Use of vibegron for treating overactive bladder

Abstract

The present disclosure is directed to a method for treating overactive bladder, comprising orally administering vibegron in an amount of about 60 mg to about 90 mg (e.g., about 75 mg) per day to a subject in need thereof. The present disclosure is also directed to a unit dosage pharmaceutical composition comprising about 60 mg to about 90 mg (e.g., about 75 mg) of vibegron for oral administration.

Description

Background Art

[0001] Overactive bladder (OAB) is a chronic and sometimes debilitating condition of the lower urinary tract. The function of the lower urinary tract is to store urine and release it periodically. This requires a coordinated integration of storage and micturition reflexes, including various afferent and efferent neural pathways that result in the regulation of central and peripheral neuroeffector mechanisms, and the consequent coordinated control of the sympathetic and parasympathetic components of the autonomic nervous system as well as the somatic motor pathways. These proximally control the smooth muscle of the bladder (detrusor) and urethra in the contracted state, as well as the striated muscle of the urethral sphincter.

[0002] From a pathophysiological perspective, overactive bladder is associated with detrusor overactivity. OAB is characterized by symptoms of urinary urgency, with or without urge incontinence, usually accompanied by frequency and nocturia. The prevalence of OAB in the United States and Europe is estimated to be 16 to 17% in both women and men over 18 years of age. Overactive bladder is most often classified as idiopathic, but may also be secondary to neurological conditions, bladder outlet obstruction, and other causes.

[0003] Currently, the mainstream class of drugs used to treat OAB is antimuscarinics. The clinical use of antimuscarinics is limited by their modest efficacy and poor tolerability due to mechanism-based side effects, including the potential for dry mouth, constipation, and CNS adverse effects (e.g., cognitive impairment). High discontinuation rates have been seen for both tolterodine and oxybutynin, two antimuscarinics commonly prescribed in both clinical trials and real-life settings.

[0004] β3-adrenergic receptor (β 3 -AR) activation is an effective way to relax the detrusor muscle in normal and pathological states. Functional evidence supporting an important role for β 3 -AR in urine storage comes from in vivo studies. β 3 -AR agonists have shown efficacy in the alleviation of OAB symptoms. To date, β3 - Only mirabegron (Astellas Pharma Global Development, Inc.), an AR agonist, has received marketing approval for the treatment of OAB in the United States and Japan. Mirabegron activates β 3 -AR in the detrusor muscle of the bladder, which results in muscle relaxation and an increase in bladder capacity. Using mirabegron, a decrease in urinary frequency, urinary incontinence, and urgency episodes, as well as an increase in the average single voided volume, have been observed.

[0005] Vibegron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide, is a potent and highly selective β3-adrenergic receptor (β 3 -AR) agonist that shows >9,000-fold selectivity for β 2 -AR activation over β 1 -AR and β 3 -AR in cell-based in vitro assays. See Edmondson et al., J. Med. Chem. 59:609-623 (2016).

Chemical Structure

[0006] Vibegron is disclosed as a β 3 -AR agonist in U.S. Patent Nos. 8,399,480 and 8,247,415. Synthetic methods for preparing vibegron are disclosed in U.S. Patent Application Publication Nos. 2017 / 0145014, 2015 / 0087832, 2016 / 0176884, and 2014 / 0242645. All of the cited publications are hereby incorporated by reference in their entirety into this specification.

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure provides a method for treating overactive bladder, the method comprising orally administering to a subject in need thereof an amount of vibegron from 60 mg to 90 mg per day.

[0009] The present disclosure further provides a unit dosage pharmaceutical composition comprising 60 mg to 90 mg of vibegron, which is a unit dosage composition suitable for oral administration.

Mode for Carrying Out the Invention

[0010] To make the present disclosure more easily understandable, certain terms are first defined. As used in this application, unless otherwise explicitly defined herein, each of the following terms shall have the meaning described below. Throughout this application, additional definitions are described.

[0011] In this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more" and "at least one", can be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single". In other embodiments, the term "a" or "an" includes "two or more" or "plural".

[0012] Furthermore, as used herein, "and / or" shall be regarded as each individual disclosure of two specified features or components, including or excluding others. Thus, the term "and / or" as used in expressions such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in expressions such as "A, B, and / or C" is intended to include 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 (alone); B (alone); and C (alone).

[0013] Unless defined otherwise, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0014] The term "about" as used throughout this specification and the claims in relation to numerical values represents a width of accuracy that is well known and acceptable to those skilled in the art. Such a width of accuracy is ±10%.

[0015] The term "overactive bladder" generally refers to a clinical syndrome characterized by urinary urgency, which may or may not be accompanied by frequency and nocturia, and may or may not be accompanied by urge incontinence.

[0016] The term "urge urinary incontinence" (UUI) as used herein means urinary incontinence accompanied by a sudden strong need to urinate and can be used interchangeably with "urge incontinence" or "urgent incontinence". UUI is distinguished from stress urinary incontinence, which is urinary incontinence during labor or physical activity (e.g., sports activities) or during sneezing or coughing.

[0017] The term "disorder" as used herein means acute or chronic functional decline. For example, renal dysfunction refers to a medical condition in which the kidneys are unable to maintain their normal function, resulting in the accumulation of waste products and metabolites in the blood.

[0018] As used herein, the term "urgency" means a sudden, overwhelming urge to urinate that is difficult to defer.

[0019] As used herein, the term "frequency" refers to the frequent need to empty the bladder.

[0020] As used herein, the term "free base" refers to the basic compound itself, not in the form of a salt. For example, vibegron free base refers to (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide.

