does not provide adequate treatment of their symptom and / or condition (for example, uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or one or more symptoms, associated with uterine fibroids). Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, the combination contains about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 0.5 to about 2 mg, about 0.5 to about 1.5 mg, about 0.5 to about 1 mg, or about 1 to about 2 mg of estradiol or an appropriate amount of estradiol equivalent does not adequately treat one or more of the side effects of a hypoestrogenic condition (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache). There may also be a population of premenopausal women who experience one or more side effects from the administration of a GnRH antagonist (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) when their levels serum estradiol is between 20 and 50 pg/mL, and for whom this experience has a more negative impact on their quality of life than if their symptom and/or condition (eg, uterine fibroids, heavy menstrual bleeding associated with fibroids uterus, pain associated with uterine fibroids, or one or more symptoms associated with uterine fibroids) will not receive adequate treatment (for example, if their serum estradiol levels were above 50 pg/mL). Thus, some women may choose to administer a higher dose of hormone replacement so that their mean daily serum estradiol level is about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL, about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg/ml ml or about 150 pg/ml. Administration of a higher dose of a hormone replacement drug may achieve such mean daily circulating serum levels of estradiol, may further reduce one or more side effects from administration of the GnRH antagonist, and still provide some treatment for the symptom and/or condition. Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains about 1.5 to about 5.0 mg, about 2 to about 5 mg, about 3 to about 5, about 4 to about 5 mg, about 1.5 to about 4 mg, about 2 to about 4 mg, about 3 to about 4 mg, about 1.5 to about 3 mg, or about 2 to about 3 mg of estradiol or estradiol equivalent . For example, in some embodiments, the combination contains about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg of estradiol or estradiol equivalent.

As discussed above, in some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug may more rapidly treat one or more symptoms associated with uterine fibroids, or heavy menstrual bleeding associated with uterine fibroids, or pain, associated with uterine fibroids, since progesterone and estrogen levels can be suppressed without the addition of estradiol, estradiol equivalent and/or progestin. However, also as discussed above, one or more negative side effects (eg loss of bone mineral density) may result from longer treatment without the use of a hormone replacement drug. Thus, in some embodiments of the methods provided herein, for the treatment of uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptomatic uterine fibroids, prior to administration of the combination of Compound 1 or a pharmaceutically acceptable thereof salt and a hormone replacement drug, Compound 1 or a pharmaceutically acceptable salt thereof is orally administered to a premenopausal woman once a day. In certain embodiments, about 10 to about 60 mg orally, or about 20 to about 50 mg, or about 30 to about 50 mg, such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily prior to administration of any of the combinations described herein. In other embodiments, about 65 to about 140 mg of Compound 1, or about 65 to about 120 mg of Compound 1, or an appropriate amount of Compound 1, is orally administered to a premenopausal woman.

- 32 041715 pharmaceutically acceptable salt, for example, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or the appropriate amount of a pharmaceutically acceptable salt thereof, once daily prior to any of the combinations described herein. Additionally contemplated is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment in accordance with any of these methods.

In some embodiments, a premenopausal woman is orally administered Compound 1 or a pharmaceutically acceptable salt thereof once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks or up to 24 consecutive weeks before the introduction of any of the combinations described in this document. In one embodiment, about 10 to about 60 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 40 mg of compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, is orally administered to a premenopausal woman once a day at for at least 4 consecutive weeks and up to 24 consecutive weeks prior to administration of the combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Administration of Compound 1 or a pharmaceutically acceptable salt thereof without concomitant administration of a hormone replacement drug during the period of time prior to co-administration of the combination may treat one or more symptoms of uterine fibroids, or heavy menstrual bleeding associated with uterine fibroids, or pain associated with fibroids uterus, more aggressive at the beginning, before switching to longer treatment. This may be desirable, for example, in a woman with severe symptoms or multiple symptoms, or if one or more symptoms are to be relieved more quickly.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation may be administered orally to a premenopausal woman once a day for at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks or at least 96 consecutive weeks in a method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptoms of uterine fibroids as described above. In some embodiments, administration of the combination is suspended for conception and/or pregnancy. The administration of the combination may be resumed after delivery. In certain embodiments, the bone mineral density of a premenopausal woman during treatment according to one of the above methods is within ±3% or ±2% of the bone mineral density prior to treatment. Bone mineral density can be assessed, for example, using x-rays or dual energy x-ray absorptiometry.

As discussed above, loss of bone mineral density can be a problem in subjects treated with GnRH agonists or antagonists. In some embodiments, long-term treatment with Compound 1 is administered in combination with a hormone replacement drug, either as a fixed dose or as two or more separate dosage forms administered together. This forced adherence to a hormone replacement therapy regimen may provide women with protection from certain adverse effects caused by Compound 1, for example, by preventing and/or minimizing loss of bone mineral density due to reduced estrogen levels. This protection against bone loss through oral fixed combination dosage creates a long-term dosing regimen that may be safe for most women.

In addition, the administration of a single daily dose of Compound 1 or a pharmaceutically acceptable salt thereof may allow women to start with a stable, consistent baseline of extremely low estrogen levels. The hormone replacement drug, which is also administered with Compound 1, can replace the dose of estradiol in a controlled manner, which is believed to prevent loss of bone mineral density in most women, and can mitigate other adverse tolerability effects such as vasomotor symptoms. In particular, it is believed that at estradiol concentrations between 30-50 pg/ml, most of the symptomatic benefits associated with estrogen suppression can be achieved, while side effects, including loss of bone mineral density, are minimized. An estradiol concentration of 20 to 50 pg/ml can also provide symptomatic benefits associated with estrogen suppression while side effects, including loss of bone mineral density, are minimized. Co-administration of Compound 1 and a hormone replacement drug as described herein can achieve this target estradiol level in most women. Compound 1 and the hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

In accordance with this disclosure, a method is provided for reducing menstrual blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to uterine fibroids.

- 33 041715

The method includes: administering to the subject in a first oral dose or dosage form of 10 to 60 mg per day of Compound 1 or a pharmaceutically acceptable salt thereof and simultaneously administering to the subject in a second oral dose or dosage form of 0.05 to 5 mg per day of at least least one of estrogen and progestogen. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Further, according to this disclosure, another method is provided for reducing blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to uterine fibroids. The method includes administering to the subject 10 to 60 mg per day of Compound 1 and 0.05 to 5 mg per day of at least one of an estrogen and a progestogen. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Yet another method according to this disclosure is provided for reducing menstrual blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to uterine fibroids. The method includes administering to the subject 10 to 60 mg per day of Compound 1 and 0.01 to 5 mg of NETA as the sole hormone replacement drug. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

In addition, according to this disclosure, a method for suppressing sex hormones in a subject with uterine fibroids is provided. The method includes administering 10 to 60 mg per day of Compound 1 to the subject. Sex hormones suppressed include estradiol, LH and FSH. In addition, in some embodiments, the implementation of the postovulatory increase in the level of progesterone in the subject is suppressed. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

In an embodiment, for the treatment of uterine fibroids in a premenopausal woman, an oral fixed dosage form is administered to a subject. An oral fixed dose combination is 10 to 60 mg, preferably 40 mg per day of Compound 1 or an equivalent pharmaceutically acceptable salt thereof, and 0.01 to 5 mg per day of estrogen and/or progestogen. The single oral dosage form may be administered once a day. The single oral dosage form may be administered daily for long term therapy or for a shorter treatment period. A shorter treatment period may include daily administration for at least 7 consecutive days, 14 consecutive days, 28 consecutive days, 56 consecutive days, 84 consecutive days, or 168 consecutive days. Preferably, the treatment period is long-term therapy, which may include daily administration for consecutive periods of at least 48 weeks, which may be consecutive periods of at least two separate 24 week periods. In addition, preferred longer periods of administration may include: consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

According to this disclosure, oral therapy, which can be used for a longer period of time, may allow women to avoid surgery, which may lead to postoperative complications or complications in a future pregnancy, or even eliminate the possibility of a future pregnancy. In particular, the fixed combination oral dosage form, which is one once-daily tablet containing both Compound 1 or a pharmaceutically acceptable salt thereof, and low doses of estrogen and progesterone, can be used longer than other approved currently being treated with GnRH agonists. This low dose may minimize the loss of bone mineral density in a hypoestrogenic state, as well as other hypoestrogenic symptoms such as hot flushes commonly associated with GnRH agonists and antagonists.

Although Compound 1 may be administered at 10 mg, 20 mg, 40 mg or 60 mg per day, it is preferably administered at a dose of 40 mg. In addition, the excipient base can optimize the stability in the formulation and the 40 mg amount of Compound 1 can maintain an effective dose for treating symptoms of uterine fibroids. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

In another embodiment, for the treatment of uterine fibroids in a premenopausal woman, a first oral dose or dosage form and a second oral dose or dosage form are administered to the subject. In one embodiment, the first oral dosage is 10 to 60 mg per day of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, and the second oral dosage is 0.01 to 5 mg per day of estrogen and/or progestogen. The first and second oral dosage forms may be administered once or twice a day. For example, the first and second oral dosage forms may be administered daily for a shorter treatment period. In some embodiments, the treatment period is daily administration for consecutive periods of at least 48 weeks, which may be consecutive periods of at least two separate 24

- 34 041715 week period. In addition, in some embodiments, the preferred periods of long-term administration are: consecutive periods of 48 weeks or more, consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

In some embodiments, the first oral dosage form is a tablet or capsule and the second oral dosage form is a tablet or capsule. Both oral dosage forms preferably have an immediate release profile in certain embodiments.

In some embodiments, a hormone replacement drug, such as estradiol, is administered in an amount per day of 0.5 mg, 1.0 mg, 1.5 mg, or 2.0 mg, and norethisterone acetate is administered in an amount per day of 0.1 mg or 0.5 mg. Estradiol and NETA can be administered once a day for the same period as Compound 1. As with Compound 1, in some embodiments, it is preferred that a hormone replacement drug such as estradiol and norethisterone acetate be used for administration to over the entire treatment period, for example, consecutive periods of 48 weeks or more, including consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

The main symptoms of uterine fibroids are heavy menstrual bleeding, anemia, compression, and pain in the bladder or pelvis (eg, pain in the lower abdomen and back pain). These symptoms can significantly reduce the quality of life of patients with uterine fibroids.

According to this disclosure, another method of treating heavy menstrual bleeding comprises administering to the subject 10 to 60 mg per day of Compound 1 or a pharmaceutically acceptable salt thereof, and preferably 0.01 to 5 mg per day of estrogen and/or progestogen. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

In addition, in accordance with this disclosure, another method of treating heavy menstrual bleeding includes: administering to the subject in the first oral dosage form from 10 to 60 mg per day of compound 1 or its pharmaceutically acceptable salt and simultaneously administering to the subject in the second oral dosage form from 0.01 to 5 mg daily of at least one of an estrogen and a progestogen. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

In addition, in accordance with this disclosure, another method of treating heavy menstrual bleeding includes: administering to the subject in the first oral dosage form from 10 to 60 mg per day of compound 1 or its pharmaceutically acceptable salt and simultaneously administering to the subject in the second oral dosage form from 0.01 to 5 mg daily of at least one of an estrogen and a progestogen. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Some advantages may be associated with the treatment of heavy menstrual bleeding associated with uterine fibroids by administering Compound 1 or a pharmaceutically acceptable salt thereof. In particular, these benefits include reduced menstrual blood loss, improved QOL scores, and reduced fibroid and uterine volumes, as further described herein.

Typical methods used to assess the amount of menstrual blood loss associated with uterine fibroids include the graphical assessment of the amount of menstrual blood loss (PBA) and the method of alkaline hematin. In FIG. 1 shows an exemplary PBAC scoring table that includes two items (tampon and towel) in three pictographic ranges (1: lightly stained; 5: moderately stained; 10: impregnated). These points represent the level of soiled hygiene materials during the menstrual cycle, with a total score ranging from 0 (none) to infinity. Higher values indicate more profuse blood loss. The PBAC scorecard also allows subjects to indicate: whether they experienced bleeding between periods that required sanitary protection; whether they had clots and, if so, the approximate size of the clots; whether they experienced episodes of profuse bleeding and whether they required double protection (using a pad and a tampon at the same time). Profuse bleeding may include, for example, bleeding so severe that feminine hygiene products are rapidly soaked and/or saturated. Profuse bleeding can also include menstrual bleeding, which requires more than 14 feminine hygiene products.

In some embodiments, a change from baseline in the mean PBAC score may result in a 3.0-5.0-fold decrease (from 300 to 500%), such as a 3.5-4.5-fold decrease (from 350 to 450%) and more specifically 4.0 to 4.2 times (400 to 420%) the PBAC score from week 6 to week 12 of the treatment period.

In some embodiments, the percentage change from baseline

- 35 041715 the average volume of fibroids can lead to a decrease of 3.5-6.5 times (from 350 to 650%), in particular 4.05.5 times (from 400 to 550%) and more specifically 4, 5-5.1% times (450 to 510%) fibroid volume at the end of a 12-week consecutive treatment period.

In some embodiments, the percentage change from baseline in mean uterine volume may result in a 4.0 to 7.0 fold decrease (400 to 700%), such as a 4.5 to 6.5 fold (450 to 650 %) and more specifically 4.8 to 5.5 times (480 to 550%) uterine volume at the end of a 12 week consecutive treatment period.

Pain associated with uterine fibroids can be assessed using the Numerical Self-Assessment Tool. For example, the Numerical Rating Scale (NRS) is an 11-item self-assessment tool for assessing pain. As shown in FIG. 2, it includes 11 points ranging from 0 (no pain) to 10 (worst possible pain). Higher NRS scores reflect higher levels of pain.

Quality of life (QOL) can be assessed using a self-assessment tool. For example, the Uterine Fibroids Symptom Quality of Life Questionnaire (UFS-QOL) is a 37-item self-assessment tool that assesses differences in symptom severity and health-related quality of life. It includes eight symptom-related questions and 29 health-related questions about quality of life on eight subscales (symptom severity, anxiety, activities, energy/mood, control, self-awareness, sexual function, and overall health-related quality of life) with subscales and an overall score ranging from 37 (not at all/never) to 116 (very much/all the time). An exemplary UFS-QOL questionnaire is shown in FIG. 3A-C. Higher UFS-QOL scores reflect greater symptom severity and the impact of symptoms on health-related quality of life.

In some embodiments, a change from baseline in the mean UFS-QOL symptom severity score may result in a 1.0-6.0-fold decrease (from 100 to 600%), such as a 2.0-5.0-fold decrease (200 to 500%) and more specifically 2.5 to 4.5 times (250 to 450%) the severity of symptoms.

In some embodiments, a change from baseline in the mean UFS-QOL score (total FIRQL) may result in a 0.01-4.0-fold decrease (from 1 to 400%), such as 0.05-2 .0 times (5 to 200%), and more specifically 0.10 to 1.0 times (10 to 100%) of the total HRQL UFS-QOL score.

In some embodiments, a change in the average concentration of hemoglobin in the blood compared to the initial value may lead to an increase of 3.0-6.0 times (from 300 to 600%), in particular, 3.5-5.5 times (from 350 to 550%) and more specifically 3.8-5.2 times (380 to 520%) the concentration of hemoglobin in the blood.

In some embodiments, a change in mean hematocrit from baseline may result in a 3.0 to 7.0 fold increase (300 to 700%), such as a 3.5 to 6.5 fold increase (350 to 700%). 650%) and more specifically 4.2-5.4 times (420 to 540%) the hematocrit value.

In some embodiments, a change in the average value of the iron index compared to the initial value can lead to an increase of 6.0-16.0 times (from 600 to 1600%), in particular, 8.0-14.0 times (from 800 up to 1400%) and more specifically 9.0 to 13.0 times (from 900 to 1300%) of iron.

In some embodiments, a change in mean ferritin concentration from baseline may result in a 2.0-6.0-fold increase (from 200 to 600%), in particular a 2.5-5.5-fold increase (from 250 to 550% ) and more specifically 3.0 to 4.5 times (300 to 450%) the ferritin concentration.

In some embodiments, a change from baseline in median LH concentrations may result in a 3.0-9.0-fold decrease (from 300 to 900%), in particular, a 4.0-8.0-fold decrease (from 400 to 800%) and more specifically 4.7-6.7 times (from 470 to 670%) the concentration of LH.

In some embodiments, a change from baseline in median FSH concentrations may result in a 1.0-5.0-fold decrease (from 100 to 500%), in particular, a 1.5-4.5-fold (from 150 to 450%) and more specifically 2.1-4.1 times (from 210 to 410%) FSH concentrations.

In some embodiments, a change from baseline to median estradiol concentrations may result in a 0.2 to 3.2 fold decrease (20 to 320%), in particular a 0.82.6 fold (80 to 260% ) and more specifically 1.0-2.4 times (100 to 240%) estradiol concentrations.

In some embodiments, a change from baseline in median progesterone concentrations may result in a 0.5 to 4.0 fold decrease (50 to 400%), such as a 0.8 to 3.7 fold (80 to 370%) and more specifically 1.2-3.2 times (120 to 320%) progesterone concentrations.

It should be understood that a combination of two, three, four, five or more of the above embodiments may result from the methods described. For example, in some embodiments, the methods provided herein result in a change from baseline in median median LH concentration, median FSH concentration, median estradiol concentration, and median progesterone concentration, as described above. In certain embodiments of any of the above embodiments, per day

- 36 041715 administered about 40 mg of compound 1 or an equivalent amount of its pharmaceutically acceptable salt.

In certain embodiments, for any of the methods of treating uterine fibroids, treating heavy menstrual bleeding associated with uterine fibroids, treating pain associated with uterine fibroids, or treating a premenopausal woman with symptomatic uterine fibroids described above, the premenopausal woman achieves menstrual volume. blood loss <80 ml during treatment; or achieve at least a 50% reduction from baseline in menstrual blood loss during treatment compared to before treatment; or have a PBAC score of less than 10; or any combination of them. In some embodiments, a premenopausal woman achieves a menstrual blood loss <80 ml, at least a 50 percent reduction from baseline in menstrual blood loss, or a PBAC score of less than 10, or any combination thereof for at least 30 weeks, at least at least 24 weeks or at least 12 weeks after the start of treatment. In some embodiments, the amount of menstrual blood loss is measured by the alkaline hematin method.

In certain embodiments, for any of the methods of treating uterine fibroids, treating heavy menstrual bleeding associated with uterine fibroids, treating pain associated with uterine fibroids, or treating a premenopausal woman with symptomatic uterine fibroids described above, the premenopausal woman has the highest score NRS is 1 or less for uterine fibroid pain at 6, 8, or 10 weeks after starting treatment; or an increase in the number of days with an NRS score of 0 is achieved within 6 weeks, 8 weeks or 10 weeks after the start of treatment compared to 6 weeks, 8 weeks or 10 weeks immediately before the start of treatment. In some embodiments, the implementation of the average NRS over 35 days during treatment decreases by at least 30% within 6 weeks, 8 weeks or 10 weeks after the start of treatment. In some of these embodiments, the premenopausal woman has a peak NRS score for pain associated with uterine fibroids >4 within 6 weeks, 8 weeks, or 10 weeks immediately before starting treatment.

In other embodiments, for any of the methods of treating uterine fibroids, treating heavy menstrual bleeding associated with uterine fibroids, treating pain associated with uterine fibroids, or treating a premenopausal woman with symptoms of uterine fibroids described above, the premenopausal woman's hemoglobin increased by >1 g/dl during treatment compared to before treatment. In certain embodiments, the premenopausal woman had a hemoglobin level of <12 g/dL prior to treatment. In some embodiments, this increase occurs within 20 weeks, 24 weeks, or 28 weeks from the start of treatment.

In additional embodiments, for any of the methods of treating uterine fibroids, treating heavy menstrual bleeding associated with uterine fibroids, treating pain associated with uterine fibroids, or treating a premenopausal woman with symptomatic uterine fibroids described above, the premenopausal woman experiences a reduction in the effects of fibroids uterus as assessed by the UFS-QOL scale; reduction of the negative impact of uterine fibroids on physical activity as assessed by the UFS-QOL scale; reducing the negative impact of uterine fibroids on social activity as assessed by the UFS-QOL scale; reduction of embarrassment caused by uterine fibroids, as assessed by the UFS-QOL scale; reduction in symptoms associated with uterine fibroids as assessed by the UFS-QOL symptom severity scale; reduction in quality of life problems associated with uterine fibroids, as assessed by the health-related quality of life scale, UFS-QOL; change from baseline in uterine fibroids function based on a Patient Global Assessment (PGA); reduction in symptoms of uterine fibroids based on PGA; change from baseline in physical activity as measured by the menorrhagia impact questionnaire; change from baseline in social and leisure activities as measured by the menorrhagia impact questionnaire; a decrease in the volume of the uterus or a decrease in the volume of uterine fibroids. In some embodiments of any of these measures, the decrease or change is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least at least 70%, at least 80%, at least 90%, at least 100% or more. In certain embodiments, the reduction or change occurs within 6 weeks, within 12 weeks, within 18 weeks, within 24 weeks, or within 30 weeks of starting treatment.

For all methods of the present disclosure, subjects may be monitored for bone mineral density. However, as noted above, in the fixed combination oral dosage form of the present disclosure, bone mineral density loss can be minimized because the hormone replacement drug and Compound 1 are combined in a single dosage form.

Thus, in at least one embodiment, treatment with Compound 1 or a pharmaceutically acceptable salt thereof will occur without monitoring bone mineral density.

IV. Endometriosis.

- 37 041715

Endometriosis is a sex hormone-dependent benign disease in which tissues morphologically and functionally similar to the endometrium develop outside the uterine cavity. The main clinical symptoms of endometriosis are menstrual pain or dysmenorrhea and infertility. Patients with endometriosis also often experience non-menstrual pelvic pain, such as lower abdominal pain and back pain, as well as dyspareunia, painful bowel movements, and painful urination. These symptoms can significantly reduce quality of life (QOL).

Provided herein is a method of treating endometriosis in a premenopausal woman in need thereof, comprising administering orally to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an estradiol equivalent and progestin). Also provided is a method for treating pain associated with endometriosis in a premenopausal woman in need thereof, comprising administering to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Also provided is a method for treating endometriosis-related heavy menstrual bleeding in a premenopausal woman, comprising administering to the premenopausal woman once a day a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Additionally, a method for treating a premenopausal woman with symptoms of endometriosis is provided, comprising administering to the premenopausal woman once a day a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. The combination may be administered, for example, either as a fixed dose or as two or more separate dosage forms that are administered together. Additionally, combination preparations are provided for use in any of these methods. In some embodiments, the implementation of the combination drug is for simultaneous or sequential use. In certain embodiments, the combination preparation comprises Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In certain embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Further provided is the use of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment in accordance with any of these methods. In some embodiments, the implementation of the hormone replacement drug contains estradiol or an estradiol equivalent and a progestin.

In some embodiments of the methods for treating endometriosis, pain associated with endometriosis, heavy menstrual bleeding associated with endometriosis, or a premenopausal woman with symptomatic endometriosis, the premenopausal woman experiences improvement in one or more symptoms during or after treatment. One or more symptoms may be selected from the group consisting of anemia, heavy menstrual bleeding, irregular menstruation, bleeding, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, urinary incontinence, constipation, restlessness, sleep disturbance, quality of life, daily activities, female sexual dysfunction and depression. The pain may be, for example, back pain, pelvic pain, chronic pain, dyspareunia, uterine pain, pain with defecation, pain with urination, or any combination thereof. In some embodiments, a method of treating a premenopausal woman with symptomatic endometriosis suppresses the woman's endometrium. Endometrial suppression may include, for example, an endometrial thickness on transvaginal ultrasound that is less than or equal to 4 mm; or an endometrial biopsy showing endometrial atrophy or weak secretory features; or a hard-to-obtain pattern, consistent with atrophy. In some embodiments, a method of treating a premenopausal woman with symptomatic endometriosis reduces the number and size or prevents the growth of endometriomas or endometriosis lesions. Suppressing or preventing the growth of endometriosis lesions and endometriomas can reduce pain symptoms such as chronic pain, dyspareunia, pain with bowel movements, or pain with urination. Thus, provided herein is a method of treating one or more symptoms associated with endometriosis in a premenopausal woman in need thereof, comprising administering to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug.

In some embodiments, the methods for treating endometriosis, pain associated with endometriosis (such as dyspareunia, chronic pain, pain with bowel movements, or pain with urination), heavy menstrual bleeding associated with endometriosis, or a premenopausal woman with symptomatic endometriosis provided herein lead to one or both of contraception and amenorrhea during treatment.

Administration of the combination provided herein in a method for the treatment of endometriosis, pain associated with endometriosis (such as dyspareunia, chronic pain, pain with defecation or pain with urination), heavy menstrual bleeding associated with endometriosis, or a woman

- 38 041715 premenopausal women with symptomatic endometriosis can lead to suppression of ovarian estrogen production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. Suppression of ovarian estrogen production can be demonstrated by blood levels of estrogen that are in the postmenopausal range, such as estradiol levels <20 pg/ml, in a subject administered Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug. Suppression of ovarian estrogen production in a subject co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation containing estradiol or an estradiol equivalent can be demonstrated by blood estradiol levels of 20 to 50 pg/mL. In some embodiments, for example, in women who are administered a higher dose of a hormone replacement drug (containing, for example, up to 5 mg of estradiol or estradiol equivalent), suppression of ovarian estrogen production in a woman who is co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug, can be demonstrated by blood levels of estradiol between 55 and 150 pg/mL. Suppression of ovarian estrogen production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, the methods for treating endometriosis, pain associated with endometriosis (such as dyspareunia, chronic pain, pain with defecation or pain with urination), heavy menstrual bleeding associated with endometriosis, or a premenopausal woman with symptomatic endometriosis provided herein , can lead to the fact that the concentration of estradiol in the serum of a woman in premenopause will be in a certain range. In some embodiments, administration of the combination results in the serum concentration of estradiol in a premenopausal woman ranging from about 20 to about 50 pg/mL between daily doses of the combination. In some embodiments, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

Administration of the combinations provided herein in a method of treating endometriosis, pain associated with endometriosis (such as dyspareunia, chronic pain, pain with defecation or pain with urination), heavy menstrual bleeding associated with endometriosis, or a premenopausal woman with symptomatic endometriosis can lead to suppression of progesterone production by the ovaries in premenopausal women. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian progesterone production in a premenopausal woman is suppressed. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian progesterone production is suppressed in a premenopausal woman. Suppression of ovarian progesterone production can be demonstrated, for example, by blood levels of progesterone that are in the postmenopausal range, for example, by progesterone levels <2 ng/ml, in a woman who has not received progesterone. Suppression of ovarian progesterone production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, methods of treating endometriosis, pain associated with endometriosis (such as dyspareunia, chronic pain, pain with bowel movements or pain with urination), heavy menstrual bleeding associated with endometriosis, or a premenopausal woman with symptomatic endometriosis may result in that the serum progesterone concentration in a premenopausal woman will be in a certain range. In some embodiments, administration of the combination results in a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL, less than about 4 ng/mL, less than about 3 ng/mL, less than about 2 ng /ml or less than about 1 ng/ml between daily doses of the combination. In certain embodiments, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination.

- 39 041715 after at least 4 consecutive weeks of administration of the combination.

In some embodiments of any of the above methods, administration of the combination results in any combination of suppression of ovarian estrogen production in a premenopausal woman, suppression of ovarian progesterone production in a premenopausal woman, or a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL between daily doses. combinations as described above.

In some embodiments, the combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug is administered orally for at least 24 consecutive weeks. In certain embodiments, the combination contains from about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination contains about 20 to about 50 mg, or about 30 to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug may be administered as a fixed dose combination, or may be two or more separate doses administered together.

The hormone replacement drug may contain estradiol or an estradiol equivalent, a progestin, or any combination thereof. In certain embodiments, the implementation of the hormone replacement drug contains estradiol or the equivalent of estradiol. In other embodiments, the implementation of the hormone replacement drug contains a progestin. The progestin may be, for example, norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestrone acetate, promegestone or dienogest. Estradiol equivalents can be, for example, conjugated equine estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol , tibolone or stilbestrol. In certain embodiments, the hormone replacement preparation contains both estradiol or an estradiol equivalent and a progestin. The progestin may be, for example, norethisterone or a salt thereof.

In some embodiments of any of the methods described herein, the hormone replacement preparation contains from about 0.01 to about 5 mg of progestin. For example, in some embodiments, the hormone replacement drug contains about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg , about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3, 75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg progestin. In some embodiments, the hormone replacement preparation contains from about 0.1 to about 0.5 mg of progestin, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0 .5 mg progestin. In some embodiments, the progestin is a norethisterone salt, such as norethisterone acetate. In certain embodiments, the implementation of the hormone replacement drug contains about 0.5 mg of norethisterone acetate. In other embodiments, the combination contains about 0.625 to about 5 mg of nomegestrol acetate, or about 0.05 to about 0.5 mg of levonorgestrel, or about 0.5 to about 5 mg of dienogest.

In some embodiments, the implementation of the hormone replacement drug contains from about 0.5 to about 2 mg of estradiol or the corresponding amount of estradiol equivalent. For example, in some embodiments, the hormone replacement drug contains about 0.5 to about 1 mg, about 0.5 to about 1.5 mg, about 1 to about 1.5 mg, about 1 to about 2 mg , about 1.5 to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of estradiol, or the equivalent amount of estradiol.

In one embodiment, the hormone replacement drug contains about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin. In a particular embodiment, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg. In one embodiment, the progestin is norethisterone acetate (NETA). In certain embodiments, the combination contains about 0.5 mg of NETA.

In one embodiment, the combination contains about 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 10 to about 60 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, does not provide adequately treating their symptom and/or condition (eg, endometriosis, pain associated with endometriosis, heavy menstrual bleeding associated with endometriosis, or one or more other symptoms associated with endometriosis). Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to

- 40 041715 about 140 mg of compound 1 or an appropriate amount of its pharmaceutically acceptable salt. In some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, the combination contains about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 0.5 to about 2 mg, about 0.5 to about 1.5 mg, about 0.5 to about 1 mg, or about 1 to about 2 mg of estradiol or an appropriate amount of estradiol equivalent does not adequately treat one or more of the side effects of a hypoestrogenic condition (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache). There may also be a population of premenopausal women who experience one or more side effects from the administration of a GnRH antagonist (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) when their levels serum estradiol is between 20 and 50 pg/mL, and for whom this experience has a more negative impact on their quality of life (QOL) than if their symptom and/or condition (eg, endometriosis, endometriosis-related pain, profuse menstrual bleeding associated with endometriosis, or one or more other symptoms associated with endometriosis) were not treated (eg, if their serum estradiol level was above 50 pg/mL). Thus, some women may choose to administer a higher dose of hormone replacement so that their mean daily serum estradiol level is about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL. ml, about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg/ml or about 150 pg/ml. Administration of a higher dose of a hormone replacement drug may achieve such mean daily circulating serum levels of estradiol, may further reduce one or more side effects from administration of the GnRH antagonist, and still provide some treatment for the symptom and/or condition. Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains about 1.5 to about 5.0 mg, about 2 to about 5 mg, about 3 to about 5 mg, about 4 to about about 5 mg, about 1.5 to about 4 mg, about 2 to about 4 mg, about 3 to about 4 mg, about 1.5 to about 3 mg, or about 2 to about 3 mg of estradiol or equivalent estradiol. For example, in some embodiments, the combination contains about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg of estradiol or estradiol equivalent.

As discussed above, administration of Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug may more rapidly treat one or more of the symptoms associated with endometriosis, or pain associated with endometriosis, or heavy menstrual bleeding associated with endometriosis, since the levels progesterone and estrogen can be suppressed without the addition of estradiol, estradiol equivalent and/or progestin. However, also as discussed above, one or more negative side effects (eg loss of bone mineral density) may result from longer treatment without the use of a hormone replacement drug. Thus, in some embodiments of the methods provided herein, for the treatment of endometriosis of the uterus, pain associated with endometriosis, heavy menstrual bleeding associated with endometriosis, or a woman with symptomatic endometriosis, prior to administration of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone α-substitute drug, Compound 1 or a pharmaceutically acceptable salt thereof is orally administered to a premenopausal woman once a day. In certain embodiments, about 10 to about 60 mg orally, or about 20 to about 50 mg, or about 30 mg to about 50 mg, such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily prior to any of the combinations described herein. In other embodiments, about 65 mg to about 140 mg of Compound 1 or about 65 mg to about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is orally administered to a premenopausal woman, e.g., about 65 mg, about 70 mg, about 75 mg , about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg or about 140 mg of compound 1 or the appropriate amount of its pharmaceutically acceptable salt once a day before the introduction of any of the combinations described in this document. Additionally, the use of compound 1 or its pharmaceutical

- 41 041715 acceptable salt for the manufacture of a medicinal product for treatment in accordance with any of these methods.

In some embodiments, a premenopausal woman is orally administered Compound 1 or a pharmaceutically acceptable salt thereof once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks or up to 24 consecutive weeks before the introduction of any of the combinations described in this document. In one embodiment, about 10 to about 60 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, is orally administered to a patient once a day for up to at least 4 consecutive weeks and up to 24 consecutive weeks prior to administration of the combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Administration of Compound 1 or a pharmaceutically acceptable salt thereof without concomitant administration of a hormone replacement drug during the period of time preceding co-administration of the combination may treat one or more of the symptoms of endometriosis, or heavy menstrual bleeding associated with endometriosis, or pain associated with endometriosis, more than aggressively at the beginning, before switching to longer treatment. This may be desirable, for example, in a woman with severe symptoms or multiple symptoms, or if one or more symptoms are to be relieved more quickly.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation may be administered orally to a premenopausal woman once a day for at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks or at least 96 consecutive weeks in a method of treating endometriosis, heavy menstrual bleeding associated with endometriosis, pain associated with endometriosis, or one or more other symptoms associated with endometriosis, as described above. In some embodiments, administration of the combination is suspended for conception and/or pregnancy. The administration of the combination may be resumed after delivery. In certain embodiments, the bone mineral density of a premenopausal woman during treatment according to one of the above methods is within ±3% or ±2% of the bone mineral density prior to treatment.

As discussed above, loss of bone mineral density can be a problem in subjects treated with GnRH agonists or antagonists. In some embodiments, long-term treatment with Compound 1 is administered in combination with a hormone replacement drug, either as a fixed dose or as two or more separate dosage forms administered together. This forced adherence to a hormone replacement regimen may provide women with protection from certain adverse effects caused by Compound 1, for example, by preventing and/or minimizing loss of bone mineral density due to reduced estrogen levels. This protection against bone loss through oral fixed combination dosage creates a long-term dosing regimen that may be safe for most women.

In some embodiments, once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof may allow women to start with a stable baseline of extremely low estrogen levels. The hormone replacement drug, which is also administered with Compound 1, can replace the dose of estradiol in a controlled manner, which is believed to prevent loss of bone mineral density in most women, and can mitigate other adverse tolerability effects such as vasomotor symptoms. In particular, it is believed that at concentrations of estradiol between 30-50 pg/ml, most of the symptomatic benefits associated with estrogen suppression are achieved, while side effects, including loss of bone mineral density, are minimized. An estradiol concentration of 20 to 50 pg/ml can also provide symptomatic benefits associated with estrogen suppression while side effects, including loss of bone mineral density, are minimized. Co-administration of Compound 1 and a hormone replacement drug as described herein can achieve this target estradiol level in most women. Compound 1 and the hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

In accordance with this disclosure, a method is provided for reducing menstrual blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to endometriosis. The method includes: administering to the subject in a first oral dose or dosage form of 10 to 60 mg per day of compound 1 and simultaneously administering to the subject in a second oral dose or dosage form of 0.01 to 5 mg per day of at least one of an estrogen and progestin. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

- 42 041715

Further, according to this disclosure, another method is provided for reducing blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to endometriosis. The method includes administering to the subject 10 to 60 mg per day of Compound 1 and 0.01 to 5 mg per day of at least one of an estrogen and a progestin. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Yet another method according to this disclosure is provided for reducing menstrual blood loss or achieving amenorrhea in a subject having heavy menstrual bleeding due to endometriosis. The method includes administering to the subject 10 to 60 mg per day of Compound 1 and 0.01 to 5 mg of NETA as a single hormone replacement drug. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

For the treatment of endometriosis, Compound 1, or a pharmaceutically acceptable salt thereof, is preferably administered orally with pharmaceutically acceptable excipients. The oral dose may be in the form of a solid preparation. In addition, the oral dosage form may have an immediate release profile. However, the oral dosage form may have other release profiles including, for example, sustained release, controlled release, delayed release, sustained release, and the like.

The main symptoms of endometriosis include pain and infertility. In particular, pain symptoms, including not only menstrual cramps but also frequent pelvic pain (eg, lower abdominal pain and back pain) and dyspareunia outside of menstruation, can significantly reduce the quality of life of patients with endometriosis. As stated above, Compound 1 is a GnRH antagonist. Thus, it can cause endometrial atrophy by decreasing blood E2 levels. In patients with endometriosis, it may inhibit the growth of endometriosis lesions and therefore may reduce pain symptoms.

Some advantages may be associated with the treatment of pelvic pain associated with endometriosis by administering Compound 1 or a pharmaceutically acceptable salt thereof. In particular, a reduction in pelvic pain may result from such an administration as described herein. The pelvic pain may be at least one of the following: dysmenorrhea, non-menstrual pelvic pain, and dyspareunia.

Typical methods used to assess pain response associated with endometriosis include, for example, visual analog scale (VAS), modified Biberoglu & Behrman scores (M-B&B), and Biberoglu & Behrman scores (B&B). Methods for assessing pain response associated with endometriosis also include the Numerical Rating Scale (NRS) and the Endometriosis Symptom Scale (SEMS - English: Symptoms of Endometriosis Scale).

A typical method used to assess quality of life (QOL) associated with endometriosis involves an assessment of the health status of patients with endometriosis (ENP-30 - English: Endometriosis Health Profile). An example of an EHP-30 questionnaire is shown in FIG. 151A-E, it includes 30 questions with 5 possible answers each.

Exemplary scales, electronic diary formats, questionnaires, forms, and the like used in compiling M-B&B scores may include, for example: endometriosis pain questionnaire (see FIG. 144); rating scale M-B&B (see Fig. 145); SEMS according to subject testing (see FIGS. 146A-C); electronic SEMS in accordance with testing on subjects (see Fig. 147A-M); the form of mood states (see Fig. 148A-C); the initial clinical questionnaire (see Fig. 149A-C) and the final clinical questionnaire (see Fig. 150A-B).

An example of a VAS score can be assessed using a 100 mm scale. In terms of pain intensity, pain-free states (score 0) and pain as severe as possible (score 100) can be taken as the extreme points of the scale. Other questions may assess: the presence or absence of menstruation, the amount of bleeding (during menstruation); whether the subject had sexual intercourse; VAS score of dyspareunia (if the subject had intercourse); adherence to study drug regimen and use of analgesics. The above items can be assessed using the patient diary that is distributed by the sponsor. Subjects may complete a patient diary each day during the treatment period or until early termination. In the case of illicit analgesics, subjects may record this fact in a patient diary, along with associated pain symptoms, prior to using analgesics.

In some embodiments of the methods presented herein, a change from baseline in the VAS score may result in an increase of 1.5-4.5 times (from 150 to 450%), in particular, 2.0-4. 0 times (200 to 400%) and more specifically 2.25 to 3.75 times (225 to 375%) the proportion of days without pelvic pain.

In some embodiments of the methods presented herein, a change from baseline in the VAS score may result in a 1.5-4.5-fold decrease (from 150 to 450%), in particular, 2.0-4. 0 times (200 to 400%) and more specifically 2.25 to 3.75 times (225 to 375%) pelvic pain.

In some embodiments of the methods presented herein, changing

- 43 041715 compared with the initial value of the M-B&B indicator can lead to a decrease of 1.25-4.0 times (from 125 to 400%), in particular, 1.5-3.5 times (from 150 to 350 %) and more specifically 1.75-3.25 times (175 to 325%) pelvic pain.

In some embodiments of the methods provided herein, a change from baseline in M-B&B can result in a 1.25-4.5-fold increase (from 125 to 450%), in particular a 1.5- 4.0 times (150 to 400%) and more specifically 1.75 to 3.75 times (175 to 375%) the proportion of days without pelvic pain.

In some embodiments of the methods presented herein, a change from baseline in the VAS score may result in a 1.25-5.0-fold decrease (from 125 to 500%), in particular, 1.5-4. 5 times (150 to 450%) and more specifically 1.6 to 4.0 times (160 to 400%) dysmenorrhea.

In some embodiments of the methods presented herein, a change from baseline in the VAS score may result in an increase of 2.0-10.0 times (from 200 to 1000%), in particular, 4.0-8. 0 times (400 to 800%) and more specifically 4.5 to 7.5 times (450 to 750%) the proportion of days without dysmenorrhea.

In some embodiments of the methods presented herein, a change from the initial value of the M-B&B index can lead to a decrease of 3.0-11.0 times (from 300 to 1100%), in particular, 4.0- 9.0 times (400 to 900%) and more specifically 5.0 to 8.0 times (500 to 800%) dysmenorrhea.

In some embodiments of the methods provided herein, a change from baseline in M-B&B can result in an increase of 2.0-9.0 times (from 200 to 900%), in particular, 3.5- 7.5 times (350 to 750%) and more specifically 4.0 to 7.0 times (400 to 700%) the proportion of days without dysmenorrhea.

In some embodiments of the methods presented herein, a change from the initial value of the M-B&B index can lead to an increase of 25-100 times (from 2500 to 10,000%), in particular, 50-75 times (from 5000 up to 7500%) and more specifically 55-70 times (5500 to 7000%) in subjects without dysmenorrhea.

In some embodiments of the methods provided herein, a change from baseline in M-B&B can result in an increase of 1.05-2.5 times (from 105 to 250%), in particular 1.1- 1.5 times (110 to 150%) and more specifically 1.2 to 1.4 times (120 to 140%) subjects without dyspareunia.

In some embodiments of the methods presented herein, a change from the initial value of the M-B&B index can lead to an increase of 2.0-10 times (from 200 to 1000%), in particular, 3.0-9.0 times (300 to 900%) and more specifically 3.5 to 8.5 times (350 to 850%) the proportion of days without deep dyspareunia.

In some embodiments of the methods presented herein, a change from the initial value of the M-B&B index can lead to a decrease in 10-50 times (from 1000 to 5000%), in particular, 20-40 times (from 2000 to 4000%) and more specifically 25-35 times (2500 to 3500%) deep dyspareunia.

In some embodiments of the methods presented herein, a change from baseline in the VAS score may result in a decrease of 1.1-5.0 times (from 110 to 500%), in particular, 1.5-4. 0 times (150 to 400%) and more specifically 1.75 to 3.75 times (175 to 375%) pelvic pain, dysmenorrhea, and dyspareunia.

In some embodiments of the methods presented herein, a change from baseline in the EHP-30 index may result in a 1.5-7.5-fold increase (from 150 to 750%), in particular, a 2.5- 6.5 times (250 to 650%) and more specifically 3.0 to 6.0 times (300 to 600%) quality of life (QOL).

It should be understood that a combination of two, three, four, five or more of the above embodiments may result from the methods described. For example, in some embodiments, the methods provided herein result in a change from baseline in the VAS score for pelvic pain and a change from baseline in the M-B&B score for deep dyspareunia as described above. In certain embodiments of any of the above embodiments, about 40 mg of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered per day.

In certain embodiments, for any of the methods for treating endometriosis, treating pain associated with endometriosis, treating heavy menstrual bleeding associated with endometriosis, or treating a premenopausal woman with symptomatic endometriosis described above, the premenopausal woman experiences a decrease in dysmenorrhea as measured by a change in compared to baseline on the NRS scale for dysmenorrhea; pain reduction as measured by change from baseline in NMPP NRS score; reduction in dyspareunia as measured by change from baseline in the NRS score for dyspareunia; improvement in functional impairment of dyspareunia as measured by change in comp

- 44 041715 sB&B baseline value; reduction in pain as measured by change from baseline in a PGA-based severity score for pain; reduction in dysfunction as measured by change from baseline based on PGA for function; there is improvement as measured by change from baseline in each of the non-pain sections of the EHP-30 (control and impotence, social support, emotional well-being and self-perception); reduction in functional impairment of dysmenorrhea as measured by change from baseline on the sB&B scale; reduction in NMPP functional impairment as measured by change from baseline on the sB&B scale; or reduction in pain as measured by the change from baseline in the EHP-30 pain score. In some embodiments, the baseline value for any of these indicators is based on the assessment within 6 weeks, 8 weeks, or 10 weeks immediately prior to the start of treatment. In certain embodiments, for any of the methods for treating endometriosis, treating pain associated with endometriosis, treating heavy menstrual bleeding associated with endometriosis, or treating a premenopausal woman with symptomatic endometriosis described above, the premenopausal woman exhibits better or much better PGIC scores for dysmenorrhea; shows better or much better PGIC performance for NMPP; shows better or much better PGIC scores for dyspareunia compared to 6 weeks, 8 weeks, or 10 weeks immediately prior to treatment. In some embodiments of any of these measures, the decrease or change is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least at least 70%, at least 80%, at least 90%, at least 100% or more. In certain embodiments, the reduction or change occurs within 6 weeks, within 12 weeks, within 18 weeks, within 24 weeks, or within 30 weeks of starting treatment.

For all methods of the present disclosure, subjects may be monitored for bone mineral density to ensure their safety. However, as noted above, in the fixed combination oral dosage form of the present disclosure, bone mineral density loss can be minimized because the hormone replacement drug and Compound 1 are combined in a single dosage form. Thus, in at least one embodiment, treatment with Compound 1 or a pharmaceutically acceptable salt thereof will occur without monitoring bone mineral density.

V. Adenomyosis.

Adenomyosis can refer to a condition in which the lining of the uterus (endometrium) breaks into the muscular wall of the uterus (myometrium). Adenomyosis can cause dysmenorrhea, dyspareunia, decreased abdominal pressure and bloating before menstruation and can lead to heavy menstrual bleeding. The condition may be scattered throughout the uterus or localized in one place. Using magnetic resonance imaging (MRI) or transvaginal ultrasound, doctors can see the telltale signs of disease in the uterus. Because the symptoms are very similar, adenomyosis is often misdiagnosed as uterine fibroids. However, these two states are different. While fibroids are benign tumors growing in or on the uterine wall, adenomyosis is a less uniform mass of cells in the uterine wall.

Provided herein is a method of treating adenomyosis in a premenopausal woman in need thereof, comprising administering orally to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an equivalent of estradiol and progestin). Also provided herein is a method for treating heavy menstrual bleeding associated with adenomyosis in a premenopausal woman in need thereof, comprising once daily oral administration to the premenopausal woman of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Also provided is a method for treating a premenopausal woman with symptomatic adenomyosis, comprising administering to the premenopausal woman once a day a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Additionally, combination preparations are provided for use in any of these methods. In some embodiments, the implementation of the combination drug is for simultaneous or sequential use. In certain embodiments, the combination preparation comprises Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In certain embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Further provided is the use of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment in accordance with any of these methods. In some embodiments, the implementation of the hormone replacement drug contains estradiol or an estradiol equivalent and a progestin.

In some embodiments, methods for treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or a premenopausal woman

- 45 041715 with symptomatic adenomyosis, a premenopausal woman experiences improvement in one or more symptoms during or after treatment. One or more symptoms may be selected from the group consisting of anemia, heavy menstrual bleeding, irregular menstruation, bleeding, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, urinary incontinence, constipation, restlessness, sleep disturbance, quality of life, daily activities, female sexual dysfunction and depression. The pain may be, for example, back pain, pelvic pain, uterine pain, chronic pain, pain with defecation, pain with urination, or dyspareunia, or any combination thereof. Thus, provided herein is a method of treating one or more symptoms associated with adenomyosis in a premenopausal woman in need thereof, comprising administering orally to the premenopausal woman once daily a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. .

In some embodiments, the methods for treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or a premenopausal woman with symptomatic adenomyosis provided herein result in one or both of contraception and amenorrhea during treatment.

Administration of the combinations provided herein in methods of treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or a premenopausal woman with symptomatic adenomyosis may result in suppression of ovarian estrogen production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. Suppression of ovarian estrogen production can be demonstrated by blood estrogen levels that are in the postmenopausal range, such as estradiol levels <20 pg/ml, in a subject administered Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug. Suppression of ovarian estrogen production in a subject co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation containing estradiol or an estradiol equivalent can be demonstrated by blood estradiol levels of 20 to 50 pg/mL. In some embodiments, for example, in women who are administered a higher dose of a hormone replacement drug (containing, for example, up to 5 mg of estradiol or an estradiol equivalent), suppression of ovarian estrogen production in a woman who is co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug, can be demonstrated by blood levels of estradiol between 55 and 150 pg/mL. Suppression of ovarian estrogen production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, methods of treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or premenopausal women with symptomatic adenomyosis may result in the serum concentration of estradiol in a premenopausal woman to be in a certain range. In some embodiments, administration of the combination results in the serum concentration of estradiol in a premenopausal woman ranging from about 20 to about 50 pg/mL between daily doses of the combination. In some embodiments, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

Administration of the combinations provided herein in methods of treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or premenopausal women with symptomatic adenomyosis may result in suppression of ovarian progesterone production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian progesterone production in a premenopausal woman is suppressed. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian progesterone production is suppressed in a premenopausal woman. Suppression of ovarian progesterone production can be demonstrated, for example, by blood levels of progesterone that are in the postmenopausal range, for example, by progesterone levels <2 ng/ml, in a woman who has not received progesterone. Suppression of progesterone production by the ovaries can also

- 46 041715 be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

As described above, methods of treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis can result in the serum progesterone concentration of a premenopausal woman in a certain range. In some embodiments, administration of the combination results in a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL, less than about 4 ng/mL, less than about 3 ng/mL, less than about 2 ng/mL. ml or less than about 1 ng/ml between daily doses of the combination. In certain embodiments, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

In some embodiments of any of the above methods, administration of the combination results in any combination of suppression of ovarian estrogen production in a premenopausal woman, suppression of ovarian progesterone production in a premenopausal woman, or a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL between daily doses. combinations as described above.

In some embodiments, the combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug is administered orally for at least 24 consecutive weeks. In certain embodiments, the combination contains from about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination contains about 20 to about 50 mg, 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

The hormone replacement drug may contain estradiol or an estradiol equivalent, a progestin, or any combination thereof. In certain embodiments, the implementation of the hormone replacement drug contains estradiol or the equivalent of estradiol. In other embodiments, the implementation of the hormone replacement drug contains a progestin. The progestin may be, for example, norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestron acetate, promegestone or dienogest. Estradiol equivalents can be, for example, conjugated equine estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol , tibolone or stilbestrol. In certain embodiments, the hormone replacement preparation contains both estradiol or an estradiol equivalent and a progestin. The progestin may be, for example, norethisterone or a salt thereof.

In some embodiments of any of the methods described herein, the hormone replacement preparation contains from about 0.01 to about 5 mg of progestin. For example, in some embodiments, the hormone replacement drug contains about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg , about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3, 75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg progestin. In some embodiments, the hormone replacement preparation contains from about 0.1 to about 0.5 mg of progestin, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0 .5 mg progestin. In some embodiments, the progestin is a norethisterone salt, such as norethisterone acetate. In certain embodiments, the implementation of the hormone replacement drug contains about 0.5 mg of norethisterone acetate. In other embodiments, the combination contains from about 0.625 mg to about 5 mg of nomegestrol acetate, or from about 0.05 to about 0.5 mg of levonorgestrel, or from about 0.5 mg to about 5 mg of dienogest.

In some embodiments, the implementation of the hormone replacement drug contains from about 0.5 to about 2 mg of estradiol or the corresponding amount of estradiol equivalent. For example, in some embodiments, the hormone replacement preparation comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 1 mg to about 1.5 mg, about 1 mg to about 2 mg, about 1.5 to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of estradiol, or the equivalent amount of estradiol .

In one embodiment, the hormone replacement preparation contains about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin. In a particular embodiment, the progestin is norethisterone or

- 47 041715 its salt in an amount of from about 0.1 to about 0.5 mg. In one embodiment, the progestin is norethisterone acetate (NETA). In certain embodiments, the combination contains about 0.5 mg of NETA.

In one embodiment, the combination contains about 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof does not adequately treat their symptom and/or condition (eg, adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or one or more symptoms associated with adenomyosis). Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 mg to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, the combination contains about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 0.5 mg to about 2 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1 mg, or about 1 mg up to about 2 mg of estradiol or an appropriate amount of estradiol equivalent does not provide adequate treatment for one or more side effects of a hypoestrogenic condition (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache). There may also be a population of premenopausal women who experience one or more side effects from the administration of a GnRH antagonist (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) when their levels serum estradiol ranges from 20 to 50 pg/mL, and for whom this experience has a more negative impact on their quality of life than if their symptom and/or condition (eg, adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis or one or more symptoms associated with adenomyosis) will not receive adequate treatment (eg if their serum estradiol levels were above 50 pg/mL). Thus, some women may choose to administer a higher dose of hormone replacement so that their mean daily serum estradiol level is about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL, about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg/ml ml or about 150 pg/ml. Administration of a higher dose of a hormone replacement drug may achieve such mean daily circulating serum levels of estradiol, may further reduce one or more side effects from administration of the GnRH antagonist, and still provide some treatment for the symptom and/or condition. Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains about 1.5 to about 5.0 mg, about 2 mg to about 5 mg, about 3 mg to about 5, about 4 mg to about 5 mg, about 1.5 mg to about 4 mg, about 2 mg to about 4 mg, about 3 mg to about 4 mg, about 1.5 mg to about 3 mg, or about 2 mg up to about 3 mg of estradiol or estradiol equivalent. For example, in some embodiments, the combination contains about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg of estradiol or estradiol equivalent.

Administration of Compound 1 or a pharmaceutically acceptable salt thereof without concomitant administration of a hormone replacement drug may more rapidly treat one or more symptoms associated with adenomyosis, or heavy menstrual bleeding associated with adenomyosis, or pain associated with adenomyosis, as progesterone and estrogen levels can be suppressed without the addition of estradiol, estradiol equivalent and/or progestin. However, as discussed above, one or more negative side effects (eg loss of bone mineral density) may result from longer treatment without the use of a hormone replacement drug. Thus, in some embodiments of the methods provided herein, for the treatment of adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or a woman with symptomatic adenomyosis, prior to administration of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone- replacement drug, a premenopausal woman is orally administered compound 1 or a pharmaceutically acceptable salt thereof once a day. In definition

In other embodiments, a premenopausal woman is orally administered about 10 mg to about 60 mg, or about 20 to about 50 mg, or about 30 mg to about 50 mg, such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily prior to administration of any of the combinations described herein. In other embodiments, about 65 mg to about 140 mg of Compound 1 or about 65 mg to about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is orally administered to a premenopausal woman, e.g., about 65 mg, about 70 mg, about 75 mg , about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg or about 140 mg of compound 1 or the appropriate amount of its pharmaceutically acceptable salt once a day before the introduction of any of the combinations described in this document. Additionally contemplated is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment in accordance with any of these methods.

