EA045454B1 - USE OF VIBEGRON FOR TREATMENT OF HYPERACTIVE BLADDER - Google Patents

Description

Prerequisites for creating the invention

Overactive bladder (OAV) is a chronic and sometimes debilitating condition of the lower urinary tract. The function of the lower urinary tract is to store and periodically release urine. This requires coordination of storage and voiding reflexes, which involve various afferent and efferent neural pathways, which leads to modulation of central and peripheral neuroeffector mechanisms and, as a consequence, to the coordinated regulation of the sympathetic and parasympathetic components of the autonomic nervous system, as well as somatic motor pathways. It proximally regulates the contractile state of the bladder (detrusor), smooth muscle of the urethra and striated muscle of the urethral sphincter.

Overactive bladder, from a pathophysiological point of view, has been associated with detrusor overactivity. OAV is characterized by symptoms of urinary urgency, with or without urge incontinence, and is typically associated with urinary frequency and nocturia. The prevalence of OAV in the United States and Europe is estimated to be 16–17% among women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to a neurological condition, bladder outlet obstruction, or other causes.

Currently, the predominant class of drugs used to treat OAV are antimuscarinics. Clinical use of antimuscarinics is limited by poor efficacy and poor tolerability due to mechanism-related side effects, including dry mouth, constipation, and the potential for adverse CNS effects (eg, cognitive impairment). High rates of patients discontinuing therapy were observed for both tolterodine and oxybutynin, two commonly prescribed antimuscarinics, in both clinical trials and real-world settings.

Activation of beta-3 adrenergic receptors (e ₃ -AR) is an effective way to relax the detrusor in normal and pathogenic conditions. Functional evidence supporting an important role for ₃ -AR in urine storage comes from in vivo studies. ₃ -AR agonists have demonstrated effectiveness in relieving symptoms of OAV. To date, only one β ₃ AR agonist, mirabegron (Astellas Pharma Global Development, Inc), has received marketing approval in the United States and Japan for the treatment of OAV. Mirabegron activates e ₃ -AR in the detrusor muscle in the bladder, which leads to muscle relaxation and increased bladder capacity. Reductions in urinary frequency, urinary incontinence, and urgency episodes, as well as an increase in mean urinary volume per voiding event were observed with mirabegron use.

Vibegron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo7,8-dihydro -6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide, is a potent and highly selective beta-3-adrenergic receptor agonist ( ₃ -AR), demonstrating more than 9000-fold selectivity for activation at ₃ -AR. compared with 32-AR and e1-AR in in vitro cell-based assays. See Edmondson et al., J. Med. Chem. 59:609-623 (2016).

Vibegron is disclosed as an e ₃ -AR agonist in US Patent Nos. 8,399,480 and 8,247,415.

Synthetic methods for obtaining Vibegron are disclosed in US Publications No. US 2017/0145014, US 2015/0087832, US 2016/0176884 and US 2014/0242645. All publications cited are incorporated herein by reference in their entirety.

Brief description of graphic materials

In fig. Figure 1 shows an overlay of the distribution density of exposure using Vibegron in amounts of 100 and 75 mg, calculated for special groups of the population.

In fig. Figure 2 shows the chemical structure of Vibegron metabolites.

Brief description of the invention

The present invention provides a method of treating overactive bladder, comprising orally administering Vibegron in an amount of 60 to 90 mg per day to a subject in need thereof.

The present invention further provides a pharmaceutical composition in unit dosage form containing from 60 to 90 mg of Vibegron, wherein the composition in unit dosage form is suitable for oral administration.

Detailed description

In order that the present invention may be more easily understood, definitions are first given.

- 1,045,454 individual terms. As used herein, unless otherwise expressly provided herein, each of the following terms has the meaning set forth below. Additional definitions are set forth in the invention.

In this specification and the accompanying claims, the singular forms include the plural unless the context clearly indicates otherwise. The singular forms, as well as the terms one or more and at least one, may be used interchangeably herein. In certain aspects, singular forms mean single. In other aspects, singular forms include two or more or many.

In addition, the use of and/or herein should be understood as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term and/or, as used herein in a phrase such as A and/or B, is intended to include A and B, A or B, A (alone) and B (alone). Likewise, the term and/or, when used in a phrase such as A, B and/or C, is intended to cover each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (separately); B (separately); and C (separately).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention relates.

The term approximately, as used in connection with a numerical value in the specification and claims, denotes a range of accuracy familiar and acceptable to one skilled in the art. This accuracy interval is ±10%.

The term overactive bladder generally refers to a clinical syndrome characterized by urinary urgency, with or without urge incontinence, not necessarily associated with urinary frequency and nocturia.

The term urge urinary incontinence (UUI), as used herein, refers to involuntary urinary incontinence accompanied by a strong, sudden need to urinate, and may be used interchangeably with the terms urge incontinence or urge incontinence. UUI is different from stress urinary incontinence, which is involuntary incontinence of urine during stress or physical activity (such as playing sports), or when sneezing or coughing.

As used herein, the term impairment refers to an acute or chronic decline in function. For example, kidney failure refers to a health condition in which the kidneys are unable to maintain their normal function, causing waste products and metabolites to accumulate in the blood.

Urinary urgency, as used herein, refers to a sudden, overwhelming need to urinate that is difficult to hold in.

As used herein, the term urinary frequency refers to the need to empty the bladder frequently.

As used herein, the term free base refers to the underlying chemical compound itself, not in salt form. For example, the free base of Vibegron refers to (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4- oxo-7,8-dihydro6H-pyrrole[1,2-a]pyrimidine-6-carboxamide.

As used herein, the term wet OAV refers to an overactive bladder, defined by urinary frequency and urgency, with urinary incontinence.

As used herein, dry OAV refers to overactive bladder, defined by urinary frequency and urgency, without urinary incontinence.

The term pharmaceutically acceptable salt means those salts of compounds that are safe and effective for use in subjects and that have the desired biological activity.

Pharmaceutically acceptable salts of the base compound may be salts of organic or inorganic acids. In some embodiments, organic and inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid, mandelic acid, succinic acid, and methanesulfonic acid. See generally Journal of Pharmaceutical Science, 66, 2 (1977), which is incorporated herein by reference in its entirety.

As used herein, the term _Cmax refers to the maximum plasma concentration of a drug following administration.

As used herein, the term T _max refers to the time after drug administration when the maximum plasma concentration is reached.

As used herein, the term AUC refers to the area under the curve of a graph of plasma concentration versus time after administration of a drug.

The term steady state means that the amount of drug entering the

- 2 045454 system, approximately equal to the amount of drug leaving the system. Thus, at steady state, the patient's body eliminates the drug at approximately the same rate at which the drug becomes available to the patient's circulatory system through absorption into the bloodstream.

The term treatment period means the period of time during which the drug is administered to the subject. For example, the treatment period may range from about 2 weeks to about 2 years. In some embodiments, the treatment period may be about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 24, about 52, about 76, or about 104 weeks. . The effectiveness of a drug can be assessed by measuring certain parameters and calculating changes from baseline over the treatment period. Efficacy parameters include unrestricted voiding, urge incontinence episodes, total incontinence episodes, and urgency episodes.

Methods of treatment.

The present invention relates to a method of treating overactive bladder, comprising orally administering to a subject in need thereof a dose of Vibegron such that the desired effectiveness is maintained while undesirable side effects are minimized. Surprisingly, side effects associated with increased _Cmax can be disproportionately reduced by adjusting the dosage of Vibegron.

The present invention provides a method of treating overactive bladder, comprising orally administering to a subject in need of treatment Vibegron in an amount of 50 to 100 mg per day.

The present invention also provides a method of increasing bladder smooth muscle relaxation comprising orally administering Vibegron in an amount of 50 to 100 mg per day to a subject in need thereof.

In some embodiments, the amount of Vibegron administered per day is from about 55 to about 100 mg, from about 60 to about 100 mg, from about 65 to about 100 mg, from about 70 to about 100 mg, from about 75 to about 100 mg, from about 80 to about 100 mg, from about 85 to about 100 mg, from about 90 to about 100 mg, or from about 95 to about 100 mg.

In some embodiments, the amount of Vibegron administered per day is from about 50 to about 95 mg, from about 50 to about 90 mg, from about 50 to about 85 mg, from about 50 to about 80 mg, from about 50 to about 75 mg, from about 50 to about 70 mg, from about 50 to about 65 mg, from about 50 to about 60 mg, or from about 50 to about 55 mg.

In some embodiments, the amount of Vibegron administered per day is from about 60 to about 90 mg, from about 65 to about 85 mg, or from about 70 to about 80 mg. In some embodiments, the amount of Vibergone administered per day is 60 to 90 mg, 65 to 85 mg, or 70 to 80 mg.

In some embodiments, the amount of Vibegron administered per day is about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 95 mg. In some embodiments, the amount of Vibegron administered per day is approximately 75 mg. In some embodiments, the amount of Vibegron administered per day is 75 mg.

In some embodiments, the amount of Vibegron administered per day is not approximately 50 mg. In some embodiments, the amount of Vibegron administered per day is not approximately 100 mg. In some embodiments, the amount of Vibegron administered per day is not 50 mg. In some embodiments, the amount of Vibegron administered per day is not 100 mg.

In some embodiments, the subject has symptoms of urge incontinence, urgency, and urinary frequency.

In some embodiments, the subject has one or more symptoms of urge urinary incontinence (or urge urinary incontinence), urgency, urinary frequency, and nocturia.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or animal. In some embodiments, the subject is a human.

In some embodiments, the subject is over 18 years of age. In some embodiments, the subject is under approximately 18 years of age. In some embodiments, the subject is aged

- 3 045454 from about 6 to about 18 years, from about 6 to about 12 years, or from about 12 to about 18 years. In some embodiments, the subject is over about 20 years of age. In some embodiments, the subject is over about 25 years of age. In some embodiments, the subject is over about 30 years of age. In some embodiments, the subject is over about 35 years of age. In some embodiments, the subject is over 40 years of age. In some embodiments, the subject is over 45 years of age. In some embodiments, the subject is over 50 years of age. In some embodiments, the subject is over 55 years of age. In some embodiments, the subject is over 60 years of age. In some embodiments, the subject is over 65 years of age. In some embodiments, the subject is over 70 years of age. In some embodiments, the subject is over 75 years of age.

In some embodiments, the method includes crushing the pharmaceutical composition into a unit dosage form containing Vibegron prior to administration to a subject. In some embodiments, the subject is orally administered a crushed pharmaceutical unit dose containing Vibegron.

In some embodiments, the subject has renal failure or is at risk of developing renal failure. In some embodiments, the subject suffers from mild renal impairment, moderate renal impairment, or severe renal impairment.

In some embodiments, the subject has been pretreated with OAV. In some embodiments, the subject has not been pretreated with OAV.

In some embodiments, the subject has renal failure and is administered approximately 75 mg of Vibegron per day.

In some embodiments, Vibegron is administered with a second pharmaceutical agent, including, for example, any one specified in the present invention. In some embodiments, Vibegron is administered simultaneously with a second pharmaceutical agent. In some embodiments, Vibegron and the second pharmaceutical agent are administered sequentially. In some embodiments, Vibegron is administered before and/or after the second pharmaceutical agent. The embodiments described below include such sequential administrations.

In some embodiments, the subject is concurrently receiving, taking, or otherwise being exposed to a cytochrome P450 inhibitor, such as a CYP3A inhibitor, and drugs that are substrates of the following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

In some embodiments, the subject concurrently receives, takes, or is otherwise exposed to a P-glycoprotein inhibitor.

CYP3A/P-glycoprotein inhibitors include, but are not limited to, amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil, curcumin, cyclosporine A, eltrombopag, atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampicin (eg, single dose), simeprevir, paminohypuric acid (PAA)(b), probenecid, teriflunomide, cimetidine, dolutegravir, isavuconazole, ranolazine, trimetho approx. and vandetanib.

In some embodiments, the subject simultaneously receives, takes, or is otherwise exposed to a muscarinic receptor antagonist.

Muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, cyclopentolate, atropine methylnitrate, trihexyphenidyl/trihexyphenidyl, tolterodine, solifenacin, darifena cin, benzatropine, mebeverine , procyclidine and aclidinium bromide.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and is simultaneously receiving, taking, or otherwise being exposed to a muscarinic receptor antagonist.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and is simultaneously receiving, receiving, or otherwise exposed to a CYP3A inhibitor.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and is simultaneously receiving, receiving, or otherwise exposed to a Pgp inhibitor.