[0021] As used herein, the term "OAB wet" means overactive bladder defined by frequency and urgency, with incontinence.

[0022] As used herein, the term "OAB dry" means overactive bladder defined by frequency and urgency, without incontinence.

[0023] The term "pharmaceutically acceptable salt" means a salt of a compound that is safe and effective for use in a subject and has the desired biological activity.

[0024] Pharmaceutically acceptable salts of basic compounds can 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.

[0025] As used herein, the term "C max " refers to the maximum plasma concentration of a drug after administration.

[0026] As used herein, the term "T" max refers to the time after drug administration when the maximum plasma concentration is reached.

[0027] As used herein, the term "AUC" refers to the area under the curve of the plot of plasma concentration against time after drug administration.

[0028] The term "steady state" means that the amount of drug reaching the whole body is approximately the same as the amount of drug leaving the whole body. Thus, in the "steady state", the patient's body excretes the drug at approximately the same rate at which the drug becomes available to the whole body of the patient through absorption into the bloodstream.

[0029] The term "treatment period" means the period during which the drug is administered to the subject. For example, the treatment period can be from about 2 weeks to about 2 years. In some embodiments, the treatment period can 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 the drug can be evaluated by measuring certain parameters and calculating the change from baseline over the treatment period. Effectiveness parameters include, but are not limited to, urination, urge incontinence episodes, total incontinence episodes, and urgency episodes.

[0030] Methods of treatment The present disclosure relates to a method of treating overactive bladder, comprising orally administering to a subject in need thereof a dosage of vibegron that minimizes undesirable side effects while maintaining the desired effectiveness. Unexpectedly, the selection of the dosage of vibegron can disproportionately reduce side effects associated with C max elevation.

[0031] The present disclosure provides a method of treating overactive bladder, comprising orally administering to a subject in need thereof an amount of vibegron from 50 mg to 100 mg per day.

[0032] The present disclosure also provides a method of increasing bladder smooth muscle relaxation, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount from 50 mg to 100 mg per day.

[0033] In some embodiments, the quantity of vibegron administered per day is from about 55 mg to about 100 mg, from about 60 mg to about 100 mg, from about 65 mg to about 100 mg, from about 70 mg to about 100 mg, from about 75 mg to about 100 mg, from about 80 mg to about 100 mg, from about 85 mg to about 100 mg, from about 90 mg to about 100 mg, or from about 95 mg to about 100 mg.

[0034] In some embodiments, the quantity of vibegron administered per day is from about 50 mg to about 95 mg, from about 50 mg to about 90 mg, from about 50 mg to about 85 mg, from about 50 mg to about 80 mg, from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, or from about 50 mg to about 55 mg.

[0035] In some embodiments, the quantity of vibegron administered per day is from about 60 mg to about 90 mg, from about 65 mg to about 85 mg, or from about 70 mg to about 80 mg. In some embodiments, the quantity of vibegron administered per day is from 60 mg to 90 mg, from 65 mg to 85 mg, or from 70 mg to 80 mg.

[0036] In some embodiments, the quantity 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 quantity of vibegron administered per day is about 75 mg. In some embodiments, the quantity of vibegron administered per day is 75 mg.

[0037] In some embodiments, the amount of vibegron administered per day is not about 50 mg. In some embodiments, the amount of vibegron administered per day is not about 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.

[0038] In some embodiments, the subject has the symptoms of urge incontinence, urinary urgency, and urinary frequency.

[0039] In some embodiments, the subject has one or more of the symptoms of urge incontinence (or urgent urinary incontinence), urinary urgency, urinary frequency, and nocturia.

[0040] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or an animal. In some embodiments, the subject is a human.

[0041] In some embodiments, the subject is over 18 years old. In some embodiments, the subject is about under 18 years old. In some embodiments, the subject is about 6 to about 18 years old, about 6 to about 12 years old, or about 12 to about 18 years old. In some embodiments, the subject is over about 20 years old. In some embodiments, the subject is over about 25 years old. In some embodiments, the subject is over about 30 years old. In some embodiments, the subject is over about 35 years old. In some embodiments, the subject is over 40 years old. In some embodiments, the subject is over 45 years old. In some embodiments, the subject is over 50 years old. In some embodiments, the subject is over 55 years old. In some embodiments, the subject is over 60 years old. In some embodiments, the subject is over 65 years old. In some embodiments, the subject is over 70 years old. In some embodiments, the subject is over 75 years old.

[0042] In some embodiments, the method includes milling a unit dose pharmaceutical composition comprising vibegron prior to administration to a subject. In some embodiments, the subject is administered the milled pharmaceutical unit dose comprising vibegron orally.

[0043] In some embodiments, the subject has or is at risk of having renal impairment. In some embodiments, the subject has mild renal impairment, moderate renal impairment, or severe renal impairment.

[0044] In some embodiments, the subject has received prior OAB therapy. In some embodiments, the subject has not received prior OAB therapy.

[0045] In some embodiments, the subject has renal impairment and is administered about 75 mg of vibegron per day.

[0046] In some embodiments, vibegron is administered with a second pharmaceutical, including, for example, any of those recited in this application. In some embodiments, vibegron is administered simultaneously with the second pharmaceutical. In some embodiments, vibegron is administered sequentially with the second pharmaceutical. In some embodiments, vibegron is administered before and / or after the second pharmaceutical. Such sequential administrations are included in the embodiments described below.

[0047] In some embodiments, the subject is receiving, ingesting, or otherwise exposed to a cytochrome P450 inhibitor, such as a CYP3A inhibitor, with a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

[0048] In some embodiments, the subject is receiving, ingesting, or otherwise exposed to a P-glycoprotein inhibitor.