In some embodiments, a premenopausal woman is orally administered Compound 1 or a pharmaceutically acceptable salt thereof once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks or up to 24 consecutive weeks before the introduction of any of the combinations described in this document. In one embodiment, about 10 to about 60 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is orally administered to a patient once daily for at least 4 consecutive weeks and up to 24 consecutive weeks prior to administration of the combination of Compound 1 or a pharmaceutically acceptable salt thereof. and a hormone replacement drug. Administration of Compound 1 or a pharmaceutically acceptable salt thereof without concomitant administration of a hormone replacement drug during the period of time prior to co-administration of the combination may treat one or more of the symptoms of adenomyosis, or heavy menstrual bleeding associated with adenomyosis, or pain associated with adenomyosis, more aggressively in beginning, before switching to longer treatment. This may be desirable, for example, in a woman with severe symptoms or multiple symptoms, or if one or more symptoms are to be relieved more quickly.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation may be administered orally to a premenopausal woman once a day for at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks or at least 96 consecutive weeks in a method of treating adenomyosis, heavy menstrual bleeding associated with adenomyosis, pain associated with adenomyosis, or a premenopausal woman with symptomatic adenomyosis, or one or more other symptoms associated with adenomyosis, as described above . In some embodiments, administration of the combination is suspended for conception and/or pregnancy. The administration of the combination may be resumed after delivery. In certain embodiments, the bone mineral density of a premenopausal woman during treatment according to one of the above methods is within ±3% or ±2% of the bone mineral density prior to treatment.

VI. Other symptoms and conditions.

Additionally, this document provides methods of treatment and pharmaceutical compositions for use in such methods of treating one or more symptoms or conditions selected from the group consisting of heavy menstrual bleeding, infertility, female sexual dysfunction (for example, decreased libido, decreased arousal, or decreased sexual activity). ), gender transition, spotting, sex hormone-induced cancers, reduced use of analgesic compounds, amenorrhea and fertility preservation, anemia (associated with heavy menstrual bleeding or not associated with heavy menstrual bleeding), pain (such as dyspareunia, chronic pain, pain with bowel movements or pain with urination), inflammation, irregular menstruation, symptoms related to the size and/or volume of uterine fibroids, miscarriage, depression, chronic fatigue, anxiety, and sleep disturbance in a premenopausal woman in need of it. Also provided is a method of contraception in a premenopausal woman in need of it. One or more symptoms or conditions may be associated with endometriosis, uterine fibroids, or adenomyosis, or may not be associated with endometriosis, uterine fibroids, or adenomyosis. For example, in some embodiments, a premenopausal woman has been diagnosed with one or more of endometriosis, uterine fibroids, or adenomyosis. In other embodiments, the premenopausal woman has not been diagnosed with one or more of endometriosis, uterine fibroids, or adenomyosis. Additionally, combination preparations are provided for use in any of these methods. In some embodiments, the implementation of the combination drug is for simultaneous or sequential use. In certain embodiments, the implementation of the combined preparation contains compound 1 or its pharmaceutically when

- 49 041715 acceptable salt and hormone replacement drug. In certain embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Additionally, the use of compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment in accordance with any of these methods is proposed. In some embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin.

These methods may include administering to a premenopausal woman in need thereof a combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug (eg, a combination of estradiol or an equivalent of estradiol and a progestin). In some embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent, or a progestin, or a combination thereof. The combination may be administered, for example, either as a fixed dose or as two or more separate dosage forms that are administered together.

Provided herein are methods of treating heavy menstrual bleeding in a premenopausal woman in need thereof, comprising administering orally to the premenopausal woman once daily a combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Heavy menstrual bleeding may be, for example, heavy menstrual bleeding associated with a non-malignant etiology such as, for example, uterine fibroids, endometriosis, adenomyosis, and the like. The methods for treating heavy menstrual bleeding described herein should not be used to treat heavy menstrual bleeding. bleeding associated with a malignant etiology, such as endometrial cancer. Treatment of heavy menstrual bleeding may include reducing menstrual blood loss by more than 50% compared to baseline before treatment. Treatment for heavy menstrual bleeding may include menstrual blood loss of less than 80 ml.

In some embodiments, heavy menstrual bleeding is associated with one or more of uterine fibroids, endometriosis, or adenomyosis. The methods for treating heavy menstrual bleeding in a premenopausal woman with uterine fibroids provided herein can reduce the number of uterine fibroids, the size of one or more uterine fibroids, or a combination thereof during and/or after treatment compared to the number or size of uterine fibroids before treatment. .

Provided herein are methods of treating pain associated with uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman in need thereof, comprising once daily oral administration to the premenopausal woman of a combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (for example, a combination of estradiol or the equivalent of estradiol and a progestin). The pain may be, for example, pelvic pain, back pain, uterine pain, chronic pain, pain with defecation, pain with urination, or dyspareunia, or any combination thereof. In some embodiments, the pain is associated with endometriosis. In other embodiments, the pain is associated with adenomyosis.

Additionally provided herein are methods of treating anemia in a premenopausal woman in need thereof, comprising administering once daily orally to the premenopausal woman a combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an estradiol equivalent and progestin). In some embodiments, a premenopausal woman is experiencing heavy menstrual bleeding. Heavy menstrual bleeding may be due to a non-malignant etiology such as endometriosis or uterine fibroids. In some embodiments, the premenopausal woman has one or more of the following conditions: uterine fibroids, endometriosis, heavy menstrual bleeding, or symptoms associated with one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

This document provides methods for improving fertility in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or several symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising once daily oral administration to a premenopausal woman of a combination containing Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin), for at least 12 consecutive weeks; and then stopping treatment for at least 4 weeks while the premenopausal woman tries to conceive. This document also provides methods for preventing miscarriage in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising oral administration to a woman in

- 50 041715 premenopausal once a day combination containing compound 1 or its pharmaceutically acceptable salt and a hormone replacement drug for at least 12 consecutive weeks; and then stopping treatment for at least 4 weeks while the premenopausal woman tries to conceive. In certain embodiments, the combination is orally administered to a premenopausal woman once daily for at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 72 weeks or more before stopping treatment. In certain embodiments, treatment is stopped for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, 4 to 28 weeks, 4 to 24 weeks, 4 to 20 weeks, 4 to 16 weeks, 4 to 12 weeks, or 4 to 8 weeks while a premenopausal woman is trying to conceive. In some embodiments, the premenopausal woman will conceive, become pregnant, or give birth. In certain embodiments, the premenopausal woman experienced one or more miscarriages, or an inability to conceive, or a combination thereof prior to treatment.

Also provided is a method of contraception in a premenopausal woman in need thereof, comprising once daily oral administration to the premenopausal woman of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (e.g., a combination of estradiol or an equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains from about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin. The combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together. Contraception can be demonstrated, for example, by suppression of ovarian production of estrogen and/or progesterone, as discussed above, or by a lower pregnancy rate occurring after 10 menstrual cycles with unprotected intercourse, or by suppression of ovulation.

In some embodiments, the methods provided herein, such as for the treatment of heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, result in one or both of contraception and amenorrhea during treatment. Upon termination of the methods provided herein, a premenopausal woman, in some embodiments, may conceive a child, become pregnant, or give birth.

In other embodiments of any of the above methods, the premenopausal woman experiences improvement in one or more symptoms selected from the group consisting of anemia, irregular menstruation, bleeding, inflammation, pain, fatigue, urinary tract obstruction, urinary frequency, urinary incontinence, constipation, anxiety, sleep disorders, quality of life, daily activities, female sexual dysfunction and depression, during and/or after the methods described above, such as for the treatment of heavy menstrual bleeding, anemia or pain; or for contraception; or to improve fertility. In some embodiments, the pain is dyspareunia. In other embodiments, the pain is chronic pain. In further embodiments, the pain is pain on defecation or pain on urination.

In a premenopausal woman with uterine fibroids, the methods described above, such as for the treatment of heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, may result in a reduction in the number of uterine fibroids, a reduction in the size of one or more uterine fibroids, or prevention of growth of uterine fibroids, or any combination thereof during and/or after treatment. The size and/or number of uterine fibroids can be assessed, for example, by transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging, computed tomography, or laparoscopy. In some embodiments, a premenopausal woman with symptomatic uterine fibroids or symptomatic endometriosis is treated according to the methods described above, such as for the treatment of heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, suppresses the endometrium in a woman.

In some embodiments of the methods provided herein, for example, to treat heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, Compound 1 or a pharmaceutically acceptable salt thereof is administered at an estrogen-suppressing dose, such as a dose that results in sustained estrogen suppression over a 24-hour period. In some embodiments, the dose suppresses estradiol production to a serum level of less than 20 pg/mL or less than 10 pg/mL. In some embodiments, the co-administration of a hormone replacement drug (e.g., a combination of estradiol or an equivalent

- 51 041715 estradiol and progestin tape) with Compound 1 or a pharmaceutically acceptable salt thereof can prevent, reduce or otherwise alleviate symptoms associated with a hypoestrogenic condition such as loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise or headache. In some embodiments, one or more vasomotor symptoms are selected from hot flashes and night sweats.

Administration of the combination as provided herein in the methods described above, such as for the treatment of heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, may lead to suppression of estrogen production by the ovaries in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. Suppression of ovarian estrogen production can be demonstrated by blood levels of estrogen that are in the postmenopausal range, such as estradiol levels <20 pg/ml, in a subject administered Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug. Suppression of ovarian estrogen production in a subject co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation containing estradiol or an estradiol equivalent can be demonstrated by blood estradiol levels of 20 to 50 pg/mL. In some embodiments, for example, in women who are administered a higher dose of a hormone replacement drug (comprising, for example, up to 5 mg of estradiol or estradiol equivalent), suppression of ovarian estrogen production in a woman who is co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone -substitution drug, can be demonstrated by blood levels of estradiol from 55 to 150 pg / ml. Suppression of ovarian estrogen production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

The methods described above, such as for the treatment of heavy menstrual bleeding, anemia or pain; or for contraception; or to improve fertility, may cause the serum concentration of estradiol in a premenopausal woman to be in a certain range. In some embodiments, administration of the composition results in the serum concentration of estradiol in a premenopausal woman ranging from about 20 to about 50 pg/mL between daily doses of the combination. In certain embodiments, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks after administration of the composition . In one embodiment, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination over at least 4 consecutive weeks of administration of the combination. The combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

Administration of the combination as provided herein in the methods described above, such as for the treatment of heavy menstrual bleeding, anemia, or pain; or for contraception; or to improve fertility, may lead to suppression of ovarian progesterone production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian progesterone production in a premenopausal woman is suppressed. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone is suppressed in a premenopausal woman. Suppression of ovarian progesterone production can be demonstrated, for example, by blood progesterone levels that are in the postmenopausal range, for example, by progesterone levels <2 ng/ml, in a woman who has not received progesterone. Suppression of ovarian progesterone production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

The methods described above, such as for the treatment of heavy menstrual bleeding, anemia or pain; or for contraception; or to improve fertility, may cause the serum progesterone concentration in a premenopausal woman to be in a certain range. In some embodiments, administration of the combination results in a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL, less than

less than about 4 ng/ml, less than about 3 ng/ml, less than about 2 ng/ml, or less than about 1 ng/ml between daily doses of the combination. In certain embodiments, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

In some embodiments of any of the above methods, administration of the combination results in any combination of suppression of ovarian estrogen production in a premenopausal woman, suppression of ovarian progesterone production in a premenopausal woman, or a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL between daily doses. combinations as described above.

Any of the combinations described herein may be suitable for the treatment of the symptoms and/or conditions described above, such as heavy menstrual bleeding, anemia, or pain; or to improve fertility; or for contraception. In certain embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, or about 30 mg to about 50 mg of Compound 1, e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg, or the appropriate amount of a pharmaceutically acceptable salt thereof. The hormone replacement preparation may contain, for example, estradiol or an estradiol equivalent, or a progestin, or any combination thereof, as described herein. In certain embodiments, the combination contains from about 0.5 to about 2 mg of estradiol, for example, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg or about 2 mg of estradiol, or an equivalent amount of estradiol and about 0.01 to about 5 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg, or progestin. In some embodiments, the combination is administered once daily for at least 24 consecutive weeks.

The hormone replacement drug may contain estradiol or an estradiol equivalent, a progestin, or any combination thereof. In certain embodiments, the implementation of the hormone replacement drug contains estradiol or the equivalent of estradiol. In other embodiments, the implementation of the hormone replacement drug contains a progestin. The progestin may be, for example, norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestrone acetate, promegestone or dienogest. Estradiol equivalents can be, for example, conjugated equine estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol , tibolone or stilbestrol. In certain embodiments, the hormone replacement preparation contains both estradiol or an estradiol equivalent and a progestin. The progestin may be, for example, norethisterone or a salt thereof.

In some embodiments of any of the methods described herein, the hormone replacement preparation contains from about 0.01 to about 5 mg of progestin. For example, in some embodiments, the hormone replacement drug contains about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg , about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3, 75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg progestin. In some embodiments, the hormone replacement preparation contains from about 0.1 to about 0.5 mg of progestin, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0 .5 mg progestin. In some embodiments, the progestin is a norethisterone salt, such as norethisterone acetate. In certain embodiments, the implementation of the hormone replacement drug contains about 0.5 mg of norethisterone acetate. In other embodiments, the combination contains from about 0.625 mg to about 5 mg of nomegestrol acetate, or from about 0.05 to about 0.5 mg of levonorgestrel, or from about 0.5 mg to about 5 mg of dienogest.

In some embodiments, the implementation of the hormone replacement drug contains from about 0.5 to about 2 mg of estradiol or the corresponding amount of estradiol equivalent. For example, in some embodiments, the hormone replacement preparation comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 1 mg to about 1.5 mg, about 1 mg to about 2 mg, about 1.5 to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of estradiol, or the equivalent amount of estradiol .

In one embodiment, the hormone replacement drug contains about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin. In a particular embodiment, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg. In one embodiment, the progestin

- 53 041715 is norethisterone acetate (NETA). In certain embodiments, the combination contains about 0.5 mg of NETA.

In one embodiment, the combination contains about 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

The combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

In some embodiments, there is a population of premenopausal women for whom about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof does not adequately treat their symptom and/or condition (eg, heavy menstrual bleeding, anemia, pain, or infertility). Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 mg to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, the combination contains about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 0.5 mg to about 2 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1 mg, or about 1 mg up to about 2 mg of estradiol or an appropriate amount of estradiol equivalent does not provide adequate treatment for one or more side effects of a hypoestrogenic condition (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache). There may also be a population of premenopausal women who experience one or more side effects from the administration of a GnRH antagonist (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) when their levels serum estradiol is between 20 and 50 pg/mL, and for whom this experience has a more negative impact on their quality of life than if their symptom and/or condition (eg, heavy menstrual bleeding, anemia, pain, or infertility) will not receive sufficient treatment (for example, if their serum estradiol level was above 50 pg/ml). Thus, some women may choose to administer a higher dose of hormone replacement so that their mean daily serum estradiol level is about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL, about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg/ml ml or about 150 pg/ml. Administration of a higher dose of a hormone replacement drug may achieve such mean daily circulating serum levels of estradiol, may further reduce one or more side effects from administration of the GnRH antagonist, and still provide some treatment for the symptom and/or condition. Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains about 1.5 to about 5.0 mg, about 2 mg to about 5 mg, about 3 mg to about 5, about 4 mg to about 5 mg, about 1.5 mg to about 4 mg, about 2 mg to about 4 mg, about 3 mg to about 4 mg, about 1.5 mg to about 3 mg, or about 2 mg up to about 3 mg of estradiol or estradiol equivalent. For example, in some embodiments, the combination contains about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg of estradiol or estradiol equivalent.

Administration of Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug may more rapidly treat one or more of the symptoms or conditions described above, e.g., heavy menstrual bleeding, anemia, or pain, since progesterone and estrogen levels can be suppressed without supplementation. estradiol, estradiol equivalent and/or progestin. However, as discussed above, one or more negative side effects (eg loss of bone mineral density) may result from longer treatment without the use of a hormone replacement drug. Thus, in some embodiments of the methods provided herein, for the treatment of one or more of the symptoms or conditions described herein, such as heavy menstrual bleeding, anemia pain; or for contraception, prior to administering the combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug to a premenopausal woman, Compound 1 or a pharmaceutically acceptable salt thereof is orally administered once a day. In certain variations

about 10 mg to about 60 mg, or about 20 to about 50 mg, or about 30 mg to about 50 mg, such as about 10 mg, about 20 mg, about 30 mg, is administered orally to a premenopausal woman. , about 40 mg, about 50 mg, or about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily prior to administration of any of the combinations described herein. In other embodiments, about 65 mg to about 140 mg of Compound 1 or about 65 mg to about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is orally administered to a premenopausal woman, e.g., about 65 mg, about 70 mg, about 75 mg , about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg or about 140 mg of compound 1 or the appropriate amount of its pharmaceutically acceptable salt once a day before the introduction of any of the combinations described in this document. Additionally contemplated is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment in accordance with any of these methods.

In some embodiments, a premenopausal woman is orally administered Compound 1 or a pharmaceutically acceptable salt thereof once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks or up to 24 consecutive weeks before the introduction of any of the combinations described in this document. In one embodiment, about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is orally administered to a patient once a day at for at least 4 consecutive weeks and up to 24 consecutive weeks prior to administration of the combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug. Administration of Compound 1, or a pharmaceutically acceptable salt thereof, without concomitant administration of a hormone replacement drug during the period of time prior to co-administration of the combination may treat one or more symptoms more aggressively at the onset, before transitioning to longer treatment. This may be desirable, for example, in a woman with severe symptoms or multiple symptoms, or if one or more symptoms are to be relieved more quickly.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation may be administered orally to a premenopausal woman once a day for at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks or at least 96 consecutive weeks in a method of treating heavy menstrual bleeding, anemia or pain; or for contraception; or to improve fertility, as described above. In some embodiments, administration of the combination is suspended for conception and/or pregnancy. The administration of the combination may be resumed after delivery. In certain embodiments, the bone mineral density of a premenopausal woman during treatment according to one of the above methods is within ±3% or ±2% of the bone mineral density prior to treatment.

In one embodiment, cardiac benefits can be provided using the methods of treatment of the present invention. In addition, the methods of treatment of this disclosure may be useful in sex reassignment/gender transition. In addition, the methods of treatment of this disclosure may be useful for maintaining fertility during chemotherapy.

VII. Side effects of a GnRH antagonist.

Additionally, this document provides methods for reducing one or more side effects associated with the administration of a GnRH antagonist, such as Compound 1 or a pharmaceutically acceptable salt thereof. One or more side effects may be selected from the group consisting of loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise, and headache. In addition, this document provides methods for maintaining a lipid profile or maintaining a normal range of glucose levels in a subject who has been administered a GnRH antagonist such as Compound 1 or a pharmaceutically acceptable salt thereof. Such methods include once daily oral administration of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or an estradiol equivalent and a progestin) to a premenopausal woman in need thereof. In some embodiments, the subject has been diagnosed with uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis. In other embodiments, the subject has not been diagnosed with uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis. The combination may be administered, for example, either as a fixed dose or as two or more separate dosage forms that are administered together. Additionally, combination preparations are provided for use in any of these methods. In some embodiments, the implementation of the combination drug is for simultaneous or sequential use.

- 55 041715

In certain embodiments, the combination preparation comprises Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In certain embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin. Further provided is the use of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation for the manufacture of a medicament for treatment in accordance with any of these methods. In some embodiments, the hormone replacement preparation comprises estradiol or an estradiol equivalent and a progestin.

This document provides a method for maintaining bone density in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising once daily oral administration to a premenopausal woman of a combination of the compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin. Maintaining bone mineral density may include that the bone mineral density during treatment is within ± 3% compared to bone mineral density before treatment. In some embodiments, maintaining bone density includes keeping bone mineral density during treatment within ±2% of bone mineral density prior to treatment.

This document provides a method of treating one or both of vulvovaginal atrophy or vaginal dryness in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1 or a pharmaceutically acceptable salt thereof, comprising oral administration to a woman in premenopausal once daily combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or an equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin. Treatment of vulvovaginal atrophy or vaginal dryness may include increasing the percentage of superficial cells and decreasing the percentage of parabasal cells in the vaginal epithelium, lowering the vaginal pH from greater than 5.0 to less than 5.0, and/or improving one or more symptoms selected from dryness , dyspareunia, and bleeding, as reported by the subject.

This document provides a method of treating headache in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising once daily oral administration to a premenopausal woman of a combination of the compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg

- 56 041715 estradiol or the equivalent amount of estradiol and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin.

This document provides a method of treating fatigue or malaise in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising once-daily oral administration to a premenopausal woman of the combination Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin.

In any of the preceding methods, the combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

In some embodiments, the headache is a migraine associated with the menstrual cycle. Headache treatment may include reducing the frequency and/or severity of headache reported by the subject. Migraine may, for example, include primary headache characterized by recurrent headaches that are moderate or severe. Headaches may affect half of the head, be throbbing in nature, and last from two to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is usually aggravated by physical activity. A migraine may be accompanied by an aura, which is usually a short period of blurred vision that signals that the headache is about to come. Sometimes an aura can occur with little or no headache.

Additionally, this document provides a method of maintaining one or both of the normal lipid profile or normal range of blood glucose levels in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising comprising oral administration to a premenopausal woman once daily of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). In some embodiments, the combination is administered once a day for at least 24 consecutive weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin. In some embodiments, maintaining one or both of the normal lipid profile or normal range of blood glucose levels includes that no clinically significant changes in the lipid profile and/or range of blood glucose levels occur during treatment compared to the start of treatment. .

This document also provides a method of treating one or more of night sweats, hot flashes, or other vasomotor symptoms in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, one or more symptoms associated with uterine fibroids, one or more symptoms associated with endometriosis (eg, pain), or one or more symptoms associated with adenomyosis (eg, pain), Compound 1, or a pharmaceutically acceptable salt thereof, comprising oral administration to a premenopausal woman once a day of a combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug (eg, a combination of estradiol or the equivalent of estradiol and a progestin). In some embodiments, the combination is administered once daily for at least 24 consecutive

- 57 041715 continuous weeks, at least 28 consecutive weeks, at least 32 consecutive weeks, at least 36 consecutive weeks, or at least 40 consecutive weeks. In some embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg or about 0.1 to about 0.5 mg of progestin. Treatment of night sweats, hot flashes, or other vasomotor symptoms may include reducing the frequency and/or severity of night sweats, hot flashes, or other vasomotor symptoms reported by the subject.

In some embodiments, the methods described above, such as treating one or more side effects associated with administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, or headache ), or maintaining a lipid profile, or maintaining a normal range of glucose levels, in a premenopausal woman results in one or both of contraception and amenorrhea during treatment. Upon termination of the methods provided herein, a premenopausal woman, in some embodiments, may conceive a child, become pregnant, or give birth.

In other embodiments, the premenopausal woman experiences improvement in one or more symptoms selected from the group consisting of anemia, irregular menses, bleeding, inflammation, pain, fatigue, urinary tract obstruction, urinary frequency, urinary incontinence, constipation, anxiety, sleep disturbances , quality of life, daily activities, female sexual dysfunction and depression, during and/or after the methods described above, for example, for the treatment of one or more side effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms ( such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness or headache), or to maintain a lipid profile, or to maintain a normal range of glucose levels. In some embodiments, the pain is dyspareunia. In other embodiments, the pain is chronic pain. In further embodiments, the pain is pain on defecation or pain on urination.

In a premenopausal woman with uterine fibroids, the methods described above, such as for the treatment of one or more side effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness or headache), or to maintain a lipid profile, or to maintain a normal range of glucose levels, may result in a reduction in the number of uterine fibroids, a reduction in the size of one or more uterine fibroids, or the prevention of growth of uterine fibroids, or any combination of these during and/or after treatment. In some embodiments, the size of one or more uterine fibroids is reduced to undetectable, and/or the number of uterine fibroids is reduced to zero. The size and/or number of uterine fibroids can be assessed, for example, by transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging, computed tomography, or laparoscopy. In some embodiments, in a premenopausal woman with symptomatic uterine fibroids or symptomatic endometriosis, the woman's endometrium is suppressed by treatment in accordance with the methods described above, such as treatment of one or more side effects associated with the administration of a GnRH antagonist (such as loss of mineral density bones, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache), or to maintain a lipid profile, or to maintain a normal range of glucose levels.

Administration of the combination as provided herein in the methods described above, such as treatment of one or more side effects associated with administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, dryness vagina, fatigue, malaise, or headache), or maintaining a lipid profile, or maintaining a normal range of glucose levels, can lead to suppression of ovarian estrogen production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian estrogen production is suppressed in a premenopausal woman. Suppression of ovarian estrogen production can be demonstrated by blood levels of estrogen that are in the postmenopausal range, such as estradiol levels <20 pg/ml, in a subject administered Compound 1 or a pharmaceutically acceptable salt thereof without co-administration of a hormone replacement drug. Suppression of estrogen production by the ovaries in a subject

- 58 041715 to which Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation containing estradiol or an estradiol equivalent are co-administered can be demonstrated by blood estradiol levels of 20 to 50 pg/ml. In some embodiments, for example, in women who are administered a higher dose of a hormone replacement drug (containing, for example, up to 5 mg of estradiol or an estradiol equivalent), suppression of ovarian estrogen production in a woman who is co-administered Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug, can be demonstrated by blood levels of estradiol between 55 and 150 pg/mL. Suppression of ovarian estrogen production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

The methods described above, such as the treatment of one or more side effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache ), or maintenance of a lipid profile, or maintenance of a normal range of glucose levels, may cause the serum estradiol concentration in a premenopausal woman to be in a certain range. In some embodiments, administration of the combination results in the serum concentration of estradiol in a premenopausal woman ranging from about 20 to about 50 pg/mL between daily doses of the combination. In some embodiments, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/ml between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

Administration of a combination as provided herein in the methods described above, such as treatment of one or more side effects associated with administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, dryness vagina, fatigue, malaise, or headache), or maintaining a lipid profile, or maintaining a normal range of glucose levels, can lead to suppression of ovarian progesterone production in a premenopausal woman. For example, in some embodiments, after at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, or at least 16 consecutive weeks of administration of the combination, ovarian progesterone production in a premenopausal woman is suppressed. In some embodiments, after at least 4 consecutive weeks of administration of the combination, ovarian progesterone production is suppressed in a premenopausal woman. Suppression of ovarian progesterone production can be demonstrated, for example, by blood levels of progesterone that are in the postmenopausal range, for example, by progesterone levels <2 ng/ml, in a woman who has not received progesterone. Suppression of ovarian progesterone production can also be demonstrated by ultrasound showing no growth of ovarian follicles and/or by the presence of amenorrhea.

The methods described above, such as the treatment of one or more side effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache ), or maintaining a lipid profile, or maintaining a normal range of glucose levels, can result in a premenopausal woman's serum progesterone concentration within a certain range. In some embodiments, administration of the combination results in a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL, less than about 4 ng/mL, less than about 3 ng/mL, less than about 2 ng /ml or less than about 1 ng/ml between daily doses of the combination. In certain embodiments, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/ml between daily doses of the combination at least 4 consecutive weeks, at least 8 consecutive weeks, or at least 12 consecutive weeks of administration of the combination. In one embodiment, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination over at least 4 consecutive weeks of administration of the combination.

In some embodiments of any of the above methods, administration of the combination results in any combination of suppression of ovarian estrogen production in a premenopausal woman, suppression of ovarian progesterone production in a premenopausal woman, or a serum progesterone concentration in a premenopausal woman of less than about 5 ng/mL between daily doses. combinations as described above.

Any of the combinations described herein may be suitable for the treatment of the symptoms and/or conditions described above, for example, for the treatment of one or more side effects.

- 59 041715 effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise or headache), either to maintain a lipid profile, or to maintain a normal range of glucose levels. In certain embodiments, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, or about 30 mg to about 50 mg of Compound 1, e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg, or the appropriate amount of a pharmaceutically acceptable salt thereof. The hormone replacement preparation may contain, for example, estradiol or an estradiol equivalent, or a progestin, or any combination thereof, as described herein. In certain embodiments, the combination contains from about 0.5 to about 2 mg of estradiol, for example, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg or about 2 mg of estradiol, or an equivalent amount of estradiol and about 0.01 to about 5 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg, or progestin. In some embodiments, the combination is administered once daily for at least 24 consecutive weeks. The combination containing Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug may be administered as a fixed dose combination or may be two or more separate doses administered together.

The hormone replacement drug may contain estradiol or an estradiol equivalent, a progestin, or any combination thereof. In certain embodiments, the implementation of the hormone replacement drug contains estradiol or the equivalent of estradiol. In other embodiments, the implementation of the hormone replacement drug contains a progestin. The progestin may be, for example, norethisterone, norethisterone acetate, norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, progesterone, cyproterone, desogestrel, etonogestrel, nomegestrol acetate, medroxyprogestron acetate, promegestone or dienogest. Estradiol equivalents can be, for example, conjugated equine estrogens, synthetic conjugated estrogens, esterified estrogens (eg, cypionate, estradiol valerate, estradiol acetate, estradiol benzoate), estropipate, ethinylestradiol, estrone, estriol, sterol, mestranol, moxestrol, chinestrol, methylstradiol , tibolone or stilbestrol. In certain embodiments, the hormone replacement preparation contains both estradiol or an estradiol equivalent and a progestin. The progestin may be, for example, norethisterone or a salt thereof.

In some embodiments of any of the methods described herein, the hormone replacement preparation contains from about 0.01 to about 5 mg of progestin. For example, in some embodiments, the hormone replacement drug contains about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg , about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3, 75mg, about 4.0mg, about 4.25mg, about 4.5mg, about 4.75mg, or about 5mg progestin. In some embodiments, the hormone replacement preparation contains from about 0.1 to about 0.5 mg of progestin, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0 .5 mg progestin. In some embodiments, the progestin is a norethisterone salt, such as norethisterone acetate. In certain embodiments, the implementation of the hormone replacement drug contains about 0.5 mg of norethisterone acetate. In other embodiments, the combination contains from about 0.625 mg to about 5 mg of nomegestrol acetate, or from about 0.05 to about 0.5 mg of levonorgestrel, or from about 0.5 mg to about 5 mg of dienogest.

In some embodiments, the implementation of the hormone replacement drug contains from about 0.5 to about 2 mg of estradiol or the corresponding amount of estradiol equivalent. For example, in some embodiments, the hormone replacement preparation comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 1 mg to about 1.5 mg, about 1 mg to about 2 mg, about 1.5 mg to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of estradiol, or equivalent amount estradiol.

In one embodiment, the hormone replacement drug contains about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin. In a particular embodiment, the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg. In one embodiment, the progestin is norethisterone acetate (NETA). In certain embodiments, the combination contains about 0.5 mg of NETA.

In one embodiment, the combination contains about 0.5 mg of NETA, about 1 mg of estradiol, and about 40 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, there is a population of premenopausal women for whom about 0.5 mg to about 2 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1 mg, or about 1 mg up to about 2 mg of estradiol or an appropriate amount of estradiol equivalent does not adequately treat one or more side effects of a hypoestrogenic condition (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvo

- 60 041715 vaginal atrophy, vaginal dryness, fatigue, malaise or headache). There may also be a population of premenopausal women who experience one or more side effects from the administration of a GnRH antagonist (eg, loss of bone mineral density, one or more vasomotor symptoms, vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache) when their levels serum estradiol is between 20 and 50 pg/ml, and for whom this experience has a more negative impact on their quality of life than in other women. Thus, some women may choose to administer a higher dose of hormone replacement so that their mean daily serum estradiol level is about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL, about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg/ml ml or about 150 pg/ml. Administration of a higher dose of a hormone replacement drug can achieve such mean daily circulating serum levels of estradiol and may further reduce one or more side effects from administration of a GnRH antagonist than administration of a lower dose of a hormone replacement drug. Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains about 1.5 to about 5.0 mg, about 2 mg to about 5 mg, about 3 mg to about 5, about 4 mg to about 5 mg, about 1.5 mg to about 4 mg, about 2 mg to about 4 mg, about 3 mg to about 4 mg, about 1.5 mg to about 3 mg, or about 2 mg up to about 3 mg of estradiol or estradiol equivalent. For example, in some embodiments, the combination contains about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg of estradiol or estradiol equivalent.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation may be administered orally to a premenopausal woman once a day for at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks or at least 96 consecutive weeks in the method of treating the symptoms and/or conditions described above, such as treating one or more side effects associated with the administration of a GnRH antagonist (such as loss of bone mineral density, vasomotor symptoms (such as night sweats or hot flashes), vulvovaginal atrophy, vaginal dryness, fatigue, malaise, or headache), or maintaining a lipid profile, or maintaining a normal range of glucose levels. In some embodiments, administration of the combination is suspended for conception and/or pregnancy. The administration of the combination may be resumed after delivery. In certain embodiments, the bone mineral density of a premenopausal woman during treatment according to one of the above methods is within ±3% or ±2% of the bone mineral density prior to treatment.

In some embodiments, after administration of doses of 40 mg per day for 28 consecutive days of Compound 1 and 0.01 to 5 mg per day of at least one of an estrogen and a progestogen, bone mineral density loss is minimized. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

This document provides methods for treating one or more side effects associated with the administration of GnRH antagonists. Additional side effects associated with the administration of a GnRH antagonist include vasomotor symptoms, hot flashes, vaginal dryness, and decreased libido.

In one embodiment, Compound 1 is co-administered with a drug to counteract any decrease in libido caused by the GnRH antagonist, optionally as separate oral dosage forms and preferably as a fixed combination oral dosage form. Such female libido enhancing drugs allow the subject to maintain sexual activity during the treatment period. These drugs include 5-HT _1a receptor agonists such as flibanserin. Like compound 1, flibanserin is administered orally once a day. In another embodiment, a 5-HT _1a receptor agonist such as flibanserin is co-administered with a hormone replacement drug and Compound 1, optionally as separate oral dosage forms and preferably as a fixed combination oral dosage form. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a drug.

In one embodiment, Compound 1 is co-administered with at least one compound to reduce the incidence of hot flashes in subjects, optionally as separate oral dosage forms and preferably as a fixed combination oral dosage form. In one embodiment, at least one hot flushing compound is selected from the group consisting of gabapentin, pregabalin, venlafaxine, fluoxetine, paroxetine, aspirin (including enteric and non-enteric aspirin).

- 61 041715 cover) and NK3 receptor antagonists. In another embodiment, at least one hot flushing compound is co-administered with Compound 1 and a hormone replacement drug, optionally as separate oral dosage forms and preferably as a fixed combination oral dosage form. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with the compound.

In one embodiment, cardiac benefits can be provided using the methods of treatment of the present invention. In addition, the methods of treatment of this disclosure may be useful in sex reassignment/gender transition. In addition, the methods of treatment of this disclosure may be useful for maintaining fertility during chemotherapy.

Additional side effects associated with the administration of a GnRH antagonist may include vasomotor symptoms, hot flashes, vaginal dryness, and decreased libido.

VIII. pharmaceutical compositions.

Some of the methods provided herein involve administering to a premenopausal woman a combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. These methods may include the treatment of one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis; heavy menstrual bleeding; pain associated with uterine fibroids, endometriosis, or adenomyosis; or a premenopausal woman with symptoms of uterine fibroids or endometriosis. The methods may also include maintaining bone mineral density; treatment of hot flashes, night sweats, or other vasomotor symptoms; maintaining one or both of the lipid profile or range of blood glucose levels; treatment of one or both of vulvovaginal atrophy or vaginal dryness; treatment of fatigue or malaise; headache treatment or method of contraception in a premenopausal woman who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding. The methods may further include achieving amenorrhea, preventing miscarriage, improving fertility, or treating anemia.

The combination administered by any of the methods described herein may be in a single dosage form or contain separate dosage forms that are administered together. The individual dosage forms may be individual physical forms, eg two, three, four, five or more individual tablets. For example, in some embodiments, the implementation of the combination contains one tablet containing compound 1 or its pharmaceutically acceptable salt; and a second tablet containing a hormone replacement drug (eg, estradiol and NETA); or a second and third tablet containing a hormone replacement drug (eg, a second tablet containing estradiol and a third tablet containing NETA).

Co-administration of separate dosage forms may include administering at the same time or over time, for example, administering separate dosage forms 30 minutes or less apart, 20 minutes or less apart, 15 minutes or less different, 10 minutes apart, minutes or less, or with a difference of 5 minutes or less.

In accordance with this disclosure, several methods are provided which include treating uterine fibroids in a subject, reducing menstrual blood loss associated with uterine fibroids or achieving amenorrhea in a subject, suppressing sex hormones in a subject, or reducing loss of bone mineral density in a subject caused by administration of a GnRH antagonist, reduction of vasomotor symptoms or hot flashes in the subject, and reduction of symptoms of decreased libido in the subject. All such methods may, in some embodiments, be of longer duration, such as consecutive periods of 48 weeks or more, consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

Hormone replacement drug is sometimes called reentry therapy or reentry hormone replacement therapy. Co-administration of a hormone replacement drug will mitigate or avoid one or more of the side effects or symptoms commonly associated with a GnRH antagonist, such as loss of bone mineral density and vasomotor symptoms or hot flashes. The hormone replacement drug is co-administered with Compound 1, optionally as a separate oral dosage form or as a fixed combination oral dosage form.

In particular, fixed combination oral dosage form therapy versus single dosage forms administered together can help ensure that both Compound 1, or a pharmaceutically acceptable salt thereof, and hormone replacement drugs are correctly administered and in the correct ratios. In particular, therapy with an oral fixed combination dosage form may improve patient compliance. In addition, an oral fixed combination dosage form may improve patient outcomes by helping to always take relapse therapy to address known side effects such as loss of bone mineral density and hot flashes. In addition, an oral fixed combination dosage form may be advantageous over therapies that

- 62 041715 should not be administered as a single combination dosage form or tablet once a day. In addition, this optimal therapy may provide rapid on and off during intermittent treatment, may help maintain a woman's sexual activity, and may help preserve future fertility. In addition, during such treatment, the levels of estradiol in a woman can be controlled.

In some embodiments, for therapy (eg, treatment of uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pelvic pain), it may be important that Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug be combined with each administration. Efficacy of GnRH antagonist treatment without the adverse effects of a hypoestrogenic state may require the patient to consistently and correctly take both Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug without inadvertently taking just one of them or taking them in the wrong ratio. Thus, to help provide such treatment, the method of administering a single formulation of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug can be very useful. Thus, Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug may be administered in unit dosage form. Alternatively, Compound 1, or a pharmaceutically acceptable salt thereof, and the hormone replacement drug may be administered as a combination of separate dosage forms, eg 15 minutes apart. Separate dosage forms may contain separate physical forms, for example 2 separate tablets, where one tablet contains Compound 1 or a pharmaceutically acceptable salt thereof and the other tablet contains a hormone replacement drug.

In accordance with this disclosure, several methods are provided, which include: a method of treating endometriosis in a subject; a method for reducing pain associated with endometriosis in a subject, including non-menstrual pelvic pain, dysmenorrhea, and dyspareunia; a method of reducing menstrual bleeding associated with endometriosis or achieving amenorrhea in a subject; a method for suppressing sex hormones in a subject; a method of reducing loss of bone mineral density in a subject caused by administration of a GnRH antagonist to a subject; methods for reducing vasomotor symptoms or hot flashes in a subject; and a method for reducing symptoms of decreased libido in a subject. The methods include administering 10 to 60 mg per day of Compound 1 to a subject. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered. With respect to a method of suppressing a sex hormone in a subject, the sex hormone is preferably estradiol. In addition, luteinizing hormone (LH) and follicle stimulating hormone (FSH) can be suppressed in a subject in addition to estradiol. In addition, the postovulatory increase in progesterone in a subject can be suppressed.

Accordingly, an oral dosage form or a fixed combination product, as compared to separate dosage forms that are co-administered, can provide the correct administration of both Compound 1 and the hormone replacement drug. In addition, the oral dosage forms of the present invention containing Compound 1 at the desired dosage of 40 mg and a hormone replacement drug in an amount of not more than 5 mg may represent one solution for the long-term treatment of uterine fibroids or endometriosis. In other embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In some embodiments, as used herein, oral dosage forms are solid (including soft) preparations, including, but not limited to, tablets, capsules, caplets, pills, granules, orally soluble films, lozenges, chewing gums. and powders.

The preferred oral dosage form is a tablet or capsule.

A. Hormone replacement drug.

The hormone replacement drug in an oral fixed combination dosage form may be a single component, namely a progestogen. Progestogens include, but are not limited to, progesterone and synthetic progestins such as norethindrone acetate (also known as norethisterone acetate or NETA), norgestimate, norgestrel, levonorgestrel, drospirenone, medroxyprogesterone, cyproterone, desogestrel, and etonogestrel. In one embodiment, the hormone replacement drug is NETA.

The hormone replacement drug may also contain estrogen. Estrogen includes, but is not limited to, steroidal estrogens such as estradiol, estrone, estriol, esthetrol, estradiol esters such as cypionate, estradiol valerate, estradiol acetate and estradiol benzoate, ethinyl estradiol and derivatives such as mestranol, moxestrol and hinestrol, and other estrogens such as methylestradiol. The estrogen in the hormone replacement formulation can also be non-steroidal estrogen, including but not limited to stilbestrol estrogens. In an oral dosage form or product that contains 40 mg of Compound 1, estrogen may be present in an amount of 0.1 mg to 2 mg.

- 63 041715

A preferred hormone replacement drug is an estrogen, a progestogen, or a combination thereof. In one embodiment, the estrogen is estradiol. In another preferred embodiment, the estrogen is estradiol and the progesterone is NETA. In other embodiments, the estrogen is the equivalent of estradiol.

The specific dose of hormone replacement drug may depend on the specific estrogen and/or progestogen used. When the hormone replacement drug in the fixed dosage form is only a progestin, the amount of the hormone replacement drug may be no more than 5 mg, for example 0.01 mg to 5 mg. In one embodiment, the amount of hormone replacement drug is from 0.05 mg to 2.5 mg. In an embodiment of the present invention in which a fixed dose combination product is recommended for use in the treatment of uterine fibroids and the hormone replacement drug is NETA only, NETA may be present in amounts up to 5 mg.

When the hormone replacement drug in fixed dosage form is a combination of estrogen and progestogen, in one embodiment, a fixed dose of 40 mg of Compound 1 is co-administered with a combination of 0.1 mg to 2 mg of estradiol and 0.1 mg to 0.5 mg NETA. In another embodiment, 40 mg of Compound 1 is co-administered with a combination of 2 mg of estradiol and 0.5 mg of NETA. In yet another embodiment, 40 mg of Compound 1 is co-administered with a combination of 1.5 mg of estradiol and 0.5 mg of NETA. In a preferred embodiment, 40 mg of Compound 1 is co-administered with a combination of 1 mg of estradiol and 0.5 mg of NETA. In another embodiment, the hormone replacement drug is a combination of 0.5 mg of estradiol and 0.1 mg of NETA. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In some embodiments, estradiol and NETA can be administered once a day and for the same period as Compound 1. As with Compound 1, estradiol and NETA can be used for long-term administration, such as consecutive periods of 48 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

It is contemplated that, in addition to the above hormone replacement drugs, other ingredients may be used to mitigate or prevent side effects commonly associated with a GnRH antagonist. For example, calcium supplements, calcitonin, vitamin D supplements, strontium, or therapies such as bisphosphonates may be co-administered with the oral dosage form to minimize the loss of bone mineral density that may occur with the use of a GnRH antagonist.

In embodiments for the treatment of uterine fibroids, such possible other ingredients may include: selective estrogen receptor modulator (SERM), selective progesterone receptor modulator (SPRM), dopamine and silybin promoter. In some embodiments, by way of example, but not limitation, the SERM may be raloxifene, the SPRM may be vilaprizan, asoprisnil, or ulipristal acetate, and the dopamine promoter may be bromocriptine.

A dose of 1 mg estrogen may be sufficient to protect against loss of bone mineral density. However, due to the cardioprotective effects provided by estrogen, young patients receiving low-dose estrogen, namely the 1 mg dose of estrogen, may face an increased cardiovascular risk, especially with long-term use of a hormone replacement drug. In addition, women in their 20s and 30s who take 1 mg doses of estrogen for an extended period of time may be at risk of premature ovarian failure due to low estrogen levels. For these reasons, young women may need doses above 1 mg of estrogen and possibly up to 2 mg of estrogen to protect them from these side effects. In such patients, clinicians may start the estrogen dosage at 1 mg and increase that dosage, possibly up to 2 mg estrogen, provided the subject has symptoms (eg, pain associated with endometriosis, including non-menstrual pelvic pain, dysmenorrhea, and dyspareunia; OMC; pain associated with uterine fibroids or adenomyosis) does not recur. For young women, the higher the tolerated dose of a hormone replacement drug, the better the expected effects on bone and cardiovascular health. Hypoestrogenic symptoms can lead to loss of bone mineral density, vasomotor symptoms, fatigue, malaise, and headache. There may be some patients in whom a hormone replacement drug containing up to 2 mg of estradiol or estradiol equivalent more adequately treats one or more hypoestrogenic symptoms than a hormone replacement drug containing 1 mg or less of estradiol or estradiol equivalent.

B. Compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the methods described herein, the combination contains about 10 mg to about 60 mg, about 20 to about 50 mg, about 30 mg to about 50 mg, or about 40 mg of Compound 1, or an appropriate amount thereof. pharmaceutically acceptable

- 64 041715 salt. For example, the combination may contain about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of Compound 1, or an appropriate amount thereof. pharmaceutically acceptable salt. In one embodiment, the combination contains about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof. These methods may include the treatment of one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis; heavy menstrual bleeding or pain associated with uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman. The methods may also include maintaining bone mineral density; treatment of hot flashes, night sweats, or other vasomotor symptoms; maintaining one or both of the lipid profile or range of blood glucose levels; treatment of one or both of vulvovaginal atrophy or vaginal dryness; treatment of fatigue or malaise; headache treatment or method of contraception in a premenopausal woman who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding. The methods may further include achieving amenorrhea, preventing miscarriage, improving fertility, or treating anemia.

In some embodiments, there is a population of premenopausal women for whom 10 to 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, does not provide adequate treatment for their symptom and/or condition (e.g., endometriosis; uterine fibroids; adenomyosis; heavy menstrual bleeding; pain associated with uterine fibroids, endometriosis, or adenomyosis; or one or more other symptoms associated with endometriosis, uterine fibroids, adenomyosis; or one or more side effects of GnRH antagonist administration). Thus, in some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combination administered orally daily to a premenopausal woman contains from about 65 mg to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, the combination contains about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, it should be noted that an amount of 40 mg rather than 10 mg or 20 mg of Compound 1 is preferred as it may be effective enough to meet the needs of most patients who may need treatment. In other words, if 10 mg or 20 mg of Compound 1 is used, such doses may provide satisfactory treatment for only a minority of patients in the treatment of uterine fibroids, or endometriosis, or other symptoms and conditions described above. It has been shown that the percentage of patients with a complete response at such doses is 21-44% for uterine fibroids, and therefore they may not be an effective treatment for most patients. The percentage of patients with a complete response at these doses may not represent an effective treatment for most patients with endometriosis. In some embodiments, an appropriate amount of the pharmaceutical salt of Compound 1 is administered.

In another embodiment, Compound 1 may be administered in the form of an oral thin dissolving film that: 1) adheres to the inside of the patient's cheek; 2) dissolves in the patient's tongue; or 3) is sublingual, that is, under the patient's tongue.

In some embodiments, the weight ratio of compound 1 to hormone replacement drug may be from 10:01 to 10:5, or from 60:0.01 to 60:5. In certain embodiments, the weight ratio of the dose may be from 40:0.01 to 40:5. In some embodiments, an appropriate amount of the pharmaceutical salt of Compound 1 is administered.

In some embodiments, for the treatment of uterine fibroids or endometriosis, it may be desirable to provide chronic treatment or long-term therapy, possibly at lower doses of Compound 1, such as 20 mg per day or 10 mg per day. The level of one or two hormones in the Compound 1 20 mg dosed product required to reduce bone mineral density loss may be the same or less than that required in the Compound 1 40 mg combination product. The selected hormone replacement product may contain one of several previously listed progestogens and may also contain one of several previously listed estrogens. For example, an oral dosage product containing 20 mg of Compound 1 may contain 0.25 mg to 5 mg of NETA alone, or 0.05 mg to 2 mg of estradiol and 0.05 mg to 0.5 mg of NETA. In some embodiments, an appropriate amount of the pharmaceutical salt of Compound 1 is administered. In some embodiments, chronic or long-term therapy is for the treatment of adenomyosis or heavy menstrual bleeding.

Depending on one or more of the following factors: severity of symptoms, age of the subject, weight and sensitivity, duration and intervals of administration may be modified. However, for use in the treatment of uterine fibroids or endometriosis, the daily dose may be a fixed amount, typically 10 to 60 mg of Compound 1, preferably 20 mg to 50

- 65041715 mg and most preferably 40 mg administered preferably once a day. For use in the treatment of adenomyosis or heavy menstrual bleeding, the daily dose may be a fixed amount, typically 10 to 60 mg of Compound 1, preferably 20 mg to 50 mg, and most preferably 40 mg, administered preferably once a day.

C. Excipients.

Oral dosage forms can be solid (including soft) preparations, including, but not limited to, tablets, capsules, caplets, pills, lozenges, chewing gums, granules, and powders. The preferred oral dosage form is a tablet or capsule. The oral dosage form may contain Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, the oral dosage form contains a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable excipient.

The excipients required may be a mixture of excipients and their amounts that optimize the effectiveness of the composition. The following components are the main excipients and include various organic or inorganic excipients or carrier substances, including, but not limited to, one or more fillers or diluents, lubricants, binders, surfactants, pH adjusters, sweeteners , flavorings and disintegrants. A film coating may be present with pharmaceutical additives, including, but not limited to, one or more film formers, coating bases, coating additives, plasticizers, organic acids, pigments or antioxidants, light blocking agents, flow improvers or polishing agents, and dyes.

Diluents for use in this disclosure include organic materials and inorganic materials including, but not limited to, dextrose, lactose, mannitol, D-mannitol (e.g., PEARLITOL 50C, PEARLITOL 100SD, PEARLITOL 200SD, PEARLITOL 300 DC, and PEARLITOL 400DC) , sodium starch, sucrose, calcium phosphate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium sulfate, calcium carbonate, calcium silicate, sorbitol, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch and calcium starch carbonate. In some embodiments, the solvent is mannitol.

Diluents or excipients for use in this disclosure may include organic materials and inorganic materials including, but not limited to, hydroxypropyl cellulose, crystalline cellulose (e.g., CEOLUS KG-802 (Grade: KG-802) and CEOLUS PH-302 (Grade : PH-302)), crystalline cellulose (particles), crystalline cellulose (fine particles), microcrystalline cellulose, hydroxypropyl methylcellulose (e.g. hypromellose 2910), starch, gelatin, sucrose, dextrin, lactose, povidone (polyvinylpyrrolidone), copolyvidone, gum arabic, sodium alginate; and carboxymethylcellulose. In some embodiments, the solvent is D-mannitol. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the solvent is lactose.

Binders for use in this disclosure include, but are not limited to, hydroxypropyl cellulose, crystalline cellulose (e.g., CEOLUS KG-802 (Grade: KG-802) and CEOLUS PH-302 (Grade: PH-302)), crystalline cellulose (particles), crystalline cellulose (fine particles), microcrystalline cellulose, hydroxypropyl methylcellulose (eg hypromellose 2910), starch, gelatin, sucrose, dextrin, lactose, povidone (polyvinylpyrrolidone) and copolyvidone. Natural and synthetic resins that can be used as binders include, but are not limited to, gum arabic, sodium alginate, and carboxymethyl cellulose. In some embodiments, the binder is hydroxypropyl methylcellulose. In some embodiments, the binder is hydroxypropyl cellulose.

Disintegrants for use in the present invention include, but are not limited to, cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carboxymethyl cellulose sodium (croscarmellose sodium), cross-linked carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl starch sodium and sodium starch glycolate. Additional disintegrants for use in the present disclosure include, but are not limited to, corn starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch, and magnesium aluminometasilicate. In some embodiments, the baking powder is sodium starch glycolate. In some embodiments, the disintegrant is cross-linked sodium carboxymethyl cellulose.

Lubricants for use in the present disclosure include, but are not limited to, magnesium stearate; stearic acid; sodium stearyl fumarate; triethyl citrate; inorganic

- 66 041715 cal lubricants, namely: talc, colloidal silicon dioxide and highly dispersed silicon dioxide; polymeric lubricants such as polyethylene glycol, PEG 4000 and PEG 6000; mineral oils and hydrogenated vegetable oils. However, other compounds such as fatty acids and their metal salts, fatty acid esters and their salts, organic waxes, polymers and inorganic materials can be used. Suitable fatty acids include, but are not limited to, lauric acid, palmitic acid, and stearic acid. Suitable metal salts include, but are not limited to, calcium, magnesium and zinc salts. Suitable fatty acid esters include, but are not limited to, glyceride esters such as glyceryl monostearate, glyceryl tribehenate, glyceryl palmitostearate, and glyceryl dibehenate. Suitable sugar esters include, but are not limited to, sucrose fatty acid esters, sorbitan monostearate, and sucrose monopalmitate. Suitable salts thereof include, but are not limited to, sodium oleate, sodium benzoate, sodium acetate, magnesium lauryl sulfate, and sodium lauryl sulfate. In some embodiments, lubricants include magnesium stearate, calcium stearate, talc, and colloidal silicon dioxide. In some embodiments, the lubricant is magnesium stearate. As used herein, the term polyethylene glycol is a generic term for compounds represented by the formula H(OCH2CH2) _n OH, where n is a natural number (a compound in which n is at least 2000 is sometimes referred to as polyethylene oxide).

Examples of colorants used in the formulations of the present disclosure include, but are not limited to, food coloring such as food coloring yellow #5, food coloring red #2, food coloring blue #2 and the like, food varnishes, red oxide iron and yellow iron oxide.

Examples of pH adjusters useful in the formulations of the present disclosure include, but are not limited to, citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or a salt thereof, acetic acid or a salt thereof; and an amino acid or a salt thereof.

Examples of surfactants used in the formulations of the present disclosure include, but are not limited to, sodium lauryl sulfate, polysorbate 80, polyoxyethylene(160) and polyoxypropylene(30) glycol.

Examples of sweeteners used in the formulations of the present disclosure include aspartame (trade name), acesulfame potassium, sucralose, thaumatin, sodium saccharin, and dipotassium glycyrrhizinate.

Examples of flavoring agents used in the compositions of the present disclosure include menthol, peppermint oil, lemon oil, and vanillin.

In some embodiments, pigments for use in the present disclosure include, but are not limited to, titanium dioxide.

In some embodiments, the film former/coating base is a sugar coating base. Sugar coating bases for use in the present disclosure include, but are not limited to, sucrose in combination with one or more of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, or carnauba wax.