In some embodiments, the subject is not receiving, taking, or otherwise being concurrently exposed to a beta blocker inhibitor.

In some embodiments, the subject is not receiving, taking, or otherwise being concurrently exposed to amlodipine.

In some embodiments, Vibegron is administered with food, within 60 minutes after a meal, or within 2 hours after a meal.

- 4 045454

In some embodiments, Vibegron is administered outside of meals or before meals. In some embodiments, Vibegron is administered more than two hours before a meal. In some embodiments, Vibegron is administered regardless of whether the subject has eaten or not.

In some embodiments, Vibegron is administered once daily, twice daily, or three times daily. In some embodiments, Vibegron is administered once daily.

Changes from baseline in blood pressure (BP) and heart rate (HR) in subjects taking Vibegron were not significantly different from those in subjects taking placebo. In some embodiments, the subject experiences an average maximum change in systolic blood pressure (SBP) from baseline over a treatment period (e.g., 8 weeks or 12 weeks), and the average maximum change is less than 2.0, less than 1.9, less 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.0, less than 0.9, less 0.8, less than 0.7, less than 0.6 or less than 0.5 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 2 mm Hg. Art. compared to a subject taking a placebo. In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 1 mm Hg. Art. compared to a subject taking a placebo.

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 2 mmHg. Art. compared to a subject taking a placebo. In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 1 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 2 mm Hg. Art. compared to a subject taking a placebo. In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 1 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline over a treatment period (e.g., 8 or 12 weeks), and the average maximum change is less than less than 2.0, less than 1.9, less 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.0, less than 0.9, less 0.8, less than 0.7, less than 0.6 or less than 0.5 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 2 mm Hg. Art. compared to a subject taking a placebo. In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 1 mm Hg. Art. compared to a subject taking a placebo.

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 weeks or 12 weeks) is less than 2 mmHg. Art. compared to a subject taking a placebo. In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 1 mm Hg. Art. compared to a subject taking a placebo.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 weeks or 12 weeks) is less than 2 mmHg. Art. compared to a subject taking a placebo. In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (for example, 8 weeks or 12 weeks) is less than 1 mmHg Art. compared to a subject taking a placebo.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron once daily, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 or 12 weeks) is less than 1 mmHg . Art. compared to a subject taking placebo, and the mean maximum change in SBP from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 1 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron once daily, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 weeks or 12 weeks) is less than 1 mm rt. Art. compared to a subject taking placebo, and the mean maximum change in SBP from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 1 mmHg. Art. compared to a subject taking a placebo.

In some embodiments, the subject experiences an average maximum change in systolic blood pressure (SBP) from baseline over the treatment period (e.g., 8 weeks or 12 weeks) that is less than 10, less than 9.5, less than 9, less than 8. 5, less, less than 7.5, less than 7, less than 6.5, less than 6, less than 5.5 or less than 5 mmHg. Art.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 10 mm Hg. Art.

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 10 mmHg. Art.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in SBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 10 mmHg. Art.

In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline over the treatment period (e.g., 8 weeks or 12 weeks) that is less than 7, less than 6.5, less than 6, less than 5.5, less than 5, less than 4.5, less than 4, less than 3.5, less than 3, less than 2.5 or less than 2 mm Hg. Art.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 weeks or 12 weeks) is less than 7 mm Hg. Art.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and experiences a change from baseline during the treatment period (e.g., 8 weeks or 12 weeks) in the average number of voids per 24 hours, where the change is greater than the subject's taking a placebo. The difference from placebo is from about -0.4 to about -1.5, for example from about -0.4, -0.5, -0.6, -0.7, -0.8, -0.9 , -1.0, -1.1, -1.2, -1.3, -1.4, or 1.5, or is between any two of the previous values.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and the subject experiences a change from baseline during the treatment period (e.g., 8 weeks or 12 weeks) in the average 24-hour void count of from about -1.5 to about -2.5, for example approximately -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2 .3, 2.4, or -2.5, or between any two of the previous values.

In some embodiments, the subject has an average of >1 episode of urge urinary incontinence (UUI) per day prior to treatment and is administered approximately 75 mg of Vibegron per day and experiences a change from baseline during the treatment period (e.g., 8 weeks or 12 weeks) of the average number of UUI episodes where the change is greater than that observed in a subject taking placebo. The difference from placebo is from about -0.2 to about -1.5, for example from about -0.2, -0.3, -0.4, -0.5, -0.6, -0.7 , -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or is in the range between any two of the previous values.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and the subject experiences a change from baseline over the treatment period (e.g., 8 weeks or 12 weeks) in the average number of UUI episodes of about -1.3 to about -2 ,5, for example, approximately -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1 , -2.2, -2.3, 2.4, or -2.5, or between any two of the previous values.

In some embodiments, the subject is administered approximately 75 mg of Vibegron per day and experiences a change in urinary volume (ml) per void, where the change is greater than that of a subject receiving placebo. The difference from placebo is from about 20 ml to about 35 ml, for example, from about 20 ml, 21 ml, 22 ml, 23 ml, 24 ml,

- 6 045454 ml, 26 ml, 27 ml, 28 ml, 29 ml, 30 ml, 31 ml, 32 ml, 33 ml, 34 ml or 35 ml, or between any two of the previous values.

In some embodiments, the subject has an average of >1 episode of urge urinary incontinence (UUI) per day prior to treatment and is administered approximately 75 mg of Vibegron per day and experiences at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% reduction in the average number of daily UUI episodes over the treatment period (eg, 8 weeks or 12 weeks ).

In some embodiments, the subject has an average of >1 episode of urgency per day prior to treatment, and is receiving approximately 75 mg of Vibegron per day and experiencing at least 30, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70%, or at least 75% reduction in the average number of daily urgency episodes over the treatment period (eg, 8 or 12 weeks).

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 7 mm Hg. Art.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron per day, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (eg, 8 or 12 weeks) is less than 7 mm Hg. Art.

In some embodiments, a subject over 45 years of age is administered approximately 75 mg of Vibegron once daily, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 weeks or 12 weeks) is less than 7 mm rt. Art., and the average maximum change in SBP from baseline over the treatment period (eg, 8 or 12 weeks) is less than 10 mmHg. Art.

In some embodiments, a subject over 65 years of age is administered approximately 75 mg of Vibegron once daily, and the average maximum change in DBP that the subject experiences from baseline over the treatment period (e.g., 8 or 12 weeks) is less than 7 mmHg . Art., and the average maximum change in SBP from baseline over the treatment period (eg, 8 or 12 weeks) is less than 10 mm Hg. Art.

In some embodiments, the onset of action of Vibegron is observed after approximately 4 weeks. In some embodiments, the onset of action of Vibegron is observed after approximately 3 weeks. In some embodiments, the onset of action of Vibegron is observed after approximately 2 weeks. Onset of action, as used herein, refers to the length of time it takes for the effects of a drug to become noticeable upon administration.

Pharmaceutical composition in the form of a single dosage form.

The present invention provides pharmaceutical compositions in unit dosage form containing the dose of Vibegron disclosed herein, wherein the composition in unit dosage form is suitable for oral administration. Those skilled in the art understand that oral dosage forms include, for example, forms such as liquid formulations, tablets, capsules and gelatin capsules. In some embodiments, the unit dosage form compositions are solid dosage forms, such as tablets and capsules. In some embodiments, the unit dosage form compositions are tablets.

Pharmaceutically acceptable excipients are those generally recognized as safe, such as lactose, microcrystalline cellulose, starch, calcium carbonate, magnesium stearate, stearic acid, talc, colloidal silica, mannitol, croscarmellose sodium, hydroxypropylcellulose. In some embodiments, the pharmaceutical unit dosage form composition disclosed herein contains a diluent, a disintegrant, a binder and a lubricant. See generally Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000), which is incorporated herein by reference in its entirety.

In one embodiment, the pharmaceutical composition in unit dosage form disclosed herein contains mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose and magnesium stearate.

Oral dosage forms can be prepared using standard pharmaceutical manufacturing techniques. Such techniques include, for example, wet granulation, wet grinding, fluidized bed drying, dry grinding, lubrication, tabletting and aqueous film deposition.

In some embodiments, the pharmaceutical compositions in a unit dosage form of the present invention contain from about 50 mg to about 100 mg

- 7 045454 vibegrons.

In some embodiments, the pharmaceutical compositions in unit dosage form of the present invention contain from about 55 to about 100 mg, from about 60 to about 100 mg, from about 65 to about 100 mg, from about 70 to about 100 mg, from about 75 to about 100 mg, from about 80 to about 100 mg, from about 85 to about 100 mg, from about 90 to about 100 mg, or from about 95 to about 100 mg of Vibegron.

In some embodiments, the pharmaceutical compositions in unit dosage form of the present invention contain from about 50 to about 95 mg, from about 50 to about 90 mg, from about 50 to about 85 mg, from about 50 to about 80 mg, from about 50 to about 75 mg, from about 50 to about 70 mg, from about 50 to about 65 mg, from about 50 to about 60 mg, or from about 50 to about 55 mg of Vibegron.

In some embodiments, the pharmaceutical compositions in unit dosage form of the present invention contain from about 60 to about 90 mg, from about 65 to about 85 mg, or from about 70 to about 80 mg of Vibegron. In some embodiments, the pharmaceutical compositions in unit dosage form of the present invention contain from 60 to 90 mg, from 65 to 85 mg, or from 70 to 80 mg of Vibegron.

In some embodiments, the pharmaceutical unit dosage compositions of the present invention contain about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95 mg of Vibegron. In some embodiments, the pharmaceutical unit dosage compositions of the present invention contain approximately 75 mg of Vibegron. In some embodiments, the pharmaceutical unit dosage compositions of the present invention contain 75 mg of Vibegron.

In some embodiments, the pharmaceutical compositions in the form of a unit dosage form of the present invention can be crushed. In some embodiments, the unit dosage form pharmaceutical compositions of the present invention are crushed prior to oral administration.

In vitro assays.

Vibegron was tested in several in vitro assays to determine its agonist activity against human e3-AR, its selectivity over other human β-AR subtypes, and its activity against other species' e3-AR.

Vibegron activity was measured in a functional assay measuring the increase in cellular adenylate cyclase activity in Chinese hamster ovary (CHO) cells stably expressing human e3-AR. The degree of activation was measured in comparison with a proven full agonist (isoproterenol) along with the EC50 of the compound.

Vibegron is a potent and selective e3-AR agonist, with an EC50 of 1.1 nM and 84% activation compared to isoproterenol. A small serum shift is observed in the presence of 40% human serum (EC50 = 1.7 nM, 102% activation), consistent with the low level of plasma protein binding of this compound (49% unbound in humans).

In addition, the selectivity of Vibegron for e3-AR over the β1- and e2-AR subtypes was determined by testing in CHO cells expressing either e1-AR or e2-AR. Vibegron is highly selective for e3-AR over β1- and e2-AR, demonstrating greater than 9000-fold selectivity for e3-AR activation over e1-AR or e2-AR in an in vitro functional cell assay.

The IC50 of Vibegron was determined in a standard competitive binding assay using membranes prepared from cells expressing recombinant β1, β2 or e3-AR. Vibegron has an e3-AR IC50 of 193 nM (86 ng/mL) to compete with the radiolabeled nonspecific β-AR antagonist 125I-CYP in a filter binding assay. The relative deficiency in binding affinity compared to the strong in vitro agonistic activity of Vibegron for human e3-AR is related to the relative ability of the compound to compete for unbound versus bound receptors, both parameters could be measured using an antagonist binding assay. In addition, the compound does not bind to either e1-AR or e2-AR as demonstrated in competitive binding assays, confirming that the compound is neither an agonist nor an antagonist of these receptors.

Absorption, distribution, metabolism and excretion Vibegron reaches maximum plasma concentrations ( _Cmax ) approximately 1-3 hours after oral administration in healthy volunteers. Average _Cmax and AUC values increase more than proportionally to the dose up to 400 mg. Steady-state concentrations were achieved within 7 days of a single daily dose.

- 8 045454 vibegrona. The geometric mean AUC accumulation ratios at steady state were ~2 in young men and ~2.8 in older subjects (men and women). Exposures to Vibegron in young Japanese men were moderately increased (<2-fold) after a single dose compared to exposures in young non-Japanese men.