[0049] Examples of 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, rifampin (e.g., single dose),simeprevir, p-aminohippuric acid (PAH)(b), probenecid, teriflunomide, cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, and vandetanib.

[0050] In some embodiments, the subject is receiving, ingesting, or otherwise exposed to a muscarinic receptor antagonist simultaneously.

[0051] Examples of muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, cyclopentolate, methylatropine nitrate, trihexyphenidyl / benzhexol, tolterodine, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, and acridine bromide.

[0052] In some embodiments, the subject is administered about 75 mg of vibegron per day and is receiving, ingesting, or otherwise exposed to a muscarinic receptor antagonist simultaneously.

[0053] In some embodiments, the subject is administered about 75 mg of vibegron per day and is receiving, ingesting, or otherwise exposed to a CYP3A inhibitor simultaneously.

[0054] In some embodiments, the subject is administered about 75 mg of vibegron per day and is receiving, ingesting, or otherwise exposed to a P-glycoprotein inhibitor concomitantly.

[0055] In some embodiments, the subject is not receiving, ingesting, or otherwise exposed to a β-blocker concomitantly.

[0056] In some embodiments, the subject is not receiving, ingesting, or otherwise exposed to amlodipine concomitantly.

[0057] In some embodiments, vibegron is administered with a meal, within 60 minutes after a meal, or within 2 hours after a meal.

[0058] In some embodiments, vibegron is administered without a meal or before a meal. In some embodiments, vibegron is administered more than 2 hours before a meal. In some embodiments, vibegron is administered regardless of whether the subject has eaten.

[0059] In some embodiments, vibegron is administered once daily, twice daily, or three times daily. In some embodiments, vibegron is administered once daily.

[0060] For subjects taking vibegron, the changes in blood pressure (BP) and heart rate (HR) from baseline are not substantially different from those of subjects taking placebo. In some embodiments, the subject undergoes 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 from subjects taking placebo is less than 2.0 mmHg, less than 1.9 mmHg, less than 1.8 mmHg, less than 1.7 mmHg, less than 1.6 mmHg, less than 1.5 mmHg, less than 1.4 mmHg, less than 1.3 mmHg, less than 1.2 mmHg, less than 1.1 mmHg, less than 1.0 mmHg, less than 0.9 mmHg, less than 0.8 mmHg, less than 0.7 mmHg, less than 0.6 mmHg, or less than 0.5 mmHg.

[0061] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 2 mmHg from subjects taking placebo. In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 1 mmHg from subjects taking placebo.

[0062] In some embodiments, the subject is over 65 years old, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 2 mmHg from subjects taking placebo. In some embodiments, the subject is over 65 years old, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 1 mmHg from subjects taking placebo.

[0063] In some embodiments, the subject is over 45 years old, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in systolic blood pressure (SBP) from baseline of less than 2 mmHg over a treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 45 years old, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in SBP from baseline of less than 1 mmHg over a treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0064] In some embodiments, the subject undergoes an average maximum change in diastolic blood pressure (DBP) from baseline over a treatment period (e.g., 8 weeks or 12 weeks), and the average maximum change from subjects taking a placebo is less than 2.0 mmHg, less than 1.9 mmHg, less than 1.8 mmHg, less than 1.7 mmHg, less than 1.6 mmHg, less than 1.5 mmHg, less than 1.4 mmHg, less than 1.3 mmHg, less than 1.2 mmHg, less than 1.1 mmHg, less than 1.0 mmHg, less than 0.9 mmHg, less than 0.8 mmHg, less than 0.7 mmHg, less than 0.6 mmHg, or less than 0.5 mmHg.

[0065] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes an average maximum change in DBP from baseline of less than 2 mmHg over a treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes an average maximum change in DBP from baseline of less than 1 mmHg over a treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0066] In some embodiments, the subject is over 65 years old, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in DBP from baseline of less than 1 mmHg over a treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0067] In some embodiments, the subject is over 45 years of age, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in DBP from baseline of less than 2 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 45 years of age, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in DBP from baseline of less than 1 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo.

[0068] In some embodiments, the subject is over 45 years of age, is administered about 75 mg of vibegron once daily, and undergoes an average maximum change in DBP from baseline of less than 1 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo and an average maximum change in SBP from baseline of less than 1 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo.

[0069] In some embodiments, the subject is over 65 years of age, is administered about 75 mg of vibegron once daily, and undergoes an average maximum change in DBP from baseline of less than 1 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo and an average maximum change in SBP from baseline of less than 1 mm / Hg over a treatment period (e.g., 8 or 12 weeks) from subjects taking a placebo.

[0070] In some embodiments, the subject undergoes an average maximum change in systolic blood pressure (SBP) from baseline of less than 10 mm / Hg, less than 9.5 mm / Hg, less than 9 mm / Hg, less than 8.5 mm / Hg, less than 8 mm / Hg, less than 7.5 mm / Hg, less than 7 mm / Hg, less than 6.5 mm / Hg, less than 6 mm / Hg, less than 5.5 mm / Hg, or less than 5 mm / Hg over a treatment period (e.g., 8 or 12 weeks).

[0071] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline of less than 10 mmHg over a treatment period (e.g., 8 or 12 weeks).

[0072] In some embodiments, the subject is over 65 years of age, is administered about 75 mg of vibegron per day, and experiences an average maximum change in SBP from baseline of less than 10 mmHg over a treatment period (e.g., 8 or 12 weeks).

[0073] In some embodiments, the subject is over 45 years of age, is administered about 75 mg of vibegron per day, and experiences an average maximum change in SBP from baseline of less than 10 mmHg over a treatment period (e.g., 8 or 12 weeks).