In some embodiments, the film former/film coating base is a water soluble film coating base. Water-soluble film coating bases for use in the present disclosure include, but are not limited to, cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose (eg, hypromellose 2910, TC-5), hydroxyethylcellulose, methylhydroxyethylcellulose, and the like; synthetic polymers such as polyvinylacetaldiethylaminoacetate, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like. In some embodiments, the water-soluble film coating base is hydroxypropyl methylcellulose (eg, hypromellose 2910, TC-5). In some embodiments, the film former/coating base is hydroxypropyl methylcellulose (HGHMC). In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2910.

In some embodiments, the film former/film coating base includes cellulose polymers such as hydroxypropyl methyl cellulose phthalate, ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, and the like; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer slurry and the like; and naturally occurring substances such as shellac and the like.

In some embodiments, the flow agent/polishing agent is a carnauba wax.

In some embodiments, dyes for use according to the present disclosure

- 67 041715 include, but are not limited to, iron oxide. In some embodiments, the dye is iron oxide red. In some embodiments, the dye is iron oxide yellow. In some embodiments, the dye is a combination of iron oxide yellow and iron oxide red.

In some embodiments, plasticizers for use in the present disclosure include, but are not limited to, polyethylene glycol (eg, macrogol 6000), triethyl citrate, castor oil, polysorbates, and the like.

In some embodiments, organic acids for use in the present disclosure include, but are not limited to, citric acid, tartaric acid, malic acid, ascorbic acid, and the like.

In some embodiments, the oral formulations of the present invention contain at least one excipient that improves stability while maintaining load-bearing capacity. Oral formulations of the present disclosure that include sodium starch glycolate may have improved stability and greater carrying capacity of Compound 1 or a pharmaceutically acceptable salt thereof.

Tablets of various doses of Compound 1 can be dose proportional. That is, the weight ratio of all excipients to compound 1 in the dosage form is the same for each of the doses (for example, a 10 mg dose contains 50 mg of the first excipient and 1 mg of the second excipient, and a 20 mg dose contains 100 mg of the first excipient and 2 mg second excipient). In one embodiment, tablets containing 10 to 60 mg of Compound 1 may be formulated to be dose proportional to the 40 mg high bioavailability tablet. In some embodiments, tablets containing an appropriate amount of a pharmaceutically acceptable salt of Compound 1 may be formulated in proportion to dose.

D. Exemplary Compositions.

In an embodiment for the treatment of uterine fibroids or endometriosis, the exemplary oral dosage form may be used in an amount that contains 10 to 60 mg of Compound 1. In an embodiment, for the treatment of adenomyosis or heavy menstrual bleeding, the exemplary oral dosage form may be used in an amount that contains 10 to 60 mg of Compound 1. In certain embodiments, an appropriate amount of its pharmaceutically acceptable salt is used. In addition, the oral dosage form may further contain: 30.5 mg to 183 mg of mannitol (including D-mannitol); 10 to 60 mg microcrystalline cellulose; 1.5 mg to 9 mg hydroxypropylcellulose; 2.5 mg to 15 mg croscarmellose sodium; 0.5 mg to 3 mg magnesium stearate; from 1.78 mg to 10.68 mg of hypromellose 2910; from 0.2 mg to 1.2 mg of titanium dioxide; and optionally from 0.02 mg to 0.12 mg of iron oxide. Water is removed during processing.

In one embodiment, an exemplary oral dosage form includes: 17.54% by weight of Compound 1; 53.51 wt.%, mannitol; 17.54 wt.%, microcrystalline cellulose; 2.63 wt%, hydroxypropyl cellulose; 4.39 wt.%, croscarmellose sodium; 0.88 wt.%, magnesium stearate; 3.12 wt%, hypromellose 2910; 0.35 wt.%, titanium dioxide and 0.04 wt.%, iron oxide.

In another embodiment for the treatment of uterine fibroids or endometriosis, this disclosure provides a preferred oral dosage form for such treatment. In another embodiment for the treatment of adenomyosis or heavy menstrual bleeding, this disclosure provides a preferred oral dosage form for such treatment. The oral dosage form provided in this disclosure may be provided in an amount that includes 10 to 60 mg of Compound 1. In addition, the oral dosage form may further contain: 12.75 to 76.5 mg of mannitol (including D - mannitol); 1.25 to 7.5 mg sodium starch glycolate (type A); 0.75 to 4.5 mg hydroxypropylcellulose; 0.25 to 1.5 mg magnesium stearate; from 0.89 to 5.34 mg of hypromellose 2910; 0.1 to 0.6 mg titanium dioxide; and optionally from 0.01 to 0.06 mg of iron oxide; and enough carnauba wax. Water may be removed during processing.

In one embodiment, the oral dosage form presented in this disclosure contains: 38.46 wt.% compound 1; 49.04 wt.%, mannitol; 4.81 wt% sodium starch glycolate; 2.88 wt%, hydroxypropyl cellulose; 0.96 wt.%, magnesium stearate; 3.42 wt%, hypromellose 2910; 0.38 wt.%, titanium dioxide; 0.04 wt.%, iron oxide and a sufficient amount of carnauba wax.

An exemplary oral dosage form includes: 10 mg compound 1, 30.5 mg mannitol (including D-mannitol), 10 mg microcrystalline cellulose, 1.5 mg hydroxypropyl cellulose, 2.5 mg croscarmellose sodium, 0.5 mg magnesium stearate, 1.78 mg hypromellose 2910, 0.2 mg titanium dioxide and optionally 0.02 mg iron oxide. Water may be removed during processing of such an exemplary oral dosage form.

In another embodiment, the oral dosage form contains: 40 mg compound 1, 122 mg mannitol (including D-mannitol) (excipient/diluent), 40 mg microcrystalline cellulose (excipient/diluent), 6 mg hydroxypropyl cellulose (binder), 10 mg croscarmellose sodium

- 68 041715 (disintegrant), 2 mg magnesium stearate (lubricant), 7.12 mg hypromellose 2910 (film coating agent), 0.8 mg titanium dioxide (pigment) and optionally 0.08 mg iron oxide (color). Water may be removed during processing.

Another exemplary oral dosage form contains: Compound 1 60 mg, Mannitol 183 mg (including D-mannitol), Microcrystalline cellulose 60 mg, Hydroxypropylcellulose 9 mg, Croscarmellose sodium 15 mg, Magnesium stearate 3 mg, Hypromellose 10.68 mg 2910, 1 .2 mg of titanium dioxide and optionally 0.12 mg of iron oxide. Water may be removed during processing.

Another illustrative dosage form contains: 10 mg of compound 1, 12.75 mg of mannitol (including D-mannitol), 1.25 mg of sodium starch glycolate (type A), 0.75 mg of hydroxypropylcellulose, 0.25 mg of magnesium stearate, 0. 89 mg of hypromellose 2910, 0.1 mg of titanium dioxide, and optionally 0.01 mg of iron oxide, and a sufficient amount of carnauba wax. Water may be removed during processing.

Another preferred oral dosage form contains: 40 mg compound 1, 51 mg mannitol (including D-mannitol) (filler/diluent), 5 mg sodium starch glycolate (type A) (disintegrant), 3 mg hydroxypropyl cellulose (binder), 1 mg magnesium stearate (lubricant), 3.56 mg hypromellose 2910 (film coating agent), 0.4 mg titanium dioxide (pigment), and optionally 0.04 mg iron oxide (colorant), and a sufficient amount of carnauba wax (coating agent). tablet flow enhancer/polishing agent). Water may be removed during processing.

Another illustrative dosage form contains 60 mg of compound 1, 76.5 mg of mannitol (including D-mannitol), 7.5 mg of sodium starch glycolate (type A), 4.5 mg of hydroxypropyl cellulose, 1.5 mg of magnesium stearate, 5.34 mg of hypromellose 2910, 0.6 mg of titanium dioxide, and optionally 0.06 mg of iron oxide, and a sufficient amount of carnauba wax. Water may be removed during processing.

Another illustrative oral dosage form provided in this disclosure contains: 10 mg of Compound 1; 12.75 mg mannitol; 1.25 mg sodium starch glycolate; 0.75 mg hydroxypropylcellulose; 0.25 mg magnesium stearate; 0.89 mg hypromellose 2910; 0.1 mg titanium dioxide; 0.01 mg of iron oxide and a sufficient amount of carnauba wax. Water may be removed during processing.

Another preferred oral dosage form provided in this disclosure contains: 40 mg of Compound 1; 51 mg mannitol (filler/diluent); 5 mg sodium starch glycolate (raising agent); 3 mg hydroxypropylcellulose (binder); 1 mg magnesium stearate (lubricant); 3.56 mg hypromellose 2910 (film coating agent); 0.4 mg titanium dioxide (pigment); 0.04 mg of iron oxide (color) and a sufficient amount of carnauba wax (tabletting agent/polishing agent). The solvent (eg water) may be removed during processing.

Another exemplary oral dosage form presented in this disclosure contains: 60 mg of Compound 1; 76.5 mg mannitol; 7.5 mg sodium starch glycolate; 4.5 mg hydroxypropylcellulose; 1.5 mg magnesium stearate; 5.34 mg hypromellose 2910; 0.6 mg titanium dioxide; 0.06 mg of iron oxide and a sufficient amount of carnauba wax. Water may be removed during processing.

Any of the illustrative oral dosage forms may be used in any of the methods presented herein. These methods may include the treatment of one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis; heavy menstrual bleeding or pain associated with uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman. The methods may also include maintaining bone mineral density; treatment of hot flashes, night sweats, or other vasomotor symptoms; maintaining one or both of the lipid profile or range of blood glucose levels; treatment of one or both of vulvovaginal atrophy or vaginal dryness; treatment of fatigue or malaise; headache treatment or method of contraception in a premenopausal woman who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding. The methods may further include achieving amenorrhea, preventing miscarriage, improving fertility, or treating anemia.

For the treatment of uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, the above oral dosage forms presented in this disclosure, which include sodium starch glycolate, have been found to improve storage stability and provide greater load carrying capacity of Compound 1 or a pharmaceutically acceptable salt thereof, so that the dosage of Compound 1 can be up to 40 mg. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is used. This greater carrying capacity allows for a smaller dosage form and may improve dosing compliance.

Although Compound 1 may be administered at 10, 20, 40 or 60 mg per day, it is preferably administered at a dose of 40 mg. In addition, the excipient base can optimize the stability in the formulation, and the 40 mg amount of Compound 1 can maintain an effective dose for treating symptoms of uterine fibroids. In some embodiments, an appropriate amount is administered

- 69 041715 pharmaceutically acceptable salt of compound 1.

E. Dosed packaging.

The present invention provides dosage packs containing an oral composition containing Compound 1 or a pharmaceutically acceptable salt thereof. The present invention also provides dosage packs containing an oral composition containing Compound 1 or a pharmaceutically acceptable salt thereof; and an oral composition containing a hormone replacement drug. In some embodiments, the dosage pack contains a single oral formulation containing Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug. In other embodiments, the dosage pack contains separate oral formulations, for example, an oral formulation containing compound 1 or a pharmaceutically acceptable salt thereof, and a separate oral formulation containing a hormone replacement drug. The dosage pack may contain any of the exemplary formulations described herein.

In certain embodiments, the dosage pack is used to treat endometriosis; uterine fibroids; adenomyosis; heavy menstrual bleeding; pain associated with uterine fibroids, endometriosis or adenomyosis; or one or more other symptoms associated with endometriosis, uterine fibroids, adenomyosis; or one or more side effects from the administration of a GnRH antagonist. In some embodiments, the dosage pack contains two or more oral formulations, wherein at least one oral formulation has a color, shape, and/or size different from those of at least one other oral formulation.

In some embodiments, the dosage pack provided in this disclosure contains: an oral formulation containing excipients and about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; and an oral formulation containing from about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg progestin. In certain embodiments, the oral formulations are a single formulation, while in other embodiments, the oral formulations are two or more separate formulations.

In some embodiments, the dosage pack provided in this disclosure contains: an oral formulation containing excipients and about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof; and an oral formulation containing from about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol equivalent; and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin. In certain embodiments, the oral formulations are a single formulation, while in other embodiments, the oral formulations are two or more separate formulations. In some embodiments, the oral formulation contains from about 65 mg to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the dosage pack provided in this disclosure contains: an oral formulation containing excipients and about 10 to about 60 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In other embodiments, the dosage pack provided in this disclosure contains: an oral formulation containing excipients and about 65 to about 140 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains from about 65 mg to about 120 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some such embodiments, one or more formulations independently contain adjuvants such as one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the one or more oral formulations further independently comprise one or more film former/coating bases, one or more pigments, one or more colorants, one or more flow/polishing agents, or combinations thereof. In some such embodiments, the film former/coating base contains hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron oxide, and the flow agent/polishing agent contains carnauba wax.

In certain aspects of the disclosure, one or more oral dosage pack formulations contain at least one excipient that improves stability while maintaining load-bearing capacity. In some embodiments, the sodium starch glycolate in the oral dosage unit formulation of this disclosure improves the stability and carrying capacity of Compound 1 or a pharmaceutically acceptable salt thereof in the oral dosage formulation.

- 70 041715

In some embodiments, one or more oral dosage pack formulations of this disclosure comprise one or more tablets. In some embodiments, one or more of the oral dosage pack formulations of this disclosure have an immediate release profile.

IX. Timing of introduction.

The method of administering Compound 1 and the hormone replacement drug is not particularly limited as long as the compound of this disclosure and the hormone replacement drug are administered orally as a combination or administered together. In some embodiments, the route of administration may, for example, be (1) administering a single formulation obtained by combining compound 1 and a hormone replacement drug, (2) simultaneously administering in an identical way the two formulations obtained by formulating compound 1 and a hormone replacement drug separately, and (3) sequential and intermittent administration in an identical manner of the two formulations obtained by formulating Compound 1 and the hormone replacement drug separately. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug. Co-administration of separate dosage forms may include administering at the same time or over time, for example, administering separate dosage forms 30 minutes or less apart, 20 minutes or less apart, 15 minutes or less different, 10 minutes apart, minutes or less, or with a difference of 5 minutes or less.

In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily without a hormone replacement drug for a period of time prior to initiating administration of the combination of Compound 1, or a pharmaceutically acceptable salt thereof, and a hormone replacement drug.

The combination of Compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement preparation according to any of the methods described above may be administered once daily before meals. For example, the combination may be administered at least 1 hour before a meal or at least 2 hours after a meal. In some embodiments, the combination is administered at least 30 minutes before a meal or on an empty stomach.

In some embodiments, the methods provided herein do not include administering Compound 1 or a pharmaceutically acceptable salt thereof (alone or in combination with a hormone replacement drug) within 6 hours of administration of a P-glycoprotein (P-gp) inhibitor, a CYP3A inducer, or a P-gp inducer, or any combination thereof. P-gp mediates the export of drugs from specific cells, such as cells located in the small intestine, the blood-brain barrier, hepatocytes, and the renal proximal tube. P-gp can be affected by P-gp inducers or inhibitors that reduce P-gp mediated uptake or efflux or increase P-gp activity, respectively. CYP3A is a subfamily of monooxygenases that may be involved in drug metabolism. P-gp or CYP3A inducers may include carbamazepine, rifampin, St. John's wort, bosentan, efavirenz, mitotane, modafinil, or nafcillin. P-gp inhibitors may include amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, eliglustat, erythromycin, felodipine, itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quercetin, quinidine, reserpine, ranolazine, saquinavir, telaprevir, tipranavir, ticagrelor, tacrolimus and verapamil. A discussion of the P-gp transport system can be found in J.D. Wesslery, et al. JACC (2013) 61(25): 2495-502. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours prior to administration of a P-gp inhibitor, CYP3A inducer, or inducer P-gp or any combination thereof. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours after administration of a P-gp inhibitor, CYP3A inducer, or inducer P-gp or any combination thereof. In some embodiments, for example, when treatment is initiated that includes administering Compound 1 or a pharmaceutically acceptable salt thereof, Compound 1 or a pharmaceutically acceptable salt thereof is administered at least 16 hours, at least 20 hours, or at least 24 hours. h prior to administration of a P-gp inhibitor, CYP3A inducer, or P-gp inducer, or any combination thereof. In other embodiments, for example, when treatment is initiated that includes administering Compound 1 or a pharmaceutically acceptable salt thereof, Compound 1 or a pharmaceutically acceptable salt thereof is administered at least 16 hours later, at least 20 hours later, or at least 24 hours later. h after administration of a P-gp inhibitor, CYP3A inducer, or P-gp inducer, or any combination thereof.

In some embodiments, the combination of compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug is administered orally once a day for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks, or at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks. In some embodiments, com

- 71 041715 bination administered orally daily for at least 4 consecutive weeks and up to 24 consecutive weeks. The combination may be administered as a single dosage form or as two separate dosage forms administered together.

Daily administration over an extended period of time, such as consecutive periods of 48 weeks or more, consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more allows long-term therapy to be achieved.

When an oral dosage form is administered to a subject, the period of daily administration may vary. Daily administration may be for 7 consecutive days, 14 consecutive days, 28 consecutive days, 56 consecutive days, 84 consecutive days, or 168 consecutive days. Longer periods of daily administration may include consecutive periods of at least 48 weeks, which may be consecutive periods of at least two separate 24 week periods. Other longer periods of administration may include: consecutive periods of 48 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more. In some embodiments, the daily administration period is at least 24 weeks to no more than 48 weeks. In one embodiment, the introduction is chronic, for example, not limited to a period of treatment.

In some embodiments, for long-term administration, the first and second oral dosage forms are administered for: consecutive periods of 48 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more. In some embodiments, the first oral dosage form is a tablet or capsule and the second oral dosage form is a tablet or capsule.

In some embodiments, this therapy may allow the woman to avoid surgery that could lead to postoperative or future pregnancy complications, or even eliminate the possibility of a future pregnancy. In particular, an oral fixed combination dosage form, which can be a single once-daily tablet containing both Compound 1 and low doses of estrogen and progestogen, can be used longer than currently approved agonist therapies. GnRH. This low dose can be used to minimize loss of bone mineral density in a hypoestrogenic state, as well as other hypoestrogenic symptoms such as hot flushes commonly associated with GnRH agonists and antagonists.

In some embodiments, for example, periods of treatment to treat endometriosis in a subject, reduce pain associated with endometriosis in a subject, including non-menstrual pelvic pain, dysmenorrhea and dyspareunia, reduce menstrual bleeding associated with endometriosis in a subject, suppression of sex hormone in a subject, reduction in loss of bone mineral density in a subject caused by administration of a GnRH antagonist to a subject, reduction in vasomotor symptoms or hot flashes in a subject, and reduction in symptoms of decreased libido in a subject may be, for example, consecutive periods of 48 weeks or more, consecutive periods for 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks or more.

In some embodiments, the combination is administered daily for 24 consecutive weeks or more, or 48 consecutive weeks or more, or 96 consecutive weeks or more. In some embodiments, the combination is administered for: consecutive periods of 48 weeks or more, consecutive periods of 52 weeks or more, consecutive periods of 76 weeks or more, consecutive periods of 104 weeks or more, or consecutive periods of 128 weeks weeks or more.

X. Pharmacokinetic parameters.

On bioavailability and pharmacokinetic (PK) profile or parameters such as mean maximum plasma concentration (C _max ), mean time to maximum plasma concentration (T _max ) and mean area under the plasma concentration-time curve (AUC) after oral administration administration, may in some embodiments be positively or negatively influenced by the composition, type of excipients chosen, and particular excipients. The safety and efficacy of Compound 1 in oral dosage form may depend on such PK parameters being in the appropriate range. Thus, in some embodiments, the type and characteristics of the excipients are carefully chosen to achieve the target PK parameters for Compound 1. In some embodiments, the combination used in the methods described above contains a pharmaceutically acceptable salt of Compound 1, and the safety and efficacy are pharmaceutically acceptable salt of Compound 1 in oral dosage form depends

- 72 041715 on pharmacokinetic parameters that are in the appropriate range. In some embodiments, the implementation of pharmacokinetic parameters can be determined in healthy subjects after administration of a single or repeated dose (once a day, until a steady pharmacokinetic state is reached, at least up to 5 half-lives). The effect of food or meals can be determined, for example, after a single dose administration, where the pharmacokinetics of compound 1 before/during/after a meal is compared with fasting administration (for example, no food intake for at least 8 hours before dosing and during 4 hours after dosing). In some embodiments, following administration of Compound 1, blood samples are taken at predetermined intervals, plasma is separated, and the concentration of Compound 1 is determined using analytical methods such as high performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters (such as Cmax, AUC, and half-life) can be determined from plasma concentration-time data for each individual subject using non-compartmental assays that are implemented in software such as Phoenix® WinNonlin®. Such parameters can then be summarized or compared using statistical methods.

The PK profile of Compound 1 or a pharmaceutically acceptable salt thereof may or may not be food dependent. In another embodiment, the differences in mean _Cmax and mean plasma AUC of Compound 1 or a pharmaceutically acceptable salt thereof when administered after a meal and on an empty stomach of a fixed combination oral dosage form having Compound 1 in an amount of 40 mg (or the corresponding amount of its pharmaceutically acceptable salt ), and an immediate release hormone replacement formulation may be shown to be clinically relevant based on dose-response (exposure-response) relationships and/or pharmacokinetic-pharmacodynamic relationships of Compound 1 in human studies.

In some embodiments, administration of compound 1 at 40 mg and an immediate release hormone replacement formulation and oral administration on an empty stomach, i.e., at least 2 hours after a meal and at least 30 minutes before the next meal, may have an average T _1/2 in plasma for compound 1 in the range of 37 to 42 hours. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of compound 1 is administered with a hormone replacement drug.

Administration prior to meals can result in a number of benefits. For example, the average C _max may be higher when administered before a meal than when administered after a meal. In addition, mean plasma AUQ( ₀ - _tau ) may be higher when administered before a meal than when administered after a meal.

In an embodiment of this disclosure, a method of treating uterine fibroids is provided which comprises administering to a subject once daily for 2 consecutive weeks or more of an extended treatment period of 10 to 60 mg per day of Compound 1 such that the mean plasma half-life ( T _1/2 ) is at least 18 hours when measured at the end of treatment. In an embodiment of this disclosure, there is provided a method for treating endometriosis, uterine fibroids, or heavy menstrual bleeding, which comprises administering to a subject once daily for 2 consecutive weeks or longer treatment period 10 to 60 mg per day of Compound 1 such that the mean plasma half-life (T _1/2 ) is at least 18 hours when measured at the end of treatment. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In some embodiments, for the treatment of uterine fibroids, Compound 1 is preferably administered orally in a formulation with pharmaceutically acceptable excipients. In some embodiments, the oral dose is in the form of a solid preparation. In addition, in some embodiments, the oral dosage form preferably has an immediate release profile. However, the oral dosage form may have other release profiles including, for example, sustained release, controlled release, delayed release, sustained release, and the like. Immediate release dosage forms may include those for which >85% of the labeled amount dissolves within 30 minutes. In particular, for immediate release products, drug release rates and/or drug absorption are neither noticeably nor intentionally delayed by galenic methods. In some embodiments, the oral dosage form contains a pharmaceutically acceptable salt of Compound 1.

In some embodiments, Compound 1 is formulated to achieve effective plasma drug levels for low dose Compound 1 treatment.

- 73 041715 before meals, provides a plasma concentration of at least about 7.56 ng/ml 1 hour after dosing. In some embodiments, it provides a median plasma concentration of about 16.2 ng/mL 1 hour post-dose. In another embodiment, it provides a plasma concentration of about 28 ng/ml 1 hour post-dose. A highly bioavailable formulation can achieve the same average drug exposure in subjects as Compound 1 and a hormone replacement drug when administered separately. In some embodiments, the oral dosage form contains a pharmaceutically acceptable salt of Compound 1.

In some embodiments, Compound 1 is formulated to achieve low variability in pharmacokinetic and pharmacodynamic effects in subjects. In one embodiment, a low variability dosage form of Compound 1 containing 40 mg of Compound 1, taken orally before meals, provides pharmacokinetic and pharmacodynamic effects that are less susceptible to changes in subjects, while still achieving the same average drug exposure. in subjects as other embodiments described herein. In some embodiments, the oral dosage form contains a pharmaceutically acceptable salt of Compound 1.

In one embodiment, a 40 mg tablet is formulated that is highly bioavailable and independent of food intake and also provides desirable pharmacokinetic and pharmacodynamic effects that are less susceptible to change in subjects.

In some embodiments, the patient may take Compound 1 before or after a meal, which may require food intake to have a minimal effect on mean plasma AUC compared to a fasted state. In one embodiment, when a food-independent dosage form of compound 1 is taken orally, containing 40 mg of compound 1, the ratio of postprandial AUC to fasting AUC [mean plasma AUC( _fed )/mean Plasma AUC( _faste d)] is 0.8 to 1.25, preferably 0.95 to 1.05, more preferably 1.0. In one embodiment, the 90% confidence interval of this ratio is between 0.8 and 1.25. In some embodiments, the formulation contains an appropriate amount of a pharmaceutically acceptable salt of Compound 1.

As described herein, in some embodiments, plasma absorption of compound 1 can be reduced and delayed after a single dose administered 30 minutes after the start of the standard (in accordance with the provisions of the US Food and Drug Administration (FDA) ) high-calorie, high-fat breakfast (about 800-1000 calories, 50% from fat) compared to fasted conditions. The median T _max may increase under post-meal conditions. Mean _Cmax and mean plasma AUCn can be reduced under postprandial conditions compared to fasted conditions, indicating a clinically significant effect of food on the oral bioavailability of Compound 1. In some embodiments, when Compound 1 is administered daily 30 minutes before standardized morning meal (about 600 calories, 27% from fat), systemic exposure to Compound 1 is reduced to a lesser extent, and there are no observable changes in absorption rate when compared to fasted conditions. In some embodiments, subjects may take Compound 1 upon waking in the morning on an empty stomach and start eating approximately 30 minutes after dosing, when possible. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In one embodiment, Compound 1 is administered prior to a meal, at least 1 hour before a meal, or at least 2 hours after a meal. The introduction can also be carried out at least 30 minutes before meals or on an empty stomach.

In one embodiment, subjects may take Compound 1 upon waking in the morning on an empty stomach and begin eating approximately 60 minutes after dosing, when possible. Administration prior to meals can result in a number of benefits. For example, in one embodiment, the maximum plasma drug concentration (C _max ) of Compound 1 is higher when administered before a meal than when administered after a meal. In addition, for the same embodiment, the area under the plasma concentration-time curve (AUQ( _0.tau )) for Compound 1 is higher when administered before a meal than when _administered after a meal. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In one embodiment, administration does not require any fasting or meal schedule. Administration of the oral dosage form may be food-independent.

For a food-independent oral dosage form, the dosage of Compound 1 can be increased without changing the dosage of the hormone replacement drug. For example, a food-independent oral dosage form may be 80 to 160 mg per day or 100 to 140 mg per day of Compound 1 and 0.01 to 5 mg per day of a hormone replacement drug. In variant

For embodiments of the present disclosure, a food-independent oral dosage may be 120 mg per day of Compound 1, 1 mg of estradiol, and 0.5 mg of NETA. In some embodiments, at this higher dose, Compound 1 can significantly suppress estrogen levels (whether taken on an empty stomach or on a full stomach and taken with or without food). In some embodiments, the hormone replacement drug (eg, estradiol and NETA) is independent of food intake and brings the patient's estrogen levels into the desired range to protect against loss of bone mineral density. Thus, a higher dose of Compound 1 with a normal dose of a hormone replacement drug can provide a once-daily (anytime) dosage form that is food independent, further distinguishing it from other conventional options such as elagolix. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In one embodiment, the weight ratio of compound 1 fixed combination oral dose to hormone replacement drug (eg, estradiol and NETA) is increased to provide a food-independent dose. Although 40mg of Compound 1 may be food dependent, a higher dosage of Compound 1 is still able to (completely) suppress estrogen in patients with uterine fibroids or endometriosis, whether taken with or without food. In addition, although 40 mg of Compound 1 may be food dependent, a higher dosage of Compound 1 is still able to (completely) suppress estrogen in patients with adenomyosis or heavy menstrual bleeding, whether taken with or without food. A hormone replacement drug (eg, estradiol and NETA) may increase estrogen levels to protect against loss of bone mineral density and mitigate other potential side effects. The hormone replacement drug, estradiol and NETA, may be a food-independent ingredient. Thus, in some embodiments, to be independent of food intake in the fixed combination, the oral dose of Compound 1 may be increased to higher amounts (greater than 40 mg) and the hormone replacement drug of estradiol and NETA may remain at the same level ( e.g. 1 mg estradiol and 0.5 mg NETA). It may be desirable to provide patients with a once-daily oral medication for the treatment of uterine fibroids or endometriosis that can be taken at any time of the day to improve adherence to treatment and reduce symptoms. It may also be desirable to provide patients with a once-daily oral medication for the treatment of adenomyosis or heavy menstrual bleeding that can be taken at any time of the day to improve adherence to treatment and reduce symptoms. In addition, it may be desirable that such a food-independent drug be a fixed dose of Compound 1 and a hormone replacement drug to mitigate long term side effects such as protection against loss of bone mineral density. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

Some advantages may be obtained in the treatment of uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding by administering Compound 1 to a subject in need of treatment. For example, for a 14 day consecutive treatment period comprising 10 to 60 mg per day of Compound 1, the mean plasma half-life for Compound 1 (T _1/2 ) may be at least 18 hours as measured at the end of the treatment period. . In addition, for a 14-day consecutive treatment period comprising 10 to 60 mg per day of Compound 1, the area under the plasma drug concentration versus time curve (AUC( ₀ _ _tau )) may increase by at least 1, 5 times (150%) and preferably 2 times (200%) or more from day 1 to day 14. In one embodiment, a subject with uterine fibroids is treated. In another embodiment, a subject with endometriosis is treated. In yet another further embodiment, a subject with adenomyosis is treated. In yet another embodiment, a subject with heavy menstrual bleeding is treated. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

According to this disclosure, the mean plasma half-life of Compound 1 may be at least 18 hours, preferably at least about 30 hours, and more preferably at least about 35 hours, as measured at the end of the treatment period. In an even more preferred embodiment, the mean plasma half-life (T _1/2 ) of Compound 1 is from about 37 hours to about 42 hours. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

Compound 1 may have higher potency and longer mean plasma half-life than elagolix, another GnRH antagonist. Almost complete suppression of estrogen (less than 10 pg/ml on average) can be achieved with a lower total daily dose of compound 1 compared to elagolix. In particular, compound 1 can achieve almost complete suppression of estro

- 75 041715 gene at a dosage of 40 mg once a day on an empty stomach, while 200 mg or more of elagolix twice a day (BID) on an empty stomach may be required to achieve similar estrogen suppression. This high degree of estrogen suppression may be clinically important because a hormone replacement drug may provide controlled exposure to estrogen and/or progestogen. Compound 1 can be administered once a day due to its longer mean plasma half-life of about 37 hours to about 42 hours compared to about 2 to 6 hours for elagolix. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

Suppression of estrogen to low levels can provide a consistent baseline against which reentrant therapy with low doses of estrogen and progestogen can be added in a controlled manner. This hormonal reversal therapy can raise estradiol levels above 20 pg/mL, which is thought to protect women from loss of bone mineral density. This estrogen suppression strategy, combined with the addition of low doses of estrogen and progestogen, may retain the clinical benefit of Compound 1 by minimizing loss of bone mineral density and improving tolerability, thereby potentially providing longer-term use.

As discussed above, in certain populations of women, it may be preferable to administer a dose of a hormone replacement drug that results in a mean daily circulating estrogen level of about 55 to about 150 pg/mL, e.g., about 55 pg/mL, about 60 pg/mL. , about 65 pg/ml, about 70 pg/ml, about 75 pg/ml, about 80 pg/ml, about 85 pg/ml, about 90 pg/ml, about 95 pg/ml, about 100 pg/ml, about 105 pg/ml, about 110 pg/ml, about 115 pg/ml, about 120 pg/ml, about 125 pg/ml, about 130 pg/ml, about 135 pg/ml, about 140 pg/ml, about 145 pg /ml or about 150 pg/ml. It should be understood that the peaks and valleys accompanying daily administration of a hormone replacement drug (eg containing estradiol) can result in concentrations above and below the mean, eg 150 pg/ml.

In some embodiments, for all methods of this disclosure that include administering both Compound 1 at 40 mg and a hormone replacement drug on an empty stomach, e.g., at least 2 hours after a meal and at least 30 minutes before the next meal, the average maximum plasma concentration or Cmax for compound 1 can range from 5 to 35 ng/ml. Preferably, the average Cmax may be in the range of 10 to 30 ng/ml, and more preferably 15 to 25 ng/ml. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

In addition, in some embodiments, for all methods of this disclosure that include oral administration of both compound 1 in an amount of 40 mg and a hormone replacement drug on an empty stomach, for example, at least 2 hours after a meal and at least 30 minutes before the next meal, mean area under the plasma concentration-time curve from 0 to 24 hours for Compound 1 or AUC ₀ . ₂₄ may be in the range of 50 to 200 ng-h/ml, and more preferably in the range of 75 to 150 ng-h/ml. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is co-administered with a hormone replacement drug.

Examples

The following non-limiting examples are provided to illustrate the present disclosure.

Example 1 Preparation of Compound 1

N-(4-(1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-((methylamino)methyl)-2,4-dioxo1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (150 mg, 0.259 mmol) was dissolved in DMF (4 ml) and methyl iodide (0.010 ml, 0.164 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, combined with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=40/1) and recrystallized from dichloromethane/methanol/diethyl ether to give the title compound (17.3 mg, 17%) as colorless crystals.

- 76 041715

1 H-NMR (CDCl ₃ ) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5 .35 (2H), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m) , 7.69 (1H, s).

Example 2 Production of film-coated tablets of Compound 1.

Film-coated tablets were prepared using the compound prepared in Example 1 (40 mg), mannitol (preferably D-mannitol) (122 mg), microcrystalline cellulose (40 mg), hydroxypropyl cellulose (6 mg), croscarmellose sodium (10 mg), magnesium stearate (2 mg) and a sufficient amount of purified water. Water was removed during processing. In a fluid bed granulator dryer (LAB-1, Powrex Corporation), the compound obtained in Example 1, D-mannitol and microcrystalline cellulose were preheated and mixed, an aqueous solution of hydroxypropyl cellulose was sprayed, and the mixture was dried to obtain a granular powder. Croscarmellose sodium and magnesium stearate were added to the obtained granulated powder, and they were mixed in a bag to obtain a mixed powder. The mixed powder was tabletted using a rotary tablet machine (compact tablet machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mm φ pestle to produce core tablets. The core tablets were placed in a film coating machine (DRC-200, Powrex Corporation) and a film coating solution was sprayed with a composition of hypromellose 2910 (7.12 mg), titanium dioxide (0.8 mg) and iron oxide (0.08 mg) to give film-coated tablets. The obtained film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 3 Production of film-coated tablets of Compound 1.

Film-coated tablets were prepared using the compound obtained in Example 1 (40 mg), mannitol (including D-mannitol) (51 mg), sodium starch glycolate (type A) (5 mg), hydroxypropyl cellulose (3 mg), magnesium stearate ( 1 mg) and a sufficient amount of purified water. Water was removed during processing. In a fluid bed granulator dryer (LAB-1, Powrex Corporation), the compound obtained in Example 1, mannitol and sodium starch glycolate were preheated and mixed, an aqueous solution of hydroxypropyl cellulose was sprayed, and the mixture was dried to obtain a granular powder. Magnesium stearate was added to the obtained granular powder, and they were mixed in a bag to obtain a mixed powder. The mixed powder was tabletted using a rotary tablet machine (compact tablet machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mm φ pestle to produce core tablets. The core tablets were placed in a film coating machine (DRC-200, Powrex Corporation) and a film coating solution was sprayed with a composition of hypromellose 2910 (3.56 mg), titanium dioxide (0.4 mg), iron oxide (0.04 mg ) and enough carnauba wax to give film-coated tablets. The obtained film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 4 A double-blind, randomized, placebo-controlled, sequential panel, single and multiple incremental dose study to evaluate the effect of Compound 1 on safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy premenopausal women.

The study was a double-blind, randomized, placebo-controlled, sequential-panel, single-dose and multiple-dose incremental Phase 1 study in healthy premenopausal women. The study included ten cohorts, each consisting of 12 healthy premenopausal women (cohorts 1 to 10). The dose escalation scheme for cohorts 1-10 is shown in FIG. 4 and explained below.

Cohorts 1 through 6 are referred to as the portion of the single escalating dose (SRD) study in which the dose for the cohorts was escalated. All subjects in this cohort received their dose of study drug on the same day, with the exception of subjects in cohort 1, who were divided into 2 subcohorts (cohorts 1a and 1b). Dosing between these 2 subcohorts was separated by a minimum of 2 days. Dosing between subsequent cohorts was separated by a minimum of 7 days. The decision to move to cohort 1b was made by the investigator after evaluating subjects in cohort 1a for a minimum of 48 hours. The decision to increase the dose for the remaining SRD cohorts was based on a review of safety and pharmacokinetic data for all subjects in the previous cohort.

In cohorts 1-6, subjects were randomized to receive a single dose of Compound 1 (10 subjects per cohort) or placebo (2 subjects per cohort). Subjects were required to fast overnight (minimum 10 hours) prior to dosing and continued fasting for 4 hours post-dose. Subjects were given a dosing period menu consisting of 2 meals and an evening snack, each containing approximately 25% fat. Six escalating dose cohorts were planned: 1.0 mg (cohort 1), 5.0 mg (cohort 2), 10 mg (cohort 3), 20 mg (cohort 4), 40 mg (cohort 5), and 80 mg (cohort 6). Subjects in each of cohorts 1a, 1b, 2, 3, 4, 5, and 6 received the drug dosage for one day only.

Each cohort from 1 to 7 included 12 healthy premenopausal women aged 18 to 49 years inclusive. Subjects in cohort 7 were equally randomized to one of two sequences.

- 77 041715 values, each of which was formed in the reverse order of a single dose of compound 1 (40 mg or half the maximum tolerated dose (MTD) established in the SRD part). In one sequence, dosing was done on an empty stomach (minimum 10 hours). In another sequence, dosing occurred about 30 minutes after the start of a high-fat, high-calorie breakfast (consisting of about 1000 calories with 50% calories from fat). Thus, all 12 subjects in cohort 7 received compound 1 at both dosing periods, and all subjects received drug dosing for 2 days (days 1 and 7). Subjects had a washout period before switching to another dosing period on day 7.

Each cohort of 8 to 10 included 12 healthy premenopausal women aged 18 to 45 years inclusive. Cohorts 8 through 10 are referred to as part of the multiple escalating dose (MRD) study in which the dose for the cohorts was escalated. The MRD part was not initiated until the investigator and sponsor had evaluated all blinded safety and pharmacokinetic data in the SRD cohorts. Subjects in cohorts 8 to 10 were randomized to receive multiple daily doses of Compound 1 (9 subjects per cohort) or multiple daily doses of placebo (3 subjects) on an empty stomach approximately 35 minutes before a standard breakfast. Subjects received the first dose of study drug (Day 1) within 2-7 days of the start of their menstrual cycle. Three escalating dose groups were planned: 10 mg once daily (cohort 8), 20 mg once daily (cohort 9), and 40 mg once daily (cohort 10). Subjects in each of cohorts 8 to 10 received a dose of drug for 14 days (days 1 to 14). The highest dose in the MRD part did not exceed 50% of the MTD established in the SRD part of the study.

Each dose of compound 1 or placebo was administered to subjects with 240 ml of water. Subjects were required to drink all of the water provided with the dose of study drug. Subjects were able to consume water ad libitum except 1 hour before and 1 hour after drug administration, not including the 240 ml of water taken with dosage.

The assessment of the PK of unchanged compound 1 in plasma and urine was performed by calculating: the area under the curve of dependence of the drug concentration in plasma on time, starting from time 0 to the time of the last quantitatively measurable concentration (average value in plasma AUQ _[0 . _t i _qc ]), area under the plasma drug concentration versus time curve from time 0 to infinity (plasma mean AUQ[ ₀ _ _inf ]), areas under the plasma drug concentration versus time curve from time 0 to time tau, where tau - the length of the dosing interval (i.e., 24 h) (average value in plasma AUQ[ ₀ _ _tau ]), the average value of C _max , C _min , T _max , the rate constant of the concentration of the drug in plasma, the average value of Tsh in plasma, apparent total clearance (CL/F), apparent volume of distribution (Vz/F), renal clearance (CLr), total drug excreted in urine (Ae), dose fraction excreted in urine unchanged (Fe) where it is necessary mo, and terminal excretion rate constant (lamda-z).

The plasma PK profile for compound 1 for cohorts 1-6 is shown in FIG. 5A-C after administration of the dosages of Compound 1 described above. In particular, in FIG. 5A shows the average value of AUQ[ ₀ . _tlqc ] and mean value AUQ[ ₀ _ _inf ] of compound 1; in fig. 5B shows the average C _max , T _max and Lamba_z of compound 1; and in FIG. 5C shows mean plasma T _1/2 , CL/F and Vz/F of Compound 1.

The plasma PK profile for compound 1 for cohort 7 is shown in FIG. 6A-C after administration of the above dosage of Compound 1. In particular, in FIG. 6A shows the mean value of AUQ _[0 . _tlqc ] and mean value AUQ[ ₀ _ _inf ] of compound 1; in fig. 6B shows the C _max , T _max and Lamba_z values of compound 1; and in FIG. 6C shows mean plasma T _1/2 , CL/F and Vz/F of Compound 1.

Compound 1 plasma PK profiles for cohorts 8-10 are shown in FIG. 7A-F after administration of Compound 1 as described above. In particular, FIG. 7A shows the average C _max for compound 1 on day 1; in fig. 7B shows T _max , CL/F and Vz/F on day 1; in fig. 7C shows mean plasma AUQ[ ₀ _ _tau ] on day 1; in fig. 7D shows mean C _max and T _max on day 14; in fig. 7E shows CL/F, C _min and Vz/F on day 14; and in FIG. 7F shows the mean AUC[o. _tau ] in plasma on day 14.

In FIG. 8-13 are tables of plasma and urine PK parameters after various doses of Compound 1. In particular, FIG. 8 shows the PK parameters for cohorts 1-6; in fig. 9 and 10 show various PK parameters for cohort 7; in fig. 11 shows PK parameters for cohorts 8 to 10 on days 1 and 14; in fig. 12 shows detailed PK parameters for cohorts 8-10 on day 1; and in FIG. 13 shows detailed PK parameters for cohorts 8 to 10 on day 14.

Descriptive statistics were used to summarize pharmacodynamic parameters: serum concentrations of estradiol (E ₂ ), FSH, LH, progesterone, growth hormone (GH), prolactin (PRL), thyrotropin, adrenocorticotropic hormone (ACTH), and urinary 6β-hydroxycortisol to cortisol ratios. (Q).

To assess dose proportionality after a single dose in cohorts 1-6, a regression analysis was performed using natural log-transformed mean C _max , mean plasma AUQ( ₀ _ _tlqc ) and mean AUC( ₀ . _inf ) by log (dose).

To assess the effect of food intake, analysis of variance was performed using log(mean

- 78 041715 _Cmax value) of cohort 7, log (area under the plasma drug concentration-time curve [mean plasma AUC]) as dependent variable; treatment, sequence, period as fixed effects and subject (seq) as random effect. The ratio of the adjusted mean values of Compound 1 after a meal (test) to compound 1 on an empty stomach (control) and the corresponding 90% CI were presented for mean C _max , mean plasma AUQ( ₀ _ _tiqc ) and mean AUQ( ₀ . _in f ₎ in plasma. In FIG. 14 shows a statistical analysis of the plasma pharmacokinetic parameters for 40 mg Compound 1 after a meal compared to fasting conditions.

To assess dose proportionality after multiple dosing in cohorts 8-10, a regression analysis was performed using log-transformed mean C _max , C _min and mean plasma AUC( _0-tau ) by log (dose).

Following single and multiple doses, Compound 1 was rapidly absorbed with a median T _max ranging from 0.78 to 1.75 hours for single and multiple doses up to 40 mg. The median value of T _max after a single dose of 80 mg was 4 hours. T _max of all subjects were within 6 hours.

Compound 1 mean C _max , C _min , and AUC increased in a dose-proportional manner when Compound 1 was administered as single doses (1 mg to 80 mg) or multiple doses once daily (10 mg to 40 mg once daily). ). This disproportionality was confirmed by separate statistical analyzes of pharmacokinetic parameters for single and multiple doses. The degree of disproportionality was considered moderate, which is represented graphically by comparing the normalized mean Cmax of the dose and the mean plasma AUC. For single doses of Compound 1, intersubject variability was generally moderate to high with %CV up to 130% at the highest dose. For multiple doses of Compound 1, intersubject variability was moderate to high with %CV up to 91%. Mean Cmax and mean plasma AUC for all dose levels were higher on day 14 compared to day 1.

In FIG. 15A (linear scale) and 15B (log-linear scale) are graphs of mean plasma concentrations versus time profiles after single dosing of Compound 1. As shown in FIG. 15A and 15B, mean plasma concentrations of compound 1 increase with dose of compound 1. All subjects in cohort 1 (compound 1 1.0 mg) had plasma concentrations below the lower limit of quantification (BLQ) (0.0100 ng/mL) by time point 36 hours after dosing. All subjects in the other cohorts (cohorts 2-6) had detectable plasma Compound 1 concentrations at all time points measured (ie, up to 48 hours post-dose). Examination of the individual plasma concentration profiles shown in FIG. 15A and 15B demonstrated that most subjects had more than 1 peak (usually 2 peaks, but sometimes more). The second peak most often occurs 2-6 hours after a dose. The pharmacokinetics of Compound 1 appeared to be biphasic with a moderate distribution phase followed by a much longer elimination phase. This second peak was not evident in the MRD part of the study either on day 1 or day 14.

The mean plasma T _1/2 of Compound 1 appeared to be dose independent and ranged from about 14 to 16 hours after 5 to 80 mg doses and appeared to maintain a once daily dosing regimen. The mean plasma T _1/2 after the lowest dose (1 mg) was about 6 hours and was lower than the mean plasma T _1/2 for other doses.

The amount of compound 1 excreted in the urine (Ae and Fe) was low relative to dose, with a mean Fe of less than 3% of the dose across all observations, indicating that CLr was therefore a minor component of compound 1 elimination. The mean CLr was independent of dose or time and ranged from 5.7 to 8.3 l/h.

CL/F and Vz/F decreased with increasing dose of compound 1 and with increasing duration of dosing (ie between day 1 and day 14), indicating a possible change in bioavailability.

At all doses, steady state was achieved within 6-7 days. In FIG. 16 shows a steady state estimate of the plasma concentrations (ng/mL) of Compound 1 for cohorts 8 through 10. Tabular data in FIG. 16 were analyzed by analysis of variance (ANOVA) with a fixed effect for the day and a random effect for the subject. Day 15, as shown in FIG. 16 was the time 24 hours after dosing on day 14. The geometric mean (a) was obtained by taking the antilogarithm of the natural logarithms of the concentration values. The percentage (b) was obtained by taking the anti-log difference between the mean values on a natural logarithmic scale. The 90% confidence interval coefficient (c) was obtained by taking the antilogarithm of the 90% confidence interval of the difference between the means in natural logarithmic percentages.

In FIG. 17-19 show the mean trough compound 1 concentrations by day (days 1 to 15) in the MRD portion. In FIG. 17 shows the results for 10 mg of Compound 1, FIG. 18 shows the results for 20 mg of Compound 1 and FIG. 19 shows the results for 40 mg of Compound 1.

After single and multiple administration of Compound 1, mean plasma AUC( _0-tau ) doubled between days 1 and 14. The median T _max for Compound 1 was about 1 to 1.48

- 79 041715 h and, apparently, did not change with dose or from day 1 to day 14. T _max was reached within 2 h for all subjects in the MRD part.

Statistical analyzes comparing mean plasma AUQ( _0-tau ) on day 14 from the MRD portion with mean plasma AUQ _(0-inf ) from the SRD portion suggest that Compound 1 pharmacokinetics are time-independent (i.e., no autoinduction or autoinhibition of its metabolism). In FIG. 20 shows a statistical analysis of connection 1 time independence.

Analysis of mean C _max , C _min and mean plasma AUC( ₀ _ _tau ) suggests that compound 1 multiple dose pharmacokinetics are not dose proportional over the dose range of 10 mg to 40 mg. Following single and multiple doses, Compound 1 concentrations appeared to increase in a dose-proportional manner.

Single dose normalized mean plasma AUC( _0-inf ) from the SRD portion is shown in FIG. 21. The single dose normalized mean C _max from the SRD and MRD portions is shown in FIG. 22 and 23, respectively. Single dose normalized mean plasma AUQ( _0-tau ) from the MRD portion is shown in FIG. 24. An increase in dose-normalized mean plasma AUC( ₀ _ _inf ) with increasing dose occurs in the SRD portion as well as in the MRD portion. For both the SRD part and the MRD part, the degree of disproportionality is moderate and becomes more pronounced starting with the 40 mg dose. Dose-normalized mean C _max values for both the SRD part and the MRD part show a similar trend, although variability among subjects was generally high.

Mean plasma concentrations for Compound 1 increased with dose and were generally higher on Day 14 compared to Day 1. All subjects in all cohorts had detectable Compound 1 plasma concentrations at all time points measured. Examination of individual plasma concentration profiles suggested that the multiple peaks observed in cohorts 1-6 were not as evident in cohorts 8-10 on day 1 or 14. This observation may be due to different conditions between the SRD and MRD parts of the study. . Subjects in the SRD portion did not eat for at least 10 hours before and 4 hours after dosing, while subjects in the MRD portion received a dose 35 minutes before a standard breakfast.

In FIG. 25A (linear scale) and 25B (log-linear scale) are graphs of mean plasma concentrations after multiple doses of Compound 1.

Comparison of the pharmacokinetics of Compound 1 at a single dose of 40 mg under postprandial and fasting conditions showed a marked effect of food intake. In particular, the mean plasma concentrations of Compound 1 were lower when administered with food compared to fasting conditions, and the plasma concentration-time profiles appeared to be smoother with little evidence of a secondary peak on food intake. The comparison showed that pre-dosing food intake reduced mean _Cmax and mean plasma AUC parameters by about 60% and 45%, respectively. In FIG. 26A (linear scale) and 26B (log-linear scale) are graphs of mean Compound 1 plasma concentrations under postprandial and fasting conditions. The median Tmax was about 1 hour earlier with meals compared to fasted conditions, while T _1/2 was the same after meals and on an empty stomach (~ 17 hours). CL/F and Vz/F were higher with meals compared to fasted conditions, while the amount of compound 1 excreted in the urine (Ae and Fe) was lower with meals compared with fasted conditions. CLr was not affected by the presence of food. It is expected that future dosing regimens will take into account the influence of food in order to maximize the exposure of compound 1 to the patient.

Mean concentrations of estradiol (E ₂ ), LH, and FSH were suppressed compared to placebo in subjects treated with single doses of Compound 1, and the duration of suppression appeared to increase with increasing dose of Compound 1. Mean concentrations of E2, LH, and FSH remained suppressed. within 24-48 hours depending on the dose of compound 1. After taking a single dose of placebo, the average concentrations of estradiol (E2) decreased 6 hours after the dose, but then increased again until they returned to baseline values approximately 12-16 hours after taking a dose. Following single doses of 1 mg to 80 mg of Compound 1, mean estradiol concentrations (E ₂ ) initially decreased to the same extent compared to placebo, but then remained suppressed. The duration of suppression increased with increasing dose of Compound 1 so that mean estradiol (E ₂ ) concentrations were still completely suppressed at 36 hours post-dose of 20 mg and 40 mg of Compound 1 (with a slight increase in concentrations 48 hours post-dose). After taking 80 mg of Compound 1, mean estradiol concentrations (E ₂ ) were still completely suppressed 48 hours post-dose. In FIG. 27 is a linear scale plot of mean estradiol (E2) concentrations following single dose administration of Compound 1.

Multiple doses of Compound 1 also suppressed concentrations of estradiol (E ₂ ), LH and FSH, and progesterone (P) in a dose dependent manner. In the MRD portion of the study, mean E ₂ concentrations were significantly higher on day 14 compared to day 1 in subjects receiving placebo. This increase is consistent with what is expected at mid- and end-cycle in these premenopausal women. However, this increase in Er was not observed in subjects receiving multiple doses of Compound 1 (10 mg to 40 mg once a day).

- 80 041715 day), suggesting sustained suppression of E2 with continued administration of compound 1. Similarly, the mid-cycle peak of LH and FSH observed in the placebo group (days 8-12) was not evident in subjects receiving 40 mg of compound 1 once a day. Although the 5.0 mg dose of Compound 1 was found to show some suppression of Er in the SRD assessment, the variability in the recorded data was large. Therefore, the 10 mg dose of Compound 1 was chosen as the lowest dose in the MRD evaluation to provide apparent suppression of E2 at this level. In FIG. 28 and 29 are linear scale plots of mean E ₂ and progesterone concentrations, respectively, following multiple doses of Compound 1.

The natural endogenous increase in progesterone expected after ovulation was observed in subjects treated once daily with placebo, but not in subjects treated with compound 1 from 10 mg to 40 mg once daily. This suggests that taking Compound 1 once daily prevented ovulation.

There was no obvious effect of compound 1 on endogenous GH, PRL, thyrotropin and ACTH.

Urinary 6β-hydroxycortisol to cortisol ratios were similar to baseline values in the SRD and MRD parts of the study, suggesting that Compound 1 at single doses up to 80 mg and multiple doses up to 40 mg once daily does not inhibit or induce CYP34A.

A total of 68% of subjects experienced one or more adverse events during the study, with no apparent difference between Compound 1 and placebo groups or dose dependence. Most adverse events were considered moderate in intensity. The most common adverse event was headache, and the overall incidence of headache was similar after placebo and Compound 1. Based on these results, Compound 1 was found to be safe and well tolerated following Compound 1 at single doses up to 80 mg and multiple doses. doses up to 40 mg once daily for 14 days in healthy premenopausal women.

Overall, the incidence of adverse events was similar between the placebo and Compound 1 groups in both the single dose portion and the multiple dose portion of the study, with no apparent dose dependence. However, the incidence of drug-related adverse events was higher after the highest single dose (80 mg) and the highest multiple dose (40 mg once daily) than in comparable dose groups, with the increased frequency spread across several system organ classes. .

The average value of T _1/2 in plasma did not depend on the dose and was about 14-16 hours, maintaining the dosing regimen once a day.

CLr was not a significant route of elimination for Compound 1 as less than 3% of the dose was excreted in the urine. CLr was not dose or time dependent.

There was a noticeable effect of food. Pre-dose food intake reduced mean _Cmax and mean plasma AUC by approximately 60% and 45%, respectively. Notably, the increased exposure associated with fasted dosing was an important finding for the clinical development program as a whole. Following consideration of food exposure data, dosing regimens will be based on pre-meal dosing to ensure that Compound 1's safety assessment will include the circumstances under which potential exposure was greatest for study subjects.

Serum chemistry, hematology, urinalysis, vital signs, and ECG were monitored throughout the study up to 1 week after the last dose. There were no significant changes in these parameters in the Compound 1 dosing groups compared to placebo. QT intervals and corrected QT intervals (QTc) >450 ms and 500 ms were observed in all dosing groups, including the placebo group.