Administration of multiple oral doses of 150 mg Vibegron with food to healthy middle-aged and elderly women resulted in mean AUC0-24 and _Cmax values of ~42% and 59% on day 1 and ~20% and 43% on day 14 compared with the same dose on an empty stomach.

In a two-stage, open-label, single-dose study to study the pharmacokinetics of Vibegron in patients with hepatic impairment, the apparent volume of distribution (Vd/F) of Vibegron was approximately 9120 L. Vibegron is bound (approximately 49%) to human plasma proteins.

Vibegron is eliminated via various routes, including urinary excretion, biliary excretion, and hepatic metabolism. Although CYP3A4 is the predominant CYP responsible for metabolism in vitro, metabolism appears to play only a minor role in the elimination of Vibegron. In a mass balance study in healthy subjects, most of the extracted dose was excreted as unchanged Vibegron. The average total excretion of radioactive isotopes in feces was 79%, with approximately 59 and 20% of the dose excreted in feces and urine, respectively.

It was found that the majority of the Vibegron dose was excreted as unchanged parent drug. Seven minor metabolites were detected in urine and feces, six of which (M1, M3, M4, M6, M11, and M17) were oxidative metabolites (see Fig. 2). Metabolite M7 is an O-glucuronide conjugate of Vibegron. The concentration of the radioactive isotope provided by [14C]vibegron in the blood plasma had an average Cmax _of 0.3 µM and _{Tmax of} 2.5 hours. Radioactive profiles of blood plasma samples at 2 and 4 h showed that ~78% and ~73% of plasma radioactivity, respectively, was due to unchanged vibegron, and O-glucuronide (M7) was the predominant circulating metabolite (~12-14% of total bound with a preparation of materials). Two additional minor oxidative metabolites M4 (4-6%) and M17 (6-7%) were also detected in human plasma. Radioactivity in plasma samples at other time points 4 hours postdose was too low for profiling. The potential for accumulation of circulating metabolites in plasma has not been assessed due to a lack of data from later time points to allow estimation of half-life. Vibegron has a final t1/2 of 59-94 hours in young and elderly subjects. At steady state, mean renal clearance (CLR) in young men ranged from 150 to 187 mL/min, at all dose levels, whereas CLR in older subjects (men and women) was slightly lower at 127 mL/min . There was a trend for the proportion of dose excreted at steady state (fe0-24h, ss) to increase with increasing dose, reflecting increased bioavailability with increasing dose. Fe _{0.24 h} , ss was similar in young men and older subjects: ~14% at 100 and 150 mg in young men and ~17% at 100 mg in older subjects. Average values of fe ₀ . ₂ 4 _h and CLR in young Japanese subjects were similar to those observed in non-Japanese subjects.

Examples

Example 1.

Tablet dosage form of Vibegron.

The composition of Vibegron tablets (50, 75 and 100 mg) is shown in table. 1.

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Table 1

Compositions of Vibegron tablets

Components Function Dosage 50 mg 75 mg 100 mg Tablet core mg/tablet mg/tablet mg/tablet MK4618 Active 50.00 75.00 100.0 Mannitol Diluent 20.75 31.125 41.50 Microcrystalline Diluent 20.75 31.125 41.50 cellulose Croscarmellose sodium Baking powder 3,000 4,500 6,000 Hydroxypropyl cellulose Binder 4,500 6.75 9,000 Magnesium stearate Lubricating 1,000 1,500 2,000 substance Purified water ¹ Solvent (35.00- (52.5-67.5) (70.00- 45.00) 90.00) Total core weight 100.0 150.0 200.00 Suspension for film coatings Purified water ¹ Solvent (45.00) (67.50) (90.00) OP ADR YII Green Dye 5,000 7,500 10.00 (39К110004) Total 105.0 157.5 210.0

- deleted during processing.

Example 2: Pharmacokinetic data.

2.1. Pharmacokinetics after a single dose.

Pharmacokinetics following a single dose of Vibegron were studied in two double-blind, randomized, placebo-controlled, phase 1 studies using single escalating oral doses. All subjects were healthy adults. A summary of the _results is presented in Table 2. After a single oral dosing of Vibegron in the range of 2 to 600 mg, the mean tmax occurred between 0.8 and 3 hours after dosing, t _1/2 of final elimination averaged from 43 to 75 hours for all doses 10 to 600 mg in subjects who are healthy young men. Systemic effects were greater than dose proportional up to 600 mg.

Exposures to Vibegron in young Japanese men were moderately increased compared with exposures in young non-Japanese men. Geometric mean ratios (GMR; Japanese/non-Japanese) for Vibegron _0-bec AUC and corresponding 90% CIs decreased with increasing dose from 1.75 (1.38, 2.23) at 10 mg to 1.17 (0. 99, 1.40) at 300 mg. The GMR (Japanese/non-Japanese) and 90% CI for Vibegron _Cmax appeared to be independent of dose and were 1.75 (1.35, 2.26) combined across all doses. Median Tmax values (1 to 3 hours) and harmonic mean estimates of apparent terminal t1 _/2 (58 to 71 hours) in Japanese subjects were similar to those in non-Japanese subjects. Similar to non-Japanese subjects, AUC _0-besk and Cmax in Japanese subjects increased more than dose proportionally up to 300 mg.

Pharmacokinetics following a single 50 mg dose of Vibegron in elderly non-Japanese men and women are also presented in Table 2. In subjects who were elderly men and women, the mean AUC _0-besk and Cmax after administration of 50 mg Vibegron were ~70 % and 60% higher, respectively, compared to the corresponding values in young men after administration of 50 mg. Tmax was similar to that observed in young men (median Tmax = 1.0 h), while apparent final t1 _/2 was slightly longer in older subjects compared to younger subjects (harmonic mean t1 _/2 = 92 compared to 52 hours). Exposure to Vibegron in older women was slightly higher than in older men.

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table 2

Brief description of selected pharmacokinetic parameters of Vibegron in blood plasma after one dose

Dose (mg) ^a N AUCo-infinite (ng-h/ml) AUCo-24 (ng-h/ml) Stakh (ng/ml) gr b 1 max (h.) tl/2 ^C (h) 2 ^3d e 0.80 ±0.33 0.28 ± 0.02 3.0(1.0-3.0) ^s e 5 6 e 8.31 ±4.80 0.79 ± 0.30 1.0 (0.5-6.0) e 10 6 70.7 ±34.9 30.0 ± 12.6 4.76 ± 4.58 2.5 (1.0-6.0) 43.2 ± 13.0 10 (Japanese) 6 98.7 ±27.3 31.0 ±9.33 3.34 ± 1.97 1.0 (1.0-4.0) 57.6 ± 39.0 20 6 121 ±48.9 40.0 ±21.1 5.25 ± 4.25 0.8 (0.5-6.0) 64.2 ± 12.6 50 6 551 ±262 219 ±123 31.7 ±35.0 2.0 (0.5-6.0) 52.0 ±7.8 50 (Japanese) 6 885 ±241 385±136 62.2 ± 20.4 3.0 (0.5-3.0) 64.4 ± 8.7 50 (elderly men and 12 951 ±300 314±119 50.2 ± 23.6 1.0 (0.5-3.0) 92.1 ± 15.9 women 100 6 1890 ±698 845 ±401 142 ±108 2.0 (1.0-4.0) 72.8 ± 10.8 100 (Japanese) 6 1770 ±418 920 ±300 190 ± 123 2.5 (0.5-4.0) 57.6 ± 12.0 150 6 2270 ±911 1050 ± 551 195 ± 185 1.0 (1.0-6.0) 60.5 ± 10.5 200 18 3630 ±1110 1740 ±748 274 ± 138 1.0 (1.0-4.0) 75.3 ±9.1 200 (Japanese) 6 5200 ±791 3090 ±569 516 ±200 2.0 (0.5-4.0) 58.4 ±9.0 300 6 7380±1410 4427 ±996 618±231 2.5 (2.0-3.0) 63.4 ±3.0 300 (Japanese) 6 6270± 1570 4050 ±1240 733 ±210 2.0 (1.0-4.0) 59.7 ±9.2 450 6 9157 ± 1850 5510±1440 645 ±165 3.0 (0.5-6.0) 60.0 ± 9.4 600 5 15500±3450 10900± 2770 1330 ±529 3.0 (2.0-6.0) 60.5 ± 5.2

Concentration data converted from molar to ng/ml (vibegron molecular weight = 444.5).

a. Dose in healthy young males unless otherwise indicated.

b. Median (minimum-maximum).

c. Harmonic mean ± Pseudo SD.

d. Only 3 of 6 subjects had any concentrations above the limit of quantitation at the 2 mg dose. Summary statistics for C _max , T _max and AUC ₀ . ₂₄ is based only on data from these subjects.

e. Sampling durations were too short for 2 and 5 mg, precluding accurate determination of apparent final t _1/2 and AUC ₀ . _besk .

2.2. Pharmacokinetics after multiple doses.

Pharmacokinetics following repeated doses of Vibegron were studied in healthy young men, middle-aged men and women, and elderly non-Japanese men and women, as well as healthy young men and older Japanese men and women in two randomized, double-blind, placebo-controlled, phase 1 studies. using multiple increasing doses. Non-Japanese subjects received multiple doses of 25 to 400 mg for 7 to 28 days, while Japanese subjects received multiple doses of 50 to 200 mg for 14 days. Pharmacokinetic results after 14 days of dosing are summarized in Table. 3.

On average, women tend to have a 50% higher exposure level (AUC) compared to men, regardless of age. Steady-state AUC and _Cmax values following 100 mg Vibegron QD doses in elderly men were approximately 1.7-fold and 1.3-fold higher, respectively, compared with younger men.

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The GM accumulation C _max and AUC ratios for Japanese subjects were 1.78 and 1.84 at the 200 mg dose level. On average, steady-state exposures were 30% higher in young Japanese men than in young non-Japanese men; differences in exposure were statistically significant. GMR (Japanese/non-Japanese) and the corresponding 90% CIAUC and C _max of Vibergon combined across different doses were 1.27 (1.09, 1.48) and 1.33 (1.06, 1.67), respectively.

The average steady-state exposure on day 14 in Japanese elderly male and female subjects was 35% higher than in non-Japanese elderly male and female subjects; differences in exposure were statistically significant. Day 14 GMR (Japanese/non-Japanese) and corresponding 90% CI AUC0-24 and Vibegron C _max for older adults were 1.35 (1.09, 1.68) and 1.82 (1.32, 2.51) respectively.

Table 3

Brief description of selected pharmacokinetic parameters of Vibegron in plasma after multiple doses

Dose (mg) ^a N AUCo-24 (ng-h/ml) Stakh (ng/ml) Cmin. (ng/ml) gr b Atah (h.) tl/2 ^C (h) 25 6 164 ±25.9 15.6 ±6.93 5.07 ± 0.711 1.0 (0.5- 2.0) 94.0 ± 9.60 50 6 507 ± 176 41.5 ± 12.3 15.2 ±5.07 2.5 (0.56.0) 77.2 ±8.9 50 (Japanese) 5 613 ±296 56.9 ± 34.2 16.5 ± 6.05 3.0 (0.53.0) 69.4 ± 6.6 100 6 1280 ±529 169 ± 80.9 31.9± 11.5 1.0 (0.54.0) 79.7 ± 11.5 100 (Japanese) 6 1710 ±542 180 ±111 41.0± 11.0 2.0 (2.04.0) 56.8 ± 19.2 100 (elderly men and women) 12 2230 ±671 224 ± 92.0 54.2 ± 15.3 1.0 (0.56.0) 88.4 ± 10.7 100 (elderly Japanese) 12 2920 ±693 393 ±165 57.3 ± 12.2 1.5 (0.54.0) 75.1 ±3.9 150 6 2285± 1140 305 ±215 54.2 ± 16.6 1.5 (0.54.0) 79.2 ± 9.2 150 (middle-aged men) 9 2170 ±452 293 ±67.1 46.2 ± 8.50 1.0 (0.53.0) 72.7 ± 16.l ^d 150 (middle-aged women) 9 3180 ±925 246±139 62.7 ± 12.4 2.0 (1.04.0) 83.1 ± 17.2 200 6 3200± 1120 313 ±168 61.8 ± 12.4 2.0 (1.03.0) 64.7 ±6.5 200 (Japanese) 6 4370 ±618 631± 154 62.2 ± 9.07 1.0 (0.56.0) 59.5 ± 1.9 300 18 6980± 1040 733 ±164 128 ±23.6 2.0 (2.03.0) 61.7 ±7.3 400 6 10500± 2140 1400 ±257 189 ±54.7 1.5 (1.03.0) 58.9 ±5.9

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

a. Dose in healthy young males unless otherwise indicated.

b. Median (minimum-maximum).

