WO2016160830A1 - Procédés pour fournir une thérapie neuroprotectrice - Google Patents

Procédés pour fournir une thérapie neuroprotectrice Download PDF

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Publication number
WO2016160830A1
WO2016160830A1 PCT/US2016/024751 US2016024751W WO2016160830A1 WO 2016160830 A1 WO2016160830 A1 WO 2016160830A1 US 2016024751 W US2016024751 W US 2016024751W WO 2016160830 A1 WO2016160830 A1 WO 2016160830A1
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subject
estriol
treatment period
estrogen
administering
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PCT/US2016/024751
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English (en)
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Rhonda R. Voskuhl
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • MS Multiple sclerosis
  • brain and spinal cord central nervous system
  • MS affects more than 1 million people worldwide and is the most common neurological disease among young adults, particularly women. The exact cause of MS is still unknown.
  • MS is an autoimmune disease in which myelin sheaths surrounding neuronal axons are destroyed. This condition can cause weakness, impaired vision, loss of balance, and poor muscle coordination.
  • Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave sequelae, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign MS, although people will still build up some degree of disability in the long term. On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached a significant level of disability in a short period of time.
  • the relapsing- remitting subtype usually begins with a clinically isolated syndrome (CIS).
  • CIS a person has an attack suggestive of demyelination but does not fulfill the criteria for multiple sclerosis; 30 to 70% of persons experiencing CIS go on to develop MS. Secondary-progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The median length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.
  • Primary -progressive MS occurs in approximately 10-20% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.
  • the usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype, but similar to the age that secondary-progressive MS usually begins in relapsing-remitting MS, around 40 years of age.
  • the following agents are approved by the U.S. Food and Drug Administration (FDA) to reduce disease activity and disease progression for many people with relapsing forms of MS, including relapsing-remitting MS, as well as secondary-progressive and progressive-relapsing MS in those people who continue to have relapses: dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), glatiramer acetate (Copaxone®), interferon beta-la (Avonex® and Rebif®), interferon beta-lb (Betaseron® and Extavia®), peginterferon beta-la (Plegridy®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), alemtuzumab (Lemtrada®), and teriflunomide (Aubagio®).
  • FDA U.S. Food and Drug Administration
  • the invention relates to a method for treating multiple sclerosis in a subject who does not present with active lesions (e.g., gadolinium-enhancing lesions), comprising administering an estrogen to the subject without conjointly administering a second immunotherapeutic agent for treating multiple sclerosis.
  • active lesions e.g., gadolinium-enhancing lesions
  • the invention relates to a method for treating multiple sclerosis in a subject receiving treatment with an immunotherapeutic agent who does not present with active lesions (e.g., gadolinium-enhancing lesions), comprising administering an estrogen to the subject and discontinuing treatment with the immunotherapeutic agent.
  • an immunotherapeutic agent who does not present with active lesions (e.g., gadolinium-enhancing lesions)
  • active lesions e.g., gadolinium-enhancing lesions
  • the invention relates to a method for treating multiple sclerosis in a subject, comprising determining whether the brain of the subject presents with active lesions (e.g., gadolinium-enhancing lesions), administering an estrogen to the subject, and discontinuing any second immunotherapeutic agent that the subject is receiving if the subject lacks active lesions.
  • active lesions e.g., gadolinium-enhancing lesions
  • Figure 1 Study overview.
  • Figure 1 includes two panels, identified as panels (A) and (B).
  • Panel A shows the disposition of subjects enrolled in a clinical trial of estriol for treating multiple sclerosis.
  • Panel B shows the study design.
  • "Taper” indicates a period of reduction of either estriol or placebo over the course of 4 weeks at end of study, after month 24 clinic visit. Specifically, the dose of estriol was reduced by half (from 8 mg to 4 mg) for 2 weeks, then reduced by half again (from 4 mg to 2 mg) for 2 weeks, then discontinued,
  • "x” indicates the administration of a progestin (0.7 mg norethindrone) orally each day for 2 weeks every three months, beginning at study month 6.
  • "o” indicates the administration of a placebo for the progestin orally each day for 2 weeks every three months, beginning at study month 6.
  • Figure 2 Estriol levels and relapsing disease activity in Estriol + glatiramer acetate (GA) as compared to Placebo + GA treatment groups.
  • Figure 2 includes three panels, identified as panels (A), (B), and (C).
  • Panel (A) shows that serum estriol concentrations are significantly increased at each time point after baseline (month 0) in the Estriol + GA group (-x- ), while remaining below the assay detection limit in the Placebo + GA group (-).
  • Estriol levels are expressed as mean +/- SE in ng/mL.
  • Figure 3 Disabilities and Brain Volumes.
  • Figure 3 includes nine panels, identified as panels (A), (B), (C), (D), (E), (F), (G), (H), and (I).
  • Figure 4 Trends for MS Quality of Life and Depression.
  • Figure 4 includes three panels, identified as panels (A), (B), and (C).
  • Panel (B) shows MSQOL composite scores for Mental outcomes had trends similar to MSQOL Physical.
  • BDI Beck Depression Inventory
  • Figure 5 Change in PASAT: Subgroups by Baseline Performance.
  • Figure 5 shows the percent change in PASAT scores at 12 months from baseline for all subjects (All, left bars), those with disability scores of less than 55 at baseline ( ⁇ 55, middle bars), and those with scores from 55 to the maximum of 60 at baseline (>55, right bars).
  • a perfect PASAT score is 60, and scores lower than 55 depict disability.
  • Figure 6 Voxel-wise Gray Matter Atrophy.
  • Figure 6 shows maximum intensity projections of voxel-wise gray matter atrophy superimposed onto 3 orthogonal planes through the brain.
  • significant localized gray matter loss was observed in the Placebo + GA group as compared to baseline (top) and in the Estriol + GA group as compared to baseline (middle), each shown as gray against a black background in the 3 planes.
  • Regions of significantly more gray matter loss in the Placebo + GA group as compared to the Estriol + GA group on between group comparisons are shown in white in the 3 planes (bottom).
  • Gray matter loss is also visualized as projected onto a surface rendering of the mean template (lower right corner of each panel). All results are corrected for multiple comparisons by controlling the FDR at P ⁇ 0.05.
  • Some aspects of the invention are based on the finding that estriol protects gray matter (e.g., cortical gray matter) in subjects with relapsing-remitting multiple sclerosis who do not present with active lesions (see, e.g., Figure 3, Panel I).
  • gray matter e.g., cortical gray matter
  • estrogen therapies are efficacious for treating multiple disease states, not only relapsing-remitting multiple sclerosis, but also secondary progressive multiple sclerosis and primary progressive multiple sclerosis.