[0074] In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline of less than 7 mmHg, less than 6.5 mmHg, less than 6 mmHg, less than 5.5 mmHg, less than 5 mmHg, less than 4.5 mmHg, less than 4 mmHg, less than 3.5 mmHg, less than 3 mmHg, less than 2.5 mmHg, or less than 2 mmHg over a treatment period (e.g., 8 or 12 weeks).

[0075] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline of less than 7 mmHg over a treatment period (e.g., 8 or 12 weeks).

[0076] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes a change from baseline in the average number of urinations per 24 hours over a treatment period (e.g., 8 weeks or 12 weeks), where this change is greater than the change for subjects taking a placebo. The difference from placebo is from about -0.4 to about -1.5, e.g., 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 in the range between any two of the foregoing values.

[0077] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes a change from baseline in the average number of urinations per 24 hours over a treatment period (e.g., 8 weeks or 12 weeks) in the range from about -1.5 to about -2.5, e.g., about -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, or -2.5, or in the range between any two of the foregoing values.

[0078] In some embodiments, the subject has an average of ≥1 urgency urinary incontinence (UUI) episode per day before treatment, is administered about 75 mg of vibegron per day, and undergoes a change from baseline in the average number of UUI episodes over a treatment period (e.g., 8 weeks or 12 weeks), where this change is greater than the change for subjects taking a placebo. The difference from placebo is from about -0.2 to about -1.5, e.g., 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 in the range between any two of the foregoing values.

[0079] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes a change from baseline of about -1.3 to about -2.5, such as about -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 a range between any two of the foregoing values, in the mean number of UUI episodes over a treatment period (e.g., 8 or 12 weeks).

[0080] In some embodiments, the subject is administered about 75 mg of vibegron per day and undergoes a change in the volume voided per micturition (mL), where this change is greater than the change for subjects taking a placebo. The difference from placebo is from about 20 mL to about 35 mL, such as about 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 27 mL, 28 mL, 29 mL, 30 mL, 31 mL, 32 mL, 33 mL, 34 mL, or 30 mL, or a range between any two of the foregoing values.

[0081] In some embodiments, the subject has a mean of ≥1 urge urinary incontinence (UUI) episodes per day before treatment, is administered about 75 mg of vibegron per day, and undergoes at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, at least a 75%, at least an 80%, or at least an 85% decrease in the mean number of UUI episodes per day over a treatment period (e.g., 8 or 12 weeks).

[0082] In some embodiments, the subject has a mean of ≥1 urgency episode per day before treatment, is administered about 75 mg of vibegron per day, and undergoes at least a 30%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, or at least a 75% decrease in the mean number of urgency episodes per day over a treatment period (e.g., 8 or 12 weeks).

[0083] In some embodiments, the subject is over 65 years of age, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in DBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 7 mmHg.

[0084] In some embodiments, the subject is over 45 years of age, is administered about 75 mg of vibegron per day, and undergoes an average maximum change in DBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 7 mmHg.

[0085] In some embodiments, a subject over 45 years of age is administered about 75 mg of vibegron once daily and undergoes an average maximum change in DBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 7 mmHg and an average maximum change in SBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 10 mmHg.

[0086] In some embodiments, a subject over 65 years of age is administered about 75 mg of vibegron once daily and undergoes an average maximum change in DBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 7 mmHg and an average maximum change in SBP from baseline over a treatment period (e.g., 8 or 12 weeks) of less than 10 mmHg.

[0087] In some embodiments, vibegron provides onset of action in about 4 weeks. In some embodiments, vibegron provides onset of action in about 3 weeks. In some embodiments, vibegron provides onset of action in about 2 weeks. "Onset of action" as used herein refers to the time it takes for the effects of the drug to become apparent after administration.

[0088] Unit dose pharmaceutical composition The present disclosure provides a unit-dose pharmaceutical composition comprising a certain dosage of vibegron as disclosed herein, which is a unit-dose composition suitable for oral administration. It is recognized by those skilled in the art that oral dosage forms include, for example, dosage forms such as liquid formulations, tablets, capsules, and gelcaps. In some embodiments, the unit-dose composition is in a solid dosage form such as tablets and capsules. In some embodiments, the unit-dose composition is a tablet.

[0089] Pharmaceutically acceptable excipients are excipients that are generally recognized as safe, such as lactose, microcrystalline cellulose, starch, calcium carbonate, magnesium stearate, stearic acid, talc, colloidal silicon dioxide, mannitol, croscarmellose sodium, hydroxypropyl cellulose, etc. In some embodiments, the unit-dose pharmaceutical composition disclosed herein comprises a diluent, a disintegrant, a binder, and a lubricant. See generally Remington’s Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000), which is hereby incorporated by reference in its entirety.

[0090] In one embodiment, the unit-dose pharmaceutical composition disclosed herein comprises mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0091] Oral dosage forms can be prepared by standard pharmaceutical manufacturing techniques. Such techniques include, for example, wet granulation, wet milling, fluid bed drying, dry milling, lubrication, tableting, and aqueous film coating.

[0092] In some embodiments, the unit-dose pharmaceutical composition of the present disclosure comprises from about 50 mg to about 100 mg of vibegron.

[0093] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from about 55 mg to about 100 mg, from about 60 mg to about 100 mg, from about 65 mg to about 100 mg, from about 70 mg to about 100 mg, from about 75 mg to about 100 mg, from about 80 mg to about 100 mg, from about 85 mg to about 100 mg, from about 90 mg to about 100 mg, or from about 95 mg to about 100 mg of vibegron.