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c. Harmonic mean ± Pseudo SD.

d. t _1/2 is determined after 28 days of dosing.

2.3. Bioavailability and bioequivalence.

Five phase 1 studies were conducted using the Vibegron capsule formulation, while seven phase 1 studies and one phase 2b study used tablets. An open-label, randomized, two-period crossover PK study in healthy male subjects aged 18 to 45 years compared the pharmacokinetics following a single dose of capsule formulations (1x150 mg capsule) and tablet formulations (3x50 mg tablets) of Vibegron. .

The tablet formulation provided comparable effects to the capsule formulation, as shown in Table 1. 4. T _max and apparent final t _1/2 were also similar for the two compositions.

Table 4

Summary of compositional effects on the pharmacokinetics of Vibegron 150 mg in healthy male subjects

Pharmacokinetic parameter Geometric mean, calculated using the least squares method (95% CI) GMR 90% CI Capsule ^a Tablet ¹⁵ AUCo-besk 2840 2660 0.94 (0.87, (ng h/ml) (2512, 3220) (2350, ZOYU) 1.00) Stach (ng/ml) 237 213 0.90 (0.75, (190, 295) (172, 264) 1.08)

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

GMR = Geometric least squares ratio, tablet to capsule.

a. 1x150 mg Vibegron capsule.

b. Vibegron 3x50 mg tablets.

An open-label, single-dose, randomized, two-period, two-arm, phase 1 crossover study with two treatment regimens assessed the relative bioequivalence of two types of tablets with slightly different formulations: a water-soluble coated tablet (test) and a water-insoluble coated tablet (comparison).

Table 5

Brief description of the effect of the composition on the pharmacokinetics of 50 mg Vibegron in healthy men

Geometric mean calculated using the least squares method (95%

Pharmacokines ci) tic Tablet for Testable GMR parameter comparisons ^a tablet ¹⁵ (%) 90% CI AUCo-besk (ng h/ml) 671 (529, 853) 671 (547, 827) 100.2 (91.6, Yu9.5) Stakh (NG/ML) 38.0 (27.8, 52.1) 41.0 (30.0, 56.1) 107.7 (87.4, 132.7)

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

GMR = geometric least squares ratio of phase 3 tablet to phase 2 tablet.

A. Water insoluble coated tablet (PMF1).

b. Coated tablet, water soluble (PMFII).

2.4. The effect of food on oral absorption.

The effect of food on pharmacokinetics after a single dose of Vibegron 50 mg was assessed in healthy young non-Japanese and Japanese men in two randomized, double-blind, placebo-controlled, phase 1 studies using single ascending doses, while the effect of food on pharmacokinetics after multiple doses of Vibegron 150 mg in middle-aged women was evaluated in a randomized, double-blind, placebo-controlled, phase 1 study using multiple escalating doses. A summary of the pharmacokinetic results is given in Table. 6. Administration of 50 mg of Vibegron with a high-fat meal to non-Japanese men resulted in a decrease in AUCO. and _Cmax by 46% and 67%, respectively, and a delay in _Tmax by ~1 hour compared to administration on an empty stomach. Administration of Vibegron 50 mg with a standard Japanese breakfast to young men of Japanese descent resulted in a decrease

AUC0-infinite and _Cmax by 37% and 52%, respectively, which are approximately similar to the results in non-Japanese men administered the same dose with a high-fat meal.

Administration of multiple oral doses of 150 mg Vibegron with food to healthy middle-aged women resulted in mean AUC0-24 h and _Cmax values of 20% and 47%, respectively, on day 14 compared with the same dose in the fasted state. There was a delay in _Tmax at steady state after eating compared to fasting (6.0 vs. 2.0 hours).

Table 6

Summary of the effect of food on the pharmacokinetic parameters of Vibegron following single and multiple dose administration after meals and in the fasted state in healthy Japanese and non-Japanese male subjects and healthy middle-aged non-Japanese female subjects

Single dose (mg) in young men N Pharmacokinetic parameters ^a AUCo-infinite (ng-h/ml) AUCo-24 (ng-h/ml) Stakh (ng/ml) gr b Atah (h.) 50 (not Japanese, after 6 316 ±127 90.7 ± 22.9 7.6 ± 2.27 3.0 (2.0 - 6.0) meal) 50 6 551 ±262 219 ± 123 31.7 ± 35.0 2.0 (0.5-6.0) (not Japanese, on an empty stomach) 50 (Japanese, after 6 605 ±222 226± 112 36.2 ± 33.3 1.5 (0.5-3.0) meal) 50 5 885 ±241 385±136 62.2 ± 20.4 3.0 (0.5-3.0) (Japanese, on an empty stomach) Multiple Pharmacokinetic parameters ^a,c dose (mg) among women average AUCo-24 S _{t a} x Cmin. gr b Atah age, not (ng-h/ml) (ng/ml) (ng/ml) (h.) being Japanese N 150 (after taking 6 2540 ±334 185 ±32.3 65.3 ± 7.87 6.0 (3.0 - 6.0) food) 150 9 3180 ±925 346±139 62.7 ± 12.4 2.0(1.0-4.0) (on an empty stomach)

Concentration data converted from molar to ng/ml (vibegron molecular weight = 444.5).

a. Geometric mean (CV%).

b. Median (minimum-maximum).

c. Pharmacokinetic parameters obtained on day 14 of Vibegron dosing.

2.5. Pharmacokinetics in the population with the target disease.

A randomized, double-blind, placebo-controlled, drug-controlled, two-stage, parallel-group, phase 2b study in patients with OAV that measured only rare Vibegron trough concentrations ( _Cmin ); The mean (±SD) C _min of Vibegron in the amount of 50 and 100 mg QD was 27.4 (±18.3) ng/ml and 73.6 (±65.5) ng/ml, respectively. Average (±

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SD) C _min of Vibegron 50 mg in healthy young men was 15.2 (±5.07) ng/ml. Mean (±SD) C _min values for Vibegron 100 mg ranged from 31.9 (±11.5) in healthy young men to 54.2 (±15.3) in healthy older adults.

Example 3: Pharmacokinetics in Special Populations.

3.1. The influence of age.

Vibegron exposure was assessed in young (18 to 45 years), middle-aged (46 to 64 years), and older (65 to 85 years) men and women. Although exposure was similar in middle-aged compared to young men, plasma concentrations were higher in older subjects compared to middle-aged and young subjects. After a single dose of 50 mg, AUC values _{were 0} . Vibegron's _besk and C _max were 70% and 60% higher, respectively, in elderly subjects compared to young subjects, t1 _/2 elimination was longer in elderly subjects at 92 hours compared to 52 hours in subjects representing young adults, in a randomized, double-blind, placebo-controlled study using single ascending doses. Vibegron AUC ₀ _ ₂₄₄ and _Cmax values at steady state were ~1.7-fold and ~1.3-fold higher, respectively, in older men compared to younger men in a randomized, double-blind, placebo-controlled, multiple escalating dose study. In addition, the ratios of geometric mean AUC accumulation at steady state were ~2 in young men and ~2.8 in older men. In elderly Japanese subjects, AUC0.24 and _Cmax were increased by ~35% and 82%, respectively, compared with elderly non-Japanese subjects.

3.2. Influence of gender.

The effect of gender on Vibegron exposure at steady state following 100 or 150 mg doses was assessed in a randomized, double-blind, placebo-controlled, multiple ascending dose study. Vibegron plasma concentrations were similar in middle-aged men compared with young men; however, exposures were slightly higher in middle-aged women compared with middle-aged men (∼1.5 times the steady-state AUC in middle-aged women), which was also observed when exposures in older women were compared with those in older men.

3.3. Impact of renal failure.

Pharmacokinetics following a single 100 mg dose of Vibegron in 24 patients with renal impairment (8 severe, 8 moderate and 8 mild) were compared with 8 healthy control subjects in an open-label, single-dose pharmacokinetics study. A summary of pharmacokinetic parameters and statistical comparisons between patients with varying degrees of renal impairment and their healthy comparison subjects are presented in Table 1. 7.

AUC ₀ . _{beCk of} Vibegron in patients with mild (eGFR from >60 to <90 ml/min./1.73 ^m2 ), moderate (eGFR from >30 to <60 ml/min./1.73 ^m2 ) and severe (eGFR <30 ml/min/1.73 m ² but not on dialysis) renal failure was 49, 106 and 83% higher, respectively, compared with healthy comparison control subjects. Vibegron C _max in patients with mild, moderate, and severe renal impairment was 96, 68, and 42% higher, respectively, compared with healthy control subjects. Thus, increasing degrees of renal impairment were associated with increasing Vibegron AUC0, without a clear trend observed for _Cmax . Decreased renal function was associated with lower clearance. The relationship between clearance and renal function was modeled using linear regression. Based on the regression slope, CL/F was found to increase by ~0.8% per mL/min/1.73 ^m2 increase in eGFR. Based on this linear relationship, the CL/F ratio for mild, moderate, and severe populations compared with healthy subjects was predicted to be 0.81, 0.64, and 0.50, respectively. The corresponding predicted ratios for AUC were 1.24, 1.57, and 2.00. Modeling of the relationship between CL/F and creatinine clearance yielded similar results. Renal clearance (CLR) and the proportion of dose excreted in urine during a 48-hour collection interval (fe[urine]48 hours) decreased with increasing degree of renal impairment. Patients with mild, moderate, and severe renal impairment had 39, 65, and 82% reductions in CLR, respectively, compared with healthy comparison control subjects. Fe[urine]48 hours was comparable in patients with mild renal impairment (8.5%) and healthy control subjects (7.9%) and was 5.5% and 2.1% in patients with moderate to severe renal impairment deficiency accordingly.

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Table 7

Summary of pharmacokinetic parameters of Vibegron 100 mg in patients with severe, moderate and mild renal impairment and healthy control subjects.

Geometric mean, calculated using the least squares method (95% CI)

Healthy Heavy Moderate Lightweight compare renal renal renal s Pharmacokinet not enough not enough not enough control ical there is there is there is s parameter N subjects

AS So-beek 2820 3170 2290 1540 (ng h/ml) ABOUT (2200, 3610) (2500, 4030) (1800, 2920) (1180, 2010) Stakh (NG/ML) 8 152 (103, 225) 180 (123-262) 210 (144, 308) 107 (70.8, 162) CL/F (l/h) 8 35.5 (27.68, 45.53) 31.5 (24.80, 40.06) 43.6 (34.23, 55.61) 64.9 (49.87, 84.47) Ttah^H.) 8 0.5 (0.5-4.0) 1.3 (0.5-3.0) 1.0 (0.5-3.0) 1.5 (0.5-4.0) Apparent final ti/ ₂ ^b (h.) 8 131 (10.0) 108 (21.0) 96.2(11.5) 98.8(13.9) SC ^b (l/h.) 8 1.9 (30.9) 3.6 (34.5) 6.3 (31.1) ^s 10.4 (20.2) Re[urine]48 ^hours (%) 8 2.1 (57.6) 5.5 (53.2) 8.5 (43.9) ^s 7.9 (43.0)

GMR (90% CI) Comparison -------------------------

AUCo-6 _ecK . Stakh CL/F Patients with severe kidney disease deficiency/healthy 1.83 1.42 0.55 comparison control subjects Patients with moderate renal impairment (1.36, 2.46) (0.89, 2.27) (0.41, 0.74) deficiency/healthy 2.06 1.68 0.49 comparison control subjects Patients with mild renal disease (1.55,2.74) (1.07, 2.63) (0.36, 0.65) deficiency/healthy 1.49 1.96 0.67 comparison control subjects (1.11.2.00) (1.23, 3.13) (0.50, 0.90)

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

CI = confidence interval; GMR = geometric least squares ratio between treatment groups.

a. Median (minimum-maximum).

b. Geometric mean (percentage of geometric coefficient of variation).

c. N=7.