  • estrogen therapies are likely generally efficacious for treating various other forms of neurodegenerative disease that are not primarily autoimmune response driven.
  • the invention relates to a method for treating a neurodegenerative disease, such as multiple sclerosis, in a subject who does not present with active lesions (e.g., gadolinium-enhancing lesions), comprising administering an estrogen to the subject without conjointly administering a second immunotherapeutic agent.
  • a neurodegenerative disease such as multiple sclerosis
  • active lesions e.g., gadolinium-enhancing lesions
  • the invention relates to a method for treating a neurodegenerative disease, such as multiple sclerosis, in a subject receiving treatment with an immunotherapeutic agent who does not present with active lesions (e.g., gadolinium-enhancing lesions), comprising administering an estrogen to the subject and discontinuing treatment with the immunotherapeutic agent.
  • a neurodegenerative disease such as multiple sclerosis
  • the invention relates to a method for treating a neurodegenerative disease, such as multiple sclerosis, in a subject, comprising determining whether the brain of the subject presents with active lesions (e.g., gadolinium-enhancing lesions), administering an estrogen to the subject, and discontinuing any second immunotherapeutic agent that the subject is receiving if the subject lacks active lesions.
  • active lesions e.g., gadolinium-enhancing lesions
  • the invention relates to a method for treating a neurodegenerative disease, such as multiple sclerosis, in a subject, comprising administering an estrogen to the subject, determining whether the brain of the subject presents with active lesions, and conjointly administering to the subject a second immunotherapeutic agent if the brain of the subject presents with active lesions.
  • a neurodegenerative disease such as multiple sclerosis
  • active lesion refers to inflammation in the central nervous system associated with immune cells, such as T lymphocytes.
  • T lymphocytes may cross the blood-brain barrier in a relapsing-remitting multiple sclerosis patient.
  • T cells may mount an autoimmune response against myelin.
  • other blood cells may cross the blood-brain barrier, such as white blood cells, e.g., other lymphocytes and monocytes.
  • An active lesion may be detected, for example, by gadolinium- enhanced magnetic resonance imaging (MRI).
  • MRI gadolinium- enhanced magnetic resonance imaging
  • Gadolinium-based contrast agents generally do not cross the blood-brain barrier, and thus, a gadolinium-enhanced MRI scan may be used to detect an active lesion, termed a "gadolinium-enhancing lesion” or simply an “enhancing lesion.” Additionally, active lesions may be diagnosed by other methods. For example, an active lesion may be detected by MRI without a gadolinium-based contrast agent, e.g., by identifying a new or enlarging T2 hyperintensity in the brain, relative to a previous MRI, indicating that the subject had a recent active lesion. Active lesions may also be identified by diagnosing a relapse in a multiple sclerosis patient (e.g., by significant worsening on a walking, balance, or visual acuity test that has an acute onset, such as over 1 -7 days).
  • central nervous system is used herein as defined in the art and includes the brain and spinal cord.
  • brain is used synonymously with “central nervous system” and thus, unless otherwise apparent from context, the term “brain” includes both the brain as defined in the art and the spinal cord.
  • a subject presents with active lesions if the subject has been recently diagnosed (e.g., within the last two months, preferably within the last month) with at least one active lesion, e.g., by gadolinium-enhanced MRI.
  • a subject does not present with active lesions if the subject has not been recently diagnosed with any active lesions. For example, a subject does not present with active lesions if a gadolinium-enhanced MRI scan of the brain of the subject suggests that no gadolinium crossed the blood-brain barrier of the subject, e.g., relative to a control scan or control region of the brain. Additionally, a patient diagnosed with secondary progressive multiple sclerosis or primary progressive multiple sclerosis presents with few or no active lesions. Similarly, a subject with relapsing-remitting multiple sclerosis who is in clinical remission may or may not present with active lesions on an MRI scan.
  • Whether the brain of a subject presents with active lesions may be determined directly, e.g., by diagnosing the subject, or indirectly, by obtaining a prior diagnosis. For example, a physician may determine whether the brain of a subject presents with active lesions by identifying a breach in the blood-brain barrier of the subject, e.g., by gadolinium-enhanced MRI or by assaying the cerebrospinal fluid of the subject for a biomarker. Similarly, a physician may determine whether the brain of a subject presents with active lesions by diagnosing the subject with a relapse of multiple sclerosis, e.g., by identifying a new onset walking or other difficulty.
  • whether the brain of a subject presents with active lesions may be determined indirectly, e.g., by obtaining a diagnosis from a physician, technician, nurse, medical chart, MRI scan, or from the subject.
  • a doctor or other prescriber may administer an estrogen to a subject after determining whether the brain of a subject presents with active lesions by reviewing the medical records of the subject and/or discussing the medical history of the subject with the subject or another caretaker of the subject.
  • An active lesion may be, for example, an infratentorial lesion, juxtacortical lesion, periventricular lesion, or spinal cord lesion.
  • determining whether the brain of a subject presents with an active lesion comprises evaluating the cerebrospinal fluid of the subject, e.g. for immunoglobulin abnormalities (assessing the IgG Index in cerebrospinal fluid).
  • the subject may display evidence of cognitive decline.
  • the evidence of cognitive decline may be worsening performance on the Paced Auditory Serial Addition Test ("PASAT").
  • the subject may display evidence of brain atrophy.
  • the evidence of brain atrophy may be determined by MRI.
  • the brain atrophy may be cortical gray matter atrophy.
  • the brain atrophy may be a decrease in whole brain volume.
  • the subject may present with a cognitive disability.
  • the evidence of cognitive disability may be determined by performance on the Paced Auditory Serial Addition Test ("PASAT").
  • the method includes the steps of administering an estrogen to a subject.
  • the estrogen may be administered on a continuous basis ⁇ e.g., daily), for example, throughout two or more consecutive treatment periods.
  • the method may comprise administering to the subject, for only a portion of each treatment period, a therapeutically effective amount of a progestogen.
  • estrogen refers to any biologically active form of estrogen or precursor thereof.
  • estrogen thus embraces naturally occurring, synthetic, and semisynthetic forms of estrogen, and biologically active, pharmaceutically acceptable salts and esters thereof.
  • estrogen is selected from estriol (E3), estradiol (E2), estrone (El), an ester thereof, a pharmaceutically acceptable salt of an ester thereof, and any
  • the estrogen is estriol (E3) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof.
  • the estrogen can be estriol, estriol succinate, estriol dihexanoate, or estriol sulfate.
  • estrogen is estradiol (E2) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof, while in yet other embodiments, estrogen is estrone (El) or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof.
  • estrogen is estriol (E3).
  • estrogen is estradiol (E2).
  • estrogen is estrone (El).
  • the estrogen is administered in a dose equal or equivalent to about 200 ⁇ g to about 20 mg estriol daily.