Example 5A. Randomized, double-blind, placebo-controlled study of the efficacy and safety of Compound 1 in the treatment of uterine fibroids.

A randomized, double-blind trial was conducted to evaluate the efficacy and safety of three dose levels (10, 20, and 40 mg) of a 12-week oral formulation of Compound 1 versus placebo in premenopausal (aged >20 years) women with uterine fibroids. . The participants in the study were Japanese women with UMB (heavy menstrual bleeding) associated with UF (uterine fibroids).

The primary endpoint was the proportion of patients with total graphical menstrual blood loss (PBAC) <10 in weeks 6 to 12. Secondary endpoints included amenorrhea (PBAC score 0), fibroid and uterine volumes, hemoglobin (Hb), numerical rating scale (NRS), indicators of the quality of life questionnaire for symptoms of uterine fibroids (UFS-QOL). Serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), and progesterone (P) were assessed as pharmacodynamic endpoints. Safety endpoints included adverse events (AEs), vital signs, weight, 12-lead electrocardiogram (ECG), clinical laboratory tests, bone mineral density (BMD), and menstrual recovery.

This study consisted of a pre-treatment period of 4 to 12 weeks,

- 81 041715 treatment period of 12 weeks, observation period of 4 weeks, and the total period of participation in the study ranged from 20 to 28 weeks.

In order to participate in the pre-treatment period, the subject must have a uterine fibroids confirmed by transvaginal ultrasonography, abdominal ultrasonography, magnetic resonance imaging, computed tomography, or laparoscopy. In addition, in order for a subject to participate in the pre-treatment period (at Visit 1) and the treatment period (at Visit 3), the subject must have one or more measurable non-calcified fibroids with a largest diameter >3 cm, confirmed by transvaginal ultrasound. Only the largest fibroids measured at Visit 1 were measured throughout the study.

All subjects must have had one or more regular menstrual cycles immediately prior to Visit 1. Regular menstrual cycles are defined in this application as cycles of 25 to 38 days and include menstrual bleeding for at least 3 consecutive days. In the same way, all subjects also had regular menstrual cycles just prior to visit 2.

Subjects began to record in a patient diary on visit day 1 until the day prior to visit 7 (or prior to early termination). The study drug (placebo) was administered under single-blind conditions from the day of visit 2 to the day before visit 3. Visit 2 was on days 1 to 5 of the first menstrual period after visit 1.

During the period between visits 2 and 3, in which the subjects had at least 1 regular menstrual cycle, baseline values were collected regarding the evaluation of efficacy, including PBAC scores and pain symptoms. Baseline PBAC is the total PBAC for the entire menstrual cycle immediately prior to Visit 3. A table of demographics and baseline characteristics for the analyzes in this example is shown in FIG. 30A-H.

To be eligible to participate in the treatment period (at Visit 3), the subject must have been diagnosed with heavy menstrual bleeding and have a total PBAC score of >120 (corresponding to a blood loss of more than 80 ml) in one menstrual cycle immediately prior to Visit 3. Visit 3 took place on days 1 to 5 of the second menstrual cycle following Visit 1. On Visits 3 to 7, subjects attempted to attend clinics on an empty stomach and before taking study drug.

At visit 3, subjects were randomized to receive either placebo (57 subjects) or one of the following compound formulations 1:10 mg (48 subjects), 20 mg (56 subjects), and 40 mg (55 subjects). Compound 1 formulations (10, 20, or 40 mg) or placebo were administered from the day of visit 3 to the day before visit 7 (or until treatment was stopped) under double-blind conditions. Either compound 1 formulation or placebo was administered daily as a single oral dose each morning 30 minutes before breakfast. In the event that the pre-breakfast dose was omitted, subjects took the study drug 30 minutes before lunch or lunch on the same day.

During this study, patients visited the clinic once every two weeks for a month after the start of study drug administration in a bilaterally blinded setting (Visit 3) and monthly thereafter. Assigned examinations and assessments were carried out at each visit.

During Visit 3, blood was drawn twice from each evaluable subject: 0.5-1.5 hours post-dose and 2-5 hours post-dose. During Visits 4, 5, and 6, blood was drawn from each evaluative subject once immediately prior to dosing for each day, again 0.5-1.5 hours post-dose, and 2-5 hours post-dose. Blood was drawn only once from patients who took study drug the day before the study site visit. During visit 7, blood was drawn only once per visit.

Patients. Of the 307 patients studied, 216 were randomized and included in the complete analysis and safety analysis populations (n = 57, placebo group; n = 48, Compound 1 10 mg group; n = 56, Compound 1 20 mg group and n = 55, Compound 1 group; 40 mg of compound 1). Overall, there were no clinically significant differences in demographic and baseline characteristics between treatment groups (Table 1). There were no apparent differences between uterine volumes or fibroid volumes, and the mean baseline PBAC was slightly higher in the placebo group compared to the Compound 1 groups.

- 82 041715

Table 1

Demographic and background characteristics

Relugolix I Characteristics 20 mg (n=56) 4omg (n=55) Age (in pods) 42 43 43 41 (5.0) (4.6) (5.3) (M) And MT (kg / m ² ) 24 (4.2) 23 (2.7) 22 (2.8) 22 (2.8) Childbirth experience thirty 25 29 20 (52.6) (52.1) (51.8) (36L) Type of uterine fibroids 23 22 25 17 Subserous myoma (40.4) (45.8) (44.6) (30.9) Intramural myoma 42 39 44 45 (73.7) (81.3) (78.6) (81.8) Submucosal fibroids 12 (21.1) eleven (22.9) eleven (19.6) 11 (20.0) Myoma of the cervix 1 1 1 2 (1.8) (2.1) (1.8) (3.6) Fibroids volume (cm ¹ ) 136 116 119 138 (159.1) (127.4) (1174) (199.8) Uterine volume (cm^) 367 322 363 487 (276.6) (285.0) (304.6) (361.8) Evaluation of RVAS indicators 328 269 276 260 (292.1) (160.8) (165.9) (190.5) _______ 0.8 0.7_ 0.8 _ 0.6 Assessment of NRS indicators Evaluation of UFS-OOL indicators (0.80) 20 (1.13) (0.93) (0.60) 29 26 25 Symptom severity (17.7) (17.3) (14.4) (14.0) Overall HRQL 16 (18.8) 14 (11.9) 13 (11.5) 15 (15.5) Hemoglobin (g/dl) 12.1 12.2 12.2 12.0 (1.50) (1.16) (1.41) (1.70)

Mean value (SD) or number of patients (%)

The plasma concentration of the drug after administration of a single dose of the composition of compound 1 in an amount of from 1 mg to 80 mg reached a peak (Cmax) 0.5-4.0 hours after the dose (time to reach the maximum concentration of the drug [T _max ]) with an average period plasma elimination half-life (T _1/2 ) from 7.1 to 19.8 hours. AUC and Cmax showed an increase to a slightly greater extent than proportional to the dose. Plasma concentration on day 14 for multiple doses of 10 mg to 40 mg peaked (Cmax) 1-1.5 hours post-dose (Tmax) with a mean plasma half-life (T _1/2 ) of 19.2 to 24.6 hours. AUC from time 0 to infinity (AUC( _0-in f)) and Cmax of compound 1 usually increased in proportion to the dose. AUC( _0-tau ) and Cmax on day 1 and Cmax on day 14 increased in a roughly dose-dependent manner, but AUC( _0-tau ) on day 14 showed a somewhat more than dose-proportional increase. Plasma concentrations reached steady state by day 7 of multiple dosing, and AUC and Cmax on day 14 were higher than their values on day 1. AUC after single dosing was higher after fasting than after dosing after meals or before meals . AUC and C _max at multiple dosing were higher with pre-meal dosing than with post-meal dosing. These data indicate that, in one embodiment, food affects the pharmacokinetics of Compound 1 formulation. However, in a preferred embodiment, Compound 1 formulation pharmacokinetics are independent of food intake.

Blood concentrations of LH, FSH, E ₂ and P decreased approximately in proportion to dose after administration of a single dose of Compound 1 formulation (10 mg to 40 mg) compared with placebo. The concentrations of LH and E ₂ showed a rapid decrease after each dose in all subjects (except one) and continued to decrease throughout the treatment period. Plasma P concentrations showed a rapid decline after dosing at all dose levels and treatment regimens, and suppression was maintained throughout the treatment period. Plasma FSH concentrations also showed a rapid decline after dosing at all dose levels and treatment regimens and remained suppressed throughout the treatment period in the groups administered 40 mg of Compound 1 before or after meals.

The most common treatment-related adverse events (occurring >10% or more than placebo) include hot flashes, metrorrhagia (irregular menstrual bleeding), menorrhagia (or BMI), headache, and genital bleeding. No serious treatment-related adverse events considered to be related to the study drug were observed. The frequency of adverse events is given in table. 2.

- 83 041715

table 2

Summary table of adverse events

Variables, η (%) placebo Relugolix (n=57) 10 mg 20 mg 40 mg (n=48) (n=56) (n=55) Any AE 40(70.2) 41(85.4) 54(96.4) 49(89.1) Light 34(59.6) 36(75.0) 47(83.9) 46(83.6) Medium 6(10.5) 5(10.4) 7(12.5) 2(3.6) strong 0(0.0) 0(0.0) 0(0.0) 1(1.8) AEs associated with 23(40.4) 33(68.8) 51(91.1) 45(81.8) researched drug AEs that 1(1.8) 0(0.0) 1(1.8) 0(0.0) led to termination reception researched drug Serious AEs 1(1.8) 0(0.0) 1(1.8) 1(1.8) Common AEs (>10% p; patients in any group) Nasopharyngitis 16(28.1) 9(18.8) 4(7.1) 7(12.7) high tide 2(3.5) 2(4,2) 16(28.6) 21(38.2) metrorrhagia 10(17.5) 13(27.1) 17(30.4) 15(27.3) menorrhagia 4(7.0) 6(12.5) 13(23.2) 12(21.8) Headache 1(1.8) 1(2,1) 8(14.3) 8(14.5) Genital 2(3.5) 2(4,2) 6(10.7) 6(10.9) bleeding Irregular 0(0.0) 12(25.0) 8(14.3) 3(5.5) menses

In FIG. 31 shows overall PBAC performance, and FIG. 32 shows the change from baseline in total PBAC scores from week 6 to week 12 following administration of placebo or one of the three Compound 1 formulations (10, 20, and 40 mg) to a subject over a 12 week treatment period.

The proportion of subjects with a total PBAC <10 in weeks 6 to 12 was assessed as the primary endpoint. In FIG. 33 shows the proportion of subjects who achieved this primary endpoint based on uterine volume at baseline. The proportion of subjects with a total PBAC <10 in weeks 6 to 12 was 0% in the placebo group, 20.8% in the 10 mg compound 1 formulation group, 43.6% in the 20 mg compound 1 formulation group , and 83.6% in the Compound 1 40 mg formulation group. Thus, a higher proportion of subjects reached the primary endpoint of the study in the Compound 1 40 mg formulation group, suggesting a dose-response relationship. There was a statistically significant difference in the proportion of subjects with a total PBAC <10 in weeks 6 to 12 between each Compound 1 formulation group and placebo, and superiority of each Compound 1 formulation group over placebo was demonstrated. A dose-dependent decrease in the volume of fibroids and uterus was observed. The incidence of headache, metorrhagia, menorrhagia and hot flashes was more than 10% higher in the groups taking compound 1 at doses of 20 mg and 40 mg than in the placebo group; these adverse events were mild or moderate in severity.

The proportion of subjects with a total RVAC score <10 in weeks 2 to 6 and weeks 2 to 12 was evaluated as secondary endpoints. The proportion of subjects with a total RVAC <10 in weeks 2 to 6 was 0% in the placebo group, 16.7% in the 10 mg compound 1 formulation group, 42.9% in the 20 mg compound 1 formulation group , and 65.5% in the compound 1 40 mg formulation group. The proportion of subjects with a total PBAC <10 in weeks 2 to 12 was 0% in the placebo group, 12.5% in the compound 1 10 mg group , 32.1% in the 20 mg compound 1 formulation group and 61.8% in the 40 mg compound 1 formulation group.

The proportion of subjects who achieved amenorrhea (had an overall RVAC score of 0) in weeks 6 to 12, weeks 2 to 6, and weeks 2 to 12 was assessed as secondary endpoints. The proportion of subjects who achieved amenorrhea in weeks 6 to 12 was 0% in the placebo group, 16.7% in the 10 mg compound 1 formulation group, 38.2% in the 20 mg compound 1 formulation group, and 72.7% in the compound 1 40 mg formulation group. The proportion of subjects who achieved amenorrhea in weeks 2 to 6 was 0% in the placebo group, 12.5% in the compound 1 10 mg formulation group. , 33.9% in the compound 1 20 mg formulation group and 54.5% in the Compound 1 40 mg formulation group. The proportion of subjects who achieved amenorrhea in weeks 2 to 12 was 0% in the group placebo, 10.4% in the 10 mg compound 1 formulation group, 28.6% in the 20 mg compound 1 formulation group, and 52.7% in the 40 mg compound 1 formulation group.

- 84 041715

Total RVAC (mean ± SD) in weeks 6 to 12 was 405.2 ± 353.71 in the placebo group, 268.0 ± 276.37 in the 10 mg compound 1 formulation group, 126.0 ± 188 .55 in the 20 mg compound 1 formulation group and 21.3±56.11 in the 40 mg compound 1 formulation group. placebo group, -1.4 ± 222.94 in the 10 mg compound 1 formulation group, -153.0 ± 194.83 in the compound 1 20 mg formulation group, and -238.7 ± 203.34 in the group receiving the formulation with 40 mg of Compound 1.

Fibroids volume was assessed as a secondary endpoint. As illustrated in FIG. 34, fibroid volumes at weeks 0, 2, 4, 8, and 12 (mean±SD) were 136.13±159.111 ^cm3 , 134.42±140.559 ^cm3 , 136.44±159.095 ^cm3 , 132.79± 140.825 cm ³ and 128.26±130.414 cm ³ , respectively, in the placebo group; 115.57±127.396 ^cm3 , 116.68±152.833 ^cm3 , 90.89±108.009 ^cm3 , 97.47±117.339 ^cm3 and 97.09±126.578 ^cm3 , respectively, in the 10 mg formulation group compounds 1; 118.68±117.364 ^cm3 , 98.63±112.118 ^cm3 , 101.51±132.419 ^cm3 , 86.34±103.084 ^cm3 and 75.09±89.699 ^cm3 , respectively, in the 20 mg formulation group compound 1, and 138.00±199.758 cm ³ , 109.29±132.534 cm ³ , 100.04±139.060 cm ³ , 86.01±120.639 cm ³ and 77.88±110.873 cm ³ , respectively, in the group treated Compound 1 40 mg formulation Percentage change in fibroid volume from baseline at week 12 was 10.19±47.159% in the placebo group, -22.63±29.539% in the Compound 1 10 mg formulation, -36 .69±32.631% in the 20 mg compound 1 formulation group and -38.59±34.197% in the 40 mg compound 1 formulation group. Fibroids volume remained virtually unchanged over the treatment period in the placebo group. However, in the Compound 1 formulation groups, these volumes tended to decrease from week 2 and continued to decrease thereafter depending on the duration of treatment and Compound 1 formulation dosage levels.

Uterine volume was also assessed as a secondary endpoint. As illustrated in FIG. 35, uterine volumes at weeks 0, 2, 4, 8, and 12 (mean±SD) were 366.51±276.607 ^cm3 , 384.88±313.354 ^cm3 , 381.17±298.220 ^cm3 , 380.19 ±289.302 ^cm3 and 379.38±300.058 ^cm3 , respectively, in the placebo group; 322.12±285.002 ^cm3 , 305.07±265.810 ^cm3 , 258.10±171.703 ^cm3 , 259.64±190.452 ^cm3 and 252.93±175.064 ^cm3 in the 10 mg compound 1 group; 363.33±304.622 ^cm3 , 294.81±269.990 ^cm3 , 291.73±327.844 ^cm3 , 290.93±413.549 ^cm3 and 259.44±322.759 ^cm3 in the 20 mg compound 1 formulation group; and 406.63±361.814 ^cm3 , 293.51±288.596 ^cm3 , 267.74±275.256 ^cm3 , 224.91±227.442 ^cm3 and 208.03±209.312 ^cm3 in the 40 mg compound 1 formulation group The percent change in uterine volume at week 12 from baseline was 9.75±57.946% in the placebo group, -12.10±29.936% in the Compound 1 10 mg formulation group, -27.70±28.787%, in the 20 mg compound 1 formulation group and -40.90±37.233% in the compound 1 40 mg formulation group. Uterine volume remained virtually unchanged over the treatment period in the placebo group. However, in the Compound 1 formulation groups, these volumes tended to decrease from week 2 and decreased thereafter depending on the duration of treatment and Compound 1 formulation dosage.

Among formulations containing 10, 20 and 40 mg Compound 1, plasma drug concentrations of unchanged Compound 1 were highest at 0.5-1.5 hours post-dose in all treatment groups. Pre-administration plasma concentrations at each visit (trough values) were comparable across each treatment group, indicating that steady state had already been achieved 2 weeks after administration of Compound 1 formulation. Population PK analysis showed that the observed plasma concentration profiles unchanged formulation of Compound 1 were adequately described by a 2-compartmental model with first-order elimination (postprandial) and dose-dependent relative bioavailability, and no covariates were found to affect the pharmacokinetics of Compound 1 formulations. FIG. 38 graphically depicts plasma concentrations of unchanged Compound 1 over a 12 week treatment period according to Example 5A. In FIG. 37 is a table of plasma concentrations of the unchanged compound 1 shown in FIG. 38.

Plasma drug concentrations of unchanged Compound 1 in subjects were lower when study drug was administered 30 minutes before meals. Plasma drug concentrations of unchanged Compound 1 over a 12 week treatment period in which Compound 1 was administered 30 minutes before meals are graphically depicted in FIG. 36 and in tabular form in FIG. 39. Plasma drug concentrations of unchanged Compound 1 over a 12 week treatment period in which Compound 1 was not administered 30 minutes before meals are tabulated in FIG. 40.

It was found that the relative bioavailability was 30.9% higher in the formulation containing 40 mg of Compound 1 compared to the formulation containing 10 mg of Compound 1. Significant variability in absorption profiles was observed between subjects. The first order uptake rate constant (ka) was evaluated only for subjects from whom at least one sample was collected in the uptake phase. The calculated population values for uptake rate constant (ka) and apparent total clearance (CL/F) were 0.416 h ^-1 (CV% 21.5) and 198 l/h (CV% 7.83).

Pain symptoms, other clinical symptoms, and quality of life were measured as secondary

- 85 041715 end points. Pain symptoms were assessed in the patient's diary from visit 1 to the day before visit 7 using the NRS score. The UFS-QOL score was used to assess other clinical symptoms and patients' quality of life. Subjects completed the UFS-QOL questionnaire at visits 3, 5, 6 and 7.

The NRS scores are tabulated in FIG. 41. The NRS score at weeks 6 to 12 (mean±SD) was 0.82±0.989 in the placebo group, 0.61±1.235 in the compound 1 10 mg formulation group, 0.35±0.618 in the compound 1 20 mg formulation and 0.25 ± 0.542 in the compound 1 40 mg formulation group. The NRS in weeks 2 to 6 (mean ± SD) was 0.82 ± 1.045 in the placebo group, 0 .67±1.228 in the 10 mg compound 1 formulation group, 0.48±0.970 in the 20 mg compound 1 formulation group, and 0.29±0.564. in the compound 1 40 mg formulation group. The NRS in weeks 2 to 12 (mean ± SD) was 0.82 ± 0.992 in the placebo group, 0.63 ± 1.217 in the compound 1 10 mg formulation group , 0.44±0.855 in the 20 mg compound 1 formulation group and 0.27±0.535 in the 40 mg compound 1 formulation group.

In FIG. 42-49 show UFS-QOL scores after administration of placebo and one or more of the three Compound 1 formulations (10, 20, and 40 mg) to a subject over a 12 week treatment period. In particular, in FIG. 42 is a table of UFS-QOL scores measuring symptom severity; in fig. 43 is a table of overall UFS-QOL HRQL scores; in fig. 44 is a table of UFS-QOL scores measuring a subject's anxiety; in fig. 45 shows a table of UFS-QOL indicators that measure the impact on the activity of the subject; in fig. 46 is a table of UFS-QOL scores measuring the effect on a subject's energy/mood; in fig. 47 is a table of UFS-QOL scores measuring effect on subject control; in fig. 48 shows a table of UFS-QOL indicators that measure the impact on the subject's self-awareness; and in FIG. 49 is a table of UFS-QOL scores measuring the effect on a subject's sexual function.

As illustrated in FIG. 42, UFS-QOL scores measuring symptom severity (mean±SD) at weeks 0, 4, 8, and 12 were 27.64±17.726, 25.01±16.990, 25.68±17.291, and 23.48±17.226 , respectively, in the placebo group; 29.31±17.291, 23.78±14.736, 24.55±16.105 and 23.28±16.053 in the 10 mg compound 1 formulation group; 25.84±14.431; 23.12±14.327; ±15.187 and 14.05±15.272 in the compound 1 40 mg formulation group. The change (mean±SD) at week 12 from baseline was -3.58±13.325 in the placebo group, 6.51±18.122 in the 10 mg compound 1 formulation group, -8.97 ± 15.530 in the compound 1 20 mg formulation group, and -11.25 ± 17.274 in the compound 1 40 mg formulation group.

As illustrated in FIG. 43, UFS-QOL measures of overall health-related quality of life (HRQL total) (mean±SD) at weeks 0, 4, 8, and 12 were 16.06±18.797, 14.19±17.284, 13 .32±18.601 and 14.19±18.797, respectively, in the placebo group; 14.35±11.914, 11.28±10.342, 13.39±13.179 and 13.01±13.270 in the 10 mg compound 1 formulation group; 12.79±11.510, 11.10±13.829, 9.54±10.904, and 9.63±12.735 in the compound 1 20 mg formulation group; and 15.04±15.536, 11.31±12.082, 11.20±12.279, and 9.52±10.885 in the Compound 1 40 mg formulation group. Change (mean±SD) at week 12 from baseline was -2.20±11.555 in the placebo group, -1.61±10.586 in the 10 mg compound 1 formulation group, 2.11±10.529 in the 20 mg compound 1 formulation group, and -5.52± 15,871 in the 40 mg Compound 1 formulation group.

The bleeding profile was assessed by measuring parameters associated with anemia, including the following: hemoglobin (Hb), hematocrit (Ht), iron (Fe), and ferritin after placebo or one of the Compound 1 formulations (10, 20, and 40 mg) subject for a treatment period of 12 weeks. In particular, in FIG. 50-52 are tables of hemoglobin concentrations; in fig. 53 is a table of hematocrit percentages; in fig. 54 is a table of serum iron concentrations; and in fig. 55 is a table of ferritin concentrations. In particular, in FIG. 51 shows subjects who were taking concomitant iron supplements, and FIG. 52 shows subjects who were not taking concomitant iron supplements.

As illustrated in FIG. 50, blood Hb concentrations (mean±SD) at weeks 0, 4, 8, and 12 were 12.11±1.504 g/dl, 12.15±1.518 g/dl, 12.33±1.554 g/dl, and 12 .42±1.353 g/dl, respectively, in the placebo group; 12.18±1.159 g/dl, 12.56±1.191 g/dl, 12.55±1.164 g/dl, and 12.55±1.350 g/dl in the compound 1 10 mg formulation group; 12.15±1.407 g/dl, 12.79±1.495 g/dl, 12.88±1.379 g/dl, and 12.94±1.225 g/dl in the compound 1 20 mg formulation group; and 11.99±1.699 g/dl, 12.45±1.644 g/dl, 12.81±1.543 g/dl, and 12.91±1.380 g/dl in the Compound 1 40 mg formulation group.

The change in blood Hb concentration at week 12 from baseline was 0.20±1.003 g/dl in the placebo group, 0.35±1.055 g/dl in the 10 mg compound 1 formulation group, 0.83±1.161 g/dl in the 20 mg compound 1 formulation group and 0.92 ± 1.183 g/dl in the compound 1 40 mg formulation group. Thus, blood Hb concentrations were increased in the formulations

- 86 041715 containing 20 mg and 40 mg of Compound 1 compared to placebo. As illustrated in FIG. 51-52, blood Hb concentrations in the compound 1 formulation groups showed an upward trend regardless of the presence or absence of iron preparation.

As illustrated in FIG. 53, Ht values (mean±SD) at weeks 0, 4, 8, and 12 were 38.36±3.739%, 38.31±3.985%, 38.79±3.932%, and 39.13±3.324%, respectively, in the placebo group; 38.50±3.128%, 39.48±3.327%, 39.43±3.154% and 39.37±3.639% in the 10 mg compound 1 formulation group; 38.30±3.882%, 40.06±3.773%, 40.39±3.389% and 40.54±3.003% in the 20 mg Compound 1 formulation group; and 38.06 ± 4.275%, 39.44 ± 4.012%, 40.23 ± 3.620% and 40.53 ± 3.307% in the compound 1 40 mg formulation group. Change in Ht value at week 12 from baseline was 0.51±2.583% in the placebo group, 0.77±2.792% in the 10 mg compound 1 formulation group, 2.31±3.522% in the 20 mg compound 1 formulation group, and 2.46± 3.445% in the compound 1 40 mg formulation group. The Ht value showed little change in the placebo group and the Compound 1 10 mg formulation group over the treatment period, but in the 20 mg and 40 mg formulation groups 1 showed an upward trend.

As illustrated in FIG. 54, Fe values (mean±SD) at weeks 0, 4, 8, and 12 were 64.0±45.85 µg/dL, 68.1±55.53 µg/dL, 68.3±54.24 µg /dl and 68.1±49.17 mcg/dl, respectively, in the placebo group; 63.8±40.05 µg/dl, 72.8±40.58 µg/dl, 67.3±34.74 µg/dl, and 75.3±46.94 µg/dl in the 10 mg compound 1; 62.6±43.00 µg/dl, 77.4±49.74 µg/dl, 84.2±49.42 µg/dl, and 85.7±44.40 µg/dl in the 20 mg compound 1; and 56.5±34.85 µg/dL, 77.6±44.81, 78.2±41.91, and 82.0±36.93 µg/dL in the Compound 1 40 mg formulation group. Change Fe values at week 12 compared to baseline were 2.3±57.87 µg/dL in the placebo group, 11.0±42.94 µg/dL in the 10 mg Compound 1 formulation group, 24.7± 53.53 μg/dl in the 20 mg compound 1 formulation group and 25.5 ± 44.43 μg/dl in the 40 mg compound 1 formulation group. Fe did not show a clear upward trend in the placebo group and the Compound 1 10 mg formulation group over the treatment period, but a clinically significant increase was observed in Compound 1 20 mg and 40 mg formulation groups.

As illustrated in FIG. 55, ferritin values (mean±SD) at weeks 0, 4, 8, and 12 were 13.93±12.463 ng/mL, 11.37±9.325 ng/mL, 11.37±8.497 ng/mL, and 11.01 ±9.349 ng/ml, respectively, in the placebo group; 13.17±12.217 ng/ml, 14.71±16.372 ng/ml, 12.43±11.117 ng/ml and 10.81±9.489 ng/ml in the 10 mg compound 1 formulation group; 14.79±11.396 ng/ml, 14.77±11.536 ng/ml, 16.34±15.659 ng/ml, and 18.03±14.427 ng/ml in the 20 mg compound 1 formulation group; and 12.94±12.384 ng/mL, 15.14±15.133 ng/mL, 18.10±16.177 ng/mL and 21.84±21.509 ng/mL in the Compound 1 40 mg formulation. Change in ferritin value at week 12 compared to baseline was 3.30±7.110 ng/ml in the placebo group, -2.56±6.833 ng/ml in the group treated with 10 mg compound 1, 3.50±10.229 ng/ml in the 20 mg compound 1 formulation group and 8.91 ± 13.131 ng/mL in the 40 mg compound 1 formulation group. The ferritin value gradually decreased over the treatment period in the placebo group and the 10 mg compound 1 formulation group , but it tended to increase gradually in the groups receiving formulations containing 20 mg and 40 mg of Compound 1.

Serum LH concentrations following administration of either placebo or one of the three Compound 1 formulations (10, 20, and 40 mg) over a 12 week treatment period are plotted in FIG. 56A-D, respectively, and in tabular form in FIG. 57. In particular, the median values of LH concentrations at weeks 0, 2, 4, 8 and 12 were 3.280, 4.530, 3.600, 3.565 and 4.130 mIU / ml, respectively, in the placebo group, and, respectively: 3.480, 3.815, 2.565, 3.460 and 3.550 mIU/ml in the group receiving the formulation with 10 mg of Compound 1; 3.485, 2.520, 1.750, 2.260 and 2.685 mIU/mL in the 20 mg compound 1 formulation group; and 3.520, 0.720, 0.550, 0.570 and 0.650 mIU/mL in the Compound 1 40 mg formulation group. /ml in the 10 mg compound 1 formulation group, -0.895 mIU/ml in the 20 mg compound 1 formulation group, and -2.760 mIU/ml in the 40 mg compound 1 formulation group. Serum LH tended to decrease in the 20 mg and 40 mg Compound 1 formulation groups over the treatment period.

Serum FSH concentrations following administration of either placebo or one of the three Compound 1 formulations (10, 20 and 40 mg) over a 12 week treatment period are plotted in FIG. 58A-D, respectively, and in tabular form in FIG. 59. Specifically, mean serum FSH concentrations at weeks 0, 2, 4, 8, and 12 were 6.580, 3.570, 5.280, 5.080, and 5.140 mIU/mL, respectively, in the placebo group, and respectively: 6.645, 5.990, 5.225, 6.150 and 6.200 mIU/ml in the 10 mg compound 1 formulation group; 6.125, 5.705, 4.660, 4.840 and 5.710 mIU/ml in the 20 mg compound 1 formulation group; and 6.140, 4.280, 3.710, 3.210 and 2.950 mIU/mL in the compound 1 40 mg formulation group. 1.060 mIU/mL in the 10 mg compound 1 formulation group, -0.720 mIU/mL in the 20 mg compound 1 formulation group,

- 87041715 and -3.180 mIU/ml in the 40 mg compound 1 formulation group. Thus, serum FSH concentrations tended to be lower in the compound 1 40 mg formulation group during the treatment period.

Serum E2 concentrations following administration of either placebo or one of the three Compound 1 formulations (10, 20 and 40 mg) over a 12 week treatment period are plotted in FIG. 60A-D, respectively, and in tabular form in FIG. 61. Specifically, mean serum E2 concentrations at weeks 0, 2, 4, 8, and 12 were 41.0, 142.0, 55.0, 91.5, and 110.0, respectively, in the placebo group, and , respectively: 46.5, 82.5, 58.0, 52.0 and 57.0 pg/ml in the group receiving the composition with 10 mg of compound 1; 44.0, 25.0, 23.5, 16.0 pg/ml and 13.0 pg/ml in the 20 mg compound 1 formulation group; and 40.0, 0.0, 0.0, 0.0 pg/mL and 0.0 pg/mL in the 40 mg Compound 1 formulation group. Median change in serum E2 concentrations at week 12 compared to baseline was 59.0 pg/mL in the placebo group, 0.0 pg/mL in the 10 mg compound 1 formulation group, -18.5 pg/mL in the 20 mg compound 1 formulation group, and -35.0 pg/ml in the 40 mg compound 1 formulation group. 2 weeks and maintained up to 12 weeks. Serum E ₂ concentrations tended to be lower in the compound 1 40 mg formulation group during the treatment period.

In FIG. 172 depicts the percentage of subjects with a serum E ₂ concentration of less than 10 pg/ml as a function of dose. In FIG. 173 depicts the serum E ₂ concentration for individual subjects as a function of the plasma concentration of Compound 1 (relugolix). These figures demonstrate that Compound 1 dosage may be important to achieve effective E ₂ suppression with low inter-subject variability.

Serum P concentrations following administration of either placebo or one of the three Compound 1 formulations (10, 20, and 40 mg) over a 12 week treatment period are plotted in FIG. 62A-D, respectively, and in tabular form in FIG. 63. Specifically, mean serum P concentrations at weeks 0, 2, 4, 8, and 12 were 0.290, 7.740, 0.320, 0.300, and 0.360 ng/mL, respectively, in the placebo group and, respectively: 0.270, 0.315, 0.440 , 0.360 and 0.410 ng/ml in the group receiving the formulation with 10 mg of Compound 1; 0.325, 0.235, 0.270, 0.250 and 0.250 ng/ml in the 20 mg compound 1 formulation group; and 0.300, 0.230, 0.240, 0.220 and 0.250 ng/mL in the compound 1 40 mg formulation group. /ml in the 10 mg compound 1 formulation group, -0.090 ng/ml in the 20 mg compound 1 formulation group, and -0.060 ng/ml in the 40 mg compound 1 formulation group. Serum P concentrations did not increase in the 20 mg and 40 mg Compound 1 formulation groups over the treatment period.

Bone mineral density (BMD) of the second to fourth lumbar vertebrae (L2 to L4) was measured using dual X-ray absorptiometry (DXA). Bone mineral density values at weeks 0 and 12 (mean ± SD) were 1.1207 ± 0.16933 and 1.1188 ± 0.17186 g/cm ² , respectively, in the placebo group and, respectively: 1.0792 ± 0 .13998 and 1.0757±0.13907 g/ ^cm2 in the group treated with 10 mg formulation of Compound 1, 1.0880±0.15287 and 1.0665±0.15479 g/ ^cm2 in the group treated with formulation with 20 mg of Compound 1, and 1.0924±0.15355 and 1.0677±0.15306 g/ ^cm2 in the 40 mg formulation of Compound 1. The percentage change in bone mineral density from baseline was -0, 24±2.218% in the placebo group, -0.75±2.350% in the 10 mg compound 1 formulation group, -2.01±2.334% in the 20 mg compound 1 formulation group, and -2.28± 2.194% in the Compound 1 40mg formulation group. With respect to other GnRH agonists, bone mineral density was reported to decrease by -2.21±1.709% following administration of leuprolide acetate to subjects with uterine fibroids. The percentage change in bone mineral density in this study is considered equal to or less than this result for the leuprolide acetate group.

Biochemical markers of bone metabolism (serum NTx and VAP) were also evaluated as an additional marker of bone metabolism.

In FIG. 173 shows the percentage of subjects with a PBAC score of 0 at weeks 6 to 12 and the mean percentage change from baseline in bone mineral density at week 12 as a function of dose. This graph shows improvement in symptoms (PBAC = 0) with increasing compound 1 dose. Bone mineral density loss also increased with higher compound 1 doses, but the difference between higher doses was smaller than the difference between lower doses.

In FIG. 64 shows the return of menstrual cycles after administration of placebo or one of the three Compound 1 formulations (10, 20, and 40 mg) over a 12 week treatment period. The period from the last dose of study drug to the return of menses (mean ± SD) was 18.6 ± 8.75 days in the placebo group, 19.8 ± 9.26 days in the 10 mg compound 1, 31, 0 ± 17.65 days in the 20 mg compound 1 formulation group and 36.4 ± 7.63 days in the 40 mg compound 1 formulation group. with restored

- 88 041715 menstruation, while the period of restoration of menstruation was 20-35 days after the last dose in the groups of compound 1 (table. 3).

Table 3

Other security endpoints

end point MPC, (%) Recovery period after menstruation, days 10 mg 20 mg 40 mg η 55 47 56 55 average -0.2 -0.7 -2.0 -2.3 (SD) (2.22) (2.35) (2.33) (2.19) η 57 47 55 52 average 19 20 31 36 (SD) (8.8) (93) (17.6) (7.6)

Thus, for the secondary endpoints, the achievement of amenorrhea (total RVAC of 0) in weeks 6 to 12 was 73% in the 40 mg Compound 1 (relugolix) group compared to 0% in the placebo group (Table 4). below). Fibroids and uterine volumes in the placebo group increased by week 12, while those volumes in all Compound 1 groups decreased starting at week 2 and continued to decrease by weeks 4, 8, and 12, with a trend towards the greatest observed decrease in volumes in the group treated with 40 mg (Table 4). At week 12, uterine and fibroid volumes were reduced by ~40% in the 40 mg Compound 1 group, but increased by ~10% in the placebo group, resulting in a ~50% change from baseline for the 40 mg group compared with placebo. By week 12, there was an increase in Hb levels in the 20 mg and 40 mg compound 1 groups, with the largest increase in Hb observed in the 40 mg group (Table 4). Patient-reported NRS scores showed that, compared with the placebo group, patients treated with Compound 1 had a lower NRS score (i.e., fewer pain symptoms from weeks 6 to 12), and in the group, which was administered 40 mg of compound 1, there was the greatest benefit in reducing pain (table. 4). Compared to placebo, the 40 mg Compound 1 group had a lower UFS-QOL symptom severity score and a lower overall UFS-QOL HRQL score, indicating a trend towards greater improvement in patients in the highest Compound 1 dose group (40 mg) (Table 4). All doses of relugolix significantly reduced menstrual blood loss in weeks 6 to 12 compared to placebo in a dose-dependent manner with the highest proportion of patients in the 40 mg group (P<0.0003 for each comparison). Point estimate [95% CI]*: each relugolix group was statistically significant compared to placebo, p<0.0003.

The chi-square test was performed according to a closed testing procedure. (Fig. 68).

Table 4

Secondary Endpoints

Variable placebo Relugolix 10 mg 20 mg 40 mg (n=48) (n=56) (n=55) Amenorrhea*, η (%) 0 8 21 40 (0.0) (16.7) (38.2) (72.7) Change from exodus value at week 12, mean value (SD) Myoma volumes (%) 10 -23 -37 -39 (47.2) (29.5) (32.6) (34.2) Uterine volume (%) 10 -12 -28 -41 (57.9) (29.9) (28.8) (37.2) Hemoglobin (g/dl) 0.2 oh, s 0.8 0.9 (1.00) (1.05) (1.16) (1.18) Evaluation of indicators -4 -7 -9 -eleven UFS-QOL Symptom severity (13.3) (18.1) (15.5) (17.3) General -2 -2 -2 -6 HRQL score (11.6) (Yu.6) (Yu.5) (15.9) Index 0.8 0.6 0.4 0.2 NRS**, mean value (SD) (0.99) (1.23) (0.62) (0.54)

* PBAC scores in weeks 6 to 12 = 0.

** Average value in weeks 6 to 12.

In addition, regarding pharmacodynamics, mean serum estradiol (E ₂ ) levels decreased to <10 pg/ml (less than the lower limit of quantitation) at week 2 in the group treated with

- 89 041715 mg of compound 1 (relugolix), and these very low concentrations were maintained until week 12 (Fig. 69). The 40 mg dose of Compound 1 resulted in the largest change from baseline in LH, FSH, and R parameters.

Based on the results of the efficacy and safety evaluation in this study, it was decided that there are no clinically significant safety issues with the formulations of Compound 1. In addition, based on the results of the efficacy and safety evaluation in this study, the formulation with 40 mg of Compound 1 was considered to be an effective dose to treat symptoms associated with uterine fibroids.

Example 5B. Brief summary of example 5A.

This example summarizes some of the results as described above for example 5A.

PBAS values were used in Example 5A and provide an estimate of the amount of menstrual blood loss. The PBAC score was assessed by asking subjects to record the details associated with menstrual blood loss on a PBAC score sheet distributed by the sponsor over the treatment period. In FIG. 1 shows an exemplary PBAC scoring table that includes two items (tampon and towel) in three pictographic ranges (1: lightly stained; 5: moderately stained; 10: impregnated). These points represent the level of soiled hygiene materials during the menstrual cycle, with a total score ranging from 0 (none) to infinity. Higher readings indicate more profuse blood loss. The PBA scorecard also allows subjects to indicate: whether they experienced bleeding between periods that required sanitary protection; whether they had clots and, if so, the approximate size of the clots; whether they experienced episodes of profuse bleeding and whether they required double protection (using a pad and a tampon at the same time). Profuse bleeding is defined as overfilling or staining of clothes or underwear due to menstrual bleeding, as indicated in the PBAC Table of Example 5A.

Subjects were instructed to complete a PBAC score sheet, assigning scores as follows: 1, 5, or 10 points were added for each lightly stained, moderately stained, or fully soaked feminine hygiene product, respectively, 1 or 5 points were added for each clot less than 1 cm in diameter , or for each clot with a largest diameter of 1 cm or more, respectively, and 5 points were added for each episode of profuse bleeding. These scores are slightly different from those shown in the exemplary PBAC score chart shown in FIG. 1. The overall PBAC score was obtained by summing the scores for each of the above indicators.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks of compound 1 in the formulation (formulation of compound 1) having the following excipients: 122 mg of mannitol, 40 mg of microcrystalline cellulose, 6 mg of hydroxypropyl cellulose, 10 mg of croscarmellose sodium, 2 mg magnesium stearate, 7.12 mg hypromellose 2910, 0.8 mg titanium dioxide, and optionally 0.08 mg iron oxide, and without a hormone replacement drug, change from baseline in mean total menstrual blood loss graph (PBAC) with 6 to 12 weeks was 77.3±255.54 in the placebo group and -238.7±203.34 in the 40 mg compound 1 formulation group.

All fibroid and uterine volumes mentioned in this document were evaluated using transvaginal ultrasound. In particular, fibroid volumes were calculated using the following formula: D1xD2xD3xn/6, where D1 is the largest fibroid diameter; D2 - the largest diameter of the fibroid at an angle perpendicular to D1; and D3 is the fibroid diameter intersecting the intersection of D1 and D2 perpendicular to the D1/D2 plane.

Following a once daily dose of 40 mg per day for 12 consecutive weeks, Compound 1 formulation had a percentage change from baseline in mean fibroid volume at the end of 12 consecutive weeks of 10.19±47.159% in the placebo group and -38.59± 34.197% in the 40 mg Compound 1 formulation group.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks of compound 1 formulation, the percent change from baseline in mean uterine volume at the end of 12 consecutive weeks was 9.75±57.946% in the placebo group and -40.90± 37.233% in the 40 mg Compound 1 formulation group.

The Numerical Rating Scale (NRS) is an 11-item self-assessment tool for assessing pain. As shown in FIG. 2, it includes 11 points ranging from 0 (no pain) to 10 (worst possible pain). Higher NRS scores reflect higher levels of pain.

Following a once daily dose of 40 mg per day for 12 consecutive weeks of compound 1 formulation, the mean Numerical Rating Scale (NRS) score at weeks 6 to 12 was 0.82 ± 0.989 in the placebo group and 0.25 ± 0.542 in the group receiving the formulation with 40 mg of Compound 1.

The Uterine Fibroids Symptom Quality of Life Questionnaire (UFS-QOL) is a 37-item self-assessment tool that assesses differences in symptom severity and health-related quality of life. It includes eight symptom-related questions and 29

- 90 041715 health-related questions about quality of life on eight subscales (symptom severity, anxiety, activities, energy/mood, control, self-awareness, sexual function, and overall health-related quality of life) with subscales and an overall score ranging from 37 (not at all/never) to 116 (very significant/all the time). The UFS-QOL questionnaire used in Example 5A is shown in FIG. For-C. Higher UFS-QOL scores reflect greater symptom severity and the impact of symptoms on health-related quality of life.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the change from baseline in the formulation of Compound 1 in the mean UFS-QOL scores, measuring the severity of symptoms at the end of 12 consecutive weeks, was -3.58±13.325 in the placebo group and -11.25±17.274 in the 40 mg Compound 1 formulation group.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the change from baseline in the mean values of the quality of life questionnaire for symptoms of uterine fibroids (total HRQL) at the end of 12 consecutive weeks was -2.20± 11.555 in the placebo group and -5.52±15.871 in the 40 mg Compound 1 formulation group.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the composition of compound 1 changed from baseline in the mean concentration of hemoglobin (Hb) in the blood at the end of 12 consecutive weeks was 0.20 ± 1.003 g / dl in the placebo group and 0.92±1.183 g/dl in the group receiving the formulation with 40 mg of Compound 1.

After a once daily dose of 40 mg per day for 12 consecutive weeks, the change from baseline in mean hematocrit (Ht) at the end of 12 consecutive weeks was 0.51±2.583% in the placebo group and 2.46 ±3.445% in the 40 mg Compound 1 formulation group.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the composition of compound 1 changed from baseline in the mean value of iron (Fe) at the end of 12 consecutive weeks was 2.3 ± 57.87 μg / dl in the placebo group and 25.5±44.43 μg/dl in the group receiving the formulation with 40 mg of Compound 1.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the change in the composition of compound 1 from baseline in the mean value of ferritin at the end of 12 consecutive weeks was -3.30 ± 7.110 ng / ml in the placebo group and 8.91 ±13.131 ng/mL in the 40 mg Compound 1 formulation group.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the composition of compound 1 changed from baseline in the median concentrations of luteinizing hormone at the end of 12 consecutive weeks was 0.590 mIU / ml in the placebo group and -2.760 mIU / ml in the group who received the composition with 40 mg of compound 1.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks of the composition of compound 1, the change from baseline in the median FSH concentration was 1.040 mIU / ml in the placebo group and -3.180 mIU / ml in the group receiving the formulation with 40 mg connections 1.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the composition of compound 1 changed from baseline in the median concentrations of E ₂ at the end of 12 consecutive weeks was 59.0 pg/ml in the placebo group and -35.0 pg /ml in the group receiving the composition with 40 mg of compound 1.

After administration of a once daily dose of 40 mg per day for 12 consecutive weeks, the composition of compound 1 changed from baseline in the median concentrations of progesterone (P) at the end of 12 consecutive weeks was 0.050 ng/ml in the placebo group and -0.060 ng/ml in the group receiving the formulation with 40 mg of Compound 1.

Following a once daily dose of 40 mg per day for at least 2 consecutive weeks of Compound 1 and 0.05 mg to 2.5 mg per day of estrogen and/or progestogen, loss of bone mineral density is minimized.

Example 6 International Randomized, Double Blind, Placebo Controlled, Phase 3 Efficacy and Safety Studies to Evaluate Coadministration of Compound 1 with Low Doses of Estradiol and Progestin in Women with Heavy Menstrual Bleeding (HMB) Associated with Uterine Fibroids.

The study is a randomized, double-blind study to evaluate the safety and efficacy of a formulation containing 40 mg of compound 1 administered orally once a day with a hormone replacement drug containing 1 mg of estradiol and 0.5 mg of norethisterone acetate, compared with placebo in women with heavy menstrual bleeding associated with uterine fibroids. The study described in this example is intended to form the basis for an upcoming phase III clinical program to support the approval of Compound 1 as a treatment for women with uterine fibroids.

The study will include both a main study and a separate study

- 91 041715 extension of therapy. The main study will include a screening period of approximately 10 weeks, a drug treatment period of 24 weeks, and a follow-up period of one month. The Extension Therapy Study will allow subjects from the main study to extend the treatment period. Specifically, the Extension Therapy Study would allow placebo subjects in the main study to receive Compound 1 for 24 weeks, and those treated with Compound 1 in the main study to extend the same treatment for an additional 24 weeks. Subjects will only be allowed to participate in the Extension Therapy Study if they have a bone mineral density loss of less than -8.0%.

It is planned that the study will include about 390 subjects. Of these 390 subjects, about 260 women will be randomized to receive compound 1 treatment with hormone replacement therapy and about 130 women will be randomized to receive placebo.

To enter the study, subjects must be women aged 18-50 years, inclusive, who have been diagnosed with heavy menstrual bleeding associated with uterine fibroids, demonstrated for 2 cycles during the screening period, as measured by the method of alkaline hematin. Heavy menstrual bleeding as defined by the alkaline hematin method refers to an average menstrual blood loss >80 ml with a minimum menstrual blood loss of 70 ml per cycle during the entire menstrual cycle immediately prior to Visit 3. Visit 3 will take place approximately 8-12 weeks after the start of the study. The diagnosis of heavy menstrual bleeding can be confirmed by transabdominal or transvaginal pelvic ultrasound performed with saline or gel contrast.

Subjects will begin to record in a patient diary from Visit Day 1. During the period between Visits 2 and 3, when subjects are expected to have completed at least 2 menstrual cycles, baseline values will be collected to evaluate efficacy, including total menstrual blood loss, pain symptoms, and quality of life . Subjects will record in a patient diary each day until the end of study medication (Visit 9).

Visit 2 will take place between Days 1 and 5 of the first menstrual period following Visit 1. Visit 3 will take place between Days 1 and 5 of the second menstrual period following Visit 1. From Visit 3 to Visit 9, subjects will receive study drug once daily (of the following: formulation with Compound 1 and a hormone replacement drug, Compound 1 formulation placebo, and a hormone replacement drug placebo) under double-blind conditions along with daily supplements of calcium (up to 1300 mg) and vitamin D (up to 1000 units). Women with iron deficiency anemia will also receive oral or parenteral iron replacement if hemoglobin values are less than 10 g/dl and mean corpuscular volume is below the lower limit of normal. All women will have their bone mineral density assessed using dual energy x-ray absorptiometry and endometrial biopsy at baseline and at week 24.

Since previous studies have shown that the plasma levels of Compound 1 can be reduced when administered with a high-calorie, high-fat meal, the study drug is intended to be administered on an empty stomach during this study, namely at least 1 hour before or 2 hours after a meal. .

During this study, subjects will visit the study center for scheduled examinations and evaluations at each monthly visit after randomization and initiation of study drug administration (Visit 3) in a bilaterally blinded setting.

At Visit 3, study drug will be administered in double-blind, double-blind conditions from the day of Visit 3 to the day before Visit 9 (or early withdrawal) in double-blind conditions. Study drug will be taken once daily as a single oral dose in the morning on an empty stomach, at least one hour before or at least 2 hours after a meal. If a dose is missed in the morning, the dose can be taken later in the day at least 1 hour before the next meal and 2 hours after the previous meal.

Subjects will complete a patient diary each day. Subjects will record in a patient diary pain symptoms experienced within the last 24 h due to uterine fibroids, which will be used to calculate the NRS score; and information related to the clinical trial drug, menstrual bleeding, and the use of pain medications and supplements. The specific questions to be included in the patient diary are shown in FIG. 2 and in FIG. 65A-C.

The primary endpoint of this study is to evaluate the percentage of subjects who achieved a menstrual blood loss of less than 80 ml and a reduction of 50% or more from baseline prior to the last month of treatment in menstrual blood loss measured by the alkaline hematin (AH) method. Subjects return used feminine hygiene products for AN quantification of menstrual blood loss. The AN method measures the volume of menstrual blood loss in milliliters by processing used feminine products in solution and measuring the hematin absorption obtained from calibration curves. Approval method

- 92 041715 is valid in accordance with current FDA method validation guidelines and is an acceptable quantitative endpoint for assessing heavy menstrual bleeding. Women's products will be dispensed at Screening Visit 1 and collected at each visit until the patient completes treatment or withdraws from the study prior to completion of treatment. Each time a patient submits her menstrual feminine products for analysis, a venous blood sample will be collected and sent to the laboratory.

The secondary endpoints of this study are intended to include: 1) the percentage of subjects who achieved prolonged amenorrhea from week 5 to the last month of treatment; 2) time to amenorrhea; 3) changes in menstrual blood loss compared to baseline before the last month of treatment; 4) changes in hemoglobin concentration compared to the initial value before the last month of treatment; 5) Numeric Rating Scale (NRS) score for pain associated with uterine fibroids; 6) changes in the volume of fibroids compared with the initial value before the last month of treatment; 7) changes in uterine volume compared to baseline before the last month of treatment; 8) changes in bone mineral density from baseline up to 24 weeks (as measured by DXA); and 9) endometrial biopsies, eg, the percentage of patients with endometrial thickness greater than 4 mm at the end of treatment.

Subjects complete various questionnaires to assess the impact of uterine fibroids on quality of life. In particular, subjects complete the UFS-QOL questionnaire described in Example 5A immediately after the start of the treatment period. Subjects also complete the Work Performance Changes and Activity Impairment Questionnaire: General Health Version 2.0 (WPAI: GH), which consists of six questions designed to assess the impact of general health and specific symptoms on work performance and life outside of work. WPAI:GH questions are shown in FIG. 66A-B. Subjects are also expected to complete the EuroQol, the patient's overall impression of change questionnaire (shown in FIG. 67) and the Menorrhagia Impact Questionnaire (MIQ). Although not part of this study, participants may also complete a resource utilization questionnaire to provide an additional tool for assessing the quality of life of patients with uterine fibroids.

This study will also evaluate the pharmacokinetic and pharmacodynamic effects of Compound 1 with reversible hormone therapy. Specific parameters to be analyzed include: 1) concentrations of estradiol, luteinizing hormone, follicle-stimulating hormone, and progesterone; 2) C _max , St and AUC( ₀ - _tau ); and 3) minimum plasma drug concentrations for Compound 1, ethinylestradiol, and norethisterone acetate.

Example 7 Randomized, double-blind, placebo-controlled study of the efficacy of Compound 1 in the treatment of endometriosis.

A randomized, double-blind study was conducted to evaluate the efficacy of three dose levels (10, 20, and 40 mg) of a 12-week oral formulation of Compound 1 versus placebo in premenopausal Japanese women >20 years of age suffering from endometriosis. The efficacy of this drug has also been comparatively evaluated using injections (once every 4 weeks, 3.75 mg per dose) of leuprolide acetate (Leuplin®; also known as leuprorelin) as a control drug.

Subjects were diagnosed with endometriosis within 5 years prior to screening and had dysmenorrhea and pelvic pain, one or both of which were at least moderate as determined by the investigator using the Biberoglu & Behrman (B&B) score. The primary endpoint was change from baseline in the mean visual analog scale (VAS) score for total pelvic pain at the end of the treatment period (VAS 0 = no pain; 100 = pain as severe as possible). Secondary endpoints included VAS score for pelvic pain, dysmenorrhea, and dyspareunia over the treatment period. Safety endpoints included bone mineral density (BMD), adverse events (AEs), vital signs, weight, 12-lead electrocardiogram (ECG), clinical laboratory tests, and biochemical markers of bone metabolism (cross-linked type I collagen N telopeptide in serum and bone-specific alkaline phosphatase). A summary of demographic and baseline characteristics for groups is presented in Table 1. 5.