3.4. Effect of liver failure.

Pharmacokinetics after a single 100 mg dose of Vibegron were evaluated in 8 patients with moderate hepatic impairment (Child-Pugh score 7 to 9) and 8 healthy subjects matched for age, sex, and BMI in a two-stage, open-label, phase 1 study of pharmacokinetics after a single dose. doses. A statistical comparison of the pharmacokinetic parameters of Vibegron is presented in Table. 8. GMR AUC _0-besk and C _max (90% CI) for patients with moderate liver impairment and healthy control subjects were 1.27 (0.96, 1.67) and 1.35 (0.88, 2.06 ) respectively, indicating that moderate hepatic impairment did not have a clinically significant effect on Vibegron exposure.

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Table 8

Summary of pharmacokinetic parameters of Vibegron 100 mg in patients with moderate hepatic impairment and healthy control subjects.

Geometric mean, calculated using the least squares method (95% CI)

Pharmacokinetic parameter N Moderate liver failure Healthy compared control subjects GMR 90% C.I. AUCo-besk 1820 1440 (0.96, 8 1.27 (ng h/ml) (1440, 2300) (1140, 1810) 1.67) 168 125 (0.88, Stakh (NG/ML) 8 1.35 (118, 240) (87.6, 178) 2.06) ι,θ 1.5 Ttah ^a (Ch.) 8 (0.5-3.0) (0.5-4.0) Apparent final 8 94.5 (8.88%) 92.5 (9.37%) tl/2 (H.) CL/F ^b (l/h) 8 56.0(31.2%) 68.3 (36.0%) Vz/F ^b (l/h) 8 7640 (33.3%) 9120 (30.7%)

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

CI = confidence interval; GMR = geometric least squares ratio between treatment groups.

a. Median (minimum-maximum).

b. Geometric mean (percentage of geometric coefficient of variation).

3.5. Drug interaction studies.

There were four drug interaction studies evaluating Vibegron in combination with six compounds. In table Table 9 briefly describes the effect of ketoconazole, diltiazem, or tolterodine on the pharmacokinetics of Vibegron. In table 10 briefly describes the effect of Vibegron on the pharmacokinetics of digoxin, ethinyl estradiol, levonorgestrel or tolterodine.

Multiple doses of the strong CYP3 A4/P-gp inhibitor, ketoconazole 200 mg, and the moderate CYP3 A4/P-gp inhibitor, diltiazem 240 mg, were evaluated in combination with a single dose of Vibegron 100 mg. GM AUC ₀ _ _besk and _Cmax of Vibegron increased by 2.08 times and 2.22 times, respectively, in the presence of several doses of ketoconazole 200 mg. Vibegron's GM AUC _{0_besk} and _Cmax increased by 63% and 68% _, respectively, in the presence of multiple doses of 240 mg or 180 mg diltiazem. GM t ₁ / ₂ was 75, 75.4 and 80.2 hours, respectively, when Vibegron was administered alone, with diltiazem or with ketoconazole, respectively. This lack of increase in t _1/2 of Vibegron in the presence of ketoconazole or diltiazem indicates that the interaction occurred predominantly in the absorption phase. However, these interactions are not expected to be clinically significant. Tolterodine ER 4 mg had no effect on the pharmacokinetics of Vibegron.

Multiple doses of Vibegron were evaluated in combination with the p-gp substrate, digoxin. The 90% CI for the GMR of AUCo-free digoxin when coadministered with Vibegron was within the bioequivalence range of 80-125%, indicating that Vibegron does not affect the pharmacokinetics of digoxin to a clinically significant extent. The pharmacokinetics of ethinyl estradiol (EE) and levonorgestrel (LNG), two common components of oral contraceptives, were not altered by repeated doses of Vibegron. 90% CI for GMR (EE/LNG + Vibegron to EE/LNG separately) AUC and _Cmax EE were kept within the range of 0.8-1.25. Although LNG AUC and _Cmax increased by 18-21% in the presence of multiple doses of Vibegron, these increases were not considered clinically significant. No clinically significant pharmacokinetic interaction occurs when Vibegron 100 mg or 150 mg is administered with tolterodine ER 4 mg.

- 17 045454

Table 9

Changes in the pharmacokinetic parameters of Vibegron in the presence of co-administered drugs (Conmed)

Conmed Drug dose Conm ed (mg) Vibegr dosage (mg) η Geometric mean (95% CI) Ratio (with/without conmed product) of pharmacokinetic parameters of Vibegron; No effect = 1.00 Vibegron separately Conmed + Vibegron GMR (90% CI) Ketokona angry 200 mg every 12 hours Single dose 100 mg 1 0 AU WITH 1370 (788, 2380) 2850 (2100, 3870) 2.08 (1.66, 2.61) Stakh IZ (53,1,241) 251 (167, 379) 2.22 (1.50- 3.28) Diltiaze m ER 240 mg QD Single dose 100 mg 1 2 AU WITH 1330 (iso, 1570) 2170 (1990, 2480) 1.63 (1.44, 1.85) With _tah 99.8 (73.8, 135) 167 (129-217) 1.68 (1.41, 1.99) Tolterod hhER 4 mg QD 100 mg QD 2 4 AU WITH 1662 (1382, 2000) 1791 ^a (1533, 2094) 1.08 (0.94, 1.23) Stakh 158 (111,224) 163 ^a (127, 209) 1.03 (0.74, 1.43) 150 mg QD 2 3 AU WITH 2783 (2409, 3218) 3102 ^a (2787, 3463) 1D2 (0.98, 1.27) Stakh 269 (210, 344) 304 ^a (260, 357) 1.13 (0.90, 1.42)

A. N=12.

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

- 18 045454

Table 10

Drug interactions: changes in the pharmacokinetic parameters of the co-administered drug (Conmed) in the presence of Vibegron

Conmed Dose of the drug Sopshe d (mg) Vibegr dosage (mg) η Geometric mean (95% CI) for Conmed Ratio (with/without Vibegron) of pharmacokinetic parameters of the drug Conmed; No effect = 1.00 Conmed separately Conmed + Vibegron G.M. R (90% CI) Digoxin Single dose 0.25 mg 100 mg QD 18 AU WITH 16600 (14600, 19200) 1840 ^a (16200, 21000) 1.11 (1.03, 1.19) Stakh 1160 (965, 1400) 1410 (1170, 1700) 1.21 (1.09, 1.35) Oral contraceptive Single dose EE 0.03 mg 100 mg QD 18 AU WITH 810 (713, 920) 838 (734, 958) 1.04 (1.00, 1.07) Stakh 71.9 (62.3, 82.9) 68.8 (60.5, 78.3) 0.96 (0.90, 1.02) Single dose LNG 0.15 mg AU WITH 31000 (26800, 35900) 37600 (32300, 43700) 1.21 (1.13, 1.30) Stakh 2070 (1770, 2420) 2440 (2100, 2840) 1.18 (1.09, 1.27) Tolterod inEya 4 mg QD 100 mg QD 12 AU WITH 28.37 (15.03, 53.56) 30.66 (16.24, 57.89) 1.08 (0.97, 1.21) Stakh 2.28 (1.32, 3.96) 2.57 (1.48, 4.45) 1.12 (1.00, 1.26) 150 mg QD AU WITH 13.25 ^a (7.39, 23.76) 10.80 (6.02, 19.38) 1.23 (1,I, 1.35) Stakh 1.26 ^a (0.66, 2.39) 0.92 (0.48, 1.75) 1.37 (1.20, 1.57)

GMR = geometric mean ratio; CI = confidence interval; EE = ethinyl estradiol; LNG = levonorgestrel.

Concentration data converted from molar to ng/ml (molecular weight of Vibegron = 444.5).

a. N=17.

b. N=11.

3.6. Effect on QT interval prolongation.

The effect of Vibegron on the QTc interval was assessed in a single oral dose study. Fifty-two healthy subjects received a single dose of Vibegron 400 mg, a single dose of Vibegron 200 mg, a single dose of moxifloxacin 400 mg, and a single dose of Vibegron-matched placebo.

The 400 mg dose of Vibegron resulted in the greatest difference in mean LS (90% CI) from placebo with a QTcF of 4.60 (2.71, 6.48) ms at 1 hour post-dose. A similar result was noted in QTcF after a single 200 mg dose, where the maximum mean LS difference (90% CI) from placebo was 4.98 (3.07, 6.88) ms at 1 hour post-dose. The upper limits of the 90% CI of all mean differences were located below the 10 ms target. (Table 11). There was no statistically significant effect of moxifloxacin on QTcF.

- 19 045454

GM (CV%) Cmax and AUC0-23.5 hours achieved after a single dose of 200 mg were 366 (50.4) ng/ml and 2270 (37.3) ng/ml, respectively. The Cmax of Vibegron was 1.63 times higher than the value obtained in elderly subjects receiving multiple 100 mg doses in a double-blind, randomized, placebo-controlled, alternating (Panels A and B) phase 1 multi-period, single-ascending-dose study, in while AUC was similar. GM (CV%) Cmax and AUC0-23.5 hours achieved after a single dose of 400 mg were 1020 (39.9) ng/ml and 6450 (34.0) ng/ml, respectively. These Cmax and AUC0-23.5 h values were 4.55 times and 2.89 times higher than those obtained in elderly subjects receiving multiple doses of Vibegron 100 mg.

Target PK effects were achieved at doses of 200 mg and 400 mg. The steady-state Cmax and AUC0-24 hours achieved in elderly female subjects at the maximum clinical dose of 100 mg were 278 ng/mL and 2620 ng/mL, respectively.

Table 11

Statistical comparison of change in QTcF from baseline versus placebo (Vibegron-placebo) by treatment and time point relative to 400 mg Vibegron dose, 200 mg Vibegron dose, and single dose placebo to Vibegron

Single dose Single dose Single dose Vibegron 400 mg (ms) Vibegron 200 mg (ms) placebo to Vibegron (ms)

Hours N Average 95% CI N Average 95% CI N Average 95% CI

her her her meaning meaning significant tion tion ie LS L.S. L.S.

0.5 hours 52 2.37 (0.66, 4.07) 50 1.90 (0.16, 3.63) 50 -1.00 (-2.74, 0.73) 1 hour 52 4.49 (2.78, 6.19) 50 4.87 (3.13, 6.60) 50 -0.11 (-1.84, 1.63) 2 hours 52 0.73 (-0.97, 2.43) 50 2.06 (0.32, 3.79) 50 -0.08 (-1.81, 1.65) 3 hours 52 -0.30 (-2.00, 1.41) 50 1.14 (-0.59, 2.88) 50 0.74 (-0.99, 2.47) 4 hours 52 -2.53 (-4.23, -0.82) 50 -0.40 (-2.14, 1.33) 50 0.43 (-1.30, 2.17) 6 hours 52 -8.33 (-10.03, 6.62) 50 -6.89 (-8.63, -5.16) 50 -5.63 (-7.37, 3.90) 8 ocloc'k 52 -11.60 (-13.30, 9.89) 50 -9.59 (-11.33, 7.86) 50 -8.36 (-10.09, 6.62) 10 hours 52 -10.29 (-11.99, 8.58) 50 -8.82 (-10.56, 7.09) 50 -6.15 (-7.89, 4.42) 12 hours 52 -7.10 (-8.80, -5.39) 50 -6.82 (-8.56, -5.09) 50 -3.10 (-4.83, 1.37) 23.5 hours 52 -2.87 (-4.57, -1.17) 50 -2.15 (-3.88, -0.41) 50 -2.53 (-4.26, 0.79)

- 20 045454

Watch Difference from single dose placebo versus 400 mg dose of Vibegron (ms) Difference from single dose placebo versus 200 mg dose of Vibegron (ms) Difference for mean LS 90% CI ^a Difference for mean LS 90% CI ^a 0.5 hours 3.37 (1.49, 5.25) 2.90 (1.00, 4.80) 1 hour 4.60 (2.71, 6.48) 4.98 (3.07, 6.88) 2 hours 0.81 (-1.07, 2.69) 2.14 (0.23, 4.04) 3 hours -1.04 (-2.92, 0.85) 0.40 (-1.50, 2.30) 4 hours -2.96 (.4.84, -1.08) -0.83 (-2.73, 1.07) 6 hours -2.70 (-4.58, -0.81) -1.26 (-3.16, 0.64) 8 ocloc'k -3.24 (-5.12, -1.36) -1.24 (-3.14, 0.66) 10 hours -4.14 (-6.02, -2.25) -2.67 (-4.57, -0.77) 12 hours -4.00 (-5.88, -2.11) -3.72 (-5.63, -1.82) 23.5 hours -0.34 (-2.22, 1.54) 0.38 (-1.52, 2.28)

Abbreviations: LS mean, least squares means, CI, confidence interval.