  • a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1.25 mg of conjugated estrogens or estrone.
  • the estrogen is administered in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily.
  • the estrogen is estriol administered in a dose of about 8 mg estriol daily.
  • the estrogen is formulated for oral administration, e.g. , in a dose equal or equivalent to about 200 ⁇ g to about 20 mg estriol daily.
  • a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1.25 mg of conjugated estrogens or estrone.
  • the estrogen is formulated for oral administration in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily.
  • the estrogen is estriol formulated for oral administration in a dose of about 8 mg estriol daily.
  • the estrogen is orally administered in a dose equal or equivalent to about 200 ⁇ g to about 20 mg estriol daily.
  • a dose of 2 to 4 mg of estriol is generally considered to be equivalent to 0.6 to 1.25 mg of conjugated estrogens or estrone.
  • the estrogen is orally administered in a dose equal or equivalent to about 1 mg to about 10 mg estriol daily, preferably equal or equivalent to about 8 mg estriol daily.
  • the estrogen is estriol orally administered in a dose of about 8 mg estriol daily.
  • an “effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired biological effect.
  • a “therapeutically effective amount,” as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect.
  • a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of multiple sclerosis.
  • a therapeutically effective dose of the estrogen is, in some embodiments, one sufficient to raise the serum concentration above basal levels, and preferably to pregnancy levels or above pregnancy levels.
  • the therapeutically effective dose of the estrogen is selected to result in serum levels in a patient equivalent to the steroid hormone level of that agent in women in the second or third trimester of pregnancy.
  • estradiol levels are in the range of about 350 pg/ml serum.
  • estradiol levels rise progressively during pregnancy to levels from 3,000 to 30,000 pg/ml (3 to 30 ng/ml).
  • the dose is from about 4 to 16 milligrams daily, and more specifically, about 8 milligrams daily.
  • blood serum levels preferably reach at least about 2 ng/ml, they may reach about 10 to about 35 ng/ml, or most preferably about 20-30 ng/ml (see Sicotte et al. Neurology 56:A75 (2001)).
  • estradiol (E2) levels would preferably reach at least about 2 ng/ml, most preferably about 10 to about 35 ng/ml.
  • estrone (El) levels would preferably reach at least about 2 ng/ml, and most preferably about 5 to about 18 ng/ml (see DeGroot et al, Endocrinology 3(9):2171-223 (1994)).
  • a therapeutically effective amount of estriol is an amount of an estriol sufficient to increase the serum estriol concentration in the blood of a subject above 6 ng/mL.
  • the dosage of the estrogen may be selected for an individual patient depending upon the route of administration, severity of disease, age and weight of the patient, other medications the patient is taking and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected. In vitro or in vivo assays can be employed to help identify optimal dosage ranges.
  • the therapeutically effective dose of the estrogen included in the dosage form is selected at least by considering the type of estrogen selected and the mode of administration.
  • the dosage form may include the estrogen in combination with other inert ingredients, including adjuvants and pharmaceutically acceptable carriers, for the facilitation of dosage to the patient as known to those skilled in the pharmaceutical arts.
  • the dosage form may be any form suitable to cause the estrogen to enter into the tissues of the patient.
  • Pharmaceutically acceptable carriers can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.
  • Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, including peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can include, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject.
  • Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the dosage form of the estrogen is an oral preparation (liquid, tablet, capsule, caplet, or the like), which, when consumed, results in elevated serum estrogen levels.
  • the oral preparation may comprise conventional carriers including diluents, binders, time-release agents, lubricants, and disintegrants.
  • the dosage form of the estrogen is a sublingual preparation, which results in elevated serum estrogen levels when consumed.
  • the dosage form of the estrogen may be provided in a topical preparation (lotion, cream, ointment, patch, or the like) for transdermal application.
  • the dosage form may be provided as a suppository or the like for transvaginal or transrectal application.
  • the dosage form may also allow for preparations to be applied subcutaneously, intravenously, intramuscularly, or via the respiratory system.
  • progestogen also known as “gestagen”
  • gestagen refers to any steroid hormone that binds to and activates a progesterone receptor, or a precursor thereof.
  • progestogen thus embraces naturally occurring, synthetic, and semi-synthetic forms of progestogen, and biologically active, pharmaceutically acceptable salts and esters thereof.
  • the progestogen is selected from chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, 5a-dihydroprogesterone, drospirenone (Yasmin®), ethinodiol acetate, ethynodiol diacetate, etonogestrel (Nexplanon®), gestodene, 17- hydroxyprogesterone, levonorgestrel (Alesse®), medroxyprogesterone acetate (17a-hydroxy-6a- methylprogesterone acetate; Provera®), megestrol, megestrol acetate (17a-acetoxy-6-dehydro-6- methylprogesterone), nestorone, nomegestrol acetate, norethindrone, norethindrone acetate (also known as norethisterone acetate), norethynodrel (Eno
  • progestogen is a progestin.
  • progestin refers to a synthetic progestogen as defined herein.
  • examples of progestins include desogestrel, dienogest, drospirenone (Yasmin®), ethinodiol acetate, etonogestrel (Nexplanon®), gestodene, levonorgestrel (Alesse®), medroxyprogesterone acetate (Provera®), nestorone, nomegestrol acetate, norethindrone, norethindrone acetate, norethynodrel (Enovid®), norgestimate, norgestrel, and trimegestone.
  • the progestogen is selected from progesterone, 17- hydroxyprogesterone, 5a-dihydroprogesterone, norethindrone, norethindrone acetate (also known as norethisterone acetate), medroxyprogesterone acetate (17a-hydroxy-6a- methylprogesterone acetate), megestrol acetate (17a-acetoxy-6-dehydro-6-methylprogesterone), desogestrel, levonorgestrel, chlormadinone acetate, and cyproterone acetate, pharmaceutically acceptable salts of any of the foregoing, and any combination thereof.
  • progestogen is selected from progesterone, 17-hydroxyprogesterone, 5a-dihydroprogesterone, norethindrone, norethindrone acetate (also known as norethisterone acetate), desogestrel, levonorgestrel, chlormadinone acetate, and cyproterone acetate, pharmaceutically acceptable salts and esters of any of the foregoing, and any combination thereof.
  • progestogen is norethindrone or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof, preferably norethindrone.
  • progestogen is progesterone or an ester thereof, or a pharmaceutically acceptable salt of an ester thereof.
  • the progestogen is administered in a dose equal or equivalent to about 70 ⁇ g to about 7 mg norethindrone daily, such as about 100 ⁇ g to about 1 mg
  • norethindrone daily most preferably in a dose equal or equivalent to about 0.7 mg norethindrone daily.
  • the progestogen is norethindrone administered in a dose of 0.7 mg norethindrone daily.