[0094] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from about 50 mg to about 95 mg, from about 50 mg to about 90 mg, from about 50 mg to about 85 mg, from about 50 mg to about 80 mg, from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, or from about 50 mg to about 55 mg of vibegron.

[0095] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from about 60 mg to about 90 mg, from about 65 mg to about 85 mg, or from about 70 mg to about 80 mg of vibegron. In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from 60 mg to 90 mg, from 65 mg to 85 mg, or from 70 mg to 80 mg of vibegron.

[0096] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises 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 of vibegron. In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises about 75 mg of vibegron. In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises 75 mg of vibegron.

[0097] In some embodiments, the unit dose pharmaceutical composition of the present disclosure can be pulverized. In some embodiments, the unit dose pharmaceutical composition of the present disclosure can be pulverized before oral administration.

[0098] In vitro assay Vibegron was tested in several in vitro assays for human β 3-Its agonist efficacy in -AR, its selectivity for other human β-AR subtypes, and β from other species 3 -Its efficacy in -AR was determined.

[0099] Human β 3 Vibegron activity was measured in a functional assay that measures the increase in cellular adenylyl cyclase activity in Chinese hamster ovary (CHO) cells stably expressing human β-AR. The degree of activation relative to the proven full agonist (isoproterenol) was measured with compound EC 50 -and measured together.

[0100] Vibegron is a potent and selective agonist of β-AR with an EC 50 -of 1.1 nM and 84% activation relative to isoproterenol. In the presence of 40% human serum, small serum changes are observed (EC 3 -AR consistent with the low plasma protein binding of this compound (49% unbound in humans) (= 1.7 nM, 102% activation). 50

[0101] Furthermore, the selectivity of vibegron for β-AR compared to β- and β-AR subtypes was determined by testing in CHO cells expressing β-AR or β-AR. Vibegron is more highly selective for β-AR than β-AR and β-AR, showing >9000-fold selectivity for the activation of β-AR in cell-based in vitro functional assays compared to β-AR or β-AR. 1 -and β 2 -AR 3 -AR 1 -AR or β 2 -AR 3 -AR 1 -AR and β 2 -AR 3 -AR 1 -AR or β 2 -AR

[0102] The IC 50 of vibegron was determined using recombinant β 1 -AR, β 2 -AR, or β 3Determined in a standard competitive binding assay using membranes prepared from cells expressing -AR. Viberon is a radiolabeled antagonist of non-specific -AR in a filter binding assay 125 Regarding the competition of I-CYP, β 3 -AR IC 50 = 193 nM (86 ng / mL). The relative lack of binding affinity of viberon for the potent in vitro agonist activity at the human β 3 -AR is related to the relative ability of the compound to compete for unbound receptor-versus-bound receptor (both of which would be measured by an antagonist binding assay). Furthermore, this compound does not bind to either β 1 -AR or β 2 -AR, confirming that this compound is neither an agonist nor an antagonist of these receptors.

[0103] Absorption, Distribution, Metabolism, and Excretion Viberon reaches its maximum plasma concentration (C max ) approximately 1 to 3 hours after oral administration in healthy subjects. The mean C max and AUC increase more than proportionally to the dose up to 400 mg. The steady-state concentration was obtained within 7 days of once-daily dosing of viberon. The geometric mean accumulation ratio of the steady-state AUC was approximately 2 in young male subjects and approximately 2.8 in elderly subjects (male and female). Viberon exposure in young Japanese male subjects increased moderately (<2-fold) after single-dose administration compared to exposure in young non-Japanese male subjects.

[0104] Administration of 150 mg viberon in repeated oral doses with food in healthy middle-aged and elderly women resulted in mean AUC 0-24 and C max values that were approximately 42% and 59% on day 1 and approximately 20% and 43% on day 14 compared to the same dose in the fasting state.

[0105] In a two-part, open-label, single-dose study to investigate 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 to human plasma proteins (approximately 49%).

[0106] Vibegron is excreted by various routes, including urinary excretion, biliary excretion, and hepatic metabolism. CYP3A4 is the major CYP responsible for in vitro metabolism, but metabolism appears to play only a minor role in the elimination of vibegron. In a mass balance study in healthy subjects, the majority of the recovered dose was excreted as unchanged vibegron. The mean total recovery rate of radioactivity in the excreta was 79%, and approximately 59% and 20% of this dose were recovered in feces and urine, respectively.

[0107] The majority of the vibegron dose was found to be 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 Figure 2). Metabolite M7 is an O-glucuronide conjugate of vibegron. The concentration of radioactivity from 14 C] vibegron in plasma had a mean C max of 0.3 μM and a T max of 2.5 hours. The radioactivity profiles of plasma samples at 2 and 4 hours showed that approximately 78% and approximately 73% of the plasma radioactivity, respectively, was accounted for by unchanged vibegron, and that O-glucuronide (M7) was the major circulating metabolite (approximately 12 - 14% of the total circulating drug-related substances). Two additional minor oxidative metabolites, M4 (4 - 6%) and M17 (6 - 7%), were also detected in human plasma. The radioactivity in plasma samples at other time points beyond 4 hours after dosing was too low to profile. Thanks to sufficient data from subsequent time points that enabled estimation of the half-life, the potential for accumulation of circulating metabolites in plasma was not assumed.