- 93 041715

Table 5 Demographic and Baseline Characteristics

Average performance value (SD) Placebo (N=99) 10mg(#103) Relugolix 40 mg(#103) Leuprorelin 1 (Ν = 82) Age (years) 35.7 (6.06) 35.3 (6.22) 35.1 (6.78) 35.6 (6.04) 36.1 (6.13) BMI [kg/ ^m2 ] ¹ 21.1 (3.01) 21.5(3.35) 20.4 (2.46) 21.6 (3.14) 21.8 (3.40) Duration 3.9 (4.65) 3.8 (5.04) 3.2 (3.84) 4.3 (5.47) 2.9 (3.78) Average VAS [mm] General pelvic pain ¹ 15.6 (14.32) 14.6 (11.99) 15.6 (15.06) 15.3(11.99) 15.2 (15.10) Dysmenorrhea ¹ 28.4 (16.59) 28.2 (17.64) 27.7 (18.94) 30.4 (17.04) 27.1 (19.78) Dyspareunia ² 11.0 (14.25) 8.8(14.24) 12.5 (16.48) 9.4 (15.42) 9.5(10.71) Modified B&B Score (Patient Rating) Non-menstrual pelvic pain ¹ 0.6 (0.45) 0.7 (0.46) 0.6 (0.47) 0.7 (0.44) 0.7 (0.55) Dysmenorrhea ¹ 1.2 (0.44) 1.2 (0.47) 1.2 (0.48) 1.2 (0.47) 1.2 (0.47) Dyspareunia ² 0.6 (0.45) 0.6 (0.60) 0.6 (0.55) 0.5 (0.48) 0.6 (0.45) Percentage of days using analgesics [%] ¹ 10.0 (11.55) 12.5 (12.32) 13.3 (16.43) 12.0 (14.53) 11.6 (13.84)

¹ Placebo: N=97, compound 1 (relugolix), 10 mg: N=103, 20 mg: N=100, 40 mg: N=103, leuprorelin: N=81, total: (N=484).

² Placebo: N=41, compound 1 10 mg: N=46, 20 mg: N=47, 40 mg: N=44, leuprorelin: N=26, total: (N=204).

Subjects began to record in a patient diary on visit day 1. During the period between visits 2 and 3, in which subjects had at least 1 menstrual cycle, baseline measures of efficacy were collected, including quality of life (QOL) and pain symptoms. . Subjects record in a patient diary each day until the end of treatment. Visit 2 took place on days 1 to 5 of the first menstrual cycle after visit 1. Study drug (Compound 1 formulation placebo and leuplin placebo) were administered under single-blind conditions from visit 2 to the day before visit 3. Visit 3 took place on days 1 to 5 of the second menstrual cycle after Visit 1. At Visits 3 to 7, subjects were instructed to attend clinics on an empty stomach and before taking study drug. At visit 3, subjects were randomized to receive either compound 1:10 mg, 20 mg, 40 mg and placebo formulations or leuplin in a 2:2:2:2:1 ratio, respectively. Compound 1 formulation (10, 20 or 40 mg) and placebo Leuplin, Compound 1 formulation placebo and Leuplin placebo, or Compound 1 formulation placebo and Leuplin were administered from visit day 3 to the day prior to visit 7 (or until treatment was stopped) under double-blind conditions. Compound 1 formulation or Compound 1 formulation placebo was administered daily as a single oral dose each morning 30 minutes before breakfast, and leuplin (or leuplin placebo) was administered subcutaneously once every 4 weeks. The study consisted of a pre-treatment period of 4 to 12 weeks, a treatment period of 12 weeks, and a total study period of 16 to 24 weeks. During this study, patients visited the clinic once every two weeks for a month after the start of study drug administration in a bilaterally blinded setting (Visit 3) and monthly thereafter. Assigned examinations and assessments were carried out at each visit.

The concentration of compound 1 in plasma after administration of a single dose of the composition of compound 1 in an amount of from 1 to 80 mg reached a peak mean value of C _max after 0.5-4.0 hours after dosing (Tmax) with a mean value of T _1/2 in plasma from 7.1 to 19.8 hours. Mean plasma AUC and mean C _max showed an increase somewhat greater than dose proportional. The plasma concentration of Compound 1 on day 14 for multiple doses of 10 mg to 40 mg reached a peak mean C _max 1-1.5 hours post-dose (T _max ) with a mean plasma T _1/2 of 19.2 up to 24.6 hours. The average value of AUC( _0-inf ) in plasma and the average value of C _max for compound 1 usually increased in proportion to the dose. Mean plasma AUC( _0-tau ) and mean C _max on day 1 and mean C _max on day 14 increased in a roughly dose-dependent manner, but mean plasma AUQ( _0-tau ) on day 14 showed an increase in slightly more than dose proportional. Plasma concentration of Compound 1 reached steady state by day 7 of multiple dosing, and the mean plasma AUC and mean Cmax on day 14 were higher than those on day 1. The mean single dose AUC was higher after fasting than after a dose after a meal or before a meal. The mean plasma AUC and mean multiple dose Cmax were higher with pre-meal dosing than with post-meal dosing. These data suggest that food influences the pharmacokinetics of Compound 1 formulation.

Blood concentrations of LH, FSH, estradiol (E ₂ ) and progesterone (P) decreased approximately in proportion to dose after administration of a single dose of Compound 1 (10 mg to 80 mg) compared with placebo. LH and estradiol concentrations showed a rapid decrease after each dose in all subjects and continued to decrease throughout the treatment period. Plasma progesterone concentrations showed a rapid decline after dosing at all dose levels and treatment regimens, and the suppression was maintained throughout the treatment period. Plasma FSH concentrations also showed a rapid decline after dosing at all dose levels and treatment regimens and remained suppressed throughout the treatment period in the groups administered 40 mg of Compound 1 before or after meals.

Table 6

Additional endpoints

Variables Mean value (SD) placebo Relugolix Leipro-1 1 relin 1 Modified B&B Scale (Patient Rating) Non-menstrual pelvic pain -0.18 (0.361) -0.21 (0.300) -0.22 (0.440) -0.33 (0.414) -0.41 (0.448) Dysmenorrhea -0.17 (0.538) -0.48 (0.645) -0.76 (0.673) -1.16 (0.487) -1.16 (0.480) Deep dysparurenia B&B (doctor's assessment) -0.07 (0.363) -0.08 (0.485) -0.10 (0.566) -0.07 (0.492) -0.36 (0.520) Non-menstrual pelvic pain -0.5 (0.75) -0.6 (0.76) -6.8 (0.94) -0.9 (0.84) -1.1 (0.73) Dysmenorrhea -0.4 (0.76) -1.0 (0.93) -1.5 (0.91) -2.0 (0.51) -2.1 (0.49) Dyspareunia Change from original value indicators of ENR-30 -0.2 (0.72) -0.2 (0.68) -0.2 (0.81) -0.1 (0.60) -0.6 (0.68) Pain -5.6 (18.99) -18.3 (19.76) -17.8 (20.36) -25.3 (20.87) -23.2 (20.41) control and impotence -8.2 (18.74) -13.7 (18.71) -14.6 (23.59) -17.2 (22.48) -19.6 (23.27) Emotional well-being -6.3 (14.48) -8.3 (16.44) -8.9 (18.62) -10.4 (17.77) -8.8 (17.25) Social support -3.2 (14.59) -6.6 (10.29) -8.4 (16.95) -6.8 (15.19) -6.8 (16.36) Self-esteem -3.9 (16.42) -5.5 (11.56) -6.3 (14.90) -8.4 (16.18) -6.1 (16.35) Change from baseline in proportion of days using analgesics -2.0 (10.38) -6.6 (10.80) -6.3 (14.00) -10.1 (13.44) -8.3 (12.69) Patients who achieved amenorrhea [N (%)] 2 (2.1) 26 (25.2) 54 (54.0) 95 (92.2) 79 (97.5)

Note. Physician B&B and change from baseline in EHP-30 scores are week 12 results. Other additional endpoints are outcomes at the end of treatment.

All study drug related adverse events were mild to moderate in severity and resolved during or after completion of study drug administration. The main adverse events were headaches, but the incidence of headaches was the same in groups treated with compound 1 and placebo groups.

For efficacy outcomes, the primary endpoint was the change from baseline in mean VAS scores for pelvic pain at the end of the treatment period in the complete analysis (FAS) population. Changes from baseline in mean VAS (mean±SD) were -3.753±10.5018 mm in the placebo group, 6.168±9.1411 mm in the 10 mg Compound 1 formulation group, -8.070±13.3707 mm in the 20 mg compound 1 formulation group, -10.418±11.0171 mm in the compound 1 40 mg formulation group, and -10.460±10.3013 mm in the leuprolide acetate group, respectively. A statistically significant difference was observed between each Compound 1 treatment group and the placebo group in the change from baseline in mean VAS for pelvic pain at the end of the treatment period. The change from baseline in mean VAS in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group.

VAS scores for pelvic pain, dysmenorrhea, and dyspareunia over the treatment period were assessed as secondary endpoints. With respect to pelvic pain, the changes from baseline in mean VAS at days 1-28, days 29-56, days 57-84 and at the end of the treatment period in the 40 mg compound 1 formulation group were - 3.761 mm ± 7.8831, -8.960 ± 9.8226 mm, -10.464 ± 11.0995 mm and -10.418 ± 11.0171 mm, respectively. These values at the end of the treatment period were -3.753±10.5018 mm in the placebo group, -6.168±9.1411 mm in the group receiving the 10 mg compound 1 formulation, -8.070±13.3707 mm in the group receiving the 20 mg formulation. mg of compound 1, -10.418±11.0171 mm in the 40 mg compound 1 formulation group, and -10.460±10.3013 mm in the leuprolide acetate group.

Changes from baseline in VAS scores were greater at higher compound 1 dose levels, and change from baseline in mean VAS scores increased with time. The VAS profile of the 40 mg Compound 1 formulation group was similar to that of the leuprolide acetate group.

The percentage change in bone mineral density reduction from baseline (mean ± SD) was -0.07±1.727%, -0.95±1.875%, -1.34±2.087%, and -2.08±2.220% in the placebo group; and the groups receiving compound 1 formulation at doses of 10, 20, and 40 mg, respectively. In this study, a similar effect was observed in the group receiving the formulation with 40 mg of Compound 1 and the group receiving

- 95 041715 treated with leuprolide acetate (-2.21±1.709%).

For dysmenorrhea, changes from baseline in mean VAS scores were greater at higher compound 1 dose levels, and VAS scores decreased over time. However, in patients with dyspareunia, no clear trend was observed at any dose levels of Compound 1.

Among formulations containing 10, 20 and 40 mg Compound 1, plasma concentrations of unchanged Compound 1 were at higher levels at 0.5-1.5 hours or 2-5 hours after administration in all treatment groups. Pre-dose plasma drug concentrations at each visit (trough values) were comparable across each treatment group and were proportional to Compound 1 dose levels. Population PK analysis showed that the observed plasma concentration profiles of unchanged Compound 1 formulations were adequately described by 2 compartmental model with first-order elimination (postprandial) and dose-dependent relative bioavailability, and no covariates were found to affect the pharmacokinetics of Compound 1 formulations.

The median serum concentrations of LH, FSH and progesterone in the 40 mg compound 1 formulation group declined steadily from early treatment throughout the treatment period in a manner comparable to that of the leuprolide acetate group. The median serum estradiol concentration decreased to below the lower limit of quantitation (LLQ) from week 2 in the 40 mg Compound 1 formulation group and decreased steadily throughout the treatment period. In the leuprolide acetate group, the mean serum estradiol concentration decreased to below the LLQ from week 4 and decreased steadily throughout the treatment period.

The percentage change from baseline in serum CA125 concentration increased in line with the increase in Compound 1 levels. The percentage change in the Compound 1 40 mg formulation group was comparable to that in the leuprolide acetate or leuprorelin group.

In this study, the efficacy and safety of an orally administered formulation of Compound 1 was investigated in patients with endometriosis at doses of 10, 20, and 40 mg for 12 weeks, compared with placebo and leuprolide acetate or leuprorelin as the active reference compound.

When evaluating efficacy against the primary endpoint in this study, change from baseline in mean VAS for pelvic pain at the end of the treatment period, a statistically significant difference was observed between each Compound 1 treatment group and the placebo group. The change from baseline in mean VAS in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group.

The change from baseline in the mean VAS score for each visit for pelvic pain and dysmenorrhea increased with time scores starting early in treatment at higher compound 1 dose levels. bleed rates decreased and the proportion of subjects who achieved amenorrhea increased with time and with compound 1 dose level. , was approximately the same as in the leuprolide acetate group.

The reduction in overall pelvic pain with Compound 1 treatment for 12 weeks is shown in FIG. 157. The mean percentage change from baseline in VAS for total pelvic pain at the end of the treatment period is shown in FIG. 158. The mean percentage change from baseline in VAS for total pelvic pain and dysmenorrhea at the end of the treatment period is shown in FIG. 159. The change from baseline in VAS for generalized pelvic pain, non-menstrual pelvic pain, dysmenorrhea, and dyspareunia for each visit is shown in FIG. 160. The serum concentration (median) of pharmacodynamic markers determined in this example is shown in FIG. 161. The fast onset and fast offset effects on serum estradiol of Compound 1 are shown in FIG. 162.

Based on the results of the efficacy and safety evaluation in this study, it was determined that there were no clinically significant safety concerns with Compound 1 formulations. In addition, based on the results of the efficacy and safety evaluation in this study, 40 mg of Compound 1 was considered to be an effective dose for treatment endometriosis.

Example 8A. Study of the safety of compound 1 in the extension of therapy for the treatment of endometriosis.

This study was an open-label extension study following the study of Example 7 to evaluate the safety and efficacy of a three dose level formulation (10, 20 and 40 mg) of Compound 1 administered orally once a day for a total of 24 weeks. compared with placebo in women with endometriosis. The aim of this phase 2 study was

- 96 041715 evaluation of the safety of compound 1 when administered for 24 weeks in women with pain associated with endometriosis. In addition, the pharmacokinetic and pharmacodynamic effects of Compound 1 formulation were evaluated. Leuprolide acetate (Leuplin® or leuprorelin) was used as a reference to study the clinical context of Compound 1 formulation.

Study participants were premenopausal Japanese women (>20 years) with pain associated with endometriosis (EM) who had completed a prior 12-week study and were eligible for a further 12-week treatment period. Participants had confirmed normal regular menstrual cycles (25 to 38 day cycle) and were diagnosed with EM and EM-associated dysmenorrhea and at least moderate pelvic pain as defined by a physician's B&B scale. The primary endpoint was safety, including changes in bone mineral density (BMD) using dual-energy x-ray absorptiometry, adverse events, vital signs, weight, 12-lead electrocardiogram, and clinical laboratory tests. Analysis populations were defined as all patients treated with Compound 1. The secondary endpoint was 24 weeks of efficacy, including visual analog scale (VAS) scores for pelvic pain, dysmenorrhea, and dyspareunia at the end of treatment, defined as 28 days until the end of treatment (VAS 0 = no pain; 100 = pain as severe as possible). Data from a previous phase 2 study were pooled with data from the current extension study to analyze the safety, efficacy, and pharmacodynamics of 24 weeks of compound 1 administration. Of the randomized patients in the previous study (N = 487), 397 were enrolled in this extension study; 77 - in the placebo group, 78-89 - in the compound 1 groups, 69 - in the leuprorelin group. Baseline characteristics were similar in randomized patients and in all patients who entered the extension study. Overall, there were no significant differences in demographic and baseline characteristics between treatment groups (Table 7).

Table 7

Demographic and background characteristics

Characteristics Placebo (#99) 10 mg(#103) Relugolix 20 mg(#100) 40 mg(#103) Leiproreli n (#82) Age (in years) 35.7 (6.06) 35.3 (6.22) 35.1 (6.78) 35.6 (6.04) 36.1 (6.13) BMI (kg / m ² ) ¹ 21.1 (3.01) 21.5 (3.35) 20.4 (2.46) 21.6 (3.14) 21.8 (3.40) Disease duration (years) 3.9 (4.65) 3.8 (5.04) 3.2 (3.84) 4.3 (5.47) 2.9 (3.78) Average VAS [mm] ² Pelvic pain (general) ¹ 15.6 (14.32) 14.6 (11.99) 15.6 (15.06) 15.3 (11.99) 15.2 (15.10) Dysmenorrhea ¹ 28.4 (16.59) 28.2 (17.64) 27.7 (18.94) 30.4 (17.04) 27.1 (19.78) Dyspareunia ³ 11.0 (14.25) 8.8 (14.24) 12.5 (16.48) 9.4 (15.42) 9.5 (10.71) Modified B&B Mean (Patient Rating) Non-menstrual pelvic pain ¹ 0.6 (0.45) 0.7 (0.46) 0.6 (0.47) 0.7 (0.44) 0.7 (0.55) Dysmenorrhea ¹ 1.2 (0.44) 1.2 (0.47) 1.2 (0.48) 1.2 (0.47) 1.2 (0.47) Dyspareunia ³ 0.6 (0.45) 0.6 (0.60) 0.6 (0.55) 0.5 (0.48) 0.6 (0.45) Proportion of days using analgesics (%) ¹ 10.0 (11.55) 12.5 (12.32) 13.3 (16.43) 12.0 (14.53) 11.6 (13.84)

Note. Mean value (Co) or n number of patients (%).

*: N=103, N=100, and N=103 in the relugolix group, the groups treated with

10, 20 and 40 mg, respectively, and N=81 in the leuprorelin group and N=97 in the placebo group.

² Mean VAS from baseline: Mean VAS during the placebo run-in period.

³ N=46, N=47, and N=44 in the relugolix, 10 and 40 mg groups, respectively, and N=26 in the leuprorelin group and N=41 in the placebo group.

As noted in Example 7, the (previous phase 2 study) consisted of a pre-treatment period of 4 to 12 weeks with a placebo run-in period that began during the first menstrual cycle and continued until randomization, and a treatment period of 12 weeks. The current extension study consisted of an additional treatment period of 12 weeks and a follow-up period of 4 weeks. General

- 97 041715 treatment duration was 24 weeks from the start of the previous phase 2 study. Patients were assigned to the same treatment arm as in the previous phase 2 study. Study arms included Compound 1 10 mg, 20 mg, 40 mg, placebo once a day day orally or leuprorelin 3.75 mg (injection once every 4 weeks).

The frequency of adverse events, including metrorrhagia, menorrhagia and hot flashes, in the 40 mg compound 1 group was similar to that in the leuprorelin group. A dose-dependent loss of bone mineral density was observed with Compound 1 treatment, with the result of a 40 mg dose of Compound 1 consistent with that of leuprorelin. The change from baseline in the mean visual analogue scale for pelvic pain (in mm) during the last 4 weeks of the treatment period was -3.222 in the placebo group, -6.849, -9.032 and -11.924 in the groups treated with 10, 20 and 40 mg of Compound 1, respectively, and -12.552 in the leuprorelin group. Estradiol levels decreased with increasing dose of compound 1 and were maintained below postmenopausal levels during the 24-week treatment period using 40 mg of compound 1. Treatment with compound 1 for 24 weeks was generally well tolerated and showed the same reduction in pelvic pain, as leuprorelin in women with EM. Compound 1, a once-daily, non-peptide GnRH receptor antagonist, showed a similar benefit to injectable leuprorelin in this Phase 2 study. pelvis and dysmenorrhea compared with placebo treatment and was generally well tolerated according to its mechanism of action (Table 8).

Table 8

Summary table of adverse events (AEs)

Variables, N (%) Placebo (N=97) 10 mg (#103) 20 mg (#100) 40 mg (#103) Leuprorelin (N = 81) Any NAEPL 79 (81.4) 89 (86.4) 96 (96.0) 98 (95.1) 79 (97.5) Light 68 [70.1] 83 (80.6) 82 (82.0) 83 (80.6) 65 (80.2) Medium 9 (9.3) 6 (5.8) 14 (14.0) 15 (14.6) 14 (17.3) strong 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) NAEPNL related to study drug 38 (39.2) 68 (66.0) 88 (88.0] 91 (88.3) 73 (90.1) NAEPNL leading to discontinuation of study drug 6 (6.2) 1 (1.0) 7 (7.0) 2 (1.9) 9 (11.1) Serious AEDL 5 (5.2) 0 (0.0) 2 (2.0) 0 (0.0) 0 (0.0) Common NAEPNL (>10% of patients in any group) N azopharyngitis 32 (33.0) 31 (30.1) 31 (31.0) 31 (30.1) 26 (32.1) Headache 10 (10.3) 5 (4.9) 12 (12.0) 11 (10.7) 11 (13.6) metrorrhagia 8 (8.2) 28 (27.2) 36 (36.0) 30 (29.1) 32 (39.5) Irregular menstruation 5 (5.2) 21 (20.4) 21 (21.0) 7(6.8) 5 (6.2) menorrhagia 5 (5.2) 11 (10.7) 16 (16.0) 15 (14.6) 9(11.1) Oligomenorrhea 2 (2.1) 12 (11.7) 12 (12.0) 1 (th) 0 (0.0) Hyperhidrosis 1 (1.0) 4 (3.9) 11 (11.0) 10 (9.7) 11 (13.6) high tide 8 (8.2) 12 (11.7) 23 (23.0) 55 (53.4) 38 (46.9)

Note. An adverse event was defined as any adverse medical event occurring during or after the first dose and up to the end of the study. If a patient reported one or more events, they were counted once.

The incidence of treatment-related adverse events (TEAEs), including metrorrhagia, menorrhagia, and hot flashes, was similar in the 40 mg Compound 1 (relugolix) group to that in the leuprorelin group. Compound 1 groups experienced a time- and dose-dependent decrease in bone mineral density from baseline. The reduction in bone mineral density in the 40 mg Compound 1 group was the same as in the leuprorelin group (Table 9). The recovery period for menstruation ranged from 21 to 37 days after the last dose in the Compound 1 groups, and the recovery period in the leuprorelin group was approximately twice that of the 40 mg Compound 1 group (Table 9). There were no clinically significant changes in treatment groups in terms of laboratory test results, vital signs, weight, or ECG parameters, and no pregnancy occurred during the study.

- 98 041715

Table 9

Other security endpoints

end point placebo 75 Compound 1 Leuprorelin 64 10 mg 81 20 mg 77 40 mg 88 Change by N compared to original IPC value Average -0.2 -1.6 -2.6 -4.9 -4.4 at 24 weeks (CO) (1.99) (2.34) (2.94) (2.91) (2.16) (%) Period N 93 103 95 97 72 recovery menses Average 17 21 26 37 73 (days) (CO) (8.5) (12.3) (13.0) (9.5) (21.2)

BMD - bone mineral density; SD - standard deviation.

Plasma concentrations of unchanged Compound 1 were at higher levels at 0.5-1.5 or 2-5 hours after administration in all treatment groups and increased with increasing dose among the 10, 20 and 40 mg doses of Compound 1. pre-administration plasma levels at each visit (trough values) were consistent with Compound 1 dose levels and were comparable across each treatment group over a treatment period of 24 weeks, demonstrating a dose-proportional trend in Compound 1 plasma concentrations following oral administration, namely reaching steady state as early as 2 weeks after administration and no change in PK aspects with long-term administration of Compound 1 formulation for 24 weeks. Plasma concentrations of unchanged Compound 1 over a 24 week treatment period are plotted in FIG. 70 and in tabular form in FIG. 71.

When plasma concentrations of unchanged compound 1 were separately tabulated for subjects who could not receive study drug 30 minutes before a meal, plasma concentrations of unchanged compound 1 were lower than those who received study drug 30 minutes before a meal. . Plasma concentrations of unchanged Compound 1 over a 24 week treatment period in which Compound 1 was administered 30 minutes before meals are graphically depicted in FIG. 72 and in tabular form in FIG. 73, and in which Compound 1 was not administered 30 minutes before a meal, are graphically depicted in FIG. 74 and in tabular form in FIG. 75.

Plasma absorption of Compound 1 was reduced and delayed following a single dose administered 30 minutes after the start of a standard (FDA) high-calorie, high-fat breakfast (about 800- 1000 calories, 50% from fat), compared to fasted conditions. The median value of T _max increases in post-meal conditions. Mean _Cmax and mean plasma AUC^ were reduced under postprandial conditions compared to fasted conditions, indicating a clinically significant effect of food on the oral bioavailability of Compound 1 formulation. In this study, Compound 1 formulation was administered daily 30 minutes prior to ingestion. standardized morning meal (about 600 calories, 27% fat). Under these conditions, the systemic exposure of compound 1 formulation was reduced to a lesser extent, and no apparent change in absorption rate was observed compared to fasted conditions. Therefore, in the studies, subjects were instructed to take the Compound 1 formulation upon waking in the morning on an empty stomach and begin eating approximately 30 minutes post-dose, whenever possible.

Serum LH concentrations over a 24 week treatment period are plotted in FIG. 77 and in tabular form in FIG. 78A-B. A table of demographic and baseline characteristics for the assays in this example is shown in FIG. 76A-C. The median change in serum LH concentrations at week 24 from baseline was 0.945 mIU/mL in the placebo group, 0.300 mIU/mL in the 10 mg compound 1 formulation group, -0.785 mIU/mL in the 20 mg formulation group compound 1, -2.480 mIU/ml in the 40 mg compound 1 formulation group, and -3.140 mIU/ml in the leuprolide acetate group. Serum LH concentrations were lower in the 40 mg Compound 1 formulation groups over the treatment period, as in the leuprolide acetate group.

Serum FSH concentrations over a 24 week treatment period are plotted in FIG. 79 and in tabular form in FIG. 80A-B. The median change in serum FSH concentrations at week 24 from baseline was -0.985 mIU/mL in the placebo group, -0.630 mIU/mL in the 10 mg Compound 1 formulation group, -0.990 mIU/mL in the formulation with 20 mg Compound 1, and -3.550 mIU/mL in the 40 mg Compound 1 formulation group and -2.730 mIU/mL in the leuprolide acetate group. Serum FSH concentrations were lower in the compound 1 40 mg formulation group over the treatment period. The leuprolide acetate group showed a similar but slightly higher profile than the 40 mg Compound 1 formulation group.

- 99 041715

Serum estradiol (E2) concentrations over a 24 week treatment period are plotted in FIG. 81 and in tabular form in FIG. 82A-B. The median change in serum E2 concentrations at week 24 from baseline was 56.0 pg/mL in the placebo group, 1.0 pg/mL in the 10 mg Compound 1 formulation group, -9.0 pg/mL in the group , receiving the formulation with 20 mg of compound 1, 39.0 pg/ml in the group receiving the formulation with 40 mg of compound 1, and -40.0 pg/ml in the group receiving leuprolide acetate. Serum E ₂ concentrations were lower in the dose-dependent manner of compound 1 formulations over the treatment period. In the compound 1 40 mg formulation group, the median serum E ₂ concentration decreased to 0.0 pg/mL (below the lower limit of quantitation: LLQ) at week 2 and was maintained below the lower limit of quantitation (LLQ) thereafter. ) up to 24 weeks. In the leuprolide acetate group, the median serum E2 concentration decreased to the LLQ level at week 4 and was then maintained at the LLQ level until the 24th week. Serum P concentrations over a 24 week treatment period are plotted in FIG. 83 and in tabular form in FIG. 84A-B. The median change in serum progesterone (P) concentrations at week 24 from baseline was 0.110 ng/ml in the placebo group, 0.000 ng/ml in the 10 mg Compound 1 formulation group, 0.005 ng/ml in the formulation with 20 mg Compound 1, and -0.080 ng/ml in the 40 mg Compound 1 formulation group, and -0.070 ng/ml in the leuprolide acetate group. Serum P concentration was slightly lower in the Compound 1 formulation groups than in the placebo group over the treatment period, as in the leuprolide acetate group.

The percentage change from baseline in endometriosis biochemical marker (CA125) concentrations over a 24 week treatment period is tabulated in FIG. 86. Percentage change from baseline in the concentration of the biochemical biomarker for the effectiveness of endometriosis (CA125) at week 24 (mean ± SD) was -14.01±55.858% in the placebo group, -39.08±41.893% in the group receiving the composition with 10 mg Compound 1, -46.24±33.099% in the 20 mg formulation group of Compound 1, -56.69±45.139% in the 40 mg Compound 1 formulation group, and -54.15±46.359% in the leuprolide acetate group, respectively. Greater changes in CA125 concentration at higher dose levels of Compound 1 formulation were observed early in the administration. The change in the 40 mg compound 1 formulation group was also comparable to that in the leuprolide acetate group. The proportion of subjects whose CA125 concentration was less than or equal to 35 U/ml at week 24 was 54.8%, 75.3%, 81.1%, 88.5% and 88.9% in the placebo group, groups, 10 mg Compound 1 formulation, Compound 1 20 mg formulation, Compound 1 40 mg formulation, and the leuprolide acetate group, respectively. Concentrations of a biochemical marker of endometriosis (CA125) over a 24 week treatment period are tabulated in FIG. 85.

The change from baseline in the mean VAS scores for pelvic pain at the end of the treatment period was -3.222±12.1616 mm in the placebo group, -6.849±10.5616 mm in the 10 mg Compound 1 formulation group, -9.032 ±11.8432 mm in the 20 mg compound 1 formulation group, -11.924 ± 11.2609 mm in the compound 1 40 mg formulation group, and -12.552 ± 12.5609 mm in the leuprolide acetate group, and were higher at higher dose levels of Compound 1 formulations as a function of time over a 24 week treatment period. Scores for dysmenorrhea were also higher at higher dose levels of Compound 1 formulation as a function of time throughout the treatment period. The changes and profiles of the VAS score for pelvic pain and dysmenorrhea in the 40 mg Compound 1 formulation group were the same as in the leuprolide acetate group.

The mean VAS scores for each visit for pelvic pain over a treatment period of 168 days are plotted in FIG. 87 and in tabular form in FIG. 88. In addition, while the mean VAS score for pelvic pain at baseline was about 15 mm in each treatment group, the mean VAS score (mean ± SD) on days 1-28, days 57-84, days 141-168 and at the end of the treatment period was 13.315±13.1953 mm, 11.776±13.5443 mm, 10.444±12.3696 mm, and 12.387±12.7540 mm, respectively, in the placebo group; 9.988±10.3249 mm, 8.400±10.1329 mm, 6.861±9.2099 mm, and 7.746±9.0900 mm in the 10 mg compound 1 formulation group;

11.627±14.7324 mm, 6.675±10.8072 mm, 5.486±9.1562 mm and 6.557±11.2902 mm in the 20 mg compound 1 formulation group; 11.498±13.2341 mm, 4.785±8.9162 mm, 2.979±6.1704 mm and 3.335±6.4059 mm in the 40 mg compound 1 formulation group; and 10.899±14.8866 mm, 5.013±12.0454 mm, 2.167±5.1999 mm, and 2.629±5.5783 mm in the leuprolide acetate group.

Changes from baseline in the mean VAS for pelvic pain on days 1-28, days 57-84, days 141-168 and at the end of the treatment period were -2.294±8.9903 mm, -3.945±10.7499 mm , -4.866±12.4477 mm and -3.222±12.1616 mm, respectively, in the placebo group; -4.606±7.1304 mm, -6.282±9.1659 mm, -7.872±11.2457 mm and -6.849±10.5616 mm in the 10 mg compound 1 formulation group; -3.962±6.6751 mm, -8.547±13.8568 mm, -8.678±10.6479 mm, and -9.032±11.8432 mm in the 20 mg compound 1 formulation group; -3.761±7.8831 mm, -10.537±11.0516 mm, -12.919±11.8210

- 100041715 mm and -11.924±11.2609 mm in the group treated with 40 mg compound 1 formulation; and -4.282±7.3628 mm, -10.364±10.4428 mm, -13.804±12.8288 mm, and -12.552±12.5609 mm in the leuprolide acetate group. The change from baseline in mean VAS scores for each visit for pelvic pain over a treatment period of 168 days is graphically depicted in FIG. 89 and in tabular form in FIG. 90. Changes from baseline in mean VAS scores for each visit (versus leuprolide acetate) for pelvic pain over a treatment period of 168 days are tabulated in FIG. 91.

Changes from baseline in mean VAS scores for pelvic pain were greater at higher dose levels of Compound 1 formulation as a function of time over the treatment period. The VAS profile for pelvic pain in the 40 mg Compound 1 formulation group was similar to that in the leuprolide acetate group.

The mean VAS scores for each visit for dyspareunia over a treatment period of 168 days are plotted in FIG. 92 and in tabular form in FIG. 93. While the mean VAS score for dyspareunia at baseline was 8.8-12.5 mm in each treatment group, the mean VAS score (mean±SD) on days 1-28, days 57-84, days 141-168 and at the end of the treatment period were 10.676±16.5317 mm, 11.445±15.5573 mm, 9.192±12.7469 mm, and 11.318±15.7393 mm, respectively, in the placebo group; 9.608±15.4027 mm, 10.110±18.5404 mm, 5.550±11.1157 mm and 6.218±10.6280 mm in the 10 mg compound 1 formulation group; 10.809±15.5738 mm, 9.229±16.6530 mm, 3.806±8.9781 mm and 6.363±13.1847 mm in the 20 mg compound 1 formulation group; 9.522±13.6408 mm, 4.126±7.9652 mm, 3.531±9.6053 mm and 4.842±9.1145 mm in the 40 mg compound 1 formulation group; and 7.288±16.2960 mm, 5.478±10.7612 mm, 5.565±12.5556 mm, and 4.913±10.6249 mm in the leuprolide acetate group.

Changes from baseline in mean VAS for dyspareunia on days 1-28, days 57-84, days 141-168 and at the end of the treatment period were -1.464±6.1084 mm, -5.018±14.8372 mm, -3.256 ±15.8951 mm and -1.145±12.6625 mm, respectively, in the placebo group; 1.642±10.6212 mm, -1.033±12.2047 mm, -4.124±10.5641 mm and -3.454±10.8509 mm in the 10 mg compound 1 formulation group; 0.953±12.3795 mm, -0.191±10.6032 mm, -4.012±12.5050 mm and -3.553±11.5544 mm in the 20 mg compound 1 formulation group; 2.995±9.7916 mm, -1.860±10.3161 mm, -0.830±13.6774 mm and -0.925±12.0373 mm in the 40 mg compound 1 formulation group; and -3.126±17.0520 mm, -6.752±10.5824 mm, -4.953±16.9523 mm, and -4.593±15.0878 mm in the leuprolide acetate group. The change from baseline in the mean VAS for each visit for dyspareunia over a treatment period of 168 days is graphically depicted in FIG. 94 and in tabular form in FIG. 95. Changes from baseline in mean VAS for each visit (versus leuprolide acetate) for dyspareunia over a treatment period of 168 days are tabulated in FIG. 96.

The mean VAS scores for each visit for dysmenorrhea over a treatment period of 168 days are plotted in FIG. 91 and in tabular form in FIG. 98. While the mean baseline VAS for dysmenorrhea in each treatment group was 27 to 30 mm, the mean VAS (mean±SD) on days 1-28, days 57-84, days 141-168 and at the end of the treatment period was 23.832±17.8381 mm, 21.728±18.3520 mm, 18.797±14.8825 mm and 22.607±17.5557 mm, respectively, in the placebo group; 17.556±17.0427 mm, 13.568±15.5954 mm, 11.758±15.4431 mm and 12.857±15.0429 mm in the 10 mg compound 1 formulation group; 18.545±19.2141 mm, 6.626±13.5146 mm, 6.132±13.2012 mm and 7.878±14.2406 mm in the 20 mg compound 1 formulation group; 19.452±19.1065 mm, 0.569±2.5367 mm, 0.430±2.3141 mm and 0.918±4.3438 mm in the 40 mg compound 1 formulation group; and 17.133±19.4179 mm, 0.000±0.0000 mm, 0.000±0.0000 mm, and 0.174±1.1623 mm in the leuprolide acetate group.

Changes from baseline in the mean VAS for dysmenorrhea at days 128, days 57-84, days 141-168 and at the end of the treatment period were -4.547±16.4741 mm, -6.857±15.8099 mm, -8.676±16 .4615 mm and -5.772±17.1295 mm, respectively, in the placebo group; -10.657±17.0824 mm, -14.747±16.8648 mm, -15.191±17.6754 mm and -15.356±18.0506 mm in the 10 mg compound 1 formulation group; -9.158±16.6375 mm, -20.689±21.4387 mm, -19.860±19.1617 mm and -19.825±20.4332 mm in the 20 mg compound 1 formulation group; -10.979±14.8545 mm, -30.094±17.2623 mm, -31.210±17.7668 mm and -29.513±17.5379 mm in the 40 mg compound 1 formulation group; and -9.985±15.7027 mm, -27.558±19.9878 mm, -28.373±20.7287 mm, and -26.944±19.9212 mm in the leuprolide acetate group. The change from baseline in the mean VAS for each visit for dysmenorrhea over a treatment period of 168 days is graphically depicted in FIG. 99 and in tabular form in FIG. 100. Changes from baseline in mean VAS for each visit (versus leuprolide acetate) for dysmenorrhea over a treatment period of 168 days are tabulated in FIG. 101.

As noted, for pelvic pain, changes from baseline in mean VAS for dysmenorrhea were greater at higher compound 1 dose levels as a function of time over the treatment period. Profile of VAS scores for dysmenorrhea in

- 101 041715 the 40 mg compound 1 formulation was also comparable to that of the leuprolide acetate group.

For pelvic pain, changes from baseline in peak VAS (mean ± SD) at the end of the treatment period were -8.1 ± 27.50 mm in the placebo group, -24.0 ± 27.54 mm in the treated group. formulation with 10 mg of compound 1, -33.3 ± 30.14 mm in the group receiving the formulation with 20 mg of compound 1, -49.7 ± 26.47 mm in the group receiving the formulation with 40 mg of compound 1, and -46 .8±26.29 mm in the leuprolide acetate group. The same values for dysmenorrhea were -9.3 ± 30.27 mm in the placebo group, -26.4 ± 27.37 mm in the group receiving the composition with 10 mg of compound 1, -39.1 ± 34.29 mm in the group , receiving the formulation with 20 mg of compound 1, -57.1 ± 25.00 mm in the group receiving the formulation with 40 mg of compound 1, and -51.8 ± 27.01 mm in the group of leuprolide acetate. Changes from baseline in pelvic pain and dysmenorrhea were greater at higher compound 1 dose levels throughout the treatment period. The VAS profile of the Compound 1 40 mg formulation group was also comparable to that of the leuprolide acetate group.

Changes from baseline in the maximum VAS scores for dyspareunia at the end of the treatment period were -5.1 ± 16.63 mm in the placebo group, -4.2 ± 16.30 mm in the group receiving the composition with 10 mg of compound 1, - 7.0 ± 15.29 mm in the 20 mg compound 1 formulation group, -2.5 ± 17.17 mm in the 40 mg compound 1 formulation group, and -10.3 ± 19.76 mm in leuprolide acetate group.

For pelvic pain, the change from baseline in the proportion of days without pain in terms of VAS (mean ± SD) at the end of the treatment period was 12.82±26.535% in the placebo group, 17.90±24.924% in the formulation group with 10 mg Compound 1, 21.50±28.859% in the 20 mg Compound 1 formulation group, 36.59±34.849% in the 40 mg Compound 1 formulation group, and 40.70±33.342% in the acetate group leuprolide. The same rates for dysmenorrhea were 13.48±34.975% in the placebo group, 29.28±43.277% in the group treated with 10 mg compound 1, 50.91±42.602% in the group treated with 20 mg compound 1, 78.45±29.838% in the compound 1 40 mg formulation group and 82.09±24.051% in the leuprolide acetate group.

Changes from baseline in the proportion of pain-free days in VAS scores for pelvic pain were greater at higher Compound 1 dose levels as a function of time over the treatment period. The VAS profile for pelvic pain in the 40 mg Compound 1 formulation group was similar to that in the leuprolide acetate group.

Compared with cases of dysmenorrhea and/or pelvic pain, the change from baseline in the proportion of days without pain in VAS scores for dyspareunia at the end of the treatment period was 6.29±36.617% in the placebo group, 9.72±38.401% in 10 mg Compound 1 formulation group 15.14±47.793% Compound 1 20 mg formulation group 4.50±40.796% Compound 1 40 mg formulation group and 21.76±43.266 % in the leuprolide acetate group.

For pelvic pain, the percentage of subjects without pain on VAS scores at the end of the treatment period was 0.0, 6.8, 20.0, 49.5, and 56.8% in the placebo group, formulation groups with 10, 20, 40 mg of compound 1, and the leuprolide acetate group, respectively. A higher percentage of subjects were observed at higher dose levels of Compound 1 formulation. The percentage profile in the Compound 1 40 mg formulation group was comparable to that in the leuprolide acetate group.

The percentage of subjects without pain on VAS scores for dysmenorrhea at the end of the treatment period was 5.2, 27.2, 59.0, 93.2, and 97.5%, respectively. A higher percentage of subjects were observed at higher dose levels of compound 1 formulation throughout the treatment period. The percentage profile in the 40 mg Compound 1 formulation group was also comparable to that in the leuprolide acetate group.

The percentage of subjects without pain on VAS scores for dyspareunia at the end of the treatment period was 38.9%, 48.0%, 47.5%, 48.7%, and 56.5%, respectively.

For pelvic pain, changes from baseline in mean MB&B (mean±SD) at the end of the treatment period were -0.172±0.3851 in the placebo group, -0.260±0.3624 in the 10 mg Compound 1 formulation group , -0.268±0.3913 in the 20 mg compound 1 formulation group, -0.400±0.4491 in the 40 mg compound 1 formulation group, and -0.483±0.4860 in the leuprolide acetate group, respectively. The same values for dysmenorrhea were -0.185 ± 0.5491 in the placebo group, -0.509 ± 0.6675 in the group receiving the formulation with 10 mg of compound 1, -0.795 ± 0.6490 in the group receiving the formulation with 20 mg of compound 1, -1.144 ± 0.5014 in the compound 1 40 mg formulation group and -1.160 ± 0.4802 in the leuprolide acetate group, respectively, and for profound dyspareunia were -0.003 ± 0.3796 in the placebo group, -0.171 ± 0 .4683 in the 10 mg compound 1 formulation group, -0.210±0.4936 in the 20 mg compound 1 formulation group, -0.097±0.4325 in the 40 mg compound 1 formulation group, and -0.208±0 .5604 in the leuprolide acetate group, respectively.

Mean M-B&B scores over a treatment period of 168 days are tabulated in FIG. 102 for pain

- 102 041715 in the pelvis, in Fig. 103 for dysmenorrhea and in FIG. 104 for deep dyspareunia.

Changes from baseline to mean M-B&B over a treatment period of 168 days are tabulated: FIG. 105 for pelvic pain, FIG. 106 for dysmenorrhea and in FIG. 107 for deep dyspareunia.

Changes from baseline to mean M-B&B (vs. leuprolide acetate) over a treatment period of 168 days are tabulated: FIG. 108 for pelvic pain, FIG. 109 for dysmenorrhea and in FIG. 110 for deep dyspareunia.

As noted in the VAS scores, changes from baseline in M-B&B for pelvic pain and dysmenorrhea were greater at higher dose levels of compound 1 formulation as a function of time throughout the treatment period. The change and profile of M-B&B scores in the compound 1 40 mg formulation group were also comparable to those in the leuprolide acetate group.

Changes from baseline in peak M-B&B scores (mean ± SD) for pelvic pain at the end of the treatment period were -0.4 ± 0.87 in the placebo group, -0.7 ± 0.94 in the treated group. formulation with 10 mg of Compound 1, -0.7 ± 0.79 in the group receiving formulation with 20 mg of Compound 1, -1.0 ± 0.89 in the group receiving formulation with 40 mg of Compound 1, and -1.3 ±0.82 in the leuprolide acetate group, respectively. The same values for dysmenorrhea were -0.2 ± 0.86 in the placebo group, -0.7 ± 1.01 in the group receiving the formulation with 10 mg of compound 1, -1.4 ± 1.12 in the group receiving the formulation with 20 mg of Compound 1, -2.0 ± 0.76 in the group receiving the formulation with 40 mg of Compound 1, and -1.9 ± 0.69 in the leuprolide acetate group, respectively. The 40 mg Compound 1 formulation group experienced a response comparable to that of the leuprolide acetate group. The change from baseline in peak M-B&B scores at the end of the treatment period for dyspareunia was 0.0±0.57 in the placebo group, -0.2±0.69 in the Compound 1 10 mg formulation group, -0, 3±0.59 in the 20 mg compound 1 formulation group, -0.1±0.54 in the 40 mg compound 1 formulation group, and -0.4±0.78 in the leuprolide acetate group.

For pelvic pain, the change from baseline in the proportion of days without pain in terms of M-B&B (mean ± SD) at the end of the treatment period was 12.98±27.490% in the placebo group, 17.18±26.101% in the 10 mg formulation of Compound 1, 17.75±30.339% in the 20 mg formulation of Compound 1 group, 31.00±36.746% in the 40 mg Compound 1 formulation group, and 33.42±34.007% in leuprolide acetate group. The same rates for dysmenorrhea were 13.75±34.741% in the placebo group, 29.55±42.700% in the group receiving the formulation with 10 mg of Compound 1, 50.92±41.641% in the group receiving the formulation with 20 mg of Compound 1, 73.98±29.567% in the compound 1 40 mg formulation group and 80.29±23.327% in the leuprolide acetate group.

Changes from baseline in the proportion of days without pain in terms of M-B&B for dysmenorrhea were more significant at higher dose levels of Compound 1 formulation as a function of time throughout the treatment period. The same scores for pelvic pain were also greater at higher dose levels of Compound 1 formulation, but were less than those for dysmenorrhea. The change and profile of M-B&B scores in the 40 mg Compound 1 formulation group were the same as in the leuprolide acetate group.

Compared with cases of dysmenorrhea and pelvic pain, the change from baseline in the proportion of days without pain on M-B&B scores for profound dyspareunia at the end of the treatment period was 1.69±35.861% in the placebo group, 8.32±35.972% in the 10 mg compound 1 formulation group, 18.04±47.892% in the 20 mg compound 1 formulation group, 8.15±43.207% in the 40 mg compound 1 formulation group, and 21.76± 43.266% in the leuprolide acetate group.

With respect to pelvic pain, the percentage of subjects without pain on M-B&B scores at the end of the treatment period was 18.6%, 24.3%, 34.0%, 52.4%, and 63.8% in the placebo group, in the formulation group with 10 mg of Compound 1, in the group receiving the formulation with 20 mg of Compound 1, in the group receiving the formulation with 40 mg of Compound 1, and in the group of leuprolide acetate, respectively. The same figures for dysmenorrhea were 6.2, 27.2, 61.0, 93.2 and 97.5%, respectively.

With respect to dysmenorrhea, the percentage of subjects without pain on M-B&B scores at the end of the treatment period was higher at higher dose levels of Compound 1 formulation. The percentage profile in the Compound 1 40 mg formulation group was comparable to that in the leuprolide acetate group. . The same scores for pelvic pain were also higher at higher dose levels of Compound 1 formulation, but were lower than those for dysmenorrhea.

The percentage of subjects without pain on M-B&B scores for dyspareunia at the end of the treatment period was 38.9%, 56.0%, 52.5%, 51.3%, and 56.5%, respectively.

The change from baseline in the mean B&B (mean±SD) for dysmenorrhea at week 24 was -0.3±0.64 in the placebo group, -1.0±0.87 in the 10 mg formulation group 1, -1.5±0.94 in the 20 mg compound 1 formulation group, -2.0±0.61 in the 40 mg compound 1 formulation group, and -2.1±0.49 in the leuprolide acetate group, respectively.

- 103 041715

The same scores in the placebo group, the 10 mg compound 1 formulation group, the 20 mg compound 1 formulation group, the 40 mg compound 1 formulation group, and the leuprolide acetate group were -0.2± 0.83, -0.3±0.67, -0.4±0.70, -0.1±0.43 and -0.5±0.88, respectively, for dyspareunia, -0.6± 0.85, -0.8±0.79, -0.9±0.85, -1.0±0.86 and -1.2±0.72 for pelvic pain, -0.6± 0.74, -0.7±0.83, -0.8±0.79, -1.0±0.92 and -1.1±0.78 for pelvic sensitivity and -0.5±0, 72, -0.6±0.81, -0.7±0.85, -0.8±0.81 and -0.8±0.82 for induration.

Mean B&B scores for each visit over a 24 week treatment period are tabulated: FIG. 111 for dysmenorrhea, in FIG. 112 for dyspareunia, in FIG. 113 for pelvic pain, FIG. 114 for pelvic tenderness and in FIG. 115 for induration.

The change from baseline in mean B&B for each visit over a 24 week treatment period is tabulated: FIG. 116 for dysmenorrhea, in FIG. 117 for dyspareunia for dyspareunia, FIG. 118 for pelvic pain, FIG. 119 for pelvic tenderness and in FIG. 120 for induration.

The proportion of subjects without pain on B&B scores for dysmenorrhea at week 24 was 1.5% in the placebo group, 27.8% in the 10 mg compound 1 formulation group, 64.9% in the 20 mg compound 1 formulation group , 94.3% in the 40 mg compound 1 formulation group and 100% in the leuprolide acetate group, respectively. A higher percentage of subjects were observed at higher dose levels of compound 1 formulation throughout the treatment period. The percentage profile in the 40 mg Compound 1 formulation group was also comparable to that in the leuprolide acetate group.

The proportion of subjects without pain on B&B scores for pelvic pain was 27.9, 30.4, 39.2, 58.6, and 68.9%, respectively, and 42.9, 63.9, 53.6, 56 .7 and 70.6% for dyspareunia, 30.9, 35.4, 37.8, 57.5 and 70.5% for pelvic tenderness and 33.8, 53.2, 44.6, 57.5 and 75.4% for induration. There appeared to be no clear dose-related or time-dependent changes in the composition percentage of Compound 1.

The change from baseline in the proportion of days with pain medication at the end of the treatment period (mean±SD) was -0.60±10.251% in the placebo group, -6.32±9.817% in the compound 10 mg formulation group 1, -7.36±14.585% in the 20 mg compound 1 formulation group, -9.95±14.214% in the 40 mg compound 1 formulation group, and -10.06±13.063% in the leuprolide acetate group . A lower percentage of days with painkiller use from early on was noted with dose-dependent decline profiles. The percentage profile in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group. The proportion of days with pain medication over a treatment period of 168 days is tabulated in FIG. 121. Changes from baseline in the proportion of days with pain medication over a treatment period of 168 days are tabulated in FIG. 122. Changes from baseline in the proportion of days with pain medication (versus leuprolide acetate) over a treatment period of 168 days are tabulated in FIG. 123.

The change from baseline in the mean Bleeding Count (self-reported amount, rated from 0 to 5) at the end of the treatment period (mean ± SD) was -0.056 ± 0.7274 in the placebo group, -0.529 ± 1, 2185 in the 10 mg compound 1 formulation group, -1.264±1.3280 in the 20 mg compound 1 formulation group, -2.207±0.8149 in the 40 mg compound 1 formulation group, and -2.320± 0.7281 in the leuprolide acetate group. Stronger changes in the amount of blood on bleeding at higher dose levels of the compound 1 formulation were observed throughout the treatment period. The percentage profile in the 40 mg compound 1 formulation group was similar to that in the leuprolide acetate group. The mean amount of blood on bleeding over a treatment period of 168 days is tabulated in FIG. 124. Changes from baseline in mean bleeding over a treatment period of 168 days are tabulated in FIG. 125. Changes from baseline in mean bleeding (versus leuprolide acetate) over a treatment period of 168 days are tabulated in FIG. 126.

The percentage of subjects achieving amenorrhea at the end of the treatment period was 4.1%, 22.3%, 54.0%, 91.3%, and 97.5% in the placebo group, in the group receiving the 10 mg compound 1 formulation, in the group receiving formulation with 20 mg of Compound 1, in the group receiving the formulation with 40 mg of Compound 1, and the leuprolide acetate group, respectively. A higher percentage of subjects achieving amenorrhea was observed at higher dose levels of Compound 1 formulation. The percentage profile in the Compound 1 40 mg formulation group was comparable to that in the leuprolide acetate group. The number of subjects who achieved amenorrhea during a treatment period of 168 days is tabulated in FIG. 127A-B. The proportion of subjects who achieved amenorrhea (versus leuprolide acetate) over a treatment period of 168 days is tabulated in FIG. 128.

Subjects assessed and recorded their own quality of life (QOL) using the EHP-30 scale,

- 104 041715 once a month during the study visit.

Changes from baseline in the EHP-30 pain score at week 24 (mean±SD) were -5.41±18.421 in the placebo group, -16.98±20.286 in the Compound 1 10 mg formulation, -20 .58±19.650 in the 20 mg compound 1 formulation group, -25.94±19.902 in the compound 1 40 mg formulation group, and -26.38±20.341 in the leuprolide acetate group, respectively. During the treatment period, a more significant change in EHP-30 values was observed at all dose levels of Compound 1 formulation compared to the placebo group. The profile of EHP-30 in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group.

Changes from baseline in the EHP-30 score for control and impotence were -6.92±15.848 in the placebo group, -13.97±17.502 in the Compound 1 10 mg formulation group, -20.04±21.880 in the , receiving the formulation with 20 mg of compound 1, -20.88±21.676 in the group receiving the formulation with 40 mg of compound 1, and -24.80±23.839 in the leuprolide acetate group, respectively. A more significant change in EHP-30 values at higher dose levels of compound 1 formulation was observed throughout the treatment period. The profile of EHP-30 in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group.

In contrast, changes from baseline in the EHP-30 score in the placebo group, in the 10 mg formulation group of Compound 1, in the 20 mg Compound 1 formulation group, in the 40 mg Compound 1 formulation group 1 and leuprolide acetate group were -6.74±17.669, -8.38±15.918, -15.37±17.858, -13.26±16.316, and -12.37±18.332, respectively, for emotional well-being, -3 .21±16.612, -7.52±10.840, -13.44±17.055, -10.28±17.109 and -10.46±17.923 for social support and -5.39±15.421, -5.91±12.811 -10.59±15.256, -9.68±17.744 and -9.42±15.553 for self-report.

Statistics for quality of life (EHP-30) over a treatment period of 24 weeks are tabulated: for pain in FIG. 129; with respect to control and impotence in FIG. 130; in relation to emotional well-being in FIG. 131; with respect to social support in FIG. 132 and with respect to the self-assessment in FIG. 133.

Statistical data on change from baseline quality of life value (ENP-30) over a treatment period of 24 weeks are tabulated: for pain in FIG. 134; with respect to control and impotence in FIG. 135; in relation to emotional well-being in FIG. 136; with respect to social support in FIG. 137 and with respect to the self-assessment in FIG. 138.

Change statistics from baseline in quality of life (ENP-30) (versus leuprolide acetate) over a 24 week treatment period are tabulated: for pain, FIG. 139; with respect to control and impotence in FIG. 140; in relation to emotional well-being in FIG. 141; with respect to social support in FIG. 142 and with respect to the self-assessment in FIG. 143.

Other VAS-related endpoints (peak value, proportion of pain-free days, proportion of subjects without pain) for pelvic pain, dysmenorrhea, and dyspareunia were comparable to mean VAS scores.

Plasma concentrations of unchanged Compound 1 prior to administration at each visit (trough values) were consistent with Compound 1 dose levels and were comparable across each treatment group over a treatment period of 24 weeks, showing a dose-proportional trend in Compound 1 plasma concentrations. This indicated that steady state had been reached as early as 2 weeks post-administration and that there were no changes in PK aspects with long-term administration of Compound 1 formulation for 24 weeks.

Serum concentrations of LH, FSH and progesterone (P) tended to be lower at higher dose levels of compound 1 formulation over a 24 week treatment period. The profiles in the 40 mg compound 1 formulation group were similar to those in the leuprolide acetate group. The median serum E2 concentration decreased below the lower limit of quantification (LLQ) from week 2 in the compound 1 40 mg formulation group and steadily decreased throughout the treatment period for 24 weeks, while in the leuprolide acetate group, the median E concentration ₂ in serum decreased to the level of LLQ from 4 weeks, and then constantly decreased throughout the treatment period for 24 weeks. Serum CA125 concentration decreased with increasing dose of compound 1, and the results in the 40 mg compound 1 formulation group were the same as in the leuprolide acetate group.