  • the progestogen is formulated for oral administration, e.g., in a dose equal or equivalent to about 70 ⁇ g to about 7 mg norethindrone daily, such as about 100 ⁇ g to about 1 mg norethindrone daily, most preferably in a dose equal or equivalent to about 0.7 mg norethindrone daily.
  • the progestogen is norethindrone formulated for oral administration in a dose of 0.7 mg norethindrone daily.
  • the progestogen is orally administered in a dose equal or equivalent to about 70 ⁇ g to about 7 mg norethindrone daily, such as about 100 ⁇ g to about 1 mg norethindrone daily, most preferably in a dose equal or equivalent to about 0.7 mg ⁇ i.e., 700 ⁇ g) norethindrone daily.
  • the progestogen is norethindrone orally administered in a dose of 0.7 mg ⁇ i.e., 700 ⁇ g) norethindrone daily.
  • the therapeutically effective dose of the progestogen included in the dosage form can be selected at least by considering the type of progestogen selected and the mode of administration.
  • the dosage form may include the progestogen in combination with other inert ingredients, including adjuvants and pharmaceutically acceptable carriers for the facilitation of dosage to the patient as known to those skilled in the pharmaceutical arts.
  • the dosage form may be any form suitable to cause the progestogen to enter into the tissues of the patient.
  • the dosage form of the progestogen is an oral preparation (liquid, tablet, capsule, caplet, or the like), which results in elevated serum progestogen levels when consumed.
  • the oral preparation may comprise conventional carriers including diluents, binders, time-release agents, lubricants, and disintegrants.
  • the dosage form of the progestogen may be provided in a topical preparation (lotion, cream, ointment, patch, or the like) for transdermal application.
  • the dosage form may be provided as a suppository or the like for transvaginal or transrectal application.
  • the estrogen is preferably administered to the subject on a continuous basis, e.g., for at least one treatment period, such as throughout two or more consecutive treatment periods.
  • a continuous basis is daily, i.e., on consecutive days.
  • estrogen administered ⁇ e.g., orally to the subject on a daily basis throughout two or more consecutive treatment periods is deemed to be estrogen administered to the subject on a continuous basis throughout two or more consecutive treatment periods.
  • estrogen administered transdermally to a subject on a daily basis throughout two or more consecutive treatment periods is deemed to be estrogen administered to the subject on a continuous basis throughout two or more consecutive treatment periods, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21 , 22, 23, or 24 treatment periods.
  • a “treatment period” refers to a period of time during which a subject is receiving, on a continuous or daily basis, at least one therapeutic agent administered for the purpose of treating a neurodegenerative disease in the subject.
  • each treatment period is at least 28 consecutive days, at least 56 consecutive days, at least 84 consecutive days, at least 112 consecutive days, at least 140 consecutive days, or at least 168 consecutive days.
  • each treatment period may be 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 40, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124
  • each treatment period is 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.
  • each treatment period may be 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , or 52 consecutive weeks.
  • each treatment period is at least one month, at least two consecutive months, at least three consecutive months, at least four consecutive months, at least five consecutive months, or at least six consecutive months.
  • each treatment period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months.
  • the progestogen may be administered to the subject for only a portion of each treatment period.
  • “for only a portion of each treatment period” refers generally to a period of time that occurs during, but is at least one day shorter than, a treatment period.
  • the phrase “for only a portion of each treatment period” refers generally to a period of consecutive days that occurs during, but is at least one day shorter than, a treatment period.
  • the portion of each treatment period is daily for all but at least 7 consecutive days of each treatment period.
  • the portion of such treatment period may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 consecutive days.
  • such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 , days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, or 1 to 21 of the treatment period.
  • the portion of each treatment period is daily for all but at least 14 consecutive days of each treatment period.
  • the portion of such treatment period may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.
  • such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1, days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, or 1 to 14 of the treatment period.
  • the portion of each treatment period is daily for up to 7 consecutive days of each treatment period.
  • the portion of such treatment period may be 1 , 2, 3, 4, 5, 6, or 7 consecutive days.
  • such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1, days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 of the treatment period.
  • the portion of each treatment period is daily for up to 14 consecutive days of each treatment period.
  • the portion of such treatment period may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.
  • such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1, days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, or 1 to 14 of the treatment period.
  • the portion of each treatment period is daily for all but at least half of each treatment period.
  • the portion of such treatment period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.
  • such portion can begin on day 1 of a treatment period, such that, for this example, the portion can encompass day 1 , days 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, or 1 to 14 of the treatment period.
  • the progestogen is administered to the subject for only a portion of each treatment period.
  • the subject can receive estrogen but neither progestogen nor a placebo in place of the progestogen.
  • the subject can receive both estrogen and a placebo in place of the progestogen.
  • An aspect of the invention is a method of treating multiple sclerosis.
  • the method includes the steps of administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), about 8 mg of estriol daily; and administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), about 0.7 mg of progestogen daily.
  • the 14 consecutive days (2 weeks) are the first 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks). That is, if the 84 consecutive days of estrogen administration are deemed to start on day 1 , the progestogen is administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and then stopped.
  • the subject may then continue to receive estrogen but neither progestogen nor a placebo in place of the progestogen for the remaining 70 days.
  • the method further includes the step of administering to the subject a placebo in place of the progestogen on each of the days the progestogen is not administered to the subject. That is, the subject may then receive both estrogen and a placebo in place of the progestogen for the remaining 70 days.
  • An aspect of the invention is a method of treating multiple sclerosis.
  • the method includes the steps of administering orally to a subject in need thereof, on a continuous basis for 84 consecutive days (12 weeks), about 8 mg of estriol daily; and administering orally to the subject, for 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks), about 0.7 mg of norethindrone daily.
  • the 14 consecutive days (2 weeks) are the first 14 consecutive days (2 weeks) of the 84 consecutive days (12 weeks). That is, if the 84 consecutive days of estrogen administration are deemed to start on day 1 , the norethindrone is administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and then stopped.
  • the subject may then continue to receive estrogen but neither norethindrone nor a placebo in place of the norethindrone for the remaining 70 days.
  • the method further includes the step of administering to the subject a placebo in place of the norethindrone on each of the days the norethindrone is not administered to the subject. That is, the subject may then receive both estrogen and a placebo in place of the norethindrone for the remaining 70 days.
  • the estrogen and the progestogen are formulated separately from one another, e.g., the subject receives the estrogen as a single formulation and the progestogen as a separate formulation.
  • a given dose of each formulation can comprise one or more pills, tablets, capsules, or the like ⁇ i.e., unit doses).