Vibegron 400 mg: single dose of Vibegron 400 mg (8 tablets of 50 mg).

Vibegron 200 mg: single dose of Vibegron 200 mg (4 tablets of 50 mg Vibegron + 4 placebo tablets corresponding to Vibegron).

Placebo: single dose of placebo corresponding to Vibegron (8 placebo tablets corresponding to Vibegron).

QTcF results at baseline (arithmetic mean): placebo = 407.38, 400 mg Vibegron = 407.64, 200 mg Vibegron = 406.75, moxifloxacin = 407.77.

A. Two-sided 90% confidence intervals are equivalent to one-sided upper 95% confidence intervals.

Example 4: Clinical Efficacy Data.

A randomized, double-blind, placebo- and active-controlled, two-stage, parallel-group, phase 2b study in men and women with OAV (stratified by wet OAV and dry OAV) was completed. Part 1 was a dose-ranging study to evaluate the safety, tolerability, and efficacy of Vibegron and a proof-of-concept study for co-dosing Vibegron with tolterodine ER 4 mg. Approximately 980 subjects in Part 1 were equally randomized, double-blind, to one of seven treatment groups: Vibegron 3, 15, 50, or 100 mg once daily for 8 weeks; tolterodine ER 4 mg once daily for 8 weeks; placebo once daily for 8 weeks; or Vibegron 50 mg with tolterodine ER 4 mg for 4 weeks, then Vibegron 50 mg for 4 weeks. Part 2 was designed to continue to evaluate the safety and effectiveness of concurrent dosing. In Part 2, 408 subjects were randomized, double-blind, to one of four treatment groups in a 2:2:2:1 ratio: Vibegron 100 mg, tolterodine ER 4 mg, Vibegron 100 mg with tolterodine ER. 4 mg or placebo once daily for 4 weeks. Subjects in both Part 1 and Part 2 had the opportunity to enroll for 1 year. Participants were required to keep a voiding diary, recording the occurrence of each urgency, complete incontinence, and urge incontinence episode. The efficacy data for Part 1 and Part 2 are summarized in this document.

At baseline, subjects were required to have an average number of voids >8 voids per day during the voiding diary period. In addition, subjects in the wet OAV groups were required to have an average number of >1 urge incontinence episodes per day during the diary period. Subjects in the dry OAV groups were required to have an average of >3 urgency episodes per day during the diary period and an average of <1 urgency incontinence episode per day during the diary period. The total number of urge incontinence episodes must exceed the total number of stress incontinence episodes for all subjects.

The primary objectives of this study were to evaluate the safety and tolerability of treatment with selected doses of Vibegron (alone or in combination with tolterodine) and to examine dose-related reductions in the mean number of daily voids compared with placebo at week 8.

In Part 1, a statistically significant reduction in the mean number of daily voids was observed in the treatment groups receiving Vibegron 100 mg and 50 mg compared to the placebo group at week 8. Statistically significant reductions from baseline compared to placebo were also observed in the Vibegron 100 mg and 50 mg treatment groups for secondary endpoints that included urge and total incontinence (in subjects with wet OAV) and urgency episodes. urination in all subjects. Statistically significant increases from baseline compared to placebo were also observed for the secondary endpoint of urine volume per void in the Vibegron 15, 50 and 100 mg treatment groups (Tables 12 and 13).

Table 12

Analysis of changes from baseline in urine volume (ML) per void at week 8

Difference compared to placebo

Week 8

Difference in averages

Treatment N LS values p-value Vibegron 3 mg 144 15.99 0.032 Vibegron 131 28.23 <0.001 15 mg Vibegron 50 mg 146 29.05 <0.001 Vibegron 100 mg 148 23.36 0.002 Tolterodine ER 4 mg 133 30.77 <0.001

Table 13

Analysis of Changes from Baseline in Average Daily Events at Week 8 - Constrained Longitudinal Data Analysis (cl.DA) Model (Full Analysis Population - Part 1, Main Study)

Daily number of occurrences Change from baseline Difference compared to placebo Elementary time Week 8 Weeks 8 Weeks 8 Phenomenon Treatment 14 Average SD Average SD Average SD Differences in means value Mochenspuzkani 11lapebo 141 10.86 2.84 9.77 2.51 -1.09 2.17 c/o But I Vibegron 5 mg 144 10.93 2.35 9.35 2.43 1.56 1.97 -0.46 0.056 Vibegron 13 mg 132 11.32 3.48 9.53 2.85 -1.71 2.22 -0.45 0.064 Vibegron 50 mt 148 1 1.21 3.16 9.05 2.28 -1.87 1.78 -0.64 0.007 Vibeg-ron 100 mg 148 11.15 2.32 9.02 2.59 -2.11 1.81 41.91 < ϋ.οοι Tpleterodine ER 4 mg 134 11.00 2.17 9.24 2.11 -1.73 2.02 4),54 0.026 EiN-YUDY Placebo 118 3.11 2.68 1.71 2.50 -1.34 1.77 But But imperative™ Vibegron Zmg FROM 2.70 1.94 1.21 1.68 -1.38 1.38 -0.28 0.167 lzderzhainya ^with Vibegron 15 mj 111 2.94 2.23 1.12 2.06 -1.81 1.60 -0.57 0.005 Vibegron 50 mg 121 2.81 2.06 0.86 1.16 -1.90 1.75 -0.72 <0.001 Vibegron 100 mg 122 2.96 2.42 0.84 1.74 2.05 1.99 -0.71 <0.001 Tolterodine ER 4 mg 100 2.80 2.13 1.15 2.18 1.67 1.55 -0.46 0.030 Enitodes Placebo I8 3.61 3.26 1.88 2.68 -1.68 2.01 di Ei-O full Vibegron 3 mg FROM 3.05 2.11 1.38 1.75 -1.56 1.55 -0.18 0.401 incontinence ¹² Vibegron 15 mg H1 3.32 2.44 1.31 2.26 1.99 1.64 -0.48 0.029

- 22 045454

Contribution 50 mg 121 3J0 2.26 1.02 1.40 2.02 1.82 0.60 0.005 Vibegron 100 mg 122 3.43 2.83 1.12 2.08 -2.26 2.41 -0.58 0.007 Toltsridine ER 4 mg 100 3.08 2.39 1.32 2.38 -1.80 1.47 -0.34 0.140 Episodes Plzzebo |4| 6.52 4.37 4.99 3.77 -1.57 3.28 By and about imperative Vibegron 5 mg 144 6.49 3.66 4.68 4.16 -1.69 2.65 -0.18 0.598 urges to Vibegron 15 mg 132 6.93 4.69 4.42 4.40 -2.35 2.50 -0.67 0.052 urination Viberon 50 mi 148 6.43 4.22 3.71 3.76 2.36 2.35 0.76 0.024 Vibsgrsch! 100 mg 148 7.34 4.14 4.22 4.36 -2.98 2.84 -1.24 <0.001 Tolterodip FR 4 mg 134 6.39 3.78 3.91 3.65 -2.52 2.73 -0.94 0.007 a Constrained longitudinal data analysis model includes periods for time, region, and treatment-by-time interactions. b. Negative mean differences in desire favor previous treatments when compared. C. Only in subjects with wet OAV,

A double-blind, randomized, placebo-controlled, multicenter, phase 3 study was conducted to evaluate the safety and effectiveness of Vibegron in men and women with OAV. After completing the placebo run-in period, 1232 patients were randomized to receive treatment in a blinded study for 12 weeks, including: Vibegron 50 mg (N=370), Vibegron 100 mg (N=369), placebo (N =369) or imidafenacin in the amount of 0.2 mg (comparison drug; N=117). The results demonstrate that once daily use of Vibegron caused statistically significant reductions in performance parameters including voiding, UUI episodes, total incontinence episodes, and urgency episodes (Table 14).

Table 14

Analysis of Change from Baseline in Average Daily Number of Events at Week 12—Constrained Longitudinal Data Analysis (cLDA) Model

Dose 50 mg Dose 100 mg Phenomenon Urination -0.86 (-1.12, -0.60) p<0.0001 -0.81 (-1.07, -0.55) p<0.0001 Episodes of urge urinary incontinence -0.27 (-0.44, -0.10) p = 0.0015 -0.39 (-0.55, -0.22) p < 0.0001 Episodes full incontinence -0.30 (-0.49, -0.12) p = <0.0015 -0.43 (-0.61, -0.24) p<0.0001 Episodes of urinary urgency -0.51 (-0.76, -0.25) p = 0.0001 -0.67 (-0.93, -0.42) p < 0.0001 Urine volume (ml) 25.76 (20.02, 31.46) p<0.0001 22.16(16.44, 27.89) p < 0.0001

A. Results are presented as placebo-adjusted least squares change from baseline (95% confidence interval [CI]), p value.

Example 5: Safety Data.

5.1. Phase I safety data.

Safety data were collected from 16 phase 1 studies, which included 15 completed phase 1 studies and 1 study that was stopped early (this study was stopped for reasons unrelated to efficacy or safety). In the phase 1 program, a total of 466 subjects received at least one dose of Vibegron; 238 subjects received single doses ranging from 2 to 600 mg, and 238 subjects received multiple doses ranging from 25 to 400 mg for a maximum of 28 days. Vibegron was generally well tolerated in the Phase 1 program. There were no reports of treatment-emergent serious adverse events (SAEs) or deaths, and most adverse events (AEs) were transient and mild or moderate in intensity.

In phase 1 studies, isolated cases of orthostatic hypotension (a decrease in systolic blood pressure >20 mmHg and/or a decrease in diastolic blood pressure >10 mmHg) with or without symptoms (eg, weakness, dizziness, lightheadedness) were observed. state). The incidence of orthostatic AEs after co-administration of Vibegron 100 mg or 150 mg and tolterodine ER 4 mg was similar to the incidence of such AEs after administration of Vibegron or tolterodine alone. At doses up to 100 mg in phase studies

- 23 045454 with repeated doses, AEs such as postural dizziness, dizziness, lightheadedness or syncope did not demonstrate a clear dose-response relationship. However, postural dizziness appeared to be increased at doses of 100 mg and above, and the incidence of AE symptomatic orthostatic hypotension tended to be higher at Vibegron doses >200 mg. There were no cases of orthostatic AEs observed with co-administration of 100 mg Vibegron to patients with essential hypertension who were stable on either metoprolol (a typical beta-blocker) or amlodipine (a typical vasodilator).

Review of preliminary phase 1 safety data does not suggest clinically significant changes in laboratory safety parameters (chemical composition, complete blood count, and urinalysis) or ECG parameters, including PR, QRS, and QTc intervals. Extensive QT testing was performed and showed no clinically significant effect on QTc or blood pressure.

5.2. Phase II safety data.

Phase 2 safety data were collected from one completed phase 2B study in which 933 subjects received at least one dose of Vibegron. Subjects received doses of Vibegron ranging from 3 to 100 mg for a maximum of 8 weeks during the main study (alone or in combination with tolterodine). Of those who completed the initial study, 605 people received doses of Vibegron 50 mg (alone) or Vibegron 100 mg (alone or in combination with tolterodine 4 mg) for a maximum of 52 weeks during the extension study. The placebo group was included in the main study, and the tolterodine monotherapy group was included in the main study and extension study. There were no deaths reported during the study. In general, Vibegron was well tolerated. No significant differences in the overall incidence or severity of AEs or drug-related AEs were observed among treatment groups compared with placebo.

Adverse events were reported in 607 (43.6%) of the 1393 subjects allocated in the main study. The proportion of subjects with one or more AEs in the Vibegron 50 mg and Vibegron 100 mg treatment groups was similar to placebo (see Table 14). A higher proportion of patients reported one or more AEs in the Vibegron 15 mg and Vibegron 50 mg + tolterodine 4 mg treatment groups compared with placebo. The most common AEs noted included dry mouth, headache, urinary tract infection (UTI), and nasopharyngitis.

The incidence of dry mouth was higher in groups receiving tolterodine (alone or with Vibegron) compared with groups receiving placebo or Vibegron alone.