In this study, the efficacy and safety of an orally administered formulation of Compound 1 was investigated in patients with endometriosis at doses of 10, 20, and 40 mg for 24 weeks, compared with placebo and leuprolide acetate or leuprorelin as the active reference compound.

In terms of efficacy, in patients with endometriosis, the effects of Compound 1 formulation on pelvic pain and dysmenorrhea after administration for 12 weeks in the study of Example 5A were maintained for the next 12 weeks (24 weeks total) and were approximately the same in the group, sex

- 105 041715 formulated with 40 mg of Compound 1, and a group of leuprolide acetate or leuprorelin. E2 values were suppressed throughout the study period.

Thus, the decrease in the mean VAS score from baseline for total pelvic pain (Fig. 152A-B), dysmenorrhea (Fig. 153A-B), and non-menstrual pelvic pain (Fig. 154A-B) in groups treated with compound 1 were dose-dependent with the largest decrease in the group treated with 40 mg of compound 1 during the entire treatment period. The reduction in mean VAS from baseline for generalized pelvic pain, non-menstrual pelvic pain and dysmenorrhea in the Compound 1 40 mg group was the same as in the leuprorelin group. There was no clear trend in mean VAS scores from baseline in the dyspareunia dosing groups (FIGS. 155A-B), although there was a downward trend over time for the Compound 1 40 mg group and the leuprorelin group. The sample size for these analyzes of dyspareunia was small, as not all of the women included in the study experienced dyspareunia at baseline or were sexually active. The proportion of patients without pain as measured by VAS scores for total pelvic pain at the end of treatment was 0%, 20%, 50%, and 57% for placebo, Compound 1 10, 20, 40mg, and leuprorelin, respectively. The decrease from baseline in mean VAS was greatest for dysmenorrhea in the 40 mg Compound 1 group, showing results similar to those for leuprorelin at the end of the treatment period (FIG. 156A). A dose-dependent decrease from baseline in mean VAS was also observed for non-menstrual pelvic pain (FIG. 156A). Overall, similar results were obtained for the mean modified (patient-rated) B&B scale (FIG. 156B) and standard B&B (physician-rated) scores for pelvic pain, dysmenorrhea, and dyspareunia. Accordingly, dose-dependent reductions were observed for Compound 1 compared to placebo, and the 40 mg dose of Compound 1 consistently showed the greatest reduction in pain. The proportion of patients without pain as measured by VAS for total pelvic pain at the end of treatment was 0%, 7%, 20%, 50%, and 57% for the placebo group, the Compound 1 10, 20, 40 mg groups, and the leuprorelin group, respectively.

Based on the results of the efficacy and safety evaluation in this study, it was determined that there were no clinically significant safety concerns with Compound 1 formulations. In addition, based on the results of the efficacy and safety evaluation in this study, 40 mg of Compound 1 was considered to be an effective dose for treatment endometriosis.

In this study, in patients with endometriosis, the therapeutic effect of a formulation containing Compound 1 was evaluated over a long period of administration lasting 24 consecutive weeks. The change from baseline in mean VAS for pelvic pain at the end of the treatment period was -3.222±12.1616 mm in the placebo group, -6.849±10.5616 mm in the 10 mg Compound 1 formulation group, -9.032± 11.8432 mm in the 20 mg compound 1 formulation group, -11.924±11.2609 mm in the compound 1 40 mg formulation group, and -12.552±12.5609 mm in the leuprolide acetate group.

Changes from baseline in mean VAS scores for pelvic pain were greater at higher dose levels of Compound 1 formulation over time over a 24 week treatment period. Changes from baseline in mean VAS scores for dysmenorrhea (mean VAS score for pelvic pain on menstrual days during the evaluation period) were also greater at higher dose levels of Compound 1 as a function of time over a treatment period of 24 weeks. The changes and profiles of the VAS score for pelvic pain and dysmenorrhea in the 40 mg Compound 1 formulation group were the same as in the leuprolide acetate group.

Other VAS-related endpoints (peak value, proportion of pain-free days, proportion of subjects without pain) for pelvic pain, dysmenorrhea, and dyspareunia were comparable to mean VAS scores.

Mean M-B&B (pain self-assessment tool) for pelvic pain, dysmenorrhea, and deep dyspareunia decreased over time at higher dose levels of Compound 1 over a 24 week treatment period.

The B&B score (instrument for assessing pain symptoms through interview by the investigator) decreased as a function of time and as a function of the dose level of Compound 1 dysmenorrhea formulation.

In addition, the proportion of days with painkiller use and the number of menstrual bleeding decreased, and the proportion of subjects who achieved amenorrhea increased as a function of time in accordance with the dose level of the compound 1 formulation, with the indicators in the group receiving the formulation with 40 mg of compound 1 being about the same as in the leuprolide acetate group.

To assess the quality of life of patients, an assessment was carried out using EHP-30. EHP-30 scores for pain and control and impotence decreased from baseline at higher compound 1 formulation dose levels as a function of time over the duration of treatment.

- 106 041715 for 24 weeks. The profile of EHP-30 in the 40 mg Compound 1 formulation group was comparable to that in the leuprolide acetate group.

Plasma concentrations of unchanged compound 1 before administration at each visit (trough values) corresponded to the dose levels of the compound 1 formulation and were comparable in each treatment group over a treatment period of 24 weeks, demonstrating a dose-proportional trend in plasma concentrations of compound 1, namely, the achievement of a stable state as early as 2 weeks after administration and no change in PK aspects with long-term administration of Compound 1 for 24 weeks.

Serum concentrations of LH, FSH and progesterone (P) were lower at higher dose levels of compound 1 formulation over a 24 week treatment period. The profiles in the 40 mg compound 1 formulation group were similar to those in the leuprolide acetate group. In contrast, the median serum E ₂ concentration decreased below the LLQ level from week 2 in the compound 1 40 mg formulation group and steadily decreased over the entire treatment period of 24 weeks, while in the leuprolide acetate group, the median serum E2 concentration decreased. to the level of LLQ from 4 weeks, and then constantly decreased during the entire treatment period of 24 weeks.

Serum CA125 concentration decreased with increasing dose of compound 1 formulation and the results in the compound 1 40 mg formulation group were the same as in the leuprolide acetate group. The results after administration for 24 weeks were similar to those after administration for 12 weeks.

All study drug-related adverse events were mild to moderate after 24 weeks and recovered during or after completion of study drug administration. The main adverse events were headaches, but the incidence of headaches was the same in groups treated with compound 1 and placebo groups.

Various questionnaires, rating scales, and the like were used in evaluating subjects. In FIG. 144 is an exemplary endometriosis pain questionnaire used for psychometric analyses. In FIG. 145 is an illustrative M-B&B scoring scale used for dysmenorrhea, pelvic pain, and deep dyspareunia. In FIG. 146A-C is an exemplary Endometriosis Symptom Scale (SEMS) used for psychometric analyses. In FIG. 147A-M is an illustrative electronic Endometriosis Symptom Scale (SEMS) used for psychometric analyses. In FIG. 148A-C is an illustrative form of mood states used for psychometric analyses. In FIG. 149A-C is an illustrative initial clinical questionnaire used for psychometric analyses. In FIG. 150A-B is an illustrative clinical summary questionnaire used for psychometric analyses. In FIG. 151A-E is an illustrative Endometriosis Health Questionnaire (ENP-30) used to analyze quality of life.

Example 8B. Summary of Examples 7 and 8A.

This example summarizes some of the results as described above for examples 7 and 8A.

The VAS used in the examples was obtained using a 100 mm rating scale. As for the intensity of pain, pain-free states (score 0) and pain as severe as possible (score 100) are taken as the extreme points of the scale. The VAS assessment of pelvic pain included: the presence or absence of menstruation, the amount of blood during bleeding (during menstruation); whether the subject had sexual intercourse; VAS score for dyspareunia (if the subject has had intercourse); adherence to the regimen of receiving the investigated Compound 1 and the use of analgesics. The above items were assessed using a patient diary distributed by the sponsor. Subjects completed a patient diary each day for the treatment period or until early termination. In the case of illicit analgesics, subjects recorded this fact in a patient diary, along with associated pain symptoms, prior to using analgesics.

When used in these examples, menstrual pain and non-menstrual pelvic pain were assessed using M-B&B and B&B scores. M-B&B scores were recorded by the subjects in a patient diary provided by the sponsor. Subjects completed a patient diary each day for the treatment period or until early termination. In the case of illicit analgesics, subjects recorded this fact in a patient diary, along with associated pain symptoms, prior to using analgesics. The investigator or co-investigator assessed each patient's pain through a questionnaire and completed the B&B once a month. The evaluated parameters are shown below. The M-B&B score included: dysmenorrhea (severe, moderate, mild, no pain or no menses); pelvic pain (severe, moderate, mild or no pain); deep dyspareunia (severe, moderate, mild, no pain or no intercourse).

The B&B score included: dysmenorrhea (severe, moderate, mild, none, or not applicable); dyspareunia (severe, moderate, mild, absent or not applicable); pelvic pain (severe, moderate, mild, or none); pelvic tenderness (severe, moderate, mild, or none) and induration (severe, moderate, mild, or none).

- 107 041715

For psychometric analyses, the Endometriosis Symptom Scale (SEMS) was used to assess M-B&B. Exemplary scales, electronic diary formats, questionnaires, forms, and the like used in deriving M-B&B scores include, for example, the following: endometriosis pain questionnaire (see FIG. 144); rating scale M-B&B (see Fig. 145); SEMS according to subject testing (see FIGS. 146A-C); electronic SEMS in accordance with testing on subjects (see Fig. 147A-M); the form of mood states (see Fig. 148A-C); the initial clinical questionnaire (see Fig. 149A-C) and the final clinical questionnaire (see Fig. 150A-B).

A typical method used to assess the quality of life (QOL) associated with endometriosis includes an assessment of the health status of patients with endometriosis (ENP-30). An example of an EHP-30 questionnaire is shown in FIG. 151A-E, it includes 30 questions with 5 possible answers each.

After administration of doses of 40 mg per day for 28 consecutive days of compound 1 in the formulation (formulation of compound 1) having the following excipients: 122 mg of mannitol, 40 mg of microcrystalline cellulose, 6 mg of hydroxypropyl cellulose, 10 mg of croscarmellose sodium, 2 mg of magnesium stearate, 7.12 mg hypromellose 2910, 0.8 mg titanium dioxide, and 0.08 mg iron oxide, and without hormone replacement, change from baseline in mean visual analogue scale (VAS) score (mean ± SD) for pain in the region pelvis at the end of 28 consecutive days was -2.294±8.9903 mm in the placebo group and -3.761±7.8831 mm in the 40 mg Compound 1 formulation group. .2-2.0 times (200%), in particular 1.4-1.8 times (from 140 to 180%) and more specifically 1.5-1.7 times (from 150 to 170%) pain in the pelvis.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in the proportion of days without pelvic pain in the average VAS at the end of 84 consecutive days was 12.82 ± 26.535% in the placebo group and 36. 59±34.849% in the 40 mg Compound 1 formulation group.

Following 40 mg daily doses for 12 consecutive weeks, Compound 1 formulation had a change from baseline in mean VAS for pelvic pain at the end of 12 consecutive weeks of -3.753±10.5018 mm in the placebo group and -10.418±11 .0171 mm in the 40 mg Compound 1 formulation group.

Following 40 mg daily doses for 84 consecutive days of compound 1 formulation, the change from baseline in the mean Biberoglu & Behrman Modified Score (M-B&B) for pelvic pain at the end of 84 consecutive days was 0.172 ± 0.3851 in the placebo group and -0.400±0.4491 in the group treated with 40 mg formulation of Compound 1.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in the proportion of days without pelvic pain in the average M-B&B at the end of 84 consecutive days was -12.98±27.490% in the placebo group and 31.00±36.746% in the 40 mg Compound 1 formulation group.

After administration of doses of 40 mg per day for 28 consecutive days of the composition of compound 1, the change from baseline in dysmenorrhea in mean VAS at the end of 28 consecutive days was -4.547 ± 16.4741 mm in the placebo group and -10.979 ± 14.8545 mm in the group receiving the formulation with 40 mg of Compound 1.

After administration of doses of 40 mg per day for 84 consecutive days, the change from baseline in the proportion of days without dysmenorrhea in mean VAS at the end of 84 consecutive days was 13.48 ± 34.975% in the placebo group and 78.45 ± 29.838 % in the group receiving the composition with 40 mg of compound 1.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in dysmenorrhea in the mean M-B&B at the end of 84 consecutive days was -0.185±0.5491 in the placebo group and -1.144±0.5014 in the group receiving the formulation with 40 mg of Compound 1.

After administration of doses of 40 mg per day for 28 consecutive days, the change from baseline in the proportion of days without dysmenorrhea in mean MB&B at the end of 28 consecutive days was 13.75±34.741% in the placebo group and 73.98±29.567 % in the group receiving the composition with 40 mg of compound 1.

After administration of doses of 40 mg per day for 84 consecutive days, the change from baseline in the composition of compound 1 in subjects without dysmenorrhea in the mean Biberoglu & Behrman (B&B) score at the end of 84 consecutive days was 1.5% in the placebo group and 94. 3% in the group receiving the formulation with 40 mg of Compound 1.

When used in the examples, the EHP-30 score was obtained by subjects who assessed and recorded their own quality of life using the EHP-30 questionnaire. The EHP-30 questionnaire contained 30 questions, each with 5 response options, as shown in FIG. 151A-E.

After administration of doses of 40 mg per day for 84 consecutive days, the composition of compound 1 changed from baseline in the health status index of patients with endometriosis

- 108 041715 (ENP-30) at the end of 84 consecutive days was -5.41 ± 18.421 in the placebo group and -25.94 ± 19.902 in the 40 mg compound 1 formulation group.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in pelvic pain, dysmenorrhea and dyspareunia in mean VAS was -3.753 ± 10.5018 mm in the placebo group and -10.418 ± 11. 0171 mm in the group receiving the formulation with 40 mg of Compound 1.

After administration of doses of 40 mg per day for 84 consecutive days, the change from baseline in the composition of compound 1 in subjects without dyspareunia in the average M-B&B at the end of 84 consecutive days was 38.9% in the placebo group and 51.3% in the group receiving the formulation with 40 mg of Compound 1.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in the proportion of days without deep dyspareunia in the average M-B&B at the end of 84 consecutive days was 1.69 ± 35.861% in the placebo group and 8. 15±43.20% in the 40 mg Compound 1 formulation group.

After administration of doses of 40 mg per day for 84 consecutive days of the composition of compound 1, the change from baseline in deep dyspareunia in the mean M-B&B at the end of 84 consecutive days was -0.003±0.3796 in the placebo group and -0.097±0. 4325 in the 40 mg Compound 1 formulation group.

Example 9 Study of the pharmacokinetics, pharmacodynamics and safety of Compound 1 with or without low doses of estradiol/norethisterone acetate in healthy premenopausal women.

The study was a randomized, open-label study of repeated doses of once daily single compound 1 or compound 1 in combination with reverse hormonal therapy (E ₂ /NETA combination) to evaluate safety, including markers of bone resorption, pharmacokinetic and pharmacodynamic endpoints.

Compound 1 (40 mg once daily) significantly reduced heavy menstrual bleeding associated with uterine fibroids in a phase 2 study: 83.6% of patients achieved a PBAC score<10 at 12 weeks of treatment compared with 0% on placebo (Hoshiai Presented at ACOG, Obstet Gynecol, 2017; May 1, 87S:29).

In this study, PK, PD, and safety data were collected during 6 weeks of treatment with 40 mg Compound 1 or Compound 1 with recurrent low-dose E2/norethisterone acetate ([E2/NETA] 1 mg/0.5 mg) treatment in healthy women. in premenopause.

Methods: A 6-week, randomized, open-label, phase 1, parallel-group study was conducted at 4 centers in the United States. Women were randomized to receive 40 mg Compound 1 or 40 mg Compound 1 with reentrant therapy (E2/NETA 1 mg/0.5 mg) once daily for 6 weeks. The first day of dosing was on days 1-6 of the menstrual cycle. Hormonal drugs were prohibited at least 3 months prior to screening. Pharmacokinetic (compound 1, E2, estrone, NETA) and pharmacodynamic samples, including N- and C-telopeptide samples, were collected throughout the study. Vasomotor symptoms were recorded using a daily diary (from screening to follow-up).

Demographics Forty-eight healthy premenopausal women were included in the study and 46 completed the study. One of them withdrew consent on day 53, and one lost contact on day 64. Most of the subjects were white (73%) or African American (17%) aged 20 to 47 years with a body mass index ranging from 19, 9 kg/ ^m2 to 33.7 kg/ ^m2 .

Pharmacokinetics Estradiol/norethisterone acetate had no significant effect on plasma levels of Compound 1 (Table 6).

The observed levels of E2 and NETA (AUC) in this study (1080 pg * h / ml and 25.1 ng * h / ml at week 3, respectively) were not higher than those observed in healthy postmenopausal women who received the same dose of the combination E ₂ /NETA in a historical study (1621 pg*h/ml and 47.7 ng*h/ml, respectively). (Activella NDA 20-970 available at www.accessdata.fda.gov. Accessed 6-Jun-2017).

Estradiol levels were 3.3 times higher during treatment with Compound 1 with reentry therapy compared to Compound 1 alone (Table 10). Such higher levels can potentially minimize the effect on bone loss.

- 109 041715

Table 10

Geometric mean (CV%) of pharmacokinetic parameters at week 6

analyte Compound 1 Estradiol Norethisterone Comp.1 Comm. 1 Comp.1 Parameter + return + return + return FC Comm. 1. therapist. Comp.1. therapist Comm. 1. therapist.

17.6(48.3%) 18.7(101%) 11.7(185%) 43.1(46.7%) N/A 5.00(30.7%) (ng/mL)

AUCo-24

116(42.3%) 130(72.9%) 229(144%) 727(46.4%) N/A 23.2(48.2%) (hh/mL)

Pharmacodynamics.

Rapid suppression of FSH, LH, estradiol (E2) and progesterone (P) was observed after initiation of treatment A (40 mg Compound 1). Serum estradiol and estrone (E1) concentrations were comparable higher in subjects treated with B (40 mg of Compound 1 with simultaneous administration of B2/NETA [1 mg/0.5 mg]) compared with Compound 1 alone (median concentration before administration dose on day 43 was 27 pg/mL compared to 5.46 pg/mL, respectively). A scatter plot of Compound 1 AUC0-24 versus estradiol Cavg concentration at week 6 is shown in FIG. 168. All subjects received the same dose of Compound 1 (40 mg once daily), but there may be some variation in the AUC0-24 of the compound due to individual metabolic patterns. As can be seen in the graph, a higher AUC0-24 of compound 1 correlated with a lower concentration of estradiol Cavg in subjects who did not simultaneously receive reverse hormone therapy. Surprisingly, however, subjects who received reentrant therapy did not have the same correlation between higher AUC0-24 and lower Cavg of estradiol. Rather, estradiol levels in subjects who received reentrant therapy were relatively uniform even when AUC0-24 differed. Complete suppression of estrogen by the administration of Compound 1 in combination with the simultaneous administration of E ₂ /NETA resulted in greater consistency of E ₂ levels compared to the administration of Compound 1 alone.

This higher concentration of estradiol reduces bone resorption and is reflected in the resorption markers N-telopeptide (NTx) and C-telopeptide (CTx), which were significantly reduced when E2/NETA 1 mg/0.5 mg was added compared with 40 mg alone. Compound 1. The addition of estradiol/norethisterone significantly inhibited the rise in C-telopeptide and N-telopeptide levels following Compound 1 treatment, indicating a reduction in bone resorption (FIG. 165). In FIG. 169 is a scatter plot of Cavg of estradiol versus change from baseline in Ntelopeptide at week 6. This figure shows that in the compound 1 group without reentry therapy, lower estradiol levels correlated with higher change from baseline in N-telopeptide, indicating higher bone turnover. However, in the concomitantly reverse therapy group, estradiol Cavg showed a narrower range among subjects, and the change from baseline in N-telopeptide was not as significant, indicating lower bone turnover. A similar trend is shown in Fig. 170 depicting a comparison of Cavg of estradiol with change from baseline in C-telopeptide at week 6. In FIG. 171 is a swing plot of the ratio of subject's reported menstrual bleeding to C _avg of estradiol at week 6. As seen in the figure, higher estradiol levels correlated with higher menstrual bleeding reported by subjects in the Compound 1 group, while no such trend was seen in Compound 1 and E ₂ /NETA treated subjects.

Subjects who received exogenous E ₂ /NETA treatment had higher estradiol and estrone levels compared to subjects treated with Compound 1 alone. After multiple doses of Treatment A (40 mg Compound 1) or Treatment B (40 mg Compound 1 and E ₂ /NETA [1 mg/0.5 mg]) mean time profiles of serum E ₂ concentration at week 3 and week 6 were similar in shape in each treatment group with a low maximum to minimum ratio. Absolute concentrations of estradiol were higher with treatment B and followed a typical oral pharmacokinetic profile. The slightly higher concentrations at week 3 compared to week 6 within each treatment may be the result of biological variability. Co-administration of Compound 1 and E2/NETA resulted in a 3.3-fold increase in total serum estradiol exposure (C _max and AUC ₀ - ₂₄ ). Median Ct-ough and C _max values of about 25 pg/mL and 45 pg/mL, respectively, are similar to the range reported as mitigating the effects of bone resorption in a hypoestrogenic state typically induced by GnRH agonists. Similarly, co-administration of Compound 1 and E2/NETA resulted in an approximately 9-12 fold increase in serum estrone peak and its total exposure ( _Cmax and AUC0-24). Percentage of subjects with pre-dose estradiol concentrations

- 110 041715 were <10 pg/ml or <20 pg/ml, was higher after the administration of compound 1 alone than compounds 1 and E ₂ /NETA. In table. Tables 11 and 12 show pharmacokinetic parameters for the two treatment groups at weeks 3 and 6. Median (25th quartile, 75th quartile) C _avg , Cmax and C _trough for estradiol from week 3 and week 6 are summarized in Table 1. 13.

Table 11

Summary statistics and non-compartmentally calculated serum estradiol pharmacokinetic parameters by treatment plan and by week (PK population)

Treatment A: 40 mg Compound 1 Treatment B: 40 mg Compound 1 and E2/NETA (1 mg/0.5 mg) Parameter Week 3 Week 6 Week 3 Week 6 FC (#23) (#21) (#23) (#22)

Stach (PG/ML) 42.8 (124) 28.5 (55.3) 68.6 (94.5) 46.8 (17.3) tmax (h) 8 (0.00, 24.00) 2 (0.00, 24.00) 6 (0.50, 12.00) 3 (0.50, 12.00) AUCo-24 (pg h/ml) 693 (1900) ^a 480 (917) ^b 1080(1050) 784 (262) Ctrough (PG/ml) 38.3 (124) 20 (54.3) 30.2 (23.2) 20.8 (7.81) Cavg (PG/ML) 28.9 (79.1) ^a 20.0 (38.2) ^b 44.9 (43.8) 32.6 (10.9) tl/2 (h) N/A 12.5 (3.23) ^s 19.7(7.16/ 17.1 (4.03) ^e

Abbreviations: h - hour; N is the number of subjects; N/A - not applicable; SD - standard deviation.

The arithmetic mean (SD) is given, with the exception of tmax, for which the median value and range (minimum, maximum) are given.

^aN =21. Values for AUC _0-24 and C _avg were not reported for subjects 1004 and 4008.

^bN =19. Values for AUC _0-24 and C _avg were not reported for 2001 and 2011 subjects.

^with N=4. Values for t _1/2 were reported for only 4 subjects (subjects 2008, 3001, 3005 and 3014).

^dN =13. Values for t _1/2 were not reported for subjects 1003, 2002, 2003, 2007, 2012, 3002, 3009, 3013, 4005 and 4012.

^eN =15. Values for t _1/2 were not reported for subjects 1003, 2007, 3004, 3006, 3009, 3011 and 4002.

Table 12

Summary Statistics of Median Serum Cmax and Ctrough of Estradiol by Treatment Plan and by Week (PK Population)

Treatment B:

Treatment A: 40 mg Compound 1 40 mg Compound 1 and E2/NETA ( 1 mg/0.5 mg) Parameter Week 3 Week 6 Week 3 Week 6 FC (#23) (#21) (#23) (#22)

Stach (PG/ML) 9.55 (4.55, 606) 7.22 (2.74, 255) 44.7 (12.2, 487) 49.2 (13.0, 78.9) Ctrough (PG/ML) 6.40 (2.56, 606) 5.77 (2.50, 255) 22.6 (3.02, 104) 21.4 (3.60, 39.0)

Abbreviations: h - hour; N is the number of subjects. Median values (minimum, maximum) are shown.

- 111 041715

Table 13

Median (min, max) [25th quartile, 75th quartile] C _avg , C _max and Ctrough for E ₂ at week 3 and week 6 Treatment B:

Treatment A:

mg Compound 1 and E2/NETA

Parameter FC_ 40 mg Compound 1 (1 mg/0.5 mg) Week 3 Week 6 Week 3 Week 6 (N=23) (N=21) (N=23) (N=22)

Cavg 7.84 (3.91, 371) 6.17 (2.89, 170) 32.8 (6.50, 227) 31.5 (7.73, 50.2) (pg/ml) [4.60, 19.7] [4.72 18.0] [26.2, 44.2] [27.2, 42.2] Stakh 9.55 (4.55, 606) 7.22 (2.74, 255) 44.7 (12.2, 487) 49.2 (13.0, 78.9) (pg/ml) [5,41,33,9] [5,10,35,1] [36.7, 56.7] [34,4,61,1] Ctrough 6.40 (2.56, 606) 5.77 (2.50, 255) 22.6 (3.02, 104) 21.4 (3.60, 39.0) (pg/ml) [3.94, 29.2] [3.66, 11.5] [16,5,29,8] [16.2, 25.7]

As can be seen from Table. 13, C _avg (pg/ml) of estradiol at week 3 in treatment group B was 32.8 with a minimum of 6.50 and a maximum of 227, 25th quartile: 26.2, 75th quartile: 44.2. At week 6, the C _avg (pg/ml) of estradiol in treatment group B was 31.5 with a minimum of 7.73 and a maximum of 50.2, 25th quartile: 27.2, 75th quartile: 42.2. These _E2 ranges are narrower than those reported for elagolix titration treatment where estrogen is not completely suppressed and a GnRH antagonist (elagolix) is administered to reduce endogenous estrogen until levels fall within the therapeutic window. . Administration of 150 mg elagolix (not a full dose of suppression) has been reported to achieve a median estradiol level of 30.3 pg/ml, but with 25th and 75th quartiles of 17.8 and 64.1, respectively (see Diamond et al., Reprod Sci March 2014, 21(3):363-371). In a separate study, it was found that the administration of 150 mg of elagolix for 12 weeks leads to the achievement of a median (minimum, maximum) estradiol concentration of 36.40 (4.5, 247.0), 39.60 (6.8, 182.00 ) and 36.70 (2.5, 521.00) at weeks 4, 8, and 12, respectively (see N. Acs, et al., Journal of Endometriosis and Pelvic Pain Disorders (2015), 7(2):56 -62). Higher consistency in estradiol levels was achieved with total estrogen suppression by administering Compound 1 along with co-administration of reentrant hormonal therapy.

Table 14

Summary statistics and non-compartmentally calculated plasma pharmacokinetic parameters of compound 1, divided by treatment plans and by weeks (PK population)

Parameter FC Treatment A: 40 mg Compound 1 Treatment B: 40 mg Compound 1 and E2/NETA (1 mg/0.5 mg) Week 3 (N=25) Week 6 (N=25) Week 3 (N=23) Week 6 (N=22) Stach (NG/ML) 21.8(14.7) 19.5 (10) 23.8 (17) 26 (21.4) tmax (h) 2.02 (0.48, 4.05) 2 (0.5, 4) 3 (0.5, 4) 3 (0.5, 6) AUCo-24 (ng-h/ml) 133 (61.2) 125 (43.3) 148 (87) 157(94.7) Ctrough (pg/ml) 2.57 (1.08) 2.45 (0.935) 2.8 (1.56) 2.96 (1.74) Cavg (pg/ml) 5.53 (2.55) 5.2(1.8) 6.17(3.62) 6.53 (3.94) tl/2 (h) 16.7 (4.88) ^a 17.1 (6.16) ^b 15.4 (5.56) ^s 17.6 (5.83) ^s

Abbreviations: h - hour; N is the number of subjects; SD - standard deviation.

The arithmetic mean (SD) is given, with the exception of tmax, for which the median value and range (minimum, maximum) are given.

^and N=22. Values for p/ ₂ were not reported for subjects 2006, 4001 and

4011.

^bN =23. Values for t _i/2 were not reported for subjects 1001 and 3014.

^C N=18. Values for p/ ₂ were not reported for subjects 1003, 2003, 2007, 3004 and 3009 for week 3 and subjects 2002, 3002, 3013 and 4002 for week 6.

Tab. 14 summarizes some pharmacokinetic parameters of the two treatment groups at week 3 and week 6. After multiple doses of treatment A (40 mg compound 1) or treatment B (40 mg compound 1 and E ₂ /NETA [1 mg/0.5 mg]) in within each treatment, the mean time profiles of Compound 1 plasma concentration at week 3 and week 6 were visually similar. Pharmacokinetic parameters of the compound

- 112041715 plasma levels after treatment A (40 mg Compound 1) and Treatment B (40 mg Compound 1 and E2/NETA [1 mg/0.5 mg]) had a similar peak and overall exposure (Cmax and AUC _{0 -24} ). In general, steady state was achieved within 1-2 weeks after administration of Compound 1 once a day. Compound 1 content was not affected by the addition of E2/NETA, consistent with the low potential for E2/NETA drug-drug interactions. There was no relationship between body mass index and compound 1 pharmacokinetics, as shown in FIG. 175.

Table 15

Summary statistics of menstruation for the last 28 days of treatment

Category Treatment A: 40 mg Compounds 1 (N = 25) n(%) Treatment B: 40 mg Compound 1 and E2/NETA (1 mg/0.5 mg) (N=23) n(%) Total (N = 48) n(%) No bleeding 18 (72.0%) 9(39.1%) 27 (56.3%) No light/normal/heavy bleeding (i.e. no 22 (88.0%) AND (47.8%) 33 (68.8%) bleeding other than small patches) No normal/excessive bleeding 23 (92.0%) 14 (60.9%) 37(77.1%)

Abbreviations: n - number of not missed observations; N is the number of subjects.

In table. 15 shows menses statistics for subjects during 28 days of treatment. Overall, most subjects reported the highest incidence of uterine bleeding on days 1 and 2 of their menstrual cycle (days 1 to 6): 42 of 48 subjects (87.5%) and 32 of 48 subjects (66.7%) reported bleeding on days 1 and 2, respectively. Day 1 of dosing was to coincide with day 1-6 of the subject's menstrual cycle. After day 2, the number of subjects reporting bleeding decreased and a total of <10 of 48 subjects (20.8%) reported bleeding each day for the duration of the study (days 3 to 58). After day 28, the number of subjects reporting bleeding was typically <5 of 48 (10.4%). Generally, a higher bleeding rate was observed after treatment B (40 mg Compound 1 and E ₂ /NETA [1 mg/0.5 mg]) than after Treatment A (40 mg Compound 1). In the last 28 days of treatment, most subjects reported no light, normal, or heavy bleeding (33 of 48 subjects [68.8%]) and no normal or heavy bleeding (37 of 48 subjects [77.1%]), and these values were higher after treatment A (40 mg compound 1) (22 out of 25 subjects [88.0%] and 23 out of 25 subjects [92.0%], respectively) than after treatment B (40 mg compound 1 and E2/ NETA [1.0 mg/0.5 mg]) (11 of 23 subjects [47.8%] and 14 of 23 subjects [60.9%], respectively).

In FIG. 163 additionally presents two graphs showing the effect on serum estradiol levels of two different treatments. As shown in the graph on the left, administration of Compound 1 once daily results in a serum estradiol concentration that is consistently below 10 pg/mL for several weeks. Subjects who received E2/NETA reentrant therapy were also measured at each study visit with a consistent trough serum estradiol concentration but above the 20 pg/mL threshold. As shown in the graph on the right, the median concentration of estradiol during the visit of week 3 remained in the range from 20 to 50 pg/ml within 24 hours after administration of compound 1 and E2/NETA. Administration of Compound 1 without a hormone replacement drug resulted in serum estradiol levels below 10 pg/mL over the next 24 hours.

Safety: The most common (>10%) reported adverse events were: hot flashes, headache, nausea and uterine bleeding (delayed, irregular). Most adverse events were of mild severity.

One subject experienced 2 serious adverse events (fainting and chest pain) unrelated to study drug and related to viral disease. There were no deaths, premature withdrawal from the study due to adverse events, or registered pregnancies.

Hot flash diary: Subjects reported a decrease in the frequency (Fig. 166) and severity of hot flashes with the addition of relapse therapy. It was noted that each of the study treatments (treatment A [40 mg compound 1] or treatment B [40 mg compound 1 and E ₂ /NETA, 1 mg/0.5 mg]) reduced the frequency of menstrual bleeding during the study; the proportions of subjects reporting no menstrual bleeding (other than small spots) during the last 28 days of treatment were 88.0% and 47.8% after treatment with Compound 1 alone or Compound 1 and E2/NETA, respectively. During week 6 of treatment, the addition of reentrant therapy allowed: (1) to reduce the proportion of subjects reporting

- 113 041715 hot flashes, from 60 to 17%; (2) reduce the subject's average number of hot flashes (of any severity) from 72.6 to 12.6; and (3) reduce the number of subjects reporting severe hot flashes from 63.2 (n=5 subjects) to 9.0 (n=2 subjects).

In general, Treatment A (40 mg Compound 1) administered once daily alone and Treatment B (40 mg Compound 1 in combination with E ₂ /NETA reversal hormone therapy [1 mg/0.5 mg]) generally was well tolerated in this study population of healthy premenopausal women treated for 6 weeks. Pharmacokinetic and pharmacodynamic data for the combination of compound 1 and E2/NETA, including median C _troug h values of estradiol of about 25 pg/ml and C _max values of about 45 pg/ml, a range associated with reduced bone resorption, support the use of this combination in studies. phase 3, evaluating heavy menstrual bleeding associated with uterine fibroids and pain associated with endometriosis.

The data presented here demonstrate that Compound 1 at 40 mg once daily reliably suppresses estradiol to low levels in women of reproductive age, but may lead to hot flushes and vasomotor symptoms, as well as increases in bone metabolism markers such as N -telopeptide and C-telopeptide. Co-administration of hormone reversal therapy consisting of 1.0 mg estradiol and 0.5 mg norethisterone acetate with Compound 1 relieved hot flashes and vasomotor symptoms in most women.

However, some women still experienced clinically significant hot flushes despite additional therapy with 1.0 mg estradiol. These data suggest that, contrary to expectations, higher doses can be used, namely 1.5-5 mg of estradiol, for example, 2.0-4.0 mg of estradiol, in combination with no more than 2.0 mg, for example 1. 5-2 mg or 1.25-2 mg, 1.5-2 mg or 1.75-2 mg norethisterone acetate co-administered with 20-120 mg Compound 1 e.g. 40 mg once a day without affecting the effectiveness of compound 1 in reducing the symptoms of uterine fibroids or endometriosis in some women. In addition, a higher amount of hormonal supplementation can relieve hot flashes even in women who experience clinically significant vasomotor symptoms when taking Compound 1 and lower dose hormone replacement therapy.

Evaluation of markers of bone metabolism may indicate that co-administration of hormone reversal therapy consisting of 1.0 mg estradiol and 0.5 mg norethisterone acetate with Compound 1, e.g. 40 mg once daily, does not completely reduce bone metabolism. tissue to baseline in all women. Bone metabolism marker data indicate that some women may require doses in excess of 1.0 mg of estradiol co-administered with Compound 1.

As shown in FIG. 164, co-administration of Compound 1 and E2/NETA reentry therapy resulted in mean serum estradiol levels within the therapeutic window of 20-50 pg/mL. However, as the error bars for each time point (standard deviation) show, the serum estradiol levels of some subjects were outside this window. This may be the result of differences in absorption or metabolism. Thus, in certain populations of women, it may be beneficial to increase the dose of Compound 1 or its pharmaceutically acceptable salt (eg, for those whose readings exceed the upper limit of 50 pg/mL) or to increase the dose of estradiol or estradiol equivalent (eg, for those whose readings are below the lower limit of 20 pg/mL).

If the serum estradiol level is too high, a decrease in the effectiveness of the treatment of symptoms of uterine fibroids (UF) and endometriosis can be expected. If serum estradiol levels are too low, increased bone mineral density loss and vasomotor symptoms/hot flashes can be expected. Thus, it would be expected that while increasing hormone reversal therapy would help increase serum estradiol levels (improving prevention of bone mineral density loss/vasomotor symptoms/hot flashes), the higher the estradiol level is outside the therapeutic window, the less effective the symptom-reducing intervention will be. uterine fibroids and endometriosis. With reentrant hormonal therapy, a decrease in the efficacy of Compound 1 can be predicted. This was seen in the phase 2 efficacy data when reentrant hormonal therapy was co-administered with elagolix, another GnRH antagonist, compared with elagolix alone. Increasing the dose of reentry therapy may result in an increase in estradiol levels and reduced efficacy in reducing bleeding associated with uterine fibroids or pain associated with endometriosis. However, contrary to these expectations, this Phase 1 study surprisingly found that Compound 1, with and without reentry therapy, was effective in relieving hypoestrogen symptoms in most, but not all, women. These results may indicate that treatment of uterine fibroids, adenomyosis, heavy menstrual bleeding and/or endometriosis with compound 1 with reentrant therapy is the preferred treatment over compound 1 alone.

In addition, these data also indicate that it may be possible to further increase the dose of reentrant hormonal therapy in order to reduce the adverse effects of GnRH antagonist therapy without loss of treatment efficacy, for example, to reduce the symptoms of uterine fibroids,

- 114 041715 nomiasis, heavy menstrual bleeding or endometriosis.

Reentrant hormone therapy resulted in plasma estradiol concentrations that reduced bone resorption and vasomotor symptoms associated with Compound 1 administration alone. This study also proposes an evaluation of Compound 1 in combination with reentrant therapy. A description of phase 3 studies of a 40 mg dose of Compound 1 in combination with reverse hormone therapy in women with uterine fibroids and endometriosis can be found at ClinicalTrials.gov; NCT03049735, NCT03103087, NCT03204318 and NCT03204331.

Example 10 A phase 3, multicenter, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of oral Compound 1 (40 mg) versus leuprorelin in the treatment of uterine fibroids.

This was a multicenter, randomized, double-blind non-inferiority, parallel-group, phase 3 study to evaluate the efficacy and safety of Compound 1 administered orally at a daily dose of 40 mg for 24 weeks compared with leuprorelin injection (once/4 weeks, 1 .88 mg or 3.75 mg subcutaneously [sc]/times) in premenopausal subjects >20 years of age with symptomatic uterine fibroids. The main purpose of this study was to evaluate the efficacy of 40 mg of Compound 1 administered orally once a day for 12 weeks.

The subjects were 20 years of age or older and were suffering from uterine fibroids. A total of 281 subjects were randomized and divided into compound 1 group (139 subjects) and leuprorelin group (142 subjects). The number of centers for this study was about 40.

Subjects in the compound 1 group were given either 40 mg compound 1 or placebo orally once a day before breakfast. Subjects in the leuprorelin group were administered 1.88 mg leuprorelin, 3.75 mg leuprorelin, or placebo subcutaneously once every 4 weeks. The duration of treatment for both groups was 24 weeks, and the observation period was 4 weeks.

The assessment included responses to the Quality of Life Questionnaire for Uterine Fibroids Symptoms presented in FIG. 3A-3C; responses to the Workplace Performance and Impairment Questionnaire: General Health, presented in FIG. 66A-66B; clinical laboratory hematological and biochemical analyses, urinalysis, hormonal analysis and biochemical markers of bone metabolism.

The primary endpoint for this study was the proportion of subjects with a total PBAC <10 in weeks 6 to 12. Secondary endpoints for this study included: the proportion of subjects with a total PBAC <10 (in weeks 2 to 6, weeks 18 to 24 and 6 weeks prior to final dose of study drug); fibroid volumes (weeks 2, 4, 8, 12, and 24) (only the largest measurable fibroids at Visit 1 were measured throughout the study; uterine volumes (weeks 2, 4, 8, 12, and 24); hemoglobin (HGB) (4, 8, 12, 16, 20, 24 weeks and follow-up), Numerical Rating Scale (NRS) score (weeks 6 to 12, weeks 2 to 6, weeks 18 to 24, and 6 weeks before administration final dose), as well as symptoms of uterine fibroids and QOL score (UFSQOL) (4, 8, 12, 16, 20, 24 weeks and follow-up).Secondary safety endpoints included the following: adverse events (AE), vital signs , weight, standard 12-lead electrocardiogram (ECG), clinical laboratory tests, bone mineral density, biochemical markers of bone metabolism (serum N-telopeptide [NTELOP] and bone-specific alkaline phosphatase [BAP]).

Other efficacy endpoints included: hematocrit (HCT), serum iron (Fe), and serum ferritin levels (weeks 4, 8, 12, 16, 20, 24 and follow-up); use of pain medication during treatment (weeks 6 to 12, weeks 2 to 6, weeks 18 to 24, and 6 weeks prior to final dose) and the Workplace Performance and Impairment Questionnaire: General Health (WPAI: GH) ( 2, 4, 8, 12 and 24 weeks).

Other safety endpoints included: period from last dose of study drug to resumption of menses, and pharmacodynamic effects included: LH, FSH, estradiol, and progesterone (2, 4, 8, 12, 16, 20, 24 weeks and follow-up).

In table. 16 summarizes the distribution of subjects in this study. In table. 17 summarizes the demographics of the subjects. In table. 18 presents a summary of adverse events. In table. 19 is a summary of adverse events reported in 5% or more of subjects in any treatment group. In table. 20 summarizes the adverse events that lead to early discontinuation of therapy. Tab. 21 is a list of subjects with apparently abnormal liver function tests.

- 115 041715

Table 16

Distribution of subjects

Number of subjects (%)

40 mg Compound 1 Leuprorelin Total (N = 139) (n=142) (n=281)

Completed study medication 122 (87.8) 131(92.3) 253 (90.0) Prematurely discontinued 16 (ID) AND (7,7) 27 (9.6) study drug Death 0 (OD) 0 (0.0) 0 (0.0) Adverse events 10 (62.5) 7 (63.6) 17 (63.0) Protocol deviations 2 (12.5) 0 (0.0) 2 (7.4) Loss of connection 0 (0.0) o(0,0) o(0,0) Subject Refusal to Continue 1 (6.3) 2 (18.2) 3 (11.1) Study terminated 0 (0.0) 0 (0.0) o(0,0) sponsor Pregnancy 0 (0.0) 0 (0.0) o(0,0) Lack of Efficiency 0 (0.0) 1 (9.1) 1 (3.7) Loss of mineral density 0 (0.0) 0 (0.0) o(0,0) bones Recovery leading to 2 (12.5) 1 (9.1) 3 (11.1) operations Decrease in HGB concentration 1 (6.3) o(0,0) 1 (3.7) Other 0 (0.0) o(0,0) o(0,0)

Table 17 Demographic data of subjects

Compound 1 (N = 139) Leuprorelin (N = 142) Age (in years) Average value 43 .2 42.6 SO 4.98 5.27 BMI (kg / m ² ) at baseline Average value 22.78 23.43 SO 3.506 3.657 Childbirth experience (N [%]) 74(53.2) 75(52.8) Duration of illness (years) Average value 4.36 4.72 SO 5.037 5.073 Type of uterine fibroid Subserous fibroids (N [%]) 54(38.8) 53(37.3) Intramural fibroids (N [%]) 117(84.2) 112(78.9) Submucosal fibroids (N [%]) 13(9.4) 20(14.1) Cervical fibroids (N [%]) 0(0.0) 0(0.0)

Fibroids volume at baseline (cm ³ )

- 116 041715

Average value SO 117.41 126.533 122.25 124.270 Uterine volume at baseline (cm ³ ) Mean value 406.25 379.07 SO 392.354 331.568 РВАС index at baseline level Average value 254.3 263.7 SO 155.28 171.33 UFS-QOL at baseline level Symptom severity Average value 28.4 29.7 SO 14.38 15.18 Health-Related Overall QOL (HRQL) Score Average value 80.2 76.8 SO 16.73 19.57 HGB at baseline (g/dl) Average value 11.49 11.62 SO 1.368 1.377 Leuprorelin vial dosage (N [%]) 1.88 mg 121(87.7) 124(87.3) 3.75 mg 17(12.3) 18(12.7)

Table 18 Summary of adverse events 40 mg Compound 1 Leuprorelin (N=138) (N=142)

adverse events,

manifested during 131 (94.9) 139 (97.9) treatment Not connected 11 (8.0) 5 (3.5) Connected 120 (87.0) 134(94.4) Lead to discontinuation 9(6.5) 7 (4.9) study drug serious adverse events, ooo) 2 (1.4) manifested during treatment Not connected o(0,0) 2 (1.4) Connected o(0,0) 0 (0.0) serious adverse events leading to termination 0 (0.0) 0 (0.0) reception study drug Lethal outcomes o(0,0) 0 (0.0)

- 117041715

Table 19

Adverse events reported in >5% of subjects in any treatment group

Class of systems and organs Preferred Term Compound 1 Leuprorelin (n=138) (n=142) General disorders and disorders at the injection site Malaise 8(5.8) 5(3.5) Infectious and parasitic diseases Viral infection of the upper respiratory tract 39(28.3) 46(32.4) Laboratory and instrumental data Increase in gamma-glutamyltransferase 7(5.1) 9(6.3) Decreased bone density 6(4,3) 8(5,6) Abnormal bone resorption test 7(5.1) 7(4.9) Musculoskeletal and connective tissue disorders Arthralgia 8(5.8) 9(6.3) Increased bone resorption 7(5.1) 8(5,6) Nervous System Disorders Headache 21(15.2) 14(9.9) Dizziness 9(6.5) 7(4.9) Drowsiness 7(5.1) 6(4,2) Reproductive system and mammary gland disorders metrorrhagia 68(49.3) 93 (65.5) menorrhagia 34(24.6) 22(15.5) genital bleeding 7(5.1) 7(4.9) Skin and subcutaneous tissue disorders Hyperhidrosis 13(9.4) 15(10.6) Vascular disorders high tide 59(42.8) 75(52.8) Table 20 Adverse events leading to discontinuation Class of systems and organs Compound 1 Leuprorelin Preferred Term (N = 138) (n=142) Gastrointestinal disorders Abdominal pain 0(0.0) 1(0.7) Nausea 0(0.0) 1(0.7) General disorders and disorders at the injection site Malaise 1(0.7) 1(0.7) Fatigue 1(0.7) 0(0.0) Fever 0(0.0) 1(0.7) Laboratory and instrumental data Increased liver function test 1(0.7) 1(0.7) High blood pressure 0(0.0) 1(0.7) Abnormal liver function test 0(0.0) 1(0.7) Musculoskeletal and connective tissue disorders Arthralgia 1(0.7) 1(0.7) Backache 0(0.0) 1(0.7) tendovaginitis 1(0.7) 0(0.0) Stenosing tendovaginitis 1(0.7) 0(0.0)

Nervous System Disorders

- 118 041715

Headache 1(0.7) 0(0.0) Mental disorders Depression 1 (0.7) Skin and subcutaneous tissue disorders 0(0.0) drug rash 0(0.0) 1(0.7) Vascular disorders high tide 4(2.9) 1(0.7) High blood pressure 0(0.0) 1(0.7)

Table 21 Subjects with clearly abnormal liver function tests Compound 1 Leuprorelin Variable (N=138) (N=142)

Any clearly violated F1111 3 (2.2) 2 (1.4) ALT > 3xULN 3 (2.2) 2 (1.4) ALT > 5xULN 1 (0.7) 0 (0.0) ACT > 3xULN 2 (1.4) 0 (0.0) ACT > 5xULN 0 (0.0) 0 (0.0) ALT or ACT > 3xULN wt. bilirub. > 2xULN 0 (0.0) 0 (0.0) ALT and ACT > 3xULN 2 (1.4) 0 (0.0) AP > 3xULN 0 (0.0) 0 (0.0)

In FIG. 176 is a graph of the proportion of subjects who responded to RVAC who reached the primary endpoint. The margin of non-inferiority between the two groups was -15%. In FIG. 177 is a graph depicting the proportion of subjects reaching the secondary endpoint. Primary endpoint results are also included for context. In FIG. 178A is a plot of fibroid volume as a secondary endpoint; in fig. 178B is a graph of uterine volume as a secondary endpoint; and in FIG. 178C is a plot of secondary hemoglobin for two different treatment groups. In FIG. 179 is a plot of bone mineral density over time in two different treatment groups.

Demographic and baseline characteristics were generally balanced across treatment groups. Similar proportions of subjects with RVAS <10 between week 6 and week 12 were observed in the Compound 1 (82.2%) and leuprorelin (83.1%) groups. Compound 1 was not statistically inferior to leuprorelin in accordance with the main goal of the study. The results for the secondary efficacy endpoints were consistent with the results for the primary endpoint. The frequency of adverse events was generally similar between treatment groups. The frequency of adverse events associated with liver function was low and generally similar between groups. In the Compound 1 groups, a reduction in bone mineral density from baseline was observed, which was similar to that observed in the leuprorelin groups.

Compound 1 was found to be effective and generally well tolerated by study subjects who had heavy menstrual bleeding due to uterine fibroids.

Example 11 A Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of oral Compound 1 (40 mg) in the treatment of pain symptoms associated with uterine fibroids.

The study is a phase 3, multicenter, randomized, double-blind, parallel-group study to evaluate the efficacy of Compound 1 (40 mg) administered orally once daily for 12 weeks versus placebo in subjects with fibroid-related pain symptoms. uterus. To be included in the study, subjects must have a diagnosed uterine fibroid confirmed by transvaginal ultrasound or other methods, and the subjects must experience pain symptoms associated with uterine fibroids (eg, pain in the lower abdomen and back pain). The total number of subjects to be randomized in double-blind conditions will be 64 (32 subjects each in the 40 mg Compound 1 group and in the placebo group). The objectives of this study will be to evaluate the efficacy and safety of Compound 1 (40 mg) administered orally once daily for 12 weeks compared with placebo in subjects presenting with pain symptoms associated with uterine fibroids. Subjects must be 20 years of age or older and have uterine fibroids. The study will be conducted in approximately 15 centers.

Subjects will be orally administered 40 mg Compound 1 or placebo once daily before breakfast. The duration of treatment will be 12 weeks and the observation period will be 4 weeks.

- 119 041715

After signing the informed consent form, subjects will begin to record in a patient diary from visit day 1. During the period between visit 2 and visit 3, during which 1 menstrual cycle is due for subjects, baseline values will be collected to assess the effectiveness of pain symptoms. Subjects will record in a patient diary each day until the end of study medication. Visit 2 will take place between the first and fifth day of the first menstrual period after Visit 1. The study drug (placebo) will be administered under single-blind conditions from the day of the first menstrual period after Visit 1 until the day before Visit 3. Visit 3 will take place between the first and fifth day of the second menstruation after Visit 1. For Visits 2 through 6, subjects will visit the Study Center in the morning on an empty stomach and before taking study drug. Subjects will be randomized in a 1:1 ratio to either receive 40 mg Compound 1 or placebo at Visit 3. Study drug (40 mg Compound 1 or placebo) will be administered from Day 3 of Visit 3 to the day prior to Visit 6 (or until early discontinuation) in double-blind conditions.

This study will consist of a screening period of approximately 1 to 6 weeks, a run-in period of 3 to 6 weeks, a treatment period of 12 weeks, and a follow-up period of 4 weeks. The total period of participation in the study will be approximately 20 to 28 weeks. If recovery of first menstrual period after treatment is not observed during the visit at the end of the follow-up period (Visit 7), the subject will be subject to further follow-up by possible means, such as a telephone interview, until recovery of first menstruation after treatment is observed. During this study, participants will visit the study center for scheduled examinations and evaluations at each visit.

Example 12 An international, randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate Compound 1 administered with and without low doses of estradiol and norethisterone acetate in women with pain associated with endometriosis.

This study will be an international, randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate oral doses of Compound 1 (relugolix) at 40 mg once daily administered co-administered for either 12 or 24 weeks of low-dose estradiol and norethisterone acetate versus placebo (1.0 mg estradiol and 0.5 mg norethisterone acetate). Approximately 600 women with pain associated with endometriosis will be enrolled and randomized 1:1:1 to Compound 1 with low-dose reversible hormone therapy (Arm A, N® 200; 24 weeks of oral 40 mg Compound 1 once daily co-administered with 1.0 mg estradiol and 0.5 mg norethisterone acetate), Compound 1 monotherapy group followed by co-administration of low-dose reversible hormone therapy (Arm B, N® 200; 12 weeks oral 40 mg Compound 1 once daily followed by 12-week oral administration of 40 mg of compound 1 once a day with 1.0 mg of estradiol and 0.5 mg of norethisterone acetate) or placebo group (group C, N ® 200). Stratification variables will include: geographic region (North America or the rest of the world) and years after the surgical diagnosis of endometriosis (<5 or >5 years). In eligible patients, endometriosis will be diagnosed or confirmed by laparoscopy or laparotomy within 10 years of the screening visit. In addition, patients will not have a history of chronic pelvic pain other than that caused by endometriosis and will not use opioid analgesics or frequent non-opioid analgesics for chronic pain or recurring pain other than pain caused by endometriosis. Patients receiving hormonal contraceptives will stop taking them at least 28 days before the start of the run-in period. An endometrial biopsy will also be performed at screening. A transvaginal ultrasound (with or without transabdominal ultrasound) will be performed at 24 weeks. An endometrial biopsy will be performed at the week 24 visit only if scheduled (endometrial thickness anywhere >4 mm or if any other endometrial abnormality is seen on the week 24 ultrasound).

Between baseline day 1 and week 24 visits, patients will return for visits every 4 weeks. During the lead-in period, and at week 12 and week 24 visits, each patient will have their bone mineral density assessed using dual energy X-ray absorptiometry (DXA). Patients will complete an electronic diary from the screening visit through to the follow-up visit (including up to 7 days after the run-in period) to record study drug treatment, NRS pain assessment, menstrual bleeding, analgesic use, and functional effects of pain associated with endometriosis (modified for subject use by the Biberoglu and Behrman [sB&B] scale). Quality of Life Questionnaires, Physician Overall Impression of Change (PGIC), and Patient Overall Assessment (PGA) will be completed during visits on an electronic tablet as outlined in the action plan. Patients will only be allowed to use protocol-mandated back-up analgesics in case of worsening symptoms, as outlined in the study reference manual, from the start of the lead-in period until the end of the follow-up period.

Example 13. International randomized, double-blind, placebo-controlled study

- 120 041715 phase 3 efficacy and safety study to evaluate co-administration of Compound 1 with and without low doses of estradiol and norethisterone acetate in women with heavy menstrual bleeding associated with uterine fibroids.