[0108] Vibegron has a terminal phase half-life t of 59 to 94 hours in both young and elderly subjects. 1 / 2 In the steady state, the mean renal clearance (CLR) in young men ranged from 150 to 187 mL / min over all dose levels, whereas the CLR in elderly subjects (men and women) was somewhat lower, at 127 mL / min. With increasing dose, there was a tendency for the proportion of the dose excreted at steady state (fe 0-24hr ,ss) to increase, which reflects an increase in bioavailability with increasing dose. fe 0-24hr ,ss was similar in young men and the elderly, being approximately 14% at 100 and 150 mg in young men and approximately 17% at 100 mg in elderly subjects. The mean fe 0-24hr and CL R in young Japanese subjects were similar to those observed in non-Japanese subjects.

Example

[0109] Example 1 Vibegron tablet formulation The composition of vibegron tablets (50 mg, 75 mg, and 100 mg) is shown in Table 1.

[0110]

Table 1

[0111] Example 2 Pharmacokinetic data 2.1 Single-dose pharmacokinetics The single-dose pharmacokinetics of vibegron were investigated in two double-blind, randomized, placebo-controlled, single-dose escalating oral administration Phase 1 studies. All subjects were healthy adults. A summary of the results is shown in Table 2. After single oral administration of vibegron in the range of 2 to 600 mg, mean t max occurred from 0.8 to 3 hours post-dose. The terminal phase elimination half-life t 1 / 2For all doses from 10 to 600 mg in healthy young male subjects, the mean was 43 to 75 hours. Total body exposure was greater than proportional to the dose up to 600 mg.

[0112] Vibegron exposure in young Japanese men was moderately increased compared to exposure in young non-Japanese men. The geometric mean ratio (GMR; Japanese / non-Japanese) and corresponding 90% CI for vibegron AUC 0-inf decreased from 1.75 (1.38, 2.23) at 10 mg to 1.17 (0.99, 1.40) at 300 mg with increasing dose. The GMR (Japanese / non-Japanese) and 90% CI for vibegron C max appeared to be unaffected by dose and were 1.75 (1.35, 2.26) (pooled) across all doses. The median T max value (1 to 3 hours) and the estimated harmonic mean apparent terminal phase half-life t 1 / 2 (58 to 71 hours) in Japanese subjects were similar to those in non-Japanese subjects. Similar to non-Japanese subjects, AUC 0-inf and C max in Japanese subjects appeared to increase more than proportional to the dose up to 300 mg.

[0113] The pharmacokinetics of a single dose of 50 mg vibegron in elderly non-Japanese male and female subjects are also shown in Table 2. In elderly male and female subjects, the mean AUC 0-inf and C max after administration of 50 mg vibegron were approximately 70% and 60% higher, respectively, than the corresponding values after 50 mg in young men. T max was similar to that observed in young men (T max median = 1.0 hour), but the apparent terminal phase half-life t 1 / 2 was slightly longer in the elderly than in the young (harmonic mean t 1 / 2 = 92 hours vs 52 hours). Vibegron exposure in elderly women was somewhat higher than in elderly men.

[0114]

Table 2

[0115] 2.2 Repeated-dose pharmacokinetics The repeated-dose pharmacokinetics of vibegron were investigated in two randomized, double-blind, placebo-controlled, escalating repeated-dose Phase 1 studies in healthy non-Japanese young male subjects, middle-aged male and female subjects, and elderly male and female subjects, and also in healthy Japanese young male subjects, and elderly male and female subjects. Non-Japanese subjects received repeated doses ranging from 25 to 400 mg for 7 to 28 days, while Japanese subjects received repeated doses of 50 to 200 mg for 14 days. The pharmacokinetic results 14 days after dosing are summarized in Table 3.

[0116] On average, females tended to have approximately 50% higher exposure (AUC) compared to males, regardless of age. The steady-state AUC and C max values after QD dosing of 100 mg vibegron in elderly subjects were approximately 1.7-fold and 1.3-fold higher, respectively, compared to young males.

[0117] GM C max and AUC accumulation ratios were 1.78 and 1.84 for Japanese subjects at the 200 mg dose level. On average, the steady-state exposure in young male Japanese subjects was approximately 30% higher than that in young male non-Japanese subjects; the difference in exposure was statistically significant. The GMR (Japanese / non-Japanese) of vibegron AUC and C max (pooled across doses) and the corresponding 90% CI were 1.27 (1.09, 1.48) and 1.33 (1.06, 1.67), respectively.

[0118] On average, the steady-state exposure on Day 14 in elderly male and female Japanese subjects was 35% higher than that in elderly male and female non-Japanese subjects; the difference in exposure was statistically significant. The vibegron AUC 0-24 and C maxOn the 14th day, the GMR (Japanese / non-Japanese) and the corresponding 90% CI were 1.35 (1.09, 1.68) and 1.82 (1.32, 2.51), respectively.

[0119]

Table 3

[0120] 2.3 Bioavailability and Bioequivalence Five Phase I studies were conducted using the capsule formulation of vibegron, while seven Phase I studies and one Phase 2b study used the tablet formulation. The pharmacokinetics of a single-dose of vibegron capsule (1×150mg capsule) and tablet (3×50mg tablet) formulations were compared in a non-blind, randomized, two-period, crossover PK study in healthy male subjects aged 18 to 45 years.

[0121] The tablet formulation provided exposure comparable to the capsule formulation, as shown in Table 4. T max and the apparent terminal-phase half-life t 1 / 2 were also similar between the two formulations.

[0122]

Table 4

[0123] The relative bioequivalence of two tablets with slightly different compositions: aqueous tablets (test) and non-aqueous tablets (reference) was evaluated in a non-blind, single-dose, randomized, two-period, two-treatment, two-sequence, crossover Phase I study.