There were 221 people with drug-related AEs, with the lowest incidence of drug-related AEs occurring in the Vibegron 100 mg treatment group. The proportion of subjects with drug-related AEs was similar in the Vibegron monotherapy groups compared with placebo and only slightly higher in the concomitant treatment groups compared with placebo or either monotherapy. The proportion of subjects who discontinued treatment due to drug-related AEs was low and similar across all treatment groups.

A total of 9 SAEs were reported in 8 subjects who were observed in the treatment groups (2 placebo; 1 Vibegron 3 mg; 1 Vibegron 50 mg; 3 tolterodine 4 mg; 1 Vibegron 50 mg + tolterodine 4 mg). SAEs noted included atrial fibrillation, anaphylactic reaction, stage IV lung adenocarcinoma, chronic obstructive pulmonary disease, hypertension, overdose, foot fracture, and one subject experienced gastroesophageal reflux disease and dizziness after a panendoscopic procedure, which prolonged hospitalization. No specific AE term was reported in more than 1 subject. All SAEs were considered by the investigator to be unrelated to the study drug.

During the 52-week extension study, there were no significant differences in the overall incidence of adverse events or serious adverse events between treatment groups.

Adverse events were reported in 531 (62.8%) of 845 subjects. The proportion of subjects with one or more AEs was similar across all treatment groups. The most common adverse events noted included UTI, nasopharyngitis, upper respiratory tract infection, and dry mouth. The incidence of dry mouth was higher in the tolterodine ER 4 mg treatment group compared with the other treatment groups. The incidence of constipation was higher in the concomitant treatment group compared to the monotherapy treatment groups.

The proportion of patients with drug-related AEs was slightly higher for the tolterodine ER 4 mg and concomitant dose groups compared with the Vibegron 50 mg and 100 mg treatment groups. The proportion of subjects who discontinued treatment due to AEs or drug-related AEs was higher for tolterodine ER 4 mg compared with other treatment groups. During the extension study, 46 SAEs were reported in 41 subjects. There was a higher overall incidence rate in the treatment groups receiving tolterodine ER 4 mg and Vibegron 50 mg compared with the treatment group receiving Vibegron 100 mg. In the group receiving tolterodine ER 4 mg,

- 24 045454 one SAE associated with paralytic ileus; the subject completed treatment due to this AE.

In the table below. 15 summarizes the adverse events commonly observed in the Vibegron phase 2 program in patients with overactive bladder.

Table 15

Adverse events in >2% of subjects in phase 2 study (first 12 weeks of treatment)

Place bo Vibegrp and 3 mg Vibegr on 15 mg Vibegr on 50 mg Vibegro and 100 mg T plterodine QC 4 mg Vnbegro n 100 mg + tolgerodine ER 4 mg Viberon 50 mg + Toltsroline EN 4 mg/ Vibsgron 50 mg Total N= 205 N=144 bl = 134 X=148 Ν = 261 Ν = 257 No. NO No. 134 Ν = 1393 And (%) ή<%) "(%) ΰ (%> 1 (%) And (%) And (%) 1 (%) * (%) > 1 AE 88 (42D) 55(382) 70 (522) 62 (41.9) 107 (41.0) 116(45.1) 40 (36.4) 69 (51.5) Serious AE 2(1.0) 1 (0.7) 0 1 (0.7} 0 3(12) 0 8 (0.7) Drug-related AEs thirty (14.6) 21 (14.6) 23 (172) 23 (15.5) 31 (11.9) 42 (16.3) 21 (19.1) 30 (14.6) Discontinuation of treatment due to AE 5 (’.4) 3(2.1) 4(3.0) 2(1.4) 0 (2.3) 4(1.6) 2(1.8) 3 (2.2) Treatment discontinuation due to drug-related AEs 3(1.5) 2(1.4) 4(3.0) 0 3(1,1) 0 1 (0.9) 2(1.5) SOCV middle term Visual disorders With dry eye treatment (0 (4.9) 2(1.4) 4(3.0) 2(1.4) 4(1D) 10(3.9) 3 (2.7) 2(%) 18(1.3) Gastrointestinal disorders Constipation 5 (2.4) 5(3.5) 6 (4.5) 6(4.1) 2 (0.8) 5(1.9) 4(3.6) 6 (4.5) 39 (2.8) Diarrhea 5 (2.4) 4(2.8) 2(1.5) 1 (0.7) 5(1.9) 9(3.5) I (0.9) 6 (4.5) 33 (2.4) Dry mouth 6 (2.9) 5(3.5) 6 (4.5) 7(4.7) 4(1.5) 22 (8.6) 13(11.8) 1 1 (8.2) 74 (5.3) Nausea 3(1.5) 2(1.4) 2(1.5) 3(2.0} 3(1.1) 6(2.3) 0 (0.0) 2(1.5) 21 (1.5) General disorders and complications at the dose site Fatigue 1 (0.5) 4(2.8) 6(4.5) 5(3.4} 2 (0.8) 6(2.3) 2(1.8) 2(1.5) 28 (2.0) Infekini n nnvlshi Nazofarishn] 14 (6.8) 3(2,1) 7(5.2) 8 (5.4) 10(3.8) 4(1.6) 2(1.8) 3 (22) 51 (3.7) Sinusitis 2(1.0) 00 2(1.5) 1 (0.7) 0 0 1 (0.4) 0 (0.0) 4 (3.0) 10 (0.7) Urinary tract infection 7 (3.4) 5(3.5) 5 (3.7) 8 (5.4) 8(3.1) 12(4.7) 5 (4.5) 7 (5.2) 57(4.1) Injuries, poisonings and complications of procedures Accidental overdose 2(1.0) 3(2,1) 6(4.5) 4(2.7) J1 (4.2) 6(2,3) 1 (OD) 2(1D) 35 (2.5) Research Elevated alanine aminotransferase levels 0 (0.0) 0 (0.0) 0 (0.0) 0(0,0) 0 (0.0) 1 (0.4) 0(0.0) 3(2.2) 4 (0.3) Elevated levels of aspartate and initransfrazy 0 (OD) 0 (0.0) 1 (0.7) 0(0.0) 0 (0.0) 0 (0.0) 0(0,0) 3 (2.2) 4 (0.3) Musculoskeletal and connective tissue disorders Arthralgia 2(1.0) 00 2(1.5) 3(2.0) 0 (0.0) 3(12) 1 (OD) 0 (0.0) 1 1 (0.8) Osteoarthritis 1 (0.5) 2(1.4) 1 (0.7) 4(2.7} 1 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 9 (0.6) Eal in limb 00 2(1.4) 00 2(1.4} 1 (0.4) 1 (0.4) z (2.7) 2(1.5) 11 (0.8) Nervous system disorders Dizziness 5 (2.4) 1 (0.7) 6(4.5) 3(2.0) 7 (2.7) 5(1.9) 3 (2.7) 1 (0.7) 31 (2.0) Headache 9 (4.4) 3(2,1) 6(4.5) 6(4.1) 12(4.6) 9(3.5) 7 (6.4) 6 (4.5) 58 (4.0) Renal and urinary tract disorders Dysuria 1 (OD) 0 (0.0) 0 (0.0) 1 (0.7) 0 (0.0) 3(12) 3 (2.7) 0 (0.0) 8 (0.6)

Serious adverse events observed during the first 12 weeks of treatment with Vibegron monotherapy included stage IV lung adenocarcinoma (n=1) and chronic obstructive pulmonary disease (n=1); SAE in the form of overdose was reported in the Vibegron-Tolterodine combination group. During the phase 2 extension study, SAEs reported by 2 or more subjects receiving monotherapy included cerebrovascular accident (n=2) and osteoarthritis (n=2). The only SAE reported in the Vibegron-Tolterodine combination group was Borrelia infection. SAEs potentially associated with changes in heart rate or blood pressure (at any time during treatment) included: loss of consciousness after 8 weeks of Vibegron treatment, which did not recur when the drug was reintroduced (n=1), and also in the monotherapy group tolterodine, atrial fibrillation (n=1) and dizziness (n=1). The incidence of injury was numerically higher in the tolterodine group than in the Vibegron group (2.1%, n=5, versus 0.9%, n=4). Considering the low number of cases and the lack of pattern for SAE, no serious events are expected with the use of Vibegron.

Potential risks that may be associated with treatment with Vibegron based on non-clinical data and data available for similar compounds include orthostatic hypotension and increased exposure (~2-fold) in patients taking concomitant strong P-gp inducers.

5.3. Safety regarding the cardiovascular system.

The cardiovascular safety of Vibegron was assessed in patients with OAV and healthy volunteers. In a randomized, placebo-controlled and active comparator-controlled (tolterodine) two-stage study of efficacy and safety with 52

- The 25 045454 week extension study identified seven orthostatic AEs (which included adverse events of postural dizziness, lightheadedness and orthostatic hypotension) in 6 (0.4%) subjects. Events were observed in one subject in each of the placebo group (0.5%), the Vibegron 15 mg group (0.3%), the Vibegron 50 mg + tolterodine ER/Vibegron 50 mg group (0.8%), and in 3 patients group receiving 100 mg Vibegron (1.1%). The events occurred at random times throughout the study and were rated as mild in severity by the investigator. None resulted in discontinuation of treatment. The overall incidence of orthostatic symptoms was low.

Changes from baseline in BP and HR in treatment groups are shown in Table. 16. For systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean changes at 1 week and mean maximum changes at 8 weeks for 50 mg and 100 mg were comparable between placebo and Vibegron, with a difference of <1 mm Hg. Art. Categorical changes in SBP and DBP were also similar with placebo and Vibegron, with a small increase at 100 mg in the percentage of subjects taking Vibegron with a change from baseline in DBP >15 mmHg. Art. (1.3% per 100 mg vs. 0.5% placebo). No dose-response pattern was found for HR, as mean maximum changes over 8 weeks were comparable to placebo (<2 bpm). The small differences in the percentages of subjects exceeding the categorical heart rate and blood pressure thresholds for Vibegron were similar to those in the tolterodine group.

Table 16

Changes in vital signs from baseline with Vibegron and tolterodine as a function of dose

Change in HR compared to baseline Treatment η Mean (95% CI) (week 1) η Mean (95% CI) maximum >5 mmHg Art. η/Ν (%) >10 beats/min. η/Ν (%) >15 beats/min. η/Ν (%) Placebo 186 0.12(-1.04, 1.28) 200 5.08 (4.02, 6.13) 17/188 (9.0) 1/188 (0.5) 0 3 mg 141 0.36 (-0.90, 1.62) 143 5.57 (4.25, 6.90) 16/140 (11.4) 5/140 (3.6) 1/140 (0.7) 15 mg 126 0.35 (-1.15, 1.85) 134 6.56 (5.20, 7.92) 17/132 (12.9) 4/132 (3.0) 1/132(0.8) 50 mg 140 0.29 (-0.88, 1.46) 146 5.49 (4.28, 6.69) 12/144 (8.3) 4/144 (2.8) 1/144 (0.7) 100 mg 237 0.35 (-0.69, 1.38) 257 6.12(5.10, 7.15) 28/237 (11.8) 7/237 (3.0) 1/237 (0.4) Tolterodine 4 mg 246 0.68 (-0.31, 1.67) 257 5.66 (4.69, 6.63) 29/242 (12.0) 11/242 (4.5) 4/242 (1.7) Average maximum from week 1 to week 8. Calculations based on 3 consecutive visits after baseline.