This study will be an international, randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate a 24-week oral administration of 40 mg compound 1 once daily with low doses of estradiol and norethisterone acetate and a 12-week oral administration of 40 mg of compound 1 once daily followed by 12 weeks of oral administration of 40 mg of compound 1 once daily with low doses of estradiol and norethisterone acetate compared to 24 weeks of placebo administration. Approximately 390 women with heavy menstrual bleeding associated with uterine fibroids will be enrolled and randomized 1:1:1 to Compound 1 with low-dose reversible hormone therapy (Arm A, N® 130; 24 weeks of oral 40 mg Compound 1 alone). once daily with 1.0 mg estradiol and 0.5 mg norethisterone acetate), Compound 1 monotherapy group followed by co-administration of low-dose reversal hormone therapy (group B, N® 130; 12 weeks of oral 40 mg Compound 1 once daily day followed by 12 weeks of oral administration of 40 mg of compound 1 once a day together with 1.0 mg of estradiol and 0.5 mg of norethisterone acetate) or placebo group (group C, N ® 130). Stratification variables will include: geographic region (North America or the rest of the world) and mean menstrual blood loss at screening (<225 ml or >225 ml) as determined by the alkaline hematin method. The study will consist of a screening period (up to ~13 weeks), a randomized treatment period (24 weeks) and an observation period (~30 days). In addition, unscheduled follow-up visits can be arranged for patients with study-related safety concerns and as needed. The diagnosis of uterine fibroids will be confirmed during the screening period with a centrally revised transvaginal ultrasound (with or without transabdominal ultrasound). Heavy menstrual bleeding will be defined as menstrual blood loss >80 ml per cycle for 2 cycles or >160 ml for 1 cycle during the screening period. During the randomized treatment period, study participants will take the blinded study drug once daily for 24 weeks. Women with iron deficiency microcytic anemia and hemoglobin >8 g/dl and <10 g/dl at screening should be on oral or parenteral iron replacement therapy. Between visits on baseline day 1 and week 24, patients will visit monthly (ie, every 4 weeks). During the screening visit and visits at week 12 and week 24, patients will have their bone mineral density assessed using dual energy X-ray absorptiometry (DXA). An endometrial biopsy will also be performed at screening. Transvaginal ultrasonography (with or without transabdominal ultrasonography) will be performed at 24 weeks followed by repeat endometrial biopsy. Paired initial and final endometrial biopsies will be performed on patients, regardless of ultrasound findings. Women's products will be standardized and will be collected and assessed for blood loss by the alkaline hematin method. Complete blood counts and biochemical tests will be performed monthly, and uterine and uterine fibroid volumes will be assessed during the screening visit and week 24 visit. Patients will complete electronic diaries (eDiary), including treatment adherence, menstrual bleeding, use of feminine products for menstrual bleeding, recording uterine fibroid-related pain on a numerical rating scale, and using painkillers to relieve pain caused by uterine fibroids. Examples of eDiary questions are shown in FIG. 180A-E. Quality of life questionnaires will be completed in accordance with the action plan. Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations including visual acuity testing, clinical laboratory tests, 12-lead electrocardiogram, endometrial biopsy, and assessment of bone mineral density. Height will be measured at Screening Visit 1 and weight will be measured at regular intervals. Samples will be collected for PK evaluation of Compound 1, estradiol and norethisterone and for pharmacodynamic evaluation of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol and progesterone. All patients completing the week 24 visit, including women randomized to placebo, will be offered the opportunity to participate in an open-label extension study in which all eligible patients will receive Compound 1 in combination with low doses of estradiol and norethisterone acetate. Patients who do not enroll in the Extension Therapy Study will be scheduled to return approximately 30 days after the end of treatment (i.e. after the last dose of study drug taken by the patient).

Example 14 An international randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate the co-administration of Compound 1 with and without low doses of estradiol and norethisterone acetate in women with heavy menstrual bleeding associated with uterine fibroids.

This study will be conducted to evaluate a 24-week oral administration of 40 mg of the compound

- 121 041715 1 (relugolix) once daily with low doses of estradiol and norethisterone acetate and 12 weeks of oral 40 mg of Compound 1 once daily followed by 12 weeks of oral 40 mg of Compound 1 once daily concomitantly with low doses of estradiol and norethisterone acetate compared with 24 weeks of placebo administration. Approximately 390 women with heavy menstrual bleeding associated with uterine fibroids will be enrolled and randomized in a 1:1:1 ratio to Compound 1 with low-dose recurrent hormone therapy (Arm A; N® 130; Compound 1 40 mg tablet administered together with capsule containing 1.0 mg estradiol/0.5 mg norethisterone acetate for 24 weeks), compound 1 monotherapy group followed by co-administration of low-dose return hormone therapy (group B; N ® 130; tablet containing 40 mg compound 1 co-administered with a Compound 1 placebo tablet for 12 weeks followed by a tablet containing 40 mg Compound 1 co-administered with a 1.0 mg estradiol/0.5 mg norethisterone acetate capsule for 12 weeks) or placebo group (group C; N ® 130). Stratification variables will include: geographic region (North America or the rest of the world) and mean menstrual blood loss at screening (<225 ml or >225 ml) as determined by the alkaline hematin method. The study will consist of a screening period (up to ~13 weeks), a randomized treatment period (24 weeks) and an observation period (~30 days). In addition, unscheduled follow-up visits can be arranged for patients with study-related safety concerns and as needed. The diagnosis of uterine fibroids will be confirmed during the screening period with a centrally revised transvaginal ultrasound (with or without transabdominal ultrasound). Heavy menstrual bleeding will be defined as menstrual blood loss >80 ml per cycle for 2 cycles or >160 ml for 1 cycle during the screening period. During the randomized treatment period, study participants will take the blinded study drug once daily for 24 weeks. Women with iron deficiency microcytic anemia and hemoglobin > 8 g/dl and < 10 g/dl at screening should be on oral or parenteral iron replacement therapy. Between visits on baseline day 1 and week 24, patients will visit monthly (ie, every 4 weeks). During the screening visit and visits at week 12 and week 24, patients will have their bone mineral density assessed using dual energy X-ray absorptiometry (DXA). An endometrial biopsy will also be performed at screening. A transvaginal ultrasound (with or without transabdominal ultrasound) will be performed at 24 weeks. An endometrial biopsy will be performed at the week 24 visit only if scheduled (endometrial thickness anywhere >4 mm or if any other endometrial abnormality is seen on the week 24 ultrasound). Women's products will be standardized and will be collected and assessed for blood loss by the alkaline hematin method. Complete blood counts and biochemical tests will be performed monthly, and uterine and uterine fibroid volumes will be assessed during the screening visit and week 24 visit. Patients will complete electronic diaries (eDiary), including treatment adherence, menstrual bleeding, use of feminine products for menstrual bleeding, recording uterine fibroid-related pain on a numerical rating scale, and using painkillers to relieve pain caused by uterine fibroids. Examples of eDiary questions are shown in FIG. 180A-E. Quality of life questionnaires will be completed in accordance with the action plan. Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations including visual acuity testing, clinical laboratory tests, 12-lead electrocardiogram, paired endometrial biopsies in a subset of patients, and evaluation of bone mineral density. Height will be measured at Screening Visit 1 and weight will be measured at regular intervals. Samples will be collected for PK evaluation of compound 1, estradiol and norethisterone and for pharmacodynamic evaluation of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol and progesterone. All patients completing the week 24 visit, including women randomized to placebo, will be offered the opportunity to participate in an open-label extension study in which all eligible patients will receive Compound 1 in combination with low doses of estradiol and norethisterone acetate. Patients who do not enroll in the Extension Therapy Study will be scheduled to return approximately 30 days after the end of treatment (i.e. after the last dose of study drug taken by the patient).

Example 15 An international randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate Compound 1 administered with and without low doses of estradiol and norethisterone acetate in women with pain associated with endometriosis.

This study will be an international, randomized, double-blind, placebo-controlled phase 3 efficacy and safety study to evaluate oral doses of Compound 1 (relugolix) 40 mg once daily administered concomitantly for either 12 or 24 weeks low-dose estradiol (1.0 mg) and norethisterone acetate (0.5 mg) compared with placebo. Approximately 600 women with pain associated with endometriosis will be included and randomly

- 122 041715 zirovany in a ratio of 1:1:1 in the group of compound 1 with low-dose return hormone therapy (group A; N ® 200; tablet containing 40 mg of compound 1, administered together with a capsule containing 1.0 mg of estradiol/0, 5 mg norethisterone acetate for 24 weeks), Compound 1 monotherapy group followed by co-administration of low-dose reentrant hormonal therapy (group B; N® 200; Compound 1 40 mg tablet co-administered with estradiol/norethisterone acetate placebo capsule for 12 weeks followed by the administration of a tablet containing 40 mg of compound 1, together with a capsule containing 1.0 mg of estradiol/0.5 mg of norethisterone acetate, for 12 weeks) or placebo group (group C; N ® 200). Stratification variables will include: geographic region (North America or the rest of the world) and years after the surgical diagnosis of endometriosis (<5 or >5 years).

In eligible patients, endometriosis will be diagnosed or confirmed by laparoscopy or laparotomy within 10 years of the screening visit. In addition, patients will not have a history of chronic pelvic pain other than that caused by endometriosis and will not use opioid analgesics or frequent non-opioid analgesics for chronic pain or recurring pain other than pain caused by endometriosis. Patients receiving hormonal contraceptives will stop taking them 28-56 days before the start of the single-blind lead-in period. During the screening visit, patients will answer questions regarding the severity of dysmenorrhea and non-menstrual pelvic pain (NMPP). Only those whose pain is characterized as moderate, severe, or very severe for both dysmenorrhea and NMPP will receive additional screening visit and lead-in procedures. Patients who were not excluded by the results available at the end of the screening visit will receive an electronic diary (eDiary) and begin the 35-day lead-in period the next day. During the single-blind lead-in period, in which only patients will be blinded, patients will take one placebo tablet and one placebo capsule each day and record their pain and pain medication in eDiary daily. Starting on the second day of the Screening Visit (if the Screening Visit is for more than 1 day), only study-related pain medications will be allowed during the lead-in period and thereafter. These medications will be taken for pain control, not prevention. Final eligibility will depend on the severity of pain as defined by the specified Numerical Rating Scale (NRS) scores for dysmenorrhea and NMPP and the Patient's Global Impression of Change (PGIC) for NMPP obtained during the run-in period (Days R1 to R35 ). The 7-day window period (days R36 to R42) between the end of the run-in period and the date of randomization (D1) is designed to allow eligibility criteria to be confirmed and to schedule a visit on Baseline Day 1, coinciding with the first 14 days of the menstrual cycle. The NRS scores for dysmenorrhea and NMPP for the lead-in period (days R1 to R35) plus the 7-day window (days R36 to R42) will serve as the baseline pain score for the study. Run-in day 1 is defined as the day on which the first dose of study drug was taken in a single-blind manner. Once eligibility is confirmed, patients will be randomized on Baseline Day 1 and begin double-blind treatment with study drug on Day 1. During the randomized treatment period, study participants will take the blinded drug (1 tablet and 1 capsule) orally once daily within 24 weeks. The last dose of study drug will be taken the day before the week 24 visit. An endometrial biopsy will also be performed at screening. Transvaginal ultrasonography (with or without transabdominal ultrasonography) will be performed at 24 weeks followed by repeat endometrial biopsy.

Between baseline day 1 and week 24 visits, patients will return for visits every 4 weeks. During the lead-in period, and at week 12 and week 24 visits, each patient will have their bone mineral density assessed using dual energy X-ray absorptiometry (DXA). Patients will complete the eDiary from the day before run-in day 1 until the follow-up visit (including up to 7 days after run-in) to record study drug treatment, NRS pain assessment, menstrual bleeding and its severity, analgesic use, and functional effects of pain associated with endometriosis (Biberoglu and Behrman [sB&B] modified for subject use). Function assessment (using endometriosis health profile [ENP] - 30), completion of quality of life questionnaires, PGIC and Global Patient Assessment (PGA) for pain will be performed during the visits using an electronic tablet, and PGA for function will be performed using a paper questionnaire as outlined in the action plan. Patients will be allowed to use only protocol-recommended back-up analgesics in case of worsening symptoms, as outlined in the study reference manual, from the second day of the screening visit throughout the administration period until the end of the follow-up period.

Safety will be assessed throughout the study by monitoring adverse events, vital signs and weight, physical examinations, including

- 123 041715 Verification of visual acuity, clinical laboratory tests, 12-lead electrocardiogram (ECG) and bone mineral density using DXA. PDA samples will be collected to assess luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and progesterone levels at intervals during the study. Eligible patients, including women randomized to placebo, will be offered the opportunity to participate in a 28-week open-label extension study where patients will receive Compound 1 in combination with low doses of estradiol and norethisterone acetate. Patients who are not enrolled in the Extension Therapy Study will be scheduled for a follow-up visit approximately 30 days after the patient's last dose of study drug. Patients who do not transition to an extension study and have >2% loss of bone mineral density in the lumbar spine (L1L4) or hip joint relative to baseline measurements at Week 24/Early Discontinuation Visit will receive additional testing and follow-up observation to assess recovery. Patients who have not resumed menstruation at the time of the follow-up visit for unexplained reasons (eg, not explained by concomitant medications or medical procedures) will be contacted by phone to determine if menstruation has resumed. Patients with reduced visual acuity will be referred for consultation with an ophthalmologist.

Example 16 An international, open-label, non-comparative Phase 3 Extension Therapy Study to evaluate the efficacy and safety of long-term co-administration of Compound 1 with low doses of estradiol and norethisterone acetate in women with heavy menstrual bleeding associated with uterine fibroids.

This study will be an international, open-label, non-comparative Phase 3 extension study to evaluate long-term efficacy and safety, and will include eligible patients who have completed their participation in one of the randomized, double-blind, placebo-controlled phase 3 initial studies described in Example 13 and Example 14. All patients will receive compound 1 40 mg orally once daily co-administered with low doses of estradiol 1.0 mg and norethisterone acetate 0.5 mg for up to 28 weeks. The study will include about 600 women with heavy menstrual bleeding associated with uterine fibroids. The objectives of the study will be to evaluate the long-term efficacy and safety of up to 52 weeks of treatment (including treatment during the initial study) with Compound 1 co-administered with low doses of estradiol/norethisterone acetate. Eligible patients completed one of the original studies and consented to participate in this extension study. Screening and baseline treatments will be performed at the same visit in this extension study (referred to as week 24 visit/baseline visit in this study), which is the same visit as week 24 of the original study and will be defined as the end date of the last treatment of the initial study. week 24 week visit/baseline visit will include vital signs, physical examination, laboratory evaluations, 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, transvaginal ultrasound, and endometrial biopsy ( if necessary). After completion of the initial study procedures at week 24, the investigator evaluates the patient's eligibility to participate in an open-label extension study. The fit assessment will be based on data available at the time of the 24 week/baseline visit. Study procedures will not be performed before signing the Consent Form for this Extension Therapy Study.

Patients will receive their last dose of study drug in the Initial Study the day before the Week 24 visit/baseline visit and will receive their first dose of study drug in this extension study at the clinic after the patient is determined to be eligible for this extension study, and providing them with informed consent to participate. Administration of the first dose of study drug for this study will determine participation in this study. Study participants will then receive the unmasked study drug (Compound 1) at a dose of 40 mg co-administered with 1.0 mg of estradiol and 0.5 mg of norethisterone acetate orally once a day for 28 weeks.

At the week 36 visit and week 52 visit/early discontinuation visit, each patient will have a dual energy x-ray absorptiometry (DXA) assessment of bone mineral density. Quality of life questionnaires will be completed in accordance with the action plan. Safety will be assessed throughout the study by monitoring side effects, vital signs and weight, physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, and transvaginal ultrasound.

Patients with >3% loss of bone mineral density in the lumbar spine (L1-L4) or hip joint at week 52 visit/early discontinuation visit

- 124 041715 The baseline measurements of the original study will be subjected to another bone densitometric scan after 6 (±1) months. The status of menses recovery will be documented at the follow-up visit. Patients who have not resumed menstruation since the follow-up visit with no explicable reasons for not resuming (e.g., due to medical procedures or medications) will be contacted by phone again 3 (+0.5) months after the follow-up visit to determine whether menstruation has resumed and ask about factors that may affect the resumption of menstruation. If the patient enrolls directly in another Compound 1 clinical study after the completion of the week 52 visit, then the follow-up visit and follow-up procedures performed in accordance with this protocol, including follow-up bone densitometry at 6 (±1) months and menses recovery status, may be cancelled.

Example 17 An open-label, randomized, three-way, phase 1 crossover study to evaluate the relative bioavailability and effect of food on Compound 1 tablet formulations in healthy subjects.

The study was an open-label, randomized, three-way, single-dose, crossover study designed to evaluate the oral bioavailability of two candidate compound 1 tablet formulations (formulation T4 B and formulation T4 C) compared to a third tablet formulation of Compound 1 (formulation T2) and the effect of food on Compound 1 PK after oral administration of T4 formulations B and C. Five single dose regimens were used.

Scheme A: 120 mg dose of formulation T2 compound 1 on an empty stomach.

Scheme B: 120 mg dose of T4 B compound 1 on an empty stomach.

Regimen C: Dose of 120 mg T4B Compound 1 postprandial (standard (FDA) high-calorie, high-fat breakfast).

Scheme D: 120 mg dose of compound 1 T4C on an empty stomach.

Regimen E: 120 mg dose of Compound 1 T4C formulation after a meal (standard (FDA approved) high-calorie, high-fat breakfast).

Screening evaluations were performed for 28 days prior to Compound 1 dosing on Day 1. After eligibility was confirmed, subjects were randomly assigned in sequence to one of two treatment groups.

Group 1: formulation T2 (scheme A serves as control group) and formulation T4 B (schemes B and C).

Group 2: Formulation T2 (Scheme A serves as control group) and Formulation T4 C (Schemes D and E).

In each study group, each subject participated in 3 treatment periods with a 10-day washout interval between each dose. Subjects received a single 120 mg oral dose of Compound 1 on Day 1, Day 11, and Day 21 for each assigned cohort and sequence, followed by serial PK blood draws at predetermined time points up to 120 hours post-dose. During each of the 3 treatment periods, subjects were required to be present at the clinical center for a total of 4 days. Each eligible subject was required to register at the clinical center on the evening of the first day and complete baseline safety assessments.

Subjects were required to be present at the clinical center from the first to the fourth day. After taking blood samples for PK assessment on day 4 (72 hours post-dose), patients were discharged from the clinical center. Subjects were asked to return to the study clinic on the morning of Day 5 for a 96-hour PK assessment and on the morning of Day 6 for a 120-hour PK assessment. Subjects were to return to the study clinic on the evening of Day 10 and stay from Day 10 to Day 14. After blood sampling for PK assessment on Day 14 (72 hours post-dose), patients were discharged from the clinical center. Subjects were asked to return to the study clinic on the morning of Day 15 for a 96 hour PK assessment and on the morning of Day 16 for a 120 hour PK assessment. Subjects were to return to the study clinic on the evening of Day 20 and stay from Day 20 to Day 24. After blood sampling for PK assessment on Day 24 (72 hours post-dose), patients were discharged from the clinical center. Subjects were asked to return to the study clinic on the morning of Day 25 for a 96-hour PK assessment and on the morning of Day 26 for a 120-hour PK assessment. Study drug was administered in the morning on days 1, 11 and 21 after a meal or on an empty stomach. During their stay in the clinic, subjects received standard meals at scheduled appointments at the same time each day. For each subject, vital signs, physical examination results, assessment of adverse events, laboratory parameters (blood chemistry, complete blood count, and urinalysis), and 12-lead electrocardiograms were obtained to assess the safety and tolerability of Compound 1. Subjects were considered to have completed study if they completed each of the 3 treatment periods and were assessed at the end of the study (EOS) (30 days after the last dose of study drug). Subjects could withdraw from the study at any time. Each subject was required to be a healthy adult male between the ages of 18 and 55 (inclusive), which

- 125 041715 would be included in this study. Tab. 22 and 23 summarize the group 1 treatment and group 2 treatment during this study.

Table 22

Sequences of treatment periods for group 1

Sequences Period 1________Period 2______Period 3

1 Scheme A ^b Scheme B ^with Scheme ^Cd 2 Scheme A Scheme C Scheme B 3 Scheme B Scheme A Scheme C 4 Scheme B Scheme C Scheme A 5 Scheme C Scheme A Scheme B 6 Scheme C Scheme B Scheme A

^a The duration of each treatment period was 10 days.

Subjects received single doses of compound 1 on the first day of each treatment period (ie day 1, day 11 and day 21).

^b Scheme A: 120 mg dose (tablets 80 mg + 40 mg) of formulation T2 compound 1 on an empty stomach.

^c Regimen B: 120 mg dose (1x120 mg tablet) formulation T4 B of Compound 1 on an empty stomach.

^d Regimen C: 120 mg dose (1 x 120 mg tablet) of Compound 1 T4B post-prandial (standard (FDA approved) high-calorie, high-fat breakfast).

Table 23 _______ Sequence of treatment periods for group 2_______

Sequence Period 1 Period 2 Period 3

1 Scheme A ^b Scheme ^Dc Scheme E ^d 2 Scheme A Scheme E Scheme D h Scheme D Scheme A Scheme E 4 Scheme D Scheme E Scheme A 5 Scheme E Scheme A Scheme D 6 Scheme E Scheme D Scheme A

^a The duration of each treatment period was 10 days.

Subjects received single doses of compound 1 on the first day of each treatment period (ie day 1, day 11 and day 21).

^b Scheme A: 120 mg dose (tablets 80 mg + 40 mg) of formulation T2 compound 1 on an empty stomach.

c Regimen D: 120 mg dose (1x120 mg tablet) formulation T4 C Compound 1 on an empty stomach.

^d Regimen E: 120 mg dose (1 x 120 mg tablet) of Compound 1 T4C composition after meals (standard (FDA-compliant) high-calorie, high-fat breakfast).

A total of 54 patients were included in the study and completed the study. There were 27 subjects in each study group. All 54 patients were included in the safety analysis population and the PK assessment population. During this study, there were no major deviations from the protocol for any subject. One subject had a slight deviation from the protocol associated with the dosing interval, which occurred more than 30 minutes after the start of breakfast. In period 3, the subject was administered the T4 B formulation under postprandial conditions; the time to start dosing Compound 1 after the start of breakfast was 31 minutes and 3 seconds. All PK parameters in this subject after oral administration of formulation T4B under postprandial conditions were basically similar to the mean PK parameters in this treatment group; therefore, the PK parameters of this subject were included in the descriptive analysis and statistical analysis of variance. In table. 24 and 25 below are summaries of some pharmacokinetic parameters following administration of various formulations.

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Table 24

Summary Statistics of Plasma Pharmacokinetic Parameters of Compound 1 Following a Single Oral Dosage of 120 mg of Compound 1 as Formulation T4 B or C in Tablet Form as Compared to Fasting Formulation T2 Tablets

Parameter (unit) Statistical cue data Group 1 Group 2 Form T2. Form T4. IN Form T2. Form T4. WITH N 27 26 27 27 tmax (h) Median 2.01 3.00 3.00 3.00 meaning Min, max 0.500, 6.00 0.502, 12.0 0.499, 6.02 0.499, 12.0 Stax (ng/ml) SG 46.7 42.0 52.0 43.5 sq% 115 153 93.3 147 AUC120 (ng"h/ml) SG 447 440 532 415 KV% 64.7 83.3 55.4 85.1 AUCco (ng"h/ml) SG 476 467 563 440 KV% 63.5 82.8 55.1 84.8 ti/2z (h) average 36.3 36.1a 34.9 35.5 SO 4.40 4.90 4.13 4.22 Min, max 28.8, 46.5 27.4, 44.7 29.2, 44.8 25.4, 46.0

KB - geometric coefficient of variation;

SG - geometric mean.

(a) N = 27.

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Table 25

Summary statistics of plasma pharmacokinetic parameters of compound 1 after a single oral administration of 120 mg of compound 1 in the form of a T4 formulation B or C in the form of a tablet after a meal Parameter (unit)

Composition T4 B Composition T4 C

Statistical data

N 27 27 tmax (h) median value 3.00 3.00 Min, max 0.500, 8.00 1.00, 8.00 Stach (NG/ML) sg 33.0 41.2 sq% 116 106 AUC120 (ng»h/ml) sg 350 386 sq% 65.0 52.4 AUCco (ng»h/ml) 372 409 sg sq% 64.1 51.8 tl/2z (h) Average value 35.1 35.4 SO 4,I 2.97 Min, max 29.9, 45.7 29.9, 42.2

KB - geometric coefficient of variation; SG - geometric mean.

All subjects included in this study were healthy males, most of whom were white (81%) and Hispanic or Latino (65%). The overall mean (SD) age of the subjects was 38.9 (10.8) years with an age range of 19 to 55 years. The total mean (SD) weight and BMI of the subjects were 83.4 (12.7) kg and 27.2 (3.2) kg/m ² , respectively. The demographic characteristics of the treatment groups were similar. No subject was excluded from the PK assessment population; therefore, the demographics for this population were the same as those in the safety assessment population. Composition information for the various formulations used in this example and other formulation examples is presented in Table 1. 26.

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Table 26 Exemplary formulations

Function 1-20 mg (T1) 40 mg (T2) 40 mg (TK) 40 mg (T4-B) 120 mg (T4-B) 120 mg (T4-S) Compound 1 SW 1-20 40 40 40 120 120 Mannitol Thinner 80-61 122 122 51 153 234 Microcrystalline cellulose Thinner 10 20 40 - - thirty Polyethylene glycol b 8000 lubricate schee substance - - - - - 1.8 Hydroxypropyl cellulose I bind schee substance 3 6 6 3 9 I,4 Croscarmellose sodium Baking powder 5 10 10 - - 19.05 Sodium starch glycolate Baking powder - - - 5 15 - magnesium stearate lubricate schee substance 1 2 2 1 3 3.75 Purified water* will dissolve spruce in sufficient quantity in sufficient quantity in sufficient quantity in sufficient quantity in sufficient quantity in the rest Intermediate 100 220 220 100 300 420

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total (tablet core) Hypromellose 2910 Film coating 2.93 7.12 7.12 3.56 10.68 13.5 Polyethylene glycol b 8000 Plastifier 0.67 - - - - - Titanium dioxide Pigment 0.33 0.8 0.8 0.4 1.2 1.5 Iron oxide, red Dye 0.07 0.02 0.02 0.04 0.12 0.15 Iron oxide, yellow Dye - - 0.06 - - - Purified water* in sufficient quantity in sufficient quantity in sufficient quantity in sufficient quantity in sufficient quantity in the rest Subtotal (film coating layer) 4 8 8 4 12 15.15 Total 104 228 228 104 312 435.15 carnauba wax 0.012 0.004 0.008 in the rest

Example 18 Endometriosis Symptom Scale (SEMS) Confirmation.

This qualitative study was conducted in 15 women with endometriosis and at least mild pain associated with endometriosis to assess the comprehensibility of the SEMS scale. Subjects represented a variety of races, ethnic groups, and educational levels, including 7 (47%) with only upper secondary education. In general, most of the subjects demonstrated the correct interpretation of instructions, elements and answer options for all tested indicators. In particular, the primary NRS endpoints for dysmenorrhea severity and NRS for NMPP severity were correctly interpreted by 100% of subjects. In addition, all SEMS-rated concepts were rated as relevant by 11 or more subjects (>73%); the following three concepts were tested by all 15 subjects (100.0%): pelvic pain, heavy bleeding, and medication for pelvic pain. For the concept of pelvic pain, the most significant aspect of improvement for subjects was reduction in severity (73% of subjects). Overall, subjects found it easy to recall their symptoms during the past 24 h (n = 14, 93.3%), the NRS assessment period used for co-primary endpoints. Potential anchors for the concurrent endpoints of PGIC for dysmenorrhea, PGIC for NMPP, and PGA for pain were also interpreted as being specific to 100% of subjects. Of the 14 subjects interviewed for PGIC, 11 (79%) expressed no difficulty in distinguishing 7 categories, suggesting that the majority were able to distinguish 1 category differences. Similarly, the majority (~93%) of subjects had no difficulty distinguishing the 5 PGA categories for pain. The usability of both ePRO devices (phone and tablet) was rated very highly by the test subjects. The content and comprehensibility of the tools for obtaining patient outcome measures, in particular the scores for the concurrent primary endpoints and the key secondary endpoint, were validated for the EHP-30 Pain Inventory without any major gaps in the concepts included in the EHP-30 Pain Inventory. thirty.

In FIG. 181 is a summary of the cognitive survey results for each unique set of response options. To assess the relevance of the concepts included in SEMS, participants were asked or spontaneously asked to report whether they experienced the symptoms included in SEMS. In FIG. 182

- 130 041715 provides a summary of each of the concepts measured by the SEMS assessed in this example, along with the number of subjects who reported the relevance of that concept. In FIG. 183AC compares symptoms reported by subjects with patient reported outcomes (PRO), such as endpoints that can be used to evaluate the effectiveness of one or more treatments. In table. 27 summarizes the self-reported demographics of the subjects in this study.

Table 27

Demographic Information

Characteristics Total samples (N = 15) and (%) Age (in years) Range 25-49 Average value (SD) 33.87 (7.74) Floor female 15 (100.0%) Race (anything that suits the chosen one) White 11 (73.3%) Black or African American 4 (26.7%) Ethnicity Not Spanish or Latin American origin 13 (86.7%) Spanish or Latin American origin 2 (13.3%) Highest level of education High school graduate (or equivalent) 7 (46.7%)

Listed Embodiments

Option I-1. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis or adenomyosis in a premenopausal woman.

Option I-2. Combination preparation for use according to embodiment I-1, wherein the treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-3. Combination preparation for use according to Embodiment I-1 or Embodiment I-2, wherein the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg.

Option I-4. A combination preparation for use according to any one of Embodiments I-1 to I-3, wherein the combination preparation contains about 20 to about 50 mg of N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylαmino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyρimidin-6-yl)phenyl)-N' -methoxyurea or the corresponding amount of its pharmaceutically acceptable salt.

Option I-5. Combination preparation for use according to any of embodiments I-1 to I-4, wherein the combination preparation contains 40 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate pharmaceutical amount thereof acceptable salt.

Option I-6. Combination preparation for use according to any one of embodiments I-1 to I-5, wherein the combination preparation contains about 1 mg of estradiol or the corresponding amount of estradiol equivalent.

Option I-7. Combination preparation for use according to any one of embodiments I-1 to I-6, wherein the progestin is norethisterone acetate (NETA) and the combination preparation contains about 0.5 mg of NETA.

Option I-8. Combination preparation for use according to any one of embodiments I-1 to I-7, wherein the combination preparation contains about 0.5 mg of NETA, about 1

- 131 041715 mg of estradiol and about 40 mg No. ,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-9. Combination preparation for use according to any one of embodiments I-1 to I-8, wherein the combination preparation is in a unit dosage form.

Option I-10. Combination preparation for use according to any one of embodiments I-1 to I-8, wherein the combination preparation comprises separate dosage forms that are administered together.

Option I-11. A combination preparation for use according to any one of Embodiments I-1 to I-10, wherein prior to administration of the combination preparation, treatment further comprises oral administration once daily of about 10 to about 60 mg of N-(4-(1 -(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine- 6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

Option I-12. Combination preparation for use according to any one of embodiments I-1 to I-11, wherein the combination preparation is for use in the treatment of endometriosis.

Option I-13. Combination preparation for use according to any one of embodiments I-1 to I-12, wherein the combination preparation is for use in the treatment of adenomyosis.

Option I-14. Combination preparation for use according to any one of embodiments I-1 to I-13, wherein the combination preparation is for use in the treatment of uterine fibroids.

Option I-15. Combination preparation for use according to any one of embodiments I-1 to I-14, wherein the combination preparation is for use in the treatment of heavy menstrual bleeding.

Option I-16. Combination preparation for use according to embodiment I-15, where heavy menstrual bleeding is associated with a non-malignant etiology.

Option I-17. Combination preparation for use according to embodiment I-15 or I-16, wherein heavy menstrual bleeding is associated with one or more of uterine fibroids, endometriosis, or adenomyosis.

Option I-18. Combination preparation for use according to any one of embodiments I-1 to I-17, wherein the combination preparation is for use in the treatment of pain associated with uterine fibroids, endometriosis, or adenomyosis.

Option I-19. Combination preparation for use according to embodiment I-18 wherein pain is associated with endometriosis.

Option I-20. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount the equivalent of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for maintaining bone mineral density in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administration of N-(4-(1 -(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d] pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-21. A combination preparation for use according to embodiment I-20, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-22. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: hot flashes, night sweats and other vasomotor symptoms in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis or profuse menstrual bleeding, administration of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2, 3,4-tetrahydrothieno[2,3

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d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-23. A combination preparation for use according to embodiment I-22, wherein the treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-24. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount the equivalent of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of maintaining one or more of the following: lipid profile or range of blood glucose levels in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or profuse menstrual bleeding, administration of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2, 3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-25. A combination preparation for use according to embodiment I-24, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-26. A combination product for use according to embodiment I-24 or I-25, wherein one or more of the following in a premenopausal woman: lipid profile or blood glucose range does not change in a clinically significant manner after or during treatment compared to with lipid profile or range of blood glucose levels prior to treatment.

Option I-27. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of treating one or both of vulvovaginal atrophy or vaginal dryness in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N -(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[ 2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-28. A combination preparation for use according to embodiment I-27, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-29. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount the equivalent of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of treating headache in a premenopausal woman, wherein the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1- (2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-30. A combination preparation for use according to embodiment I-29, wherein the treatment comprises oral administration of the combination preparation to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-31. Combination preparation for use according to embodiment I-29 or I-30, wherein the headache is a migraine associated with the menstrual cycle.

Option I-32. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method of contraception in a woman in premenopause.

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Option I-33. A combination preparation for use according to embodiment I-32, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 24 consecutive weeks.

Option I-34. A combination preparation for use according to any one of embodiments I-20 to I-33, wherein the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg.

Option I-35. A combination preparation for use according to any one of Embodiments I-20 to I-34, wherein the combination preparation contains about 20 to about 50 mg of N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea or the corresponding amount of its pharmaceutically acceptable salt.

Option I-36. Combination preparation for use according to any of Embodiments I-20 to I-35, wherein the combination preparation contains about 40 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl) -3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount thereof pharmaceutically acceptable salt.

Option I-37. Combination preparation for use according to any one of embodiments I-20 to I-36, wherein the combination preparation is in a unit dosage form.

Option I-38. Combination preparation for use according to any one of embodiments I-20 to I-36, wherein the combination preparation comprises separate dosage forms that are administered together.

Option I-39. Combination preparation for use according to any one of embodiments I-20 to I-38, wherein the combination preparation contains about 1 mg of estradiol or the corresponding amount of estradiol equivalent.

Option I-40. A combination preparation for use according to any of embodiments I-20 to I-39, wherein the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

Option I-41. Combination preparation for use according to any of Embodiments I-20 to I-40, wherein the combination preparation contains about 0.5 mg NETA, about 1 mg estradiol, and about 40 mg N-(4-(1-(2 ,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-42. A combination preparation for use according to any one of Embodiments I-20 to I-41, wherein, prior to administering the combination preparation, the method further comprises administering orally once daily about 10 to about 60 mg of N-(4-(1 -(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine- 6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

Option I-43. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for achieving amenorrhea in a premenopausal woman for at least 12 or at least 24 weeks.

Option I-44. A combination preparation for use according to embodiment I-43, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks.

Option I-45. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount the equivalent of estradiol and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for increasing fertility or preventing miscarriage in a premenopausal woman, in which the premenopausal woman is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-( 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

- 134 041715

Option I-46. A combination preparation for use according to embodiment I-45, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks and stopping treatment for at least 4 weeks while a woman is trying or trying to conceive.

Option I-47. Combination preparation containing from about 10 to about 60 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; for simultaneous or sequential use in a method for the treatment of anemia in a premenopausal woman.

Option I-48. A combination preparation for use according to embodiment I-47, wherein the method comprises administering the combination preparation orally to a premenopausal woman once daily for at least 12 or at least 24 consecutive weeks.

Option I-49. A combination preparation for use according to any one of embodiments I-43 to I-48, wherein a premenopausal woman is experiencing heavy menstrual bleeding.

Option I-50. Combination preparation for use according to embodiment I-49, wherein heavy menstrual bleeding is associated with a non-malignant etiology.

Option I-51. Combination preparation for use according to any of embodiments I-43 to I-50, wherein the premenopausal woman has one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or symptoms associated with one or several of the following conditions: uterine fibroids, endometriosis, or adenomyosis.

Option I-52. Combination preparation for use according to any one of embodiments I-1 to I-51, wherein the combination preparation is administered once a day for at least 48 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks.

Option I-53. Combination preparation for use according to any one of embodiments I-1 to I-52, wherein administration of the combination preparation is suspended for conception and pregnancy.

Option I-54. Combination preparation for use according to embodiment I-53 wherein administration is resumed after delivery.

Option I-55. A combination preparation for use according to any one of embodiments I-1 to I54, wherein the combination preparation is administered prior to a meal.

Option I-56. Combination preparation for use according to any one of embodiments I-1 to I-55, wherein administration is at least 30 minutes before a meal or on an empty stomach.

Option I-57. A combination preparation for use according to any one of Embodiments I-1 to I-56, wherein the combination preparation is administered at least 1 hour before a meal or at least 2 hours after a meal.

Option I-58. A combination preparation for use according to any one of embodiments I-1 to I-57, wherein the combination preparation is administered in one or more immediate release dosage forms.

Option I-59. Combination preparation containing from about 65 to about 140 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol, or an equivalent amount of estradiol, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin; for simultaneous or sequential use in the treatment of symptoms of uterine fibroids or endometriosis in a premenopausal woman.

Option I-60. A combination preparation for use according to embodiment I-59, wherein the treatment comprises administering the combination preparation to said woman once a day.

Option I-61. Combination preparation for use according to embodiment I-59 or I-60, wherein administration of the combination preparation suppresses the endometrium.

Option I-62. Combination preparation for use according to any one of embodiments I-59 to I-61, wherein the combination preparation is in a unit dosage form.

Option I-63. Combination preparation containing from about 65 to about 140 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable thereof

- 135 041715 my salt; about 1.5 to about 5.0 mg of estradiol, or an equivalent amount of estradiol, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin; for simultaneous or sequential use in the treatment of one or more of the following conditions: hot flashes, night sweats, vasomotor symptoms other than hot flashes or night sweats, and loss of bone mineral density in a premenopausal woman who continues to show one or more of the following symptoms: hot flashes and other vasomotor symptoms and loss of bone mineral density, when administered orally once daily combinations of about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl) -3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of it a pharmaceutically acceptable salt, about 1.0 mg of estradiol, and about 0.5 mg of norethisterone acetate, the treatment comprising administering the combined preparation to said premenopausal woman.

Option I-64. Combination preparation for use according to embodiment I-63, wherein administration of the combination preparation suppresses endometrial tissue.

Option I-65. A method of treating one or more of the following conditions: uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman in need thereof, the method comprising administering orally to the premenopausal woman once a day for at least 24 consecutive weeks of a combination containing: about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-66. The method of Embodiment I-65 wherein the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg.

Option I-67. The method of Embodiment I-65 or I-66 wherein the combination contains about 20 to about 50 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-( 6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-68. The method of any one of Embodiments I-65 to I-67 wherein the combination contains about 40 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-69. The method of any one of embodiments I-65 to I-68, wherein the combination contains about 1 mg of estradiol, or an equivalent amount of estradiol equivalent.

Option I-70. The method of any of embodiments I-65 to I-69 wherein the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

Option I-71. The method of any one of embodiments I-65 to I-70 wherein the combination contains about 0.5 mg NETA, about 1 mg estradiol, and about 40 mg N-(4-(1-(2,6-difluorobenzyl)- 5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N '-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-72. The method of any one of Embodiments I-65 to I-71 wherein the combination is in unit dosage form.

Option I-73. The method of any one of embodiments I-65 to I-71 wherein the combination comprises separate dosage forms that are administered together.

Option I-74. The method of any one of embodiments I-65 to I-73, wherein the treatment results in one or both of contraception and amenorrhea during treatment.

Option I-75. The method of any one of embodiments I-65 to I-74, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of estrogen in a premenopausal woman is suppressed.

Option I-76. The method of any one of embodiments I-65 to I-75, wherein after at least 4 consecutive weeks of administration of the combination, the serum concentration of estradiol in a premenopausal woman is from about 20 to about 50 pg/mL between daily doses of the combination.

Option I-77. The method of any one of embodiments I-65 to I-76, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone in a premenopausal woman is suppressed.

Option I-78. The method of any one of embodiments I-65 to I-77, wherein after at least 4 consecutive weeks of administration of the combination, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination.

Option I-79. The method of any one of Embodiments I-65 to I-78 wherein, prior to administering the combination, the method further comprises oral administration once a day for about

- 136 041715 to about 60 mg N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1, 2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

Option I-80. The method according to any one of embodiments I-65 to I-79, wherein during and/or after treatment, the premenopausal woman experiences an improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, heavy menstrual bleeding, irregular periods, bleeding, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, urinary incontinence, constipation, anxiety, sleep disturbances, quality of life, daily activities, female sexual dysfunction and depression.

Option I-81. The method of any one of embodiments I-65 to I-80, wherein the premenopausal woman is treated for endometriosis.

Option I-82. The method of any of embodiments I-65 to I-81, wherein the premenopausal woman is treated for adenomyosis.

Option I-83. The method of any one of embodiments I-65 to I-82, wherein the premenopausal woman is treated for uterine fibroids.

Option I-84. The method of any one of embodiments I-65 to I-83, wherein one or both of the number and size of uterine fibroids decrease during and/or after treatment compared to one or both of the number and size of uterine fibroids before treatment.

Option I-85. A method of treating heavy menstrual bleeding in a premenopausal woman in need thereof, the method comprising administering orally to the premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing from about 10 to about 60 mg N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-86. The method of embodiment I-85 wherein heavy menstrual bleeding is associated with a non-cancerous etiology.

Option I-87. The method of embodiment I-85 or I-86 wherein the heavy menstrual bleeding is associated with one or more of uterine fibroids, endometriosis, or adenomyosis.

Option I-88. The method of any one of embodiments I-85 to I-87, wherein in a premenopausal woman with uterine fibroids, one or both of the number and size of uterine fibroids decrease during and/or after treatment compared to one or both of the number and size of uterine fibroids before treatment.

Option I-89. A method of treating pain associated with uterine fibroids, endometriosis, or adenomyosis in a premenopausal woman in need thereof, the method comprising oral administration to the premenopausal woman in need thereof once daily for at least 24 consecutive weeks of the combination containing from about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-90. The method of embodiment I-89 wherein the pain is associated with endometriosis.

Option I-91. The method of any one of embodiments I-85 to I-90 wherein the progestin is norethisterone or a salt thereof in an amount of from about 0.1 mg to about 0.5 mg.

Option I-92. The method of any one of Embodiments I-85 to I-91 wherein the combination contains about 20 mg to about 50 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl) -3-(6-methoxy3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount thereof pharmaceutically acceptable salt.

Option I-93. The method of any one of Embodiments I-85 to I-92 wherein the combination contains about 40 mg of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-94. The method of any one of Embodiments I-85 to I-93 wherein the combination is in unit dosage form.

Option I-95. The method of any one of embodiments I-85 to I-93, wherein the combination comprises separate dosage forms that are administered together.

Option I-96. The method of any one of embodiments I-85 to I-95, wherein the combination contains about 1 mg of estradiol, or an equivalent amount of estradiol equivalent.

Option I-97. The method of any of embodiments I-85 to I-96 wherein the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

Option I-98. The method of any one of Embodiments I-85 through I-97, wherein the combination

- 137 041715 contains about 0.5 mg NETA, about 1 mg estradiol and about 40 mg Na(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3 -pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-99. The method of any one of embodiments I-85 to I-98, wherein the treatment results in one or both of contraception and amenorrhea during treatment.

Option I-100. The method of any one of embodiments I-85 to I-99, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of estrogen in a premenopausal woman is suppressed.

Option I-101. The method of any one of embodiments I-21 to I-100, wherein after at least 4 consecutive weeks of administration of the combination, the serum estradiol concentration in a premenopausal woman is between 20 and 50 pg/mL between daily doses of the combination.

Option I-102. The method of any one of embodiments I-85 to I-101, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone in a premenopausal woman is suppressed.

Option I-103. The method of any one of embodiments I-85 to I-102, wherein after at least 4 consecutive weeks of administration of the combination, the premenopausal woman's serum progesterone concentration is less than about 5 ng/mL between daily doses of the combination.

Option I-104. The method of any one of Embodiments I-85 to I-103 wherein, prior to administering the combination, the method further comprises orally administering once daily about 10 to about 60 mg of N-(4-(1-(2,6 -difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl )phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

Option I-105. The method according to any one of embodiments I-85 to I-104, wherein during and/or after treatment, the premenopausal woman experiences improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, irregular menses, blood discharge, inflammation, pain, fatigue, urinary tract obstruction, urinary frequency, urinary incontinence, constipation, anxiety, sleep disturbances, quality of life, daily activities, female sexual dysfunction, and depression.

Option I-106. The method of any one of embodiments I-65 to I-105, wherein said premenopausal woman becomes pregnant or gives birth upon discontinuation of treatment.

Option I-107. The method of I-106, wherein the premenopausal woman has experienced one or more miscarriages, or an inability to conceive, or a combination of such conditions prior to treatment.

Option I-108. A method of maintaining bone mineral density in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1-(2,6difluorobenzyl) -5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl) -N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising administering orally to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing from about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or the appropriate amount of a pharmaceutically acceptable salt thereof, from about 0.5 to about 2 mg of estradiol, or the appropriate amount of the equivalent of es tradiol and about 0.01 to about 5 mg of progestin.

Option I-109. A method of treating one or more of the following conditions: hot flashes, night sweats, or vasomotor symptoms other than hot flashes or night sweats in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding, by administration of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylαmino)methyl)-3-(6-methoxu-3-nurudαzenil)-2,4-duoxo-1 ,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising orally administering to a premenopausal woman in need thereof, one once daily for at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or the corresponding amount of headlights thereof a maceutically acceptable salt; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-110. A method of maintaining one or more of the following: lipid profile or blood glucose range in a premenopausal woman in need thereof, who

- 138 041715 is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administration of K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3 -(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt, the method comprising administering orally to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing about 10 to about 60 mg K-(4-(1-(2, 6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6- yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol, and about 0.01 to about 5 mg of progestin; wherein one or more of the following in a premenopausal woman: the lipid profile or range of blood glucose levels does not change in a clinically significant manner after or during treatment compared to the lipid profile or range of blood glucose levels before treatment.

Option I-111. A method of treating one or both of the following conditions: vulvovaginal atrophy or vaginal dryness in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering K-(4 -(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3 -d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof once a day for at least 24 consecutive weeks a combination containing about 10 to about 60 mg K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-112. A method of treating headache in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering K-(4-(1-(2,6-difluorobenzyl )-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl) -N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising administering orally to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing about 10 to about 60 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, from about 0.5 mg to about 2 mg of estradiol, or an appropriate amount of an equivalent of estradiol, and from about about 0.01 to about 5 mg progestin.

Option I-113. The method of Embodiment I-112 wherein the headache is a migraine associated with the menstrual cycle.

Option I-114. A method of contraception in a premenopausal woman in need thereof, the method comprising orally administering to a premenopausal woman in need thereof, once daily for at least 24 consecutive weeks, a combination containing from about 10 to about 60 mg K- (4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2 ,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-115. The method of any one of embodiments I-108 to I-114 wherein the progestin is norethisterone or a salt thereof in an amount of about 0.1 to about 0.5 mg.

Option I-116. The method of any one of embodiments I-108 to I-115 wherein the combination contains about 20 to about 50 mg of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl) -3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate pharmaceutical amount thereof acceptable salt.

Option I-117. The method of any one of embodiments I-108 to I-116 wherein the combination contains about 40 mg K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-( 6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-118. The method of any one of Embodiments I-108 to I-117, wherein the combination is in unit dosage form.

Option I-119. The method of any one of embodiments I-108 to I-117, wherein the combination comprises separate dosage forms that are administered together.

Option I-120. The method of any one of Embodiments I-108 through I-119, wherein the combination

- 139 041715 tion contains about 1 mg of estradiol or the equivalent amount of estradiol.

Option I-121. The method of any of embodiments I-108 to I-120 wherein the progestin is norethisterone acetate (NETA) and the combination contains about 0.5 mg of NETA.

Option I-122. The method of any one of embodiments I-108 to I-121, wherein the combination contains about 0.5 mg NETA, about 1 mg estradiol, and about 40 mg N-(4-(1-(2,6-difluorobenzyl)- 5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N '-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option I-123. The method of any one of embodiments I-108 to I-122, wherein the treatment results in one or both of contraception and amenorrhea during treatment.

Option I-124. The method of any one of embodiments I-108 to I-123, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of estrogen in a premenopausal woman is suppressed.

Option I-125. The method of any one of embodiments I-108 to I-124, wherein after at least 4 consecutive weeks of administration of the combination, the serum estradiol concentration in a premenopausal woman is between 20 and 50 pg/mL between daily doses of the combination.

Option I-126. The method of any one of embodiments I-108 to I-125, wherein after at least 4 consecutive weeks of administration of the combination, ovarian production of progesterone is suppressed in a premenopausal woman.

Option I-127. The method of any one of embodiments I-108 to I-126, wherein after at least 4 consecutive weeks of administration of the combination, the serum progesterone concentration in a premenopausal woman is less than about 5 ng/mL between daily doses of the combination.

Option I-128. The method of any one of embodiments I-108 to I-127, wherein in a premenopausal woman with uterine fibroids, one or both of the number and size of uterine fibroids decrease during and/or after treatment compared to one or both of the number and size of uterine fibroids before treatment.

Option I-129. The method of any one of Embodiments I-108 to I-128, wherein prior to administering the combination, the method further comprises orally administering once daily about 10 to about 60 mg of N-(4-(1-(2,6 -difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl )phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for at least 4 consecutive weeks and up to 24 consecutive weeks.

Option I-130. The method according to any one of embodiments I-108 to I-129, wherein during and/or after treatment, the premenopausal woman experiences an improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, irregular menstruation, blood discharge, inflammation, pain, fatigue, urinary tract obstruction, urinary frequency, urinary incontinence, constipation, anxiety, sleep disturbances, quality of life, daily activities, female sexual dysfunction, and depression.

Option I-131. A method of achieving amenorrhea in a premenopausal woman in need thereof for at least 12 or at least 24 weeks, the method comprising oral administration to the premenopausal woman in need once a day for at least 12 or at least 24 consecutive weeks of a combination containing about 10 to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3 -pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-132. A method of preventing miscarriage in a premenopausal woman in need thereof who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding by administering N-(4-(1-(2,6difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea, the method comprising orally administering to a premenopausal woman in need thereof, once daily for at least 12 or at least 24 consecutive weeks, a combination containing about 10 to about 60 mg of N-( 4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3,4-tetrahydrothieno[2 ,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, about 0.5 to about 2 mg of estradiol, or an appropriate amount of an equivalent of estradiol, and about 0.01 to about 5 mg progestin; and stopping treatment for at least 4 weeks while the woman tries to conceive again.

Option I-133. A method of increasing fertility in a premenopausal woman in need thereof, who is being treated for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administering N-(4-(1-(2,6-difluorobenzyl) -5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3

- 140 041715

d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, the method comprising oral administration to a premenopausal woman in need thereof once daily for at least 12 or at least 24 consecutive weeks of a combination containing about 10 to about 60 mg K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, from about 0.5 to about 2 mg of estradiol, or an equivalent amount of estradiol equivalent, and about 0.01 to about 5 mg of progestin; and stopping treatment for at least 4 weeks while the premenopausal woman is trying to conceive.

Option I-134. The method of Embodiment I-133, wherein said premenopausal woman becomes pregnant or gives birth upon cessation of treatment.

Option I-135. The method of embodiment I-133 or I-134 wherein the premenopausal woman experienced one or more miscarriages, inability to conceive, or a combination of such conditions prior to treatment.

Option I-136. A method of treating anemia in a premenopausal woman in need thereof, the method comprising administering orally to the premenopausal woman in need thereof, once daily for at least 12 or at least 24 consecutive weeks, a combination containing from about 10 up to about 60 mg K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-137. The method of any one of embodiments I-131 to I-136, wherein the premenopausal woman is experiencing heavy menstrual bleeding.

Option I-138. The method of embodiment I-137 wherein heavy menstrual bleeding is associated with a non-cancerous etiology.

Option I-139. The method of any one of embodiments I-67 to I-138, wherein the premenopausal woman has one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or symptoms associated with one or more of the following conditions : uterine fibroids, endometriosis or adenomyosis.

Option I-140. The method of any one of embodiments I-65 to I-139, wherein the combination is administered once a day for at least 48 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks.

Option I-141. The method of any one of embodiments I-65 to I-140 wherein administration of the combination is suspended for conception and pregnancy.

Option I-142. The method of embodiment I-141 wherein administration is resumed after delivery.

Option I-143. The method of any one of embodiments I-65 to I-142, wherein the combination is administered prior to a meal.

Option I-144. The method of any one of embodiments I-65 to I-143, wherein administration is at least 30 minutes before a meal or on an empty stomach.

Option I-145. The method of any one of embodiments I-65 to I-144, wherein the combination is administered at least 1 hour before a meal or at least 2 hours after a meal.

Option I-146. The method of any one of embodiments I-65 to I-145 wherein the combination is administered as one or more immediate release dosage forms.

Option I-147. The method of any one of embodiments I-65 to I-146, wherein the bone mineral density of the premenopausal woman during and/or after treatment is within ±2% of the bone mineral density of the premenopausal woman before treatment.

Option I-148. A method of treating a premenopausal woman with symptoms of uterine fibroids or endometriosis, the method comprising administering to said woman once daily a combination containing about 65 to about 140 mg K-(4-(1-(2,6-difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin, wherein administration of the combination suppresses the endometrium.

Option I-149. The method of Embodiment I-148 wherein the combination is effective for treating symptoms of uterine fibroids or endometriosis and reducing one or more side effects including one or more of the following: hot flashes, night sweats, loss of bone mineral density, or vasomotor symptoms other than hot flashes or night sweats.

Option I-150. The method of embodiment I-148 or I-149 wherein the combination is in unit dosage form.

Option I-151. A method of treating a premenopausal woman who continues to experience one

- 141 041715 or more of the following: hot flashes, night sweats, vasomotor symptoms other than hot flashes or night sweats, or loss of bone mineral density, when administered orally once a day, a combination containing about 10 to about 60 mg K-(4 -(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2, 3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, about 1.0 mg of estradiol and about 0.5 mg of norethisterone acetate, the method comprising administering to said premenopausal woman the combination, containing from about 65 to about 140 mg of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1 ,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof; about 1.5 mg to about 5 mg of estradiol, or an equivalent amount of estradiol, and about 0.5 to about 2.0 mg of norethisterone acetate or another progestin, wherein administration of the combination suppresses endometrial tissue.