  • an 8 mg dose of estriol can be administered as four 2 mg capsules, and a 0.7 mg dose of norethindrone can be administered as a single capsule, though preferably each dose is administered in a single unit dose ⁇ e.g., one unit dose each for the estrogen and the progestogen).
  • the estrogen and the placebo are formulated separately from one another.
  • the subject is administered the estrogen as a single formulation and the placebo as a separate formulation.
  • a given dose of each formulation can comprise one or more pills, tablets, capsules, or the like (i.e., unit doses).
  • an 8 mg dose of estriol can be administered as four 2 mg capsules, and a placebo can be administered as a single capsule.
  • a given dose of each formulation may comprise one or more tablets or lozenges (i.e., unit doses) or a volume of liquid (e.g., one or more drops) or a volume of spray (e.g., one or more spray pumps).
  • the individual unit doses can be administered at essentially the same time, or they can be administered at different times on a given day, provided the entire daily dose is administered within a single day.
  • four 2 mg capsules of estriol can be taken together essentially once a day, or they may be taken two at a time twice a day, or they may be taken one at a time four times a day. Additional schedules are contemplated by the invention, again provided the entire daily dose is administered within a single day. While it may be preferable that the subject follow the same schedule from one day to the next, such is not required, once again provided the entire daily dose is administered within a single day.
  • the estrogen and the progestogen are formulated separately, they can be administered essentially simultaneously, or they can be administered sequentially with respect to each other.
  • the subject is administered four 2 mg capsules of estriol and one 0.7 mg capsule of norethindrone essentially simultaneously.
  • the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the progestogen is administered essentially simultaneously with one of the divided doses of estriol.
  • the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the progestogen is administered at a separate time from either one of the divided doses of estriol.
  • the estrogen and the placebo when they are formulated separately, they can be administered essentially simultaneously, or they can be administered sequentially with respect to each other.
  • the subject is administered four 2 mg capsules of estriol and one placebo essentially simultaneously.
  • the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the placebo is administered essentially simultaneously with one of the divided doses of estriol.
  • the subject is administered estriol in divided doses, e.g., two 2 mg capsules twice daily, and the placebo is administered at a separate time from either one of the divided doses of estriol.
  • the estrogen and the progestogen are formulated together.
  • a given dose of each component, formulated together can comprise one or more pills, tablets, capsules, or the like (i.e., unit doses).
  • an 8 mg dose of estriol and a 0.7 mg dose of norethindrone can be co formulated and administered as four capsules, each containing 2 mg estriol and 0.175 mg norethindrone, though preferably, where applicable, they are coformulated as one unit dose comprising both the estrogen and the progestogen.
  • a given dose of each component, formulated together can comprise one or more pills, tablets, capsules, or the like (i.e., unit doses).
  • an 8 mg dose of estriol and a placebo can be coformulated and administered as four capsules, each containing 2 mg estriol and a suitable amount of placebo.
  • a given dose of any coformulation of estriol and progestogen (or placebo) involves administration of more than a single unit dose, e.g., four capsules, each containing 2 mg estriol and 0.175 mg norethindrone
  • the individual unit doses can be administered at essentially the same time, or they can be administered at different times on a given day, provided the entire daily dose is administered within a single day.
  • four capsules, each containing estriol and progestogen (or placebo) can be taken together essentially once a day, or they may be taken two at a time twice a day, or they may be taken one at a time four times a day.
  • Additional schedules are contemplated by the invention, again provided the entire daily dose is administered within a single day. While it may be preferable that the subject follow the same schedule from one day to the next, such is not required, once again provided the entire daily dose is
  • subject refers to a living mammal and may be interchangeably used with the term "patient.”
  • the subject is a human.
  • a human subject is female, such as a woman.
  • the subject is a
  • premenopausal or perimenopausal woman In certain embodiments, the subject is a premenopausal woman. In certain embodiments, the subject is a perimenopausal woman. In certain embodiments, the subject is a postmenopausal woman.
  • the subject may have multiple sclerosis.
  • the multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the multiple sclerosis is secondary-progressive multiple sclerosis.
  • the multiple sclerosis is primary-progressive multiple sclerosis.
  • the multiple sclerosis is progressive-relapsing multiple sclerosis.
  • the subject has a mild form of any one of the foregoing subtypes of MS.
  • the subject has a moderate form of any one of the foregoing subtypes of MS.
  • the subject has an aggressive form of any one of the foregoing subtypes of MS.
  • the multiple sclerosis is, more accurately, so-called clinically isolated syndrome (CIS).
  • Estriol can be used, in accordance with the invention, to prevent or delay the onset of relapsing-remitting MS in subjects having CIS.
  • the subject has radiologically isolated syndrome.
  • neurodegenerative diseases such as, by way of illustration, Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, cerebellar ataxia, frontotemporal dementia, prion disease, Huntington's Disease, cerebral ischemia, idiopathic Morbus Parkinson, Parkinson syndrome, Morbus Alzheimers, cerebral dementia syndrome, infection-induced neurodegeneration disorders ⁇ e.g., AIDS -encephalopathy, Creutzfe Id -Jakob disease, encephalopathies induced by rubiola and herpes viruses and borrelioses), metabolic- toxic neurodegenerative disorders (such as hepatic-, alcoholic-, hypoxic-, hypo- or
  • the neurodegenerative disease is multiple sclerosis.
  • the patient is a woman.
  • the patient is a premenopausal or perimenopausal woman.
  • the patient is a postmenopausal woman.
  • the various methods disclosed herein can be methods for improving walking, vision, balance, cognition, or other symptoms in a subject, such as a subject with multiple sclerosis, and/or methods for improving multiple sclerosis functional composite (MSFC), EDSS, or MSSS scores in a subject, such as a subject with multiple sclerosis.
  • MSFC multiple sclerosis functional composite
  • EDSS EDSS
  • MSSS scores in a subject, such as a subject with multiple sclerosis.
  • the methods of treatment disclosed herein include methods for stabilizing or improving disability in a patient, whereby the patient's disability score (as measured by either of these tests or another suitable test) after six months, one year, or two years of therapy is at least about 10%, at least about 25%, at least about 40%, at least about 50%, or even at least about 60% higher relative to a control patient not receiving the estrogen therapy (but otherwise receiving the same treatment as the estrogen-treated patient).
  • the patient's disability score (as measured by either of these tests or another suitable test) after six months, one year, or two years of therapy is within about 2% or within about 5% of an earlier assessment, or at least about 2%, at least about 5%, at least about at least about 10%, at least about 25%, at least about 40%, at least about 50%, or even at least about 60% higher than the earlier assessment.
  • the progression of a walking disability can be tested using a walking test, e.g., assessing the subject's performance on a 25-foot walk test at different points in time, such as at 0 months (baseline), 6 months, 1 year, and 2 years.