[0124]

Table 5

[0125] 2.4 Effect of Food on Oral Absorption The effect of food on the pharmacokinetics of a single 50 mg dose of vibegron was evaluated in healthy young non-Japanese and Japanese men in two randomized, double-blind, placebo-controlled, dose-escalating single-dose Phase 1 studies, whereas the effect of food on the pharmacokinetics of repeated doses of 150 mg of vibegron in middle-aged women was evaluated in a randomized, double-blind, placebo-controlled, dose-escalating repeated-dose Phase 1 study. An overview of the pharmacokinetic results is listed in Table 6.

[0126] Administration of 50 mg of vibegron with a high-fat meal in young non-Japanese men resulted in a 46% and 67% decrease in AUC 0-inf and C max respectively, and a delay in T max of approximately 1 hour compared to administration in the fasting state. Administration of 50 mg of vibegron to young Japanese men with a standard Japanese breakfast resulted in a decrease in AUC 0-inf and C max of 37% and 52% respectively, which was almost the same as the results in non-Japanese male subjects administered the same dose with a high-fat meal.

[0127] Repeated oral administration of 150 mg of vibegron with food in healthy middle-aged women resulted in a 20% and 47% decrease in mean AUC 0-24hr and C max respectively on day 14 compared to the same dose in the fasting state. T max at steady state was delayed in the fed state compared to the fasting state (6.0 hours versus 2.0 hours).

[0128]

Table 6

[0129] 2.5 Pharmacokinetics in the target disease population In patients with OAB, trough concentrations (C troughonly trough were measured; the mean (±SD) C trough for vibegron 50 mg and 100 mg QD was 27.4 (±18.3) ng / mL and 73.6 (±65.5) ng / mL, respectively. The mean (±SD) C trough for 50 mg of vibegron in healthy young men was 15.2 (±5.07) ng / mL. The mean (±SD) C

[0130] Example 3 Pharmacokinetics in Special Populations 3.1 Effect of Age Vibegron exposure was evaluated in young (18 to 45 years), middle-aged (46 to 64 years), and elderly (65 to 85 years) men and women. Exposure was similar in middle-aged men compared to young men, but plasma concentrations were higher in the elderly compared to middle-aged and young subjects. After a single 50 mg dose, vibegron AUC 0-inf and C max were 70% and 60% higher, respectively, in the elderly compared to young subjects. The elimination half-life t 1 / 2 was longer in the elderly at the 92-hour time point compared to 52 hours in young subjects in a randomized, double-blind, placebo-controlled, dose-escalating single-dose study. The steady-state vibegron AUC 0-24h and C max values were approximately 1.7-fold and approximately 1.3-fold greater in the elderly compared to young men in a randomized, double-blind, placebo-controlled, dose-escalating repeated-dose study. Furthermore, the geometric mean accumulation ratio of steady-state AUC was approximately 2 in young men and approximately 2.8 in the elderly. In elderly Japanese, AUC 0-24 and C max were increased by approximately 35% and 82%, respectively, compared to elderly non-Japanese.

[0131] 3.2 Effect of Gender The effect of gender on steady-state vibegron exposure after administration of 100 or 150 mg was evaluated in a randomized, double-blind, placebo-controlled, escalating-dose repeated-dose study. The concentration of vibegron in plasma was similar in middle-aged men compared to young men; however, exposure was slightly higher in middle-aged women compared to middle-aged men (steady-state AUC approximately 1.5-fold higher in middle-aged women), which was also observed when comparing exposure in elderly women to that in elderly men.

[0132] 3.3 Effect of Renal Dysfunction The pharmacokinetics of a single 100 mg dose of vibegron in 24 patients with renal dysfunction (8 severe, 8 moderate, and 8 mild) were compared to 8 healthy control subjects in an open-label, single-dose PK study. An overview of the pharmacokinetic parameters and the statistical comparisons between patients with various degrees of renal dysfunction and their healthy counterparts are shown in Table 7.

[0133] Mild (eGFR ≥60 to <90 mL / min / 1.73 m 2 ), moderate (eGFR ≥30 to <60 mL / min / 1.73 m 2 ), and severe (eGFR <30 mL / min / 1.73 m 2 but not on dialysis) vibegron AUC in patients with renal dysfunction 0-inf was 49%, 106%, and 83% higher, respectively, compared to healthy counterparts. Vibegron C max in mild, moderate, and severe renal dysfunction patients was 96%, 68%, and 42% higher, respectively, compared to healthy counterparts. Overall, an increase in the degree of renal dysfunction was associated with an increase in vibegron AUC 0-inf , but no clear trend was observed for C max . Decreased renal function was associated with lower clearance. The relationship between clearance and renal function was modeled using linear regression. Based on the slope from the regression, CL / F was 1 mL / min / 1.73 m of eGFR 2It was found to increase by approximately 0.8% with the increase of . Based on this linear relationship, the CL / F ratios for the mild, moderate, and severe groups for healthy subjects were 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. Similar results were obtained by modeling the relationship between CL / F and creatinine clearance. Renal clearance (CLR) and the percentage of the dose excreted in urine over a 48-hour collection period (fe[urine]48hr) decreased with the increase in the degree of renal impairment. Patients with mild, moderate, and severe renal impairment had a 39%, 65%, and 82% decrease in CLR, respectively, compared to healthy control subjects. fe[urine]48hr was equivalent between mild renal impairment patients (8.5%) and healthy control subjects (7.9%), and was 5.5% and 2.1% in moderate and severe renal impairment patients, respectively.