Option I-152. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of one or more of the following conditions: uterine fibroids, endometriosis or adenomyosis in a premenopausal woman.

Option I-153. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of heavy menstrual bleeding in a premenopausal woman.

Option I-154. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of pain associated with uterine fibroids, endometriosis or adenomyosis, in a premenopausal woman.

Option I-155. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for maintaining bone mineral density in a premenopausal woman.

Option I-156. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyrdazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of one or more of the following conditions: hot flashes, night sweats or vasomotor symptoms other than hot flashes or night sweats in a premenopausal woman.

Option I-157. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the maintenance of one or both of the lipid profile or range of glucose levels in blood in a premenopausal woman.

Option I-158. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of one or more of the following conditions: vulvovaginal atrophy or vaginal dryness in a premenopausal woman.

Option I-159. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament for the treatment of headache in a premenopausal woman.

Option I-160. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a contraceptive medicament for a premenopausal woman.

Option I-161. Use according to any of Embodiments I-155 to I-160 wherein the premenopausal woman was treated with K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea from one or more of the following conditions : uterine fibroids, endometriosis, adenomyosis or heavy menstrual bleeding.

Option I-163. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3

- 142 041715 pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or its pharmaceutically acceptable salt, estradiol or equivalent estradiol and progestin for the manufacture of a drug to achieve amenorrhea in a premenopausal woman.

Option I-164. Application of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for the prevention of miscarriage in a premenopausal woman.

Option I-165. Application of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for increasing fertility in a premenopausal woman.

Option I-166. Application of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament for the treatment of anemia in a premenopausal woman.

Option I-167. Use according to any of Embodiments I-152 to I-166, wherein the drug formulation contains about 10 mg to about 60 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino) methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or the corresponding the amount of its pharmaceutically acceptable salt; about 0.5 to about 2 mg of estradiol or an equivalent amount of estradiol; and about 0.01 to about 5 mg of progestin.

Option I-168. Application of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and norethisterone acetate or other progestin for the manufacture of a medicament for the treatment of symptoms of uterine fibroids or endometriosis in a woman in premenopause.

Option I-169. Use according to Embodiment I-168 wherein the drug formulation contains about 65 to about 140 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6 -methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol or an equivalent amount of estradiol; and about 0.5 to 2.0 mg of norethisterone acetate or another progestin.

Option I-170. Application of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and norethisterone acetate or other progestin for the manufacture of a medicament for the treatment of a premenopausal woman who continues to experience one or more of the following: hot flashes, night sweats, loss of bone mineral density, or vasomotor symptoms other than hot flashes or night sweats, when administered orally once a day, a combination containing about 10 to about 60 mg of N-(4-(1- (2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine -6-yl)phenyl)-N'-methoxyurea or an appropriate amount of its pharmaceutically acceptable salt, about 1.0 mg of estradiol and about 0.5 mg of norethisterone acetate, while the medicinal product contains from about 65 up to about 140 mg N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; about 1.5 to about 5.0 mg of estradiol, or an equivalent amount of estradiol; and about 0.5 to 2.0 mg of norethisterone acetate or another progestin.

Option I-171. Combined preparation for simultaneous or sequential use according to any one of embodiments I-1 to I-11, I-14 to I-18, or I-20 to I-64; or the method of any one of I-65 to I-80, I-83 to I-89, or I-91 to I-151; or the use of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any of Embodiments I-152 to I -170, where a premenopausal woman achieves a menstrual blood loss of <80 ml during treatment; or at least a 50% reduction from baseline in menstrual blood loss during treatment compared to before treatment; or her PBAC score is less than 10 during treatment; or any combination of them.

Option I-172. Combined preparation for simultaneous or sequential use according to the embodiment I-171; or the method of embodiment I-171; or the use of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4

- 143 041715 tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or its pharmaceutically acceptable salt, estradiol or estradiol equivalent and progestin for the manufacture of a medicinal product in accordance with embodiment I-171, where a premenopausal woman achieves menstrual blood loss <80 ml during treatment; or at least a 50% reduction from baseline in menstrual blood loss during treatment compared to before treatment; or her PBAC score is less than 10 during treatment; or any combination thereof for at least 30 weeks, for at least 24 weeks, or for at least 12 weeks from the start of treatment.

Option I-173. Combined preparation for simultaneous or sequential use according to one of the embodiments of I-1 to I-11, I-14 to I-18, I-20 to I-64, I-171 or I-172; or the method of any one of I-65 to I-80, I-83 to I-89, I-91 to I-151, I-171, or I172; or the use of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any of Embodiments I-152 to I170 , I-171, or I-172, in which a premenopausal woman has a maximum NRS score of 1 or less for uterine fibroid pain after starting treatment; or she has an increase in the number of days with an NRS score of 0 after the start of treatment compared to before the start of treatment; or her mean NRS during the 35 days of treatment decreased by at least 30% after the start of treatment.

Option I-174. Combined preparation for simultaneous or sequential use according to the embodiment with I-173; or the method of embodiment I-173; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylαmino)methyl)-3-(6-methoxyu-3-nirudαzenyl)-2,4-duoxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament according to Embodiment I-173, wherein premenopausal women have a maximum NRS score of 1 or less for uterine fibroid pain at 6 weeks, 8 weeks, or 10 weeks after starting treatment; or she has more days with an NRS score of 0 at 6 weeks, 8 weeks, or 10 weeks after starting treatment compared to 6 weeks, 8 weeks, or 10 weeks immediately before starting treatment; or her average 35-day NRS during treatment decreased by at least 30% within 6 weeks, 8 weeks, or 10 weeks after starting treatment.

Option I-175. Combined preparation for simultaneous or sequential use according to the embodiment with I-174; or the method of embodiment I-174; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxyu-3-nirudazinyl)-2,4-duoxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament according to Embodiment I-174, wherein in premenopausal women, the maximum NRS for pain associated with uterine fibroids was > 4 at 6 weeks, 8 weeks, or 10 weeks immediately prior to treatment.

Option I-176. Combined preparation for simultaneous or sequential use according to one of the embodiments of I-1 to I-11, I-14 to I-18, I-20 to I-64, or I-171 to I-175; or the method of any one of I-65 to I-80, I-83 to I-89, I-91 to I-151, or I171 to I-175; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any one of embodiments I-152 through I169 or I-171 to I-175 in which a premenopausal woman had an increase in hemoglobin of > 1 g/dL during treatment compared to pre-treatment levels.

Option I-177. Combined preparation for simultaneous or sequential use according to the embodiment with I-176; or the method of embodiment I-176; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylαmino)methyl)-3-(6-methoxyu-3-nirudαzenyl)-2,4-duoxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament according to Embodiment I-176, wherein the increase hemoglobin levels occurred within 20 weeks, 24 weeks, or 28 weeks from the start of treatment.

Option I-178. Combined preparation for simultaneous or sequential use according to one of the embodiments of I-1 to I-11, I-14 to I-18, I-20 to I-64, or I-171 to I-177; or the method of any one of I-65 to I-80, I-83 to I-89, I-91 to I-151, or I171 to I-177; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

- 144 041715 or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any of the embodiments of I-152 to I169 or I-171 to I-177, in which a premenopausal woman experiences a decrease in exposure uterine fibroids as assessed by the UFS-QOL scale; reduction of the negative impact of uterine fibroids on physical activity as assessed by the UFS-QOL scale; reducing the negative impact of uterine fibroids on social activity as assessed by the UFS-QOL scale; reduction of embarrassment caused by uterine fibroids, as assessed by the UFS-QOL scale; reduction in symptoms associated with uterine fibroids as assessed by the UFS-QOL symptom severity scale; reduction in quality of life problems associated with uterine fibroids, as assessed by the health-related quality of life scale, UFS-QOL; a change from baseline in uterine fibroids function based on a patient's global assessment (PGA); reduction in symptoms of uterine fibroids based on PGA data; change from baseline in physical activity as measured by the menorrhagia impact questionnaire; change from baseline in social and leisure activities as measured by the menorrhagia impact questionnaire; a decrease in the volume of the uterus or a decrease in the volume of uterine fibroids.

Option I-179. Combined preparation for simultaneous or sequential use according to the embodiment I-178; or the method of embodiment I-178; or the use of N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to Embodiment I-178, wherein the reduction or the change is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more.

Option I-180. Combined preparation for simultaneous or sequential use according to the embodiment I-178 or I-179; or the method of embodiment I-178 or I-179; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament according to embodiment I-178 or I-179 in which the decrease or change took place within 6 weeks, within 12 weeks, within 18 weeks, within 24 weeks, or within 30 weeks of starting treatment.

Option I-181. Combination preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-12 or from I-15 to I-64; or the method of any one of I-65 to I-81, I-85 to I-87, I-89 to I-127, or I-129 to I-151; or use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylαmino)methyl)-3-(6-methoxy-3-nurudαzenyl)-2,4-duoxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any one of Embodiments I-152 to I-169 or I-171 to I-177, in which a premenopausal woman has a decrease in dysmenorrhea as measured by the change from baseline in the NRS score for dysmenorrhea; reduction in pain as measured by change from baseline in the NRS score for NMPP; reduction in dyspareunia as measured by change from baseline in the NRS score for dyspareunia; improvement in functional impairment of dyspareunia as measured by change from baseline on the sB&B scale; reduction in pain as measured by change from baseline in a PGA-based severity score for pain; reduction in dysfunction as measured by change from baseline based on PGA for function; there is improvement as measured by change from baseline in each of the non-pain sections of the EHP-30 (control and impotence, social support, emotional well-being, and self-esteem); reduction in functional impairment of dysmenorrhea as measured by change from baseline on the sB&B scale; reduction in NMPP functional impairment as measured by change from baseline on the sB&B scale; or reduction in pain, as measured by the change from baseline in the EHP-30 pain section score, with baseline determined within 6 weeks, 8 weeks, or 10 weeks immediately prior to treatment.

Option I-182. Combination preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-12 or from I-15 to I-64; or the method of any one of I-65 to I-81, I-85 to I-87, I-89 to I-127, or I-129 to I-151; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-nurudazinyl)-2,4-duoxo-1,2,3 ,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any one of Embodiments I-152 to I-169 or I-171 to I-177, in which

- 145 041715 a premenopausal woman shows better or much better PGIC scores for dysmenorrhea; shows better or much better PGIC performance for NMPP; shows better or much better PGIC scores for dyspareunia compared to 6 weeks, 8 weeks, or 10 weeks immediately prior to treatment.

Option I-183. Combined preparation for simultaneous or sequential use according to the embodiment I-181 or I-182; or the method of embodiment I-181 or I-182; or the use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or equivalent to estradiol and progestin for the manufacture of a medicament according to embodiment I-181 or I-182 , in which the decrease or change is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more.

Option I-184. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-181 to I-183; or the method of any one of embodiments I-181 through I-183; or use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to any of Embodiments I-181 to I -183 in which the decrease or change occurred within 6 weeks, within 12 weeks, within 18 weeks, within 24 weeks, or within 30 weeks of starting treatment.

Option I-185. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-11, I-18 or I-19; or the method of any of embodiments I-80, I-89 through I-107, or I-130; or the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent and a progestin for the manufacture of a medicament according to Embodiment I-154 wherein pain is is chronic pain.

Option I-186. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-11, I-18 or I-19; or the method of any of embodiments I-80, I-89 through I-107, or I-130; or the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to Embodiment I-154 wherein pain is is dyspareunia.

Option I-187. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-11, I-18 or I-19; or the method of any of embodiments I-80, I-89 through I-107, or I-130; or the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to Embodiment I-154 wherein pain is pain during defecation.

Option I-188. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-1 to I-11, I-18 or I-19; or the method of any of embodiments I-80, I-89 through I-107, or I-130; or the use of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3, 4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to Embodiment I-154 wherein pain is is pain when urinating.

Option I-189. Combined preparation for simultaneous or sequential use according to any of the embodiments from I-32 to I-42; or the method of any one of embodiments I-114 through I-130; or use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an equivalent of estradiol and a progestin for the manufacture of a medicament according to Embodiment I160 wherein a premenopausal woman receives treatment for one or more of the following conditions: uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding, by administration of N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Option II-1. A method of treating uterine fibroids in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more per

- 146 041715 during the treatment period from 10 to 60 mg No. -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea and 0.01 mg to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-2. A method for reducing menstrual blood loss in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg per day of N-(4-(1 -(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine -6-yl)phenyl)-N'-methoxyurea and from 0.01 mg to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-3. A method for suppressing sex hormones in a subject, the method comprising administering to the subject at least once a day for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg per day of N-(4-(1 -(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine -6-yl)phenyl)-N'-methoxyurea and from 0.01 mg to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-4. A method of reducing bone mineral density loss in a subject induced by administering a GnRH antagonist to the subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg per day N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea and 0.01 mg to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-5. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg per day of N-(4- (1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d ]pyrimidin-6-yl)phenyl)-N'-methoxyurea and 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-6. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg of N-(4-(1 -(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine -6-yl)phenyl)-N'-methoxyureas; 0.01 mg to 5 mg of a hormone replacement drug; and 0.05 mg to 10 mg of an additional compound selected from the group consisting of gabapentin, pregabalin, venlafaxine, fluoxetine, paroxetine and aspirin. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-7. A method of reducing symptoms of decreased libido in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of 10 to 60 mg of N-(4-(1- (2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine- 6-yl)phenyl)-N'-methoxyurea; 0.01 mg to 5 mg of a hormone replacement drug; and 0.05 mg to 10 mg of at least one 5-HT _1a receptor agonist. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-8. The method of embodiments II-1 to II-7, wherein a PK profile is achieved in which the mean plasma AUC( ₀ _ _tau ) increases at least 1.5-fold (150%) when measured from the first to the last day period of treatment.

Option II-9. The method of Embodiment II-8 wherein at least 1.5 times the

- 147 041715 no 2 times or more.

Option II-10. The method of embodiments II-1 to 11-7, wherein the treatment period is 4 consecutive weeks (28 days) or more.

Option II-11. The method of embodiments II-1 to II-7, wherein the treatment period is 8 consecutive weeks (56 days) or more.

Option II-12. The method of embodiments II-1 to II-7, wherein the treatment period is 12 consecutive weeks (84 days) or more.

Option II-13. The method of embodiments II-1 to II-7, wherein the treatment period is 24 weeks (168 days) or more.

Option II-14. The method of embodiments II-1 to II-7, wherein the treatment period is 52 weeks (364 days) or more.

Option II-15. The method of embodiments II-1 to II-7, wherein the administration is daily and continuous for at least 48 weeks to achieve chronic status.

Option II-16. The method according to embodiments II-1 to II-13, wherein the administration is before a meal.

Option II-17. The method of embodiments II-1 to II-13, wherein the administration is at least 1 hour before a meal or at least 2 hours after a meal.

Option II-18. The method according to embodiments II-1 to II-13, wherein the administration is carried out at least 30 minutes before a meal or on an empty stomach.

Option II-19. The method according to embodiments II-1 to II-13, wherein the administration is carried out without any requirements for the absence of food.

Option II-20. The method of embodiments II-1 to II-18 wherein, when administered on an empty stomach, the mean C _max is in the range of 5 to 35 ng/mL.

Option II-21. The method of embodiments II-1 to II-18 wherein, when administered on an empty stomach, the mean plasma AUC( ₀ - ₂₄ ) is between 50 and 200 ng-h/mL.

Option II-22. The method according to embodiments II-1 to II-7, wherein the administration is carried out at least twice a day.

Option II-23. The method of embodiments II-1 to II-7 wherein the mean plasma half-life (T1/ ₂ ) is from about 37 to about 42 hours as measured at the end of the treatment period.

Option II-24. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is in an amount of up to about 5 mg.

Option II-25. The method of embodiments II-1 to II-7, wherein the hormone replacement drug is in an amount of 0.05 to 2.5 mg per day.

Option II-26. The method of embodiments II-1 to II-7, wherein the hormone replacement drug is selected from the group consisting of estrogen, progestogen, and a combination of the like.

Option II-27. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is a combination of 1 mg estradiol and 0.5 mg NETA.

Option II-28. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is a combination of 1.5 mg estradiol and 0.5 mg NETA.

Option II-29. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is a combination of 2 mg estradiol and 0.5 mg NETA.

Option II-30. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is 5 mg NETA.

Option II-31. The method of embodiments II-1 to II-7 wherein the hormone replacement drug is a progestin.

Option II-32. The method according to embodiments II-1 to II-7, wherein the administration is orally.

Option II-33. The method of embodiments II-1 to II-7, wherein the administration is via a transdermal patch, spray, or implant.

Option II-34. The method of embodiment II-7 wherein at least one 5-HT _1a receptor agonist comprises flibanserin.

Option II-35. The method of embodiment II-5 wherein the amount of hormone replacement drug administered to the subject is reduced over the treatment period.

Option II-36. The method of Embodiments II-1 to II-7 wherein the subject is a premenopausal woman.

Option II-37. The method of Embodiment II-32 wherein administration is in the form of a tablet, capsule, caplet, pill, granule, powder, lozenge, chewing gum, or an orally dissolving film.

Option II-38. A method of treating uterine fibroids in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period, an oral dose containing 10 to 60 mg per day of N-( 4-(1-(2,6

- 148 041715 difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which mean plasma AUC( _0-tau ) increases by at least 1.5-fold when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-39. A method of reducing menstrual blood loss in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period an oral dose containing 10 to 60 mg per day of N-( 4(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3 -d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which the mean plasma AUQ( _0-tau ) increases at least 1.5-fold when measured from the first until the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-40. A method for suppressing sex hormones in a subject, the method comprising administering to the subject at least once a day for 2 consecutive weeks (14 days) or more during a treatment period, an oral dose containing 10 to 60 mg per day of N-( 4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which mean plasma AUQ( ₀ _ _tau ) increases at least 1.5-fold when measured from first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-41. A method of reducing bone mineral density loss in a subject induced by administering to the subject a GnRH antagonist, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period of an oral dose containing 10 up to 60 mg daily N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2 ,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, and a hormone replacement drug, wherein the oral dose has a PK profile in which the average AUC( ₀ _ _tau ) in plasma increases at least 1.5 times when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-42. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period, an oral dose containing 10 to 60 mg of N-( 4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-niridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2, 3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea and from 0.01 to 5 mg of a hormone replacement drug, and the oral dose has a PK profile in which the average value of AUC( _0-tau ) in plasma increases by at least 1.5 times as measured from the first to the last day of the treatment period -3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option II-43. The method of embodiment II-42 wherein the oral dose further comprises 0.05 to 10 mg of an additional compound selected from the group consisting of gabapentin, pregabalin, venlafaxine, fluoxetine, paroxetine, and aspirin.

Option II-44. A method of reducing symptoms of decreased libido in a subject, the method comprising administering to the subject at least once daily for 2 consecutive weeks (14 days) or more during a treatment period, an oral dose containing 10 to 60 mg of N(4- (1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea and 0.01 to 5 mg of a hormone replacement drug; and 0.05 to 10 mg of at least one 5-HT _1a receptor agonist, wherein the oral dose has a PK profile in which mean plasma AUC _(0-tau ) increases at least 1.5-fold when measured from the first to the last day of the treatment period In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3- pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

- 149 041715

Option II-45. The method of embodiments II-38 to II-44, wherein at least 1.5 times means at least 2 times or more.

Option II-46. The method of embodiments II-38 to II-44, wherein the treatment period is 4 consecutive weeks (28 days) or more.

Option II-47. The method of embodiments II-38 to II-44, wherein the treatment period is 8 consecutive weeks (56 days) or more.

Option II-48. The method of embodiments II-38 to II-44, wherein the treatment period is 12 consecutive weeks (84 days) or more.

Option II-49. The method of embodiments II-38 to II-44, wherein the treatment period is 24 weeks (168 days) or more.

Option II-50. The method of embodiments II-38 to II-44, wherein the treatment period is 52 weeks (364 days) or more.

Option II-51. The method of embodiments II-38 to II-44, wherein the administration is before a meal.

Option II-52. The method of embodiments II-38 to II-44, wherein the administration is at least 1 hour before a meal or at least 2 hours after a meal.

Option II-53. The method of embodiments II-38 to II-44, wherein the administration is at least 30 minutes before a meal or on an empty stomach.

Option II-54. The method according to embodiments II-38 to II-44, wherein the administration is carried out without any requirements for the absence of food.

Option II-55. The method of embodiments II-38 to II-44, wherein the mean plasma AUC( _{0_tau} ) is higher when administered before a meal than when administered _after a meal at least 30 minutes later.

Option II-56. The method of embodiments II-38 to II-44, wherein the mean C _max is higher when administered before a meal than when administered after a meal.

Option II-57. The method of embodiments II-38 to II-44, wherein the oral dosage is an oral fixed combination dosage form that contains 0.01 to 5 mg of a hormone replacement drug.

Option II-58. The method of embodiments II-38 to II-44, wherein the administration is at least twice a day.

Option II-59. The method of embodiments II-38 to II-44 wherein the oral dosage is a solid oral dosage.

Option II-60. The method of embodiments II-38 to II-44 wherein the oral dosage has an immediate release profile.

Option II-61. The method of embodiments II-38 to II-44 wherein the mean plasma T _1/2 is from about 37 to about 42 hours as measured at the end of the treatment period.

Option II-62. The method of embodiments II-38 to II-44 further comprising co-administering a hormone replacement drug to the subject.

Option II-63. The method of embodiments II-38 to II-44, wherein, after administering 40 mg per day for 2 consecutive weeks or more over a treatment period, the subject's menstrual blood loss, as measured by a total graphical menstrual blood loss score (PBAC), is less than 10 according to measurements taken at the end of the treatment period.

Option II-64. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean total PBAC from weeks 6 to 12 is at least a 3-fold decrease.

Option II-65. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean total PBAC from weeks 6 to 12 is at least 3.5-fold decline.

Option II-66. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean total PBAC from weeks 6 to 12 is at least a 5-fold decrease.

Option II-67. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in the mean total PBAC from weeks 6 to 12 is 3.0-5.0- multiple reduction.

Option II-68. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the subject has a total PBAC score of zero at the end of the treatment period.

Option II-69. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the subject has a total PBAC score of zero as measured during one of the following periods: weeks 2 to 6, weeks from 6 to 12 and weeks 2 to 12 of the treatment period.

- 150 041715

Option II-70. The method of embodiments II-38 to II-44, wherein after administration of 40 mg per day for 12 consecutive weeks, the subject has a reduction in fibroid volume after treatment for 14, 28, 56, 84, 168, or 364 consecutive days.

Option II-71. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean fibroid volume is at least a 3.5-fold decrease when measured from first to the last day of the treatment period.

Option II-72. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean fibroid volume is at least a 4-fold decrease when measured from the first to the last day period of treatment.

Option II-73. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean fibroid volume is 3.5-6.5-fold reduction as measured from the first until the last day of the treatment period.

Option II-74. The method of embodiments II-38 to II-44 wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean uterine volume is at least a 4-fold decrease when measured from the first to the last day period of treatment.

Option II-75. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean uterine volume is at least a 4.5-fold decrease when measured from first to the last day of the treatment period.

Option II-76. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean uterine volume is 4.0-7.0-fold reduction as measured from the first until the last day of the treatment period.

Option II-77. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in the mean value of Numerical Rating Scale (NRS) scores in weeks 6 to 12 is a reduction in pain symptoms associated with uterine myoma, 0.1 times.

Option II-78. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in mean NRS scores in weeks 6 to 12 is a reduction in uterine fibroid-related pain symptoms of 0, 1-2.0 times.

Option II-79. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in mean quality of life score for symptoms of uterine fibroids (UFS-QOL) is at least 1-fold reduction in symptom severity when measured from the first to the last day of the treatment period.

Option II-80. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in mean UFS-QOL is at least a 2-fold reduction in symptom severity as measured from the first to the last day of the period treatment.

Option II-81. The method of embodiments II-38 to II-44 wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in mean UFS-QOL is at least a 2.5-fold reduction in symptom severity as measured from first to last days of the treatment period.

Option II-82. The method of embodiments II-38 to II-44 wherein, after administration of 40 mg per day for 12 consecutive weeks, the change in mean UFS-QOL is 1.0-6.0-fold reduction in symptom severity as measured from the first to the last day period of treatment.

Option II-83. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hemoglobin concentration is at least a 3-fold increase when measured from first to the last day of the treatment period.

Option II-84. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hemoglobin concentration is at least a 3.5-fold increase as measured from the first to the last day of the treatment period.

Option II-85. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hemoglobin concentration is at least a 3.8-fold increase as measured from the first to the last day of the treatment period.

Option II-86. The method of Embodiments II-38 to II-44 wherein, after administration of 40 mg

- 151 041715 per day for 12 consecutive weeks, the change from baseline in the average concentration of hemoglobin in the blood is at least 3.0-6.0-fold increase when measured from the first to the last day of the treatment period.

Option II-87. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hematocrit is at least a 3.0-fold increase as measured from the first to the last day of the treatment period.

Option II-88. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hematocrit is at least a 3.5-fold increase as measured from the first to the last day of the treatment period.

Option II-89. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hematocrit is at least a 4.2-fold increase as measured from the first to the last day of the treatment period.

Option II-90. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood hematocrit is at least 3.0-7.0-fold increase when measured from the first to the last day of the treatment period.

Option II-91. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood iron concentration is at least a 6.0-fold increase as measured from the first to the last day of the treatment period.

Option II-92. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood iron concentration is at least an 8.0-fold increase as measured from the first to the last day of the treatment period.

Option II-93. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood iron concentration is at least a 9.0-fold increase as measured from the first to the last day of the treatment period.

Option II-94. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood iron concentration is at least 6.0-16.0-fold increase when measured from the first to the last day of the treatment period.

Option II-95. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood ferritin concentration is at least a 2.0-fold increase as measured from the first to the last day of the treatment period.

Option II-96. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood ferritin concentration is at least a 2.5-fold increase as measured from the first to the last day of the treatment period.

Option II-97. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood ferritin concentration is at least a 3.0-fold increase as measured from the first to the last day of the treatment period.

Option II-98. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean blood ferritin concentration is at least a 2.0-6.0-fold increase when measured from the first to the last day of the treatment period.

Option II-99. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean serum luteinizing hormone (LH) concentration is at least 3.0-fold decrease when measured from the first to the last day of the treatment period.

Option II-100. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median LH concentration is at least a 4.0-fold decrease when measured from first to the last day of the treatment period.

Option II-101. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median LH concentration is at least a 4.7-fold decrease as measured from the first

- 152 041715 until the last day of the treatment period.

Option II-102. The method of embodiments II-38 to 11-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean LH concentration is at least 3.0-9.0-fold decrease at measured from the first to the last day of the treatment period.

Option II-103. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median follicle-stimulating hormone (FSH) concentration is at least a 1.0-fold decrease as measured from the first to the last day of the treatment period.

Option II-104. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median FSH concentration is at least a 1.5-fold decrease when measured from first to the last day of the treatment period.

Option II-105. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median FSH concentration is at least a 2.1-fold decrease when measured from first to the last day of the treatment period.

Option II-106. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in mean FSH concentration is at least 1.0-5.0-fold decrease at measured from the first to the last day of the treatment period.

Option II-107. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median estradiol concentration (E ₂ ) is at least a 0.2-fold decrease at measured from the first to the last day of the treatment period.

Option II-108. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median E ₂ concentration is at least a 0.8-fold decrease as measured from the first until the last day of the treatment period.

Option II-109. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median E2 concentration is at least a 1.0-fold decrease when measured from first to the last day of the treatment period.

Option II-110. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median E2 concentration is at least 0.2-3.2-fold decrease at measured from the first to the last day of the treatment period.

Option II-111. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median progesterone concentration (P) is at least a 0.5-fold decrease when measured from the first to the last day of the treatment period.

Option II-112. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median P concentration is at least a 0.8-fold decrease when measured from first to the last day of the treatment period.

Option II-113. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median P concentration is at least a 1.2-fold decrease when measured from first to the last day of the treatment period.

Option II-114. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for 12 consecutive weeks, the change from baseline in median P concentration is at least 0.5-4.0-fold decrease at measured from the first to the last day of the treatment period.

Option II-115. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for at least 2 consecutive weeks and co-administration of 0.01 to 5 mg per day of at least one of estrogen and progestogen, loss bone mineral density is less than 5% from the first to the last day of the treatment period.

Option II-116. The method of embodiments II-38 to II-44, wherein, after administration of 40 mg per day for at least 2 consecutive weeks and co-administration of 0.01 to 5 mg per day of at least one of estrogen and progestogen, loss bone mineral density is less than 2% from the first to the last day of the treatment period.

Option II-117. The method of Embodiments II-38 to II-44, wherein after administration of 40

- 153 041715 mg per day for at least 2 consecutive weeks and co-administration of 0.01 to 5 mg per day of at least one of estrogen and progestogen reduces bone mineral density loss by at least 50% compared with no simultaneous administration of 0.01 to 5 mg per day of at least one of an estrogen and a progestogen.

Option II-118. The method of embodiments II-38 to II-44 wherein the oral dosage is selected from the group consisting of tablet, capsule, caplet, pill, granule, powder, lozenge, chewing gum, and orally dissolving film.

Option II-119. The method of embodiment II-44 wherein at least one 5-HT _1a receptor agonist comprises flibanserin.

Option II-120. The method of embodiments II-1 to II-7 and II-41 to II-44, wherein the hormone replacement drug is administered as a separate dosage form.

Option II-121. The method of embodiments II-41 to II-44 wherein the oral dosage is an oral fixed combination dosage form.

Option III-1. A method of treating endometriosis in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period of 10 to 60 mg of Na(4-(1-(2,6-difluorobenzyl) -5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl) -N'-methoxyurea and from 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-2. A method of alleviating pain associated with endometriosis in a subject, the method comprising administering to the subject at least once a day for 7 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1-( 2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea and from 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4 -dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-3. A method of reducing menstrual bleeding associated with endometriosis in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1- (2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyurea and from 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea.

Option III-4. A method for suppressing sex hormones in a subject, the method comprising administering to the subject at least once a day for 7 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl) phenyl)-N'methoxyurea and 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-5. A method of reducing bone mineral density loss in a subject induced by administering a GnRH antagonist to the subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period of 10 to 60 mg of N-(4- (1-(2,6-difluorobenzyl)-5-((dmethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea and 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea.

Option III-6. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 14 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1-(2, 6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl )phenyl)-N'-methoxyurea and 0.01 to 5 mg of a hormone replacement drug. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4 -dioxo

- 154 041715

1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option Sh-7. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 14 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1-(2, 6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl )phenyl)-N'-methoxyureas; 0.01 to 5 mg of a hormone replacement drug; and 0.05 to 10 mg of at least one additional compound selected from the group consisting of gabapentin, pregabalin, venlafaxine, fluoxetine, paroxetine and aspirin. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-8. A method of reducing symptoms of decreased libido in a subject, the method comprising administering to the subject at least once daily for 14 consecutive days or more during a treatment period of 10 to 60 mg of N-(4-(1-(2.6 -difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl) phenyl)-N'-methoxyurea; 0.01 to 5 mg of a hormone replacement drug; and 0.05 to 10 mg of at least one 5-HT _1a receptor agonist. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-9. The method of embodiments III-1 to III-8, wherein, measured from the first to the last day of the treatment period, a PK profile is achieved in which the mean plasma AUQ( _0-tau ) increases by at least 1.5-fold.

at least 1.5 times which treatment period which treatment period which treatment period which treatment period which treatment period which treatment period

Option III-10. The method of Embodiment III-9 wherein starts at 2 times or more.

Option III-11. The method of Embodiments III-1 to III-8 is 14 days or more.

Option III-12. The method of Embodiments III-1 to III-8 is 28 days or more.

Option III-13. The method of Embodiments III-1 to III-8 is 56 days or more.

Option III-14. The method of Embodiments III-1 to III-8 is 12 weeks (84 days) or more.

Option III-15. The method of Embodiments III-1 to III-8 is 24 weeks (168 days) or more.

Option III-16. The method of Embodiments III-1 to III-8 has 52 weeks (364 days) or more.

Option III-17. The method of embodiments III-1 to III-8 wherein administration is daily and continuous for at least 48 weeks to achieve chronic status.

Option III-18. The method of embodiments III-1 to III-8, wherein the administration is before a meal.

Option III-19. The method of embodiments III-1 to III-8, wherein the administration is at least 1 hour before a meal or at least 2 hours after a meal.

Option III-20. The method of embodiments III-1 to III-8, wherein the administration is carried out at least 30 minutes before a meal or on an empty stomach.

Option III-21. The method of embodiments III-1 to III-8, wherein administration is carried out without any requirement for no food.

Option III-22. The method of embodiments III-1 to III-8 wherein, when administered on an empty stomach, the mean C _max is in the range of 5 ng/mL to 35 ng/mL.

Option III-23. The method of embodiments III-1 to III-8 wherein, when administered on an empty stomach, the mean plasma AUQ( _0-24 ) is between 50 and 200 ng-h/mL.

Option III-24. The method of embodiments III-1 to III-8, wherein the administration is at least twice a day.

Option III-25. The method of embodiments III-1 to III-8 wherein the mean plasma half-life T _1/2 is from about 37 to about 42 hours as measured at the end of the treatment period.

Option III-26. The method of embodiments III-1 to III-8, wherein the hormone replacement drug is selected from the group consisting of estrogen, progestogen, and a combination of the like.

Option III-27. The method of embodiments III-1 to III-8 wherein the hormone replacement drug is present in an amount of up to about 5 mg.

- 155 041715

Option Sh-28. The method of Embodiments III-1 to III-8, wherein the amount of the hormone replacement drug is 0.05 to 2.5 mg per day.

Option III-29. The method of embodiments III-1 to III-8 wherein the hormone replacement drug is a combination of 1 mg estradiol and 0.5 mg NETA.

Option III-30. The method of embodiments III-1 to III-8 wherein the hormone replacement drug is a combination of 1.5 mg of estradiol and 0.5 mg of NETA.

Option III-31. The method of embodiments III-1 to III-8 wherein the hormone replacement drug is a combination of 2 mg estradiol and 0.5 mg NETA.

Option III-32. The method of embodiments III-1 to III-8 wherein the hormone replacement drug is NETA only.

Option III-33. The method of embodiment III-32 wherein the hormone replacement drug is 5 mg NETA.

Option III-34. The method of Embodiments III-1 to III-8, wherein the hormone replacement drug is a progestin.

Option III-35. The method of Embodiments III-1 to III-8, wherein the administration is orally.

Option III-36. The method of embodiments III-1 to III-8, wherein administration is via a transdermal patch, spray, or implant.

Option III-37. The method of Embodiment III-2, wherein the pain associated with endometriosis is at least one of non-menstrual pelvic pain, dysmenorrhea, and dyspareunia.

Option III-38. The method of embodiment III-8 wherein at least one 5-HT _1a receptor agonist comprises flibanserin.

Option III-39. The method of embodiment III-6 wherein the amount of hormone replacement drug administered to the subject is reduced over the treatment period.

Option III-40. The method of Embodiments III-1 to III-8 wherein the subject is a premenopausal woman.

Option III-41. The method of Embodiment III-35 wherein administration is in a dosage form selected from the group consisting of a tablet, capsule, caplet, pill, granule, powder, lozenge, chewing gum, and oral film.

Option III-42. A method of treating endometriosis in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during the treatment period an oral dose containing 10 to 60 mg per day of N-(4-(1- (2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidine- 6-yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which the mean plasma AUQ( ₀ _ _tau ) increases at least 1.5-fold when measured from the first to the last day of the treatment period . In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea.

Option III-43. A method of alleviating pain associated with endometriosis in a subject, the method comprising administering to the subject at least once a day for 7 consecutive days or more during a treatment period an oral dose containing 10 to 60 mg per day of N-( 4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which mean plasma AUQ( ₀ _ _tau ) increases at least 1.5-fold when measured from first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-44. A method of reducing menstrual bleeding associated with endometriosis in a subject, the method comprising administering to the subject at least once a day for 7 consecutive days or more during a treatment period, an oral dose containing 10 to 60 mg per day of N- (4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2 ,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, and the oral dose has a PK profile in which the mean plasma AUQ( ₀ _ _tau ) increases at least 1.5-fold when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo -1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-45. A method for suppressing sex hormones in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more per

- 156 041715 during the treatment period of an oral dose containing 10 to 60 mg per day N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the oral dose has a PK profile in which the mean AUQ _{( 0-tau} ) in plasma increases at least 1.5-fold when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-46. A method of reducing bone mineral density loss in a subject induced by administering to the subject a GnRH antagonist, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period an oral dose containing 10 to 60 mg per day N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea and 0.01 to 5 mg hormone replacement drug, the oral dose having a PK profile in which the mean AUC _{(0- tau} ) in plasma increases by at least 1.5-fold when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-47. A method of alleviating vasomotor symptoms or flushing in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period, an oral dose containing 10 to 60 mg of N-(4-(1 -(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine- 6-yl)phenyl)-N'-methoxyurea and 0.01 to 5 mg of a hormone replacement drug, the oral dose having a PK profile in which mean plasma AUC( _0-tau ) increases by at least 1.5 times when measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy3-pyridazinyl)-2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-48. The method of Embodiment III-47 wherein the oral dose further comprises 0.05 to 10 mg of an additional compound selected from the group consisting of gabapentin, pregabalin, venlafaxine, fluoxetine, paroxetine, and aspirin.

Option III-49. A method of reducing symptoms of decreased libido in a subject, the method comprising administering to the subject at least once daily for 7 consecutive days or more during a treatment period an oral dose containing 10 to 60 mg of N-(4-(1- (2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6 -yl)phenyl)-N'-methoxyureas; 0.01 to 5 mg of a hormone replacement drug; and 0.05 to 10 mg of at least one 5-HT _1a receptor agonist, wherein the oral dose has a PK profile in which mean plasma AUC( _0-tau ) increases by at least 1.5 times as measured from the first to the last day of the treatment period. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option III-50. The method of embodiments III-42 to III-49, wherein at least 1.5 times means at least 2 times or more.

Option III-51. The method of embodiments III-42 to III-49, wherein the treatment period is 14 days or more.

Option III-52. The method of Embodiments III-42 to III-49, wherein the treatment period is 28 days or more.

Option III-53. The method of embodiments III-42 to III-49, wherein the treatment period is 56 days or more.

Option III-54. The method of Embodiments III-42 to III-49, wherein the treatment period is 12 weeks (84 days) or more.

Option III-55. The method of Embodiments III-42 to III-49, wherein the treatment period is 24 weeks (168 days) or more.

Option III-56. The method of Embodiments III-42 to III-49, wherein the treatment period is 52 weeks (364 days) or more.

Option III-57. The method of embodiments III-42 to III-49, wherein the administration is before a meal.

Option III-58. The method of embodiments III-42 to III-49, wherein the administration is at least 1 hour before a meal or at least 2 hours after a meal.

Option III-59. The method of Embodiments III-42 to III-49, wherein the administration is

- 157 041715 take at least 30 minutes before meals or on an empty stomach.

Option III-60. The method of Embodiments III-42 to III-49, wherein the administration is carried out without any requirements for the absence of food.

Option III-61. The method of embodiments III-42 to III-49, wherein the mean plasma AUC( ₀ - _tau ) is higher when administered before a meal than when administered after a meal at least 30 minutes later.

Option III-62. The method of embodiments III-42 to III-49, wherein the mean C _max is higher when administered before a meal than when administered after a meal.

Option III-63. The method of embodiments III-42 to III-45 wherein the oral dosage is an oral fixed combination dosage form that contains 0.01 to 5 mg of a hormone replacement drug.

Option III-64. The method of embodiments III-46 to III-49 wherein the oral dosage is an oral fixed combination dosage form.

Option III-65. The method of embodiments III-42 to III-49, wherein the administration is at least twice a day.

Option III-66. The method of Embodiments III-42 to III-49 wherein the oral dosage is a solid oral dosage.

Option III-67. The method of embodiments III-42 to III-49 wherein the oral dosage has an immediate release profile.

Option III-68. The method of embodiments III-42 to III-49 wherein the mean plasma T _1/2 is from about 37 to about 42 hours as measured at the end of the treatment period.

Option III-69. The method of embodiments III-42 to III-45 further comprising co-administering a hormone replacement drug to the subject.

Option III-70. The method of embodiments III-46 to III-49, wherein the hormone replacement drug is co-administered to the subject.

Option III-71. The method of embodiment III-48 wherein the additional compound is co-administered to the subject.

Option III-72. The method of embodiment III-49 wherein at least one 5-HT _1a receptor agonist is co-administered to the subject.

Option III-73. The method of Embodiment III-43, wherein the pain associated with endometriosis is at least one of non-menstrual pelvic pain, dysmenorrhea, and dyspareunia.

Option III-74. The method of embodiments III-42 to III-49, wherein the change from baseline in the mean visual analog scale (VAS) is at least a 1.4-fold reduction in pelvic pain measured from first to last days of the treatment period.

Option III-75. The method of embodiments III-42 to III-49, wherein the change from baseline in mean VAS is at least a 2-fold increase in the proportion of days without pelvic pain as measured from the first to the last day of the treatment period.

Option III-76. The method of embodiments III-42 to III-49, wherein the change from baseline in the modified Biberoglu & Behrman (M-B&B) mean score is at least a 1.5-fold reduction in pelvic pain as measured from the first to the last day of the treatment period.

Option III-77. The method of embodiments III-42 to III-49, wherein the change from baseline in mean M-B&B is at least a 1.5-fold increase in the proportion of days without pelvic pain, as measured from the first to the last day period of treatment.

Option III-78. The method of embodiments III-42 to III-49, wherein the change from baseline in mean VAS is at least a 1.5-fold reduction in dysmenorrhea as measured from the first to the last day of the treatment period.

Option III-79. The method of embodiments III-42 to III-49 wherein, after administration of 40 mg per day for 84 consecutive days, the change from baseline in mean VAS is a 4-8-fold increase in the proportion of days without dysmenorrhea as measured from the first until the last day of the treatment period.

Option III-80. The method of embodiments III-42 to III-49, wherein, after administration of 40 mg per day for 84 consecutive days, the change from baseline in mean M-B&B is at least 5-9-fold reduction in dysmenorrhea as measured from the first to the last day of the treatment period.

Option III-81. The method according to embodiments III-42 to III-49, wherein, after administration of 40 mg per day for 28 consecutive days, the change from baseline in the indicator

- 158 041715 for M-B&B is a 3.5-7.5-fold increase in the proportion of days without dysmenorrhea, measured from the first to the last day of the treatment period.

Option III-82. The method of embodiments III-42 to III-49 wherein, after administration of 40 mg per day for 84 consecutive days, the change from baseline in the mean M-B&B is a 50-75-fold increase in the fraction of days without dysmenorrhea as measured from the first to the last day of the treatment period.

Option III-83. The method of embodiments III-42 to III-49 wherein, after administration of 40 mg per day for 84 consecutive days, the change from baseline in mean M-B&B is 1.1-1.5-fold increase in fraction of days without dyspareunia when measured from the first to the last day of the treatment period.

Option III-84. The method of embodiments III-42 to III-49 wherein, after administration of 40 mg per day for 84 consecutive changes from baseline in mean M-B&B is at least a 20-40-fold reduction in deep dyspareunia as measured from the first to the last day of the treatment period.

Option III-85. The method of embodiments III-42 to III-49 wherein, after administration of 40 mg per day for 84 consecutive days, the change from baseline in mean VAS is 1.5-4.0-fold reduction in pelvic pain , dysmenorrhea and dyspareunia as measured from the first to the last day of the treatment period.

Option III-86. The method of embodiments III-42 to III-49, wherein after administration of 40 mg per day for 84 consecutive days, the change from baseline in the mean endometriosis health score (ENP-30) is 2.5-6, 5-fold improvement in quality of life when measured from the first to the last day of the treatment period.

Option III-87. The method of embodiments III-42 to III-49 wherein, after administering 40 mg per day for 28 consecutive days and co-administering 0.01 to 5 mg per day of at least one of an estrogen and a progestogen, loss of bone mineral density is less than 5% compared with the start of treatment.

Option III-88. The method of embodiments III-42 to III-49 wherein, after administering 40 mg per day for 28 consecutive days and co-administering 0.01 to 5 mg per day of at least one of an estrogen and a progestogen, loss of bone mineral density is less than 2% compared with the start of treatment.

Option III-89. The method of embodiments III-42 to III-49 wherein, after administering 40 mg per day for 28 consecutive days and co-administering 0.01 to 5 mg per day of at least one of an estrogen and a progestogen, loss of bone mineral density reduced by at least 50% compared with no simultaneous administration of 0.01 to 5 mg per day of at least one of estrogen and progestogen.

Option III-90. The method of embodiments III-42 to III-49 wherein the oral dosage is selected from the group consisting of tablet, capsule, caplet, pill, granule, powder, lozenge, chewing gum, and oral film.

Option III-91. The method of embodiment III-49 wherein at least one 5-HT _1a receptor agonist comprises flibanserin.

Option III-92. The method of embodiments III-1 to III-8 and III-46 to II-49, wherein the hormone replacement drug is administered as a separate dosage form.

Option IV-1. A method for maintaining bone mineral density in a woman receiving treatment for endometriosis or uterine fibroids, comprising: concomitant administration of an estradiol-inhibiting amount of K-(4-(1-(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or a salt thereof and 0.05 to 2.5 mg (or 0.05 to 5 mg) of a hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-2. A method of treating endometriosis-related pain in a woman suffering from endometriosis-related pain, comprising: concomitantly administering an estradiol-inhibiting amount of K-(4-(1-(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof and 0.05 to 2.5 mg (or 0.05 to 5 mg) of a hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-3. A method for reducing heavy menstrual bleeding in a woman with uterine myoma, including: concomitant administration once a day orally of an estradiol-inhibiting amount of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- and from 0.05 to 2.5 mg (or 0.05 to 5 mg) of a hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-4. A method for reducing the side effects of estradiol suppression in a woman receiving treatment with an estradiol suppressing amount of K-(4-(1-(2,6-difluorobenzyl)-5

- 159 041715 ((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl) -N'-methoxyurea or a salt thereof, comprising: concomitant once daily oral administration of an estradiol-inhibiting amount of N(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6 -methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof and from 0.05 to 2.5 mg (or 0.05 to 5 mg) hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-5. A method for reducing the side effects of estradiol suppression in a woman receiving treatment with an estradiol suppressing amount of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof, comprising: administration once a day orally from 0, 05 to 2.5 mg (or 0.05 to 5 mg) of the hormone replacement drug, wherein the hormone replacement drug is administered over about 30 minutes (or 5, 10, 15, 20, or 25 minutes) relative to the administration of N-( 4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2, 3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-6. A method for maintaining estradiol levels in a woman receiving treatment with an estradiol-suppressing amount dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof, comprising: administration once a day orally from 0.05 to 2 .5 mg (or 0.05 to 5 mg) of a hormone replacement drug, wherein the hormone replacement drug is administered within about 30 minutes (or 5, 10, 15, 20, or 25 minutes) relative to the administration of N-(4-( 1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d] pyrimidin-6-yl)phenyl)-N'-methoxyurea or salts thereof. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-7. Method of administering an estradiol-inhibiting amount of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2 ,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof and 0.05 to 2.5 mg (or 0.05 to 5 mg) of a hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-8. The method according to any one of Embodiments IV-1 to IV-7 further comprising administering N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy -3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or its salt without administration of a hormone replacement drug for up to 12 weeks prior to once-daily concomitant administration 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a salt thereof and a hormone replacement drug. In some embodiments, the salt is a pharmaceutically acceptable salt.

Option IV-9. The method according to any one of embodiments IV-1 to IV-8, wherein the hormone replacement preparation contains 0.1 to 0.5 mg of norethisterone acetate (NETA) and 0.5 to 2 mg of estradiol.

Option IV-10. The method according to any one of embodiments IV-1 to IV-8, wherein the amount of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or its salt is from 20 to 50 mg. In some embodiments, an appropriate amount of the pharmaceutically acceptable salt N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea.

Option V-1. A method of treating a woman with symptomatic uterine fibroids or endometriosis, the method comprising a single administration to said woman of a daily dose of 20-140 mg, e.g. , 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 mg of compound 1 with 1.5-5.0 mg of estradiol, e.g. 2.0 to 4.0 mg of estradiol per combinations with 0.5-2.0 mg of norethisterone acetate or other progestin to suppress the endometrium. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Option V-2. The method of Embodiment V-1 wherein the combination is effective in treating symptoms of uterine fibroids or endometriosis and reducing the side effects of hot flashes and/or other vasomotor symptoms and/or loss of bone mineral density.

Option V-3. The method according to embodiment V-1 or V-2, wherein a daily dose of 20-140 mg, for example 40 mg of compound 1, contains 1.5-5.0 mg, for example 2-4 mg of estradiol and 0.5-2. 0 mg norethisterone in single dose form. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Option V-4. A method of treating a woman who continues to experience hot flashes and/or other

- 160 041715 vasomotor symptoms, and/or loss of bone mineral density with the introduction of Compound 1 at a dose of 20-140 mg, for example 40 mg, once a day orally with 1.0 mg of estradiol and norethisterone acetate, 0.5 mg, moreover, the method comprises administering compound 1 to said woman at a dose of 20-140 mg, eg 40 mg, orally once a day or higher, together with 1.5-5 mg, eg 2.0-4.0 mg, of estradiol in combination with 0 .5-2.0 mg of norethisterone acetate or another progestin to suppress endometrial tissue. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Option V-5. The method of embodiment V-4 wherein hot flushes and/or other vasomotor symptoms and/or loss of bone mineral density are reduced without affecting the effectiveness of treating symptoms of uterine fibroids or endometriosis.

Option V-6. The method of embodiment V-4 or V-5 wherein a daily dose of 20-140 mg, such as 40 mg, of Compound 1 contains 1.5-5.0 mg, such as 2-4 mg, of estradiol and 0.5-2 0 mg norethisterone in unit dosage form. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Option V-7. A method for treating uterine fibroids and endometriosis in a woman, comprising a single administration to said woman of a daily dose of compound 1 in an amount of 20-140 mg, for example 40 mg, and additional administration of a combination of estradiol and norethisterone acetate or another progestin to suppress endometrial tissue in an amount that results in estradiol levels no greater than the mean daily concentration of 150 pg/mL in said woman. In some embodiments, an appropriate amount of a pharmaceutically acceptable salt of Compound 1 is administered.

Option V-8. The method according to any of the described methods and uses, wherein the administration of the combination of Compound 1, estradiol or estradiol equivalent and progestin is suspended for conception or pregnancy.

Claims (23)

CLAIM 1. Use of a combination containing about 40 mg of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; 0.5 to 2 mg of estradiol and 0.01 to 5 mg of progestin; for the treatment of heavy menstrual bleeding associated with uterine fibroids in a premenopausal woman in need thereof, wherein the combination is administered orally to the premenopausal woman once a day, where estrogen production by the ovaries of the premenopausal woman is suppressed as demonstrated by preventing ovulation; and where the bone mineral density of a premenopausal woman during treatment is within ±3% of the bone mineral density of a premenopausal woman before treatment. 2. Use according to claim 1, wherein the progestin is norethisterone acetate. 3. Use according to claim 2, where the combination contains 1 mg of estradiol and 0.5 mg of norethisterone acetate. 4. Use of a combination containing about 40 mg of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof; 0.5 to 2 mg of estradiol and 0.01 to 5 mg of progestin; for the treatment of heavy menstrual bleeding in a premenopausal woman in need thereof, wherein the combination is administered orally to the premenopausal woman once a day; where the production of estrogen by the ovaries in a premenopausal woman is suppressed, as demonstrated by the prevention of ovulation; and where the bone mineral density of a premenopausal woman during treatment is within ±3% of the bone mineral density of a premenopausal woman before treatment. 5. Use according to claim 4, wherein the premenopausal woman suffers from endometriosis. 6. Use according to any one of claims 1 to 5, wherein the bone mineral density of the premenopausal woman during treatment is within ±2% of the bone mineral density of the premenopausal woman before treatment. 7. Use according to any one of claims 1 to 6, wherein the daily serum concentration of estradiol in a premenopausal woman is between 20 and 50 pg/ml between daily doses of the combination. 8. Use according to any one of claims 1 to 7, wherein the premenopausal woman is a perimenopausal woman. 9. Use according to any one of claims 1 to 8, wherein during treatment in a premenopausal woman, - 161 041715 the amount of menstrual blood loss is less than 80 ml per menstrual cycle; or 50% reduction from baseline in menstrual blood loss compared to before treatment; or their combination. 10. The use according to any one of claims 1 to 9, wherein the premenopausal woman experiences a reduction in pain symptoms after the initiation of treatment compared to those before the initiation of treatment. 11. Use according to any one of claims 1 to 10, wherein the pain is pelvic pain, preferably dysmenorrhea. 12. Use according to any one of claims 1 to 11, wherein the woman has an improvement in one or more of the following symptoms after the start of treatment compared to before the start of treatment, where the symptoms are selected from the group consisting of anemia, irregular menstruation, bleeding, inflammation, pain, fatigue, urinary tract obstruction, urinary frequency, urinary incontinence, constipation, anxiety, sleep disturbances, quality of life, daily activities, female sexual dysfunction and depression. 13. Use according to any one of claims 1 to 12, wherein the premenopausal woman experiences amenorrhea after the start of treatment compared to the state before the start of treatment. 14. Use according to any one of claims 1 to 13, wherein one or both of the number and size of uterine fibroids are reduced after the start of treatment compared to one or both of the number and size of uterine fibroids prior to treatment. 15. The use according to any one of claims 1 to 14, wherein the volume of the uterus decreases after the start of treatment compared to the volume before the start of treatment. 16. Use according to any one of claims 1-15, wherein during treatment, the median serum concentration of follicle-stimulating hormone (FSH) in a premenopausal woman is reduced by 2.1-4.1 times compared to the median concentration of FSH in a woman before treatment. 17. Use according to any one of claims 1-16, wherein the combination is administered for at least 4 consecutive weeks. 18. Use according to any one of claims 1-17, wherein the combination is administered for at least 24 consecutive weeks. 19. Use according to any one of claims 1 to 18 wherein there is a lower distribution of serum C _avg levels of estradiol when the combination is administered compared to when N-(4-(1-(2,6difluorobenzyl)-5 -((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N '-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, is administered without progestin and without estradiol, as determined in a human pharmacokinetic study. 20. Use according to any one of claims 1-19, wherein the correlation of serum C _avg levels of estradiol with AUC _0-24 N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea lower when the combination is administered , compared to when N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1, 2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, is administered without progestin and without estradiol, as determined in a human pharmacokinetic study. 21. Use according to any one of claims 1 to 20, wherein the change in serum N-telopeptide concentration before treatment and after treatment is less in subjects administered the combination compared to the change in subjects treated with N-(4-(1 -(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d] pyrimidin-6-yl)phenyl)-N'methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, without progestin and without estradiol, as determined in a human pharmacokinetic study. 22. Use according to any one of claims 1-20, wherein the combination is administered as a unit dosage form. 23. Use according to any one of claims 1 to 21, wherein the combination comprises separate dosage forms that are administered together.