  • a walking test e.g., assessing the subject's performance on a 25-foot walk test at different points in time, such as at 0 months (baseline), 6 months, 1 year, and 2 years.
  • the subject is deemed to have progressive worsening in walking.
  • the subject demonstrating the progressive walking disability commences treatment with estrogen, e.g., estriol.
  • the walking test may be repeated ⁇ e.g., at 1 year and/or 2 years from the start of estrogen treatment) to assess whether the estrogen treatment slowed or halted any further worsening in walking performance, e.g., as measured by the walking test.
  • Improvements in cognition outcomes associated with MS therapy can be assessed using the PASAT ⁇ e.g., PASAT 2 or PASAT 3) or SDMT test, or alternatively the MS-COG test (see Erlanger et al, JNeuro Sci 340: 123-129 (2014)).
  • the methods of treatment disclosed herein include methods for stabilizing or improving cognition in a patient, whereby the patient's cognition outcome after one year of therapy is at least about 2%, at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, or even at least about 60% higher relative to a control patient not receiving the estrogen therapy (but otherwise receiving the same treatment as the estrogen- treated patient), e.g., as measured by any of the preceding tests.
  • the patient's cognition outcome after six months, one year, or two years of therapy may be within about 2% or within about 5% of an earlier assessment, or at least about 2%, at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, or even at least about 60% higher than the earlier assessment, e.g., as measured by any of the preceding tests at different times.
  • a subject who scores below 50 on PASAT may be deemed to have cognitive disability.
  • the subject demonstrating the cognitive disability may commence treatment with estrogen, e.g., estriol.
  • the cognitive test may be repeated ⁇ e.g., at about six months from the start of estrogen treatment) to assess whether the estrogen treatment slowed or halted any further worsening in cognitive performance, e.g., as measured by the PASAT test.
  • the patient's score may increase by at least 3 points over the course of six to twelve months of estrogen therapy.
  • any of these methods further includes the step of administering to the subject an immunotherapeutic agent, wherein the
  • immunotherapeutic agent is neither an estrogen nor a progestogen. That is, in certain
  • the subject is administered, in addition to the estrogen and progestogen (or placebo), a third agent useful in the treatment of MS.
  • agents useful in the treatment of MS are, in general, immunotherapeutic agents. At least in connection with MS, such agents are sometimes referred to as disease-modifying therapies or disease-modifying therapeutics (DMTs).
  • DMTs disease-modifying therapeutics
  • immunotherapeutic agent refers to a compound, other than an estrogen or progestogen as defined herein, with an objectively measurable effect on at least one aspect of the immune system or an immune response.
  • the immunotherapeutic agent is immunosuppressive, i.e., it exerts an objectively measurable inhibitory effect on at least one aspect of the immune system or an immune response.
  • the immunotherapeutic agent is anti-inflammatory.
  • the immunotherapeutic agent is a small molecule (molecular weight less than or equal to about 1.5 kDa) pharmaceutical compound or composition.
  • the immunotherapeutic agent is a small molecule (molecular weight less than or equal to about 1.5 kDa) pharmaceutical compound or composition.
  • immunotherapeutic agent is a biological compound or composition, e.g., an antibody, peptide, nucleic acid, etc.
  • the immunotherapeutic agent is selected from dimethyl fumarate (Tecfidera®; BG-12), fingolimod (Gilenya®), glatiramer acetate (Copaxone®, for example "longer- lasting" 40 mg/ml or 20 mg/ml versions), interferon beta- la (Avonex® or Rebif®), interferon beta-lb (Betaseron® or Extavia®), peginterferon beta-la (Plegridy®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), alemtuzumab (Lemtrada®), and teriflunomide
  • the immunotherapeutic agent is selected from dimethyl fumarate (Tecfidera®; BG-12), fingolimod (Gilenya®), glatiramer acetate (Copaxone®), interferon beta-la (Avonex® or Rebif®), interferon beta-lb (Betaseron® or Extavia®), peginterferon beta- la (Plegridy®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), alemtuzumab (Lemtrada®), and teriflunomide (Aubagio®).
  • the immunotherapeutic agent is not mitoxantrone (Novantrone®).
  • the immunotherapeutic agent is not glatiramer acetate (Copaxone®).
  • the immunotherapeutic agent is dimethyl fumarate (Tecfidera®; BG-12). In certain embodiments, the immunotherapeutic agent is fingolimod (Gilenya®). In certain embodiments, the immunotherapeutic agent is glatiramer acetate (Copaxone®). In certain embodiments, the immunotherapeutic agent is interferon beta- la (Avonex® or Rebif®). In certain embodiments, the immunotherapeutic agent is interferon beta-lb (Betaseron® or Extavia®). In certain embodiments, the immunotherapeutic agent is peginterferon beta- la (Plegridy®). In certain embodiments, the immunotherapeutic agent is mitoxantrone
  • the immunotherapeutic agent is natalizumab
  • the immunotherapeutic agent is alemtuzumab (Lemtrada®). In certain embodiments, the immunotherapeutic agent is teriflunomide
  • the subject is receiving treatment with an immunotherapeutic agent.
  • the method may comprise discontinuing treatment with the immunotherapeutic agent, e.g., if the central nervous system (i.e., brain) of the subject does not present with active lesions, e.g., gadolinium-enhancing lesions.
  • the method may comprise discontinuing treatment with the immunotherapeutic agent if no active lesions (e.g., gadolinium-enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45,46, 47, 48, 49, 50, 51, or 52 weeks.
  • active lesions e.g., gadolinium-enhancing lesions
  • the method may comprise discontinuing treatment with the immunotherapeutic agent if no active lesions (e.g., gadolinium-enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 months.
  • the method may comprise discontinuing treatment with the immunotherapeutic agent if no active lesions (e.g., gadolinium-enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years.
  • the method comprises administering an estrogen to the subject without conjointly administering an immunotherapeutic agent to the subject.
  • the method may comprise administering an estrogen to the subject without conjointly administering an immunotherapeutic agent to the subject, for example, if no active lesions (e.g., gadolinium- enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45,46, 47, 48, 49, 50, 51, or 52 weeks.
  • active lesions e.g., gadolinium- enhancing lesions
  • the method may comprise administering an estrogen to the subject without conjointly administering an immunotherapeutic agent to the subject, for example, if no active lesions (e.g., gadolinium-enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 months.
  • the method may comprise administering an estrogen to the subject without conjointly administering an immunotherapeutic agent to the subject, for example, if no active lesions (e.g., gadolinium-enhancing lesions) have been detected in the central nervous system (i.e., brain) of the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years.
  • This example describes a randomized, double-blind, placebo-controlled human clinical trial for the treatment of multiple sclerosis using glatiramer acetate (GA) and estriol.