[0134]

Table 7

[0135] 3.4 Influence of liver impairment The pharmacokinetics of a single dose of 100 mg of vibegron were evaluated in a two-part, open-label, single-dose phase 1 study in 8 patients with moderate liver impairment (Child-Pugh Score of 7 to 9) and 8 healthy subjects matched for age, sex, and BMI. The statistical comparison of vibegron pharmacokinetic parameters is shown in Table 8. The AUC 0-inf and C max GMR (90% CI) were 1.27 (0.96, 1.67) and 1.35 (0.88, 2.06), respectively, suggesting that moderate liver impairment did not have a clinically significant impact on the exposure of vibegron.

[0136]

Table 8

[0137] 3.5 Drug Interaction Studies Four drug interaction studies were conducted to evaluate vibegron in combination with six compounds. Table 9 summarizes the effects of ketoconazole, diltiazem, or tolterodine on the pharmacokinetics of vibegron. Table 10 summarizes the effects of vibegron on the pharmacokinetics of digoxin, ethinyl estradiol, levonorgestrel, or tolterodine.

[0138] The repeated administrations of the potent CYP3A4 / P-gp inhibitor, ketoconazole 200 mg, and the moderate CYP3A4 / P-gp inhibitor, diltiazem 240 mg, were evaluated in combination with a single dose of vibegron 100 mg. GM vibegron AUC 0-inf and C max were increased 2.08- and 2.22-fold, respectively, in the presence of repeated administration of 200 mg ketoconazole. GM vibegron AUC 0-inf and C max were increased 63% and 68%, respectively, in the presence of repeated administration of 240 mg or 180 mg diltiazem. GM t 1 / 2 was 75, 75.4, and 80.2 hours when vibegron was administered alone, with diltiazem, or with ketoconazole, respectively. The lack of increase in vibegron t 1 / 2 in the presence of ketoconazole or diltiazem suggests that the interaction occurred primarily at the absorption stage. However, these interactions were not considered clinically significant. Tolterodine ER 4 mg had no effect on the pharmacokinetics of vibegron.

[0139] The repeated administration of vibegron was evaluated in combination with the p-gp substrate, digoxin. The AUC of digoxin when co-administered with vibegron 0-infThe 90% CI for GMR for bivaglurant was within the range of 80 - 125% bioequivalence, suggesting that bivaglurant did not affect digoxin pharmacokinetics 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 dosing of bivaglurant. The AUC and C max The 90% CI for GMR (EE / LNG + bivaglurant vs EE / LNG alone) for EE was within 0.8 and 1.25. The AUC and C max for LNG increased by 18 - 21% in the presence of repeated dosing of bivaglurant, but these increases were not considered clinically significant. No clinically meaningful pharmacokinetic interactions occurred when bivaglurant 100 mg or 150 mg was co-administered with tordivel ER 4 mg.

[0140]

Table 9

[0141]

Table 10

[0142] 3.6 Effect on QT interval prolongation The effect of bivaglurant on the QTc interval was evaluated in a single oral dose study. Fifty-two healthy subjects received a single dose of 400 mg bivaglurant, a single dose of 200 mg bivaglurant, a single dose of 400 mg moxifloxacin, and a single dose of bivaglurant with corresponding placebo.

[0143] Vibegron at a dose of 400 mg resulted in a maximum LS mean difference (90% CI) from placebo of 4.60 (2.71, 6.48) milliseconds in QTcF at 1 hour after dosing. Similar results were recorded in QTcF after a single 200 mg dose, where the maximum LS mean difference (90% CI) from placebo was 4.98 (3.07, 6.88) milliseconds at 1 hour after dosing. The upper limit of the 90% CI for all mean differences was below the 10 millisecond target (Table 11). A statistically significant effect of moxifloxacin on QTcF was observed.

[0144] GM (CV%) C obtained after a single 200 mg dose max and AUC 0-23.5hr were 366 (50.4) ng / mL and 2270 (37.3) ng·h / mL, respectively. Vibegron C max was 1.63 times the values obtained in elderly subjects receiving repeated doses of 100 mg in a double-blind, randomized, placebo-controlled, crossover (Panels A and B), multiple-period, single-dose escalating oral administration Phase 1 study, although the AUC was approximately the same. GM (CV%) C max and AUC 0-23.5hr obtained after a single 400 mg dose were 1020 (39.9) ng / mL and 6450 (34.0) ng·h / mL, respectively. These C max and AUC 0-23.5hr values were 4.55 times and 2.89 times the values obtained in elderly subjects receiving repeated doses of 100 mg of vibegron.

[0145] Target PK exposure was achieved at both the 200 mg and 400 mg dose levels. Steady-state C max and AUC 0-24hr values obtained in elderly female subjects at the maximum clinical dose of 100 mg were 278 ng / mL and 2620 ng·h / mL, respectively.

[0146]

Table 11

[0147] Example 4 Clinical efficacy data A randomized, double-blind, placebo-controlled and active-controlled, parallel-group, two-part Phase 2b study of vibegron in men and women with OAB (stratified as OAB wet and OAB dry) was completed. Part 1 was a dose-ranging study to evaluate the safety, tolerability, and efficacy of vibegron, as well as a proof-of-concept study for co-administration with tolterodine ER 4 mg of vibegron. Approximately 980 subjects in Part 1 were randomized equally in a double-blind fashion to one of seven treatment arms: vibegron 3 mg, 15 mg, 50 mg, 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 followed by vibegron 50 mg for 4 weeks. Part 2 was designed to continue to evaluate the safety and efficacy of co-administration. In Part 2, 408 subjects were randomized in a double-blind fashion to one of four treatment arms 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 option to enroll in a 1-year extension. Participants were asked to keep a voiding diary recording the occurrence of each strong urgency, total incontinence, and urgency incontinence episode. The efficacy data for Part 1 and Part 2 are presented together here