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Change in SBP from baseline Treatment η Mean (95% CI) (week 1) η Mean (95% CI) maximum >5 mmHg Art. n/N (%) >10 mm rt. Art. n/N (%) >15 mm rt. Art. n/N (%) Placebo 186 -0.21 (-1.85, 1.43) 200 7.84 (6.27, 9.40) 24/188 (12.8) 10/188 (5.3) 3/188 (1.6) 3 mg 141 -0.35 (-2.34, 1.65) 143 7.14(5.18, 9,Yu) 21/140 (15.0) 10/140 (7.1) 4/140 (2.9) 15 mg 126 -0.34 (-2.46, 1.78) 134 8.93 (7.18, Yu.67) 22/132 (16.7) 9/132 (6.8) 1/132 (0.8) 50 mg 140 -0.79 (-2.65, 1.08) 146 7.01 (5.31, 8.70) 24/144 (16.7) 14/144 (9.7) 3/144(2.1) 100 mg 237 -0.77 (-2.22, 0.68) 257 6.51 (5.09, 7.93) 28/237 (11.8) 10/237 (4.2) 3/237 (1.3) Tolterodine 4 mg 246 0.04 (-1.36, 1.43) 257 7.29 (6.01, 8.57) 41/242 (16.9) 19/242 (7.9) 7/242 (2.9) Average maximum from week 1 to week 8. Calculations based on 3 consecutive visits after baseline. Change in DBP from baseline Treatment η Mean (95% CI) (week 1) η Average (95% CI) Max >5 mmHg Art. n/N (%) >10 mm rt. Art. n/N (%) >15 mm rt. Art. n/N (%) Placebo 186 0.11 (-0.94, 1.17) 200 4.89 (3.89, 5.89) 18/188 (9.6) 6/188 (3.2) 1/188 (0.5) 3 mg 141 -0.37 (-1.69, 0.95) 143 5.03 (3.92, 6.15) 14/140 (10.0) 3/140 (2.1) 1/140 (0.7) 15 mg 126 0.03 (-1.52, 1.59) 134 6.37 (5.20, 7.53) 15/132 (11.4) 3/132 (2.3) 1/132 (0.8) 50 mg 140 -0.70 (-2.07, 0.67) 146 4.19(3.10, 5.29) 11/144 (7.6) 5/144 (3.5) 1/144 (0.7) 100 mg 237 -0.69 (-1.72, 0.34) 257 4.80 (3.88, 5.72) 31/237 (13.1) 8/237 (3.4) 3/237 (1.3) Tolterodine 4 mg 246 -0.12(-1.10, 0.86) 257 5.19(4.26, 6.13) 30/242 (12.4) 13/242 (5.4) 3/242 (1,2) Average maximum from week 1 to week 8. Calculations based on 3 consecutive visits after baseline.

Several phase 1 studies have conducted more intensive assessments of heart rate and blood pressure in healthy volunteers. A six-phase, double-blind, randomized, placebo-controlled study to evaluate safety, tolerability, and PK after multiple doses of Vibegron in healthy subjects, which included heart rate-specific analysis. Doses ranged from 25 to 400 mg once daily for 7 to 28 days depending on the cohort. The least squares mean and 90% confidence intervals of the maximum change from baseline in moving average heart rate at 4 hours post-dose (MA4 HR) are presented in Table 1. 17. The effect on heart rate was dose dependent, with the 100 mg dose demonstrating a difference of <1 bpm compared with placebo.

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Table 17

Maximum MA4 HR and difference between Vibegron and placebo on day 14

Panel Dose (mg) N ^a Maximum MA4 HR Difference compared to placebo' Total Placebo 14 3.07 (0.26, 5.88) A 25 5 1.47 (-3.24, 6.17) -1.60 (-7.09, 3.88) IN 50 6 1.50 (-2.79, 5.79) -1.57 (-6.70, 3.56) WITH 100 6 3.28 (-1.02, 7.57) 0.21 (-4.93, 5.34) D 150 6 3.17(-1.13, 7.46) 0.10(-5.04, 5.23) G 200 5 5.67 (0.96, 10.37) 2.60 (-2.89, 8.08) N 300 6 9.06 (4.76, 13.35) 5.98 (0.85, 11.12) I 400 6 10.33 (6.04, 14.63) 7.26 (2.13, 12.39)

A. One subject each from panels A and G discontinued treatment and had no data available at day 14.

b. Least squares mean and corresponding 90% confidence interval.

C. Least squares difference (active - placebo) and corresponding 90% confidence interval estimated from a linear fixed-effects model.

Cardiovascular safety was also assessed in healthy volunteers in a rigorous QT study following single doses of 200 and 400 mg, which approximate the steady-state effects of Vibegron at 100 mg and 200 mg, respectively. The mean maximum effect on blood pressure and RR interval decreased with lower dose, as shown in Table. 18. Using a double-log regression analysis of the effects of multiple doses of Vibegron (three phase 1 studies), the calculated mean ± standard deviation _Cmax and AUC from the 75 mg dose were 120 ± 74.7 ng/mL and 1140 ± 476 ng h/mL. respectively. These estimates represent a _Cmax and AUC that are approximately 3.3-fold and 2-fold lower than the 200 mg single dose and 9.2-fold and 6-fold lower, respectively, than the 400 mg single dose.

Table 18

Post-single dose pharmacokinetic parameters and placebo-adjusted mean change from baseline in RR interval and blood pressure

Dose (mg) Average±8 D Stach (ng/ml) Average±8 D AUC (ng.p./ml) Maximum placebo-adjusted mean compared with baseline RR interval (90% CI) (ms) Maximum placebo-adjusted mean compared with baseline systolic BP (90% CI) (mmHg) Maximum placebo-adjusted mean compared with baseline diastolic BP (90% CI) (mmHg) Vibegro n 400 1100 ±436 6800±2300 -162.45 (.184.24, 140.65) 3.97 (2.12, 5.81) 3.99 (2.62, 5.36) Vibegro and 200 406± 180 2430 ± 974 -84.36 (-106.37, - 62.35) 2.20 (0.34, 4.06) 2.42 (1.04, 3.81)

Example 6. Dose selection.

6.1. Comparison of dose effectiveness.

The phase 2 study discussed in Example 4 demonstrated a dose-dependent effect on voiding as seen in Table 1. 19. Conversely, no dose-dependent effect was observed for urge incontinence or total urinary incontinence. These data show a relatively small dose-response relationship between 50 and 100 mg once daily. As Vibegron's effectiveness begins to plateau between 50 and 100 mg, 75 mg captures most of the effectiveness achieved with 100 mg.

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Table 19

Efficacy of Vibegron 50 and 100 mg in a phase 2 study

Parameter 50 mg - Placebo 100 mg - Placebo 100 mg - 50 mg Urination ^a -0.64 -0.91 -0.27 Episodes of urge incontinence ¹⁵ -0.72 -0.71 0.01 Total incontinence ¹⁵ -0.60 -0.58 0.02 Urinary urgency episodes ¹⁵ -0.76 -1.24 -0.48 Urine volume ^s (ml) 29.1 23.4 -5.69

Data are presented as differences in mean LS values.

A. change from baseline in mean number of voids at week 8.

b. change from baseline in mean number of episodes at week 8.

With. change from baseline in average voided volume per day during the 8 week diary period.

6.2. Mitigation of side effects.

Vibegron demonstrates a greater than dose proportional increase in exposure. Surprisingly, increasing the dose from 50 to 100 mg resulted in an approximately 3-fold increase in Cmax, the PK parameter considered most closely related to cardiovascular responses. To contextualize the PK parameters for the 75 mg dose, dose-Cmax and dose-AUC models were created using data from phase 1 studies. Based on simulation modeling, a 75 mg dose of Vibegron was found to avoid approximately 29% of the exposures. observed at the 100 mg dose, which subsequently reduces the upper range of effects that is achieved at the 100 mg dose. This reduction in Cmax outliers reduces the potential for clinically significant cardiovascular reactions.

In phase 1 studies using repeated doses at doses not exceeding 100 mg, adverse events such as postural dizziness, dizziness, lightheadedness, and syncope did not demonstrate a clear dose-response relationship. However, postural dizziness was increased at doses >100 mg, and the incidence of the adverse event symptomatic orthostatic hypotension was higher at doses of Vibegron >150 mg. The risk of these dose-related adverse events may be disproportionately reduced by reducing the dose from 100 mg to 75 mg, as a 25% dose reduction results in an approximately 40% decrease in Cmax (120 ng/mL at 75 mg versus 206 ng/mL at 100 mg). Without wishing to be bound by theory, it is believed that a greater than dose proportional increase in bioavailability with increasing dose may be due to saturable P-glycoprotein (P-gp)-mediated release in the intestine.

The lower exposure with the 75 mg dose compared to the 100 mg dose also disproportionately reduces the risk of adverse events in special populations. In subjects with moderate renal impairment, a mean increase in AUC of 1.6-fold was observed compared to subjects with normal renal function, whereas approximately 2-fold higher exposure was observed in subjects receiving a strong CYP3A/P-gp inhibitor. Assuming a 2-fold increase in Cmax at the 75 mg dose, the likelihood that these special populations would achieve greater Vibegron Cmax than those observed at 100 mg is 15% (see Fig. 1). Minimizing exposure in subjects who fall at the extremes is important for older adults and women, whose _Cmax is approximately 50-70% higher than that of healthy young men.

Example 7. Pharmacokinetic data for a dose of 75 mg.

A pharmacokinetic study evaluating the drug interaction between Vibegron and rifampicin was completed. All subjects were healthy adults. A brief description of the preliminary results is presented in Table. 20. Subjects received a single dose of Vibegron 75 mg on day 1, rifampicin 600 mg QD on days 10–23, and a single dose of Vibegron 75 mg on day 17 concurrently with a dose of rifampicin. The administration of Vibegron and rifampicin was well tolerated in healthy men and women. No serious TEAEs, SAEs, or deaths were reported during the study. Three of 20 subjects (15%) experienced study drug-related AEs, 2 with headache and 1 with constipation, all mild. No clinically significant changes or findings were observed in vital signs, ECG, or clinical labs.

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Claims (19)

rhetorical research. Table 20 Geometric mean (%CV) Pharmacokinetic parameters of Vibegron Treatment regimens Pharmacokinetic parameters Vibegron alone (N = 18) Vibegron + rifampicin (N = 18) tmax (i.) 1.0 (0.5, 2.0) 1.0 (0.5, 2.0) Stakh (NG/ML) 82.3 (43.2) 153.9 (47.1) AUCo-t (ngh/ml) 1160 (34.3) 1210(30.7) AUCo-οο (ngh./ml) 1310(36.4) 1310(31.5) tl/2 (h.) 84.0(15.0) 74.2 (25.2) CL/F (l/h) 57.2 (39.7) 57.3 (30.1) V/F (l) 6930 (48.6) 6140 (47.0) A. Median (minimum, maximum). Having now fully described this invention, it will be appreciated by those skilled in the art that the same can be accomplished under a wide and equivalent range of conditions, compositions and other parameters without affecting the scope of the invention or any embodiment thereof. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the description and execution of the invention disclosed herein. It is intended that the description and examples be considered as illustrative only, with the true scope and spirit of the invention set forth in the following claims. All patents, patent applications and other publications cited herein are hereby incorporated by reference in their entirety. CLAIM 1. A method of treating overactive bladder, comprising orally administering to a subject in need thereof Vibegron or a pharmaceutically acceptable salt thereof in an amount of 70 mg ±10% to 80 mg ±10% per day. 2. The method according to claim 1, where the amount of Vibegron is 75 mg ±10%. 3. The method according to claim 1 or 2, where the subject is a human. 4. The method according to any one of claims 1 to 3, wherein treating overactive bladder comprises treating one or more symptoms selected from urge urinary incontinence (UUI), urgency, urinary frequency, or a combination thereof. 5. The method of claim 4, wherein the symptoms are urge urinary incontinence (UUI), urgency, and urinary frequency. 6. Method according to any one of claims 1-5, where Vibegron is contained in the composition. 7. The method according to claim 6, where the composition is a tablet. 8. Method according to claim 7, where the tablet is crushed. 9. The method according to any one of claims 1 to 8, where Vibegron is effective in the treatment of overactive bladder after 4 weeks ±10%, 3 weeks ±10% or 2 weeks ±10%. 10. The method according to claim 8, where the composition containing Vibegron is effective in the treatment of overactive bladder after 2 weeks ±10%. 11. The method according to claim 3, where the person is a woman. 12. The method according to claim 3, where the person is a man. 13. The method according to any one of claims 1 to 12, wherein the subject suffers from severe renal failure. 14. The method according to any one of claims 1 to 12, wherein the subject suffers from moderate renal failure. 15. The method according to any one of claims 1 to 12, wherein the subject simultaneously receives a CYP3A/Pgp inhibitor. 16. The method according to any one of claims 1 to 12, wherein the subject simultaneously receives a CYP2D6 substrate, a CYP2C9 substrate, a CYP3A inhibitor, a P-glycoprotein inhibitor, an oral contraceptive, or a combination thereof. 17. Method according to any one of claims 1 to 16, wherein a pharmaceutically acceptable salt of Vibegron is administered. 18. The method of any one of claims 1 to 17, wherein the subject experiences an average change in systolic blood pressure from baseline over the treatment period, wherein the average change is less than 1 mm Hg. Art. compared with that of a subject taking a placebo. 19. The method according to any one of claims 1-17, where the percentage of subjects experiencing an average change in system -