  • GA glatiramer acetate
  • Eligible patients were females, an age of 18-50 years, a diagnosis of relapsing-remitting multiple sclerosis as defined according to the McDonald criteria (Polman C. et al, Neurology 64:987 (200)), a baseline score of 0 to 4.5 on the Expanded Disability Status Scale (EDSS, which ranges from 0 to 10, with higher scores indicating more severe disability), and disease activity as evidenced by at least two documented relapses in the previous 24 months before screening or as evidenced by at least one documented relapse within 24 months before screening with a history of at least one gadolinium-enhancing lesion on a brain or cord magnetic resonance imaging (MRI) scan performed at least 3 months before or 3 months after the clinical relapse.
  • MRI magnetic resonance imaging
  • adrenocorticotropic hormone (ACTH)
  • corticosteroids corticosteroids
  • intravenous immunoglobulins or other listed MS treatments within 2 months before screening, those who were pregnant, breastfeeding, or trying to get pregnant, those not willing to discontinue other hormonal treatments, those who underwent surgical or natural menopause for longer than 1 or 3 years, respectively, with no hormone replacement therapy, and those who had ever been treated with a major
  • H Scores on the Expanded Disability Status Scale ranged from 0 to 10, with higher scores indicating a greater degree of disability.
  • One patient in the Estriol + GA group did not have a confirmed relapse within 24 months prior to randomization, with enrollment based on disease activity evidenced by M I enhancing lesions.
  • Standardized neurologic assessments including an EDSS assessment, were performed at months 0, 3, 6, 12, 18 and 24, and at the time of a suspected relapse (as an additional unscheduled visit).
  • EDSS assessments were performed by physicians who were trained either by in-person training or online (www.Neurostatus.net). MRI scans were obtained at screening and at months 0, 3, 6, 12 and 24. Subjects were seen or contacted every 3 months for compliance assessments and for dispensing medications.
  • the primary efficacy end point was the annualized relapse rate.
  • a relapse was defined as the appearance of new neurological symptoms or the worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by an objective change in a neurological examination (i.e., a worsening of 0.5 or more points on the EDSS or a worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores, not due to fatigue alone and not associated with fever or infection).
  • the treating physician made the decision concerning whether the relapse criteria had been met, incorporating whether a change in EDSS had been documented by the examining physician. Both treating and examining physicians were unaware of study group assignments.
  • the standard treatment for relapse was a 3-5 day course of glucocorticoids at the discretion of the treating neurologist.
  • Secondary efficacy end points included the proportion of subjects with a relapse over all 24 months, the proportion of subjects with positive MRI scans for gadolinium enhancing lesions, a change in PASAT cognitive testing, a sustained improvement in PASAT cognitive testing (as defined by an increase of at least 3 points sustained over at least 6 months), a change in EDSS scores from baseline, disability progression (as defined by an increase in EDSS of at least 1.0 point in subjects with a baseline score of 1.0 or higher, or by an increase of at least a 1.5 points in subjects with a baseline score of 0, each sustained for at least 6 months).
  • Tertiary end points included gray matter atrophy on MRI, and changes in results from baseline on questionnaires including the Modified Fatigue Impact Scale, Beck Depression Inventory, and MS Quality of Life.
  • CBC complete blood count
  • chemistry panel including sodium, potassium, creatinine, BUN, glucose, total protein, albumin, bilirubin (total), alkaline phosphatase, AST (SGOT), and ALT (SGPT), and lipid profile (HDL, LDL and triglycerides, cholesterol.
  • Gynecologic exams were done at month 0, 6, 18 and at month 24 exit, with uterine ultrasounds at months 6, 18 and at month 24 exit. Mammograms were done in screening and at month 24 exit. Adverse event analysis was based on the percentage of patients who discontinued the study and the percentage of patients who discontinued the study possibly due to adverse events.
  • the sample size was determined based on the primary end point of annualized relapse rate. A total sample of 150 eligible patients would provide approximately 80% power at a two- sided significance level of 0.10 for this phase ⁇ clinical trial to detect the difference in the annualized relapse rate of 0.76 versus 1.18 for Estriol plus GA group and the Placebo plus GA group in 2 years.
  • Intention-to-treat analyses were carried out for all end points.
  • a negative binomial regression model was used to compare both 12 months and 24 months annualized relapse rates between Estriol + GA versus Placebo + GA groups adjusted for covariates.
  • a sequential testing procedure was applied to control the overall type I error.
  • a hierarchical statistical approach was used whereby results in the first 12 months of treatment would be assessed, and, if and only if, significance were met, results in the entire 24 months of treatment would be assessed.
  • the earlier timepoint was compared first since GA requires time to reach full efficacy, potentially providing a greater window to detect efficacy 12 months after initiation of GA and study drug treatment. Consistent with a phase 2 study using a clinical outcome, a p-value ⁇ 0.10 was considered statistically significant.
  • proportional hazards model was used to compare the time to relapse free probabilities between two groups adjusting for covariates.
  • the fixed effects include treatment groups (Estriol + GA vs Placebo + GA), baseline lesion number, age, and baseline EDSS score.
  • the random effect of subject is included in the model to account for within subject correlation.
  • Mixed effects models were used to assess the association among outcomes and estriol levels at all follow-ups and using subjects in both treatment groups.
  • Mixed effects logistic regression model was used to evaluate the association between the number of enhancing lesions and the occurrence of relapse at all follow-up intervals.
  • Linear mixed effects model was carried out to evaluate the association between PASAT change and percent brain volume change, as well as between PASAT change and estriol levels.
  • the pattern mixture model provides the analysis with the possibility of non-random dropout.
  • the missing data were sequentially imputed by the follow up time and the imputation model assumed that the treatment effect for patients after drop out is the same as taking placebo.
  • the sample size of 150 patients was used to provide approximately 80% power detect a one third reduction in relapse rates in Estriol + GA compared to Placebo + GA at a two-sided significance level of 0.10 for this phase 2 clinical trial to detect a difference in annualized relapse rates with an estimated rate of 0.75 versus 1.18 for Estriol + GA versus Placebo + GA, respectively, in 2 years.
  • Estriol levels remained elevated through months 3, 6 and 12 in the Estriol plus GA group.
  • Possible reasons for the significant drop in estriol levels at month 24 in the Estriol plus GA group included drop out of those with relatively higher estriol levels prior to month 24 or poorer compliance in those who remained in the study at month 24.
  • Assessment of compliance using pill return counts showed that over 75% of those patients with a reduction in estriol levels by greater than 40% at month 24 did not have pill return counts showing compliance, while in those without such reductions in estriol levels, over 75% had pill return counts showing compliance at month 24.
  • the primary outcome measure for efficacy was annualized relapse rate including all subjects on an intent-to-treat basis.
  • ⁇ Relapse rate ratio was estimated using negative binomial regression with adjustment for age, baseline EDSS ( ⁇ 2 vs. >2), number of relapse 12 months prior study entry (0-1 vs. >1), MS duration ( ⁇ 1 vs. >1 year), prior GA treatment (never vs. past/current), and prior interferon treatment (yes vs. no).
  • J Values were calculated using the Kaplan-Meier product-limit method. Progression defined as EDSS increase of at least 1.0 point in subjects with baseline score of 1.0 or higher or increase of at least 1.5 points with baseline score of 0, each sustained for at least 6 months.
  • EDSS Expanded Disability Status Scale
  • Plus-minus values are means ⁇ SD.
  • CI denotes confidence interval
  • E+GA indicates Estriol+GA .
  • P+GA indicates Placebo+GA.
  • the data in this column are: mean difference (95% Confidence interval of the mean difference) and p- value.
  • J Values were calculated using the Kaplan-Meier product-limit method. Progression defined as EDSS increase of at least 1.0 point in subjects with baseline score of 1.0 or higher or increase of at least 1.5 points with baseline score of 0, each sustained for at least 6 months.
  • MSFC Functional Composite
  • PASAT Auditory Serial Addition Test
  • VBM voxel-based morphometry
  • Estriol plus GA was found to be safe and well tolerated with regard to adverse events including gynecological outcomes (Table 8). Regarding adverse events, irregular menses occurred more with Estriol + GA (P ⁇ 0.001), while vaginal infections occurred more with Placebo + GA (P ⁇ 0.05), with no increase in discontinuations due to either.
  • the main analysis seeks to compare the relapse event rate between treatment groups based on the negative binomial regression.
  • recurrent events analysis was performed based on Andersen Gill model to compare the relapse hazard rate between treatment groups. Both analyses showed similar results, and significant and meaningful reduction in relapse rates was found in the Estriol plus GA group as compared to the Placebo plus GA group.
  • Sensitivity analyses regarding missing data were performed to demonstrate the robustness of study conclusion. For this, multiple imputation analysis were performed on the missing data according to the pattern mixture model as a sensitivity analysis to address the possibility of data being non-ignorable or missing not at random (MNAR) (Little, R. & L. Yau, Biometrics 52:1324 (1996)). The missing data were sequentially imputed by the follow up time, and the imputation model assumed that the treatment effect for patients after dropout is the same as taking placebo (Ratitch, B. & M. O'Kelly, Proc. Pharm. Industry SAS User Group, Nashville (2011)). The analyses results were compared for relapse rate with assumptions of ignorable and non-ignorable missing data. The results are similar with and without imputation, and significant and meaningful reduction in relapse rates was observed in the Estriol plus GA group as compared to the Placebo plus GA group.
  • MRI scans were performed at 0, 3, 6, 12 and 24 months using a standardized protocol implemented at each site that consisted of the following: Tl -weighted 3D volume, pre and post contrast: TR2200, TE3.4, Tl 900, 176 slices, 1mm 3 .
  • Dual-echo fast spin echo TR10000, TE12/95, 50 slices, 1x1x3mm.
  • MRI data in Dicom format were fully anonymized prior to transfer and then uploaded to the central MRI reading center database.
  • each site Prior to study onset, each site provided a dummy scan utilizing the standardized sequences for review by the central MRI reading center to verify scan quality and fidelity. Quality control was maintained at each site using standard procedures for clinical scanners (daily phantoms, stability testing). Quarterly phantoms were collected from 12 of the 15 sites, most using the standard American College of Radiology (ACR) phatom. One site upgraded from a Siemens 1.5T to a 3.0T in
  • T2 lesion areas were determined using a semi-automated intensity based segmentation procedure by a trained, experienced researcher verified by a single investigator (NLS).
  • MRI brain whole gray matter, whole white matter and cortical gray matter volumes were determined using a pairwise Jacobian integration (PJI) method.
  • Pre-processing for structural Tl - weighted images included 1) N3 non-uniformity correction, 2) histogram-based intensity normalization, 3) linear standard space registration using ICBM 2009c nonlinear symmetric template, 4) patch-based brain extraction, and 5) lesion-inpainting.
  • Inputs to PJI were a pair of baseline and follow-up pre-processed structural Tl-weighed images.
  • the PJI consisted of 1) linear skull-constrained symmetric registration, 2) halfway transformation and resampling, 3) nonlinear symmetric registration using ANTS, and 4) voxelwise Jacobian determinant calculation on the warp field.
  • Whole gray matter and whole white matter tissue masks were generated by SPM8 Segment function. Additional nonlocal means denoising was applied.
  • For whole brain tissue masks, the whole gray matter and whole white matter masks were combined.
  • cortical gray matter mask a standard cortical mask was nonlinearly transformed and merged with gray matter mask.
  • the standard template was the ICBM (ICBM 2009c nonlinear symmetric version), and the nonlinear registration was performed by ANTS.
  • the Jacobian determinants were averaged within the masks for percent volume change in cortical gray matter, whole gray matter, whole white matter, and whole brain.
  • VBM Voxel-based morphometry
  • Brain images were preprocessed utilizing SPM8 and the VBM8 toolbox.
  • White matter lesions were in-painted to minimize their impact based on manual delineations that were used for the analysis of new T2 lesions.
  • these manually delineated lesion masks were coregistered to the Tl -weighted images, corrected if necessary, and used for lesion in-painting as described by Chard et al. (J. Magn. Reson. Imaging 34:223 (2010)).
  • the lesion in-painted images were subsequently realigned for each subject using halfway-registrations and corrected for bias-field inhomogeneities.
  • the realigned, bias corrected images were then tissue-classified into gray matter, white matter, and cerebrospinal fluid and registered to MNI space through linear and non-linearly transformations (see http://dbm.neuro.uni-jena.de/vbm8/VBM8- Manual.pdf). More specifically, the tissue classification was based on maximum a posteriori segmentations, accounted for partial volume effects, and was refined by applying a spatially adaptive non-local means denoising filter as well as a hidden Markov random field model.

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Abstract

L'invention concerne des procédés pour traiter une maladie neurodégénérative, telle que la sclérose en plaques, chez un sujet qui ne présente pas de lésions actives (par exemple, des lésions rehaussées par gadolinium), comprenant l'administration d'un œstrogène au sujet sans l'administration conjointe d'un second agent immunothérapeutique. Par exemple, un agent immunothérapeutique quelconque reçu par le sujet peut être interrompu, par exemple, lorsqu'il est déterminé que le cerveau du sujet ne présente pas de lésions actives. Le procédé peut consister à déterminer si le cerveau du sujet présente des lésions actives, par exemple, par IRM rehaussée par gadolinium.
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US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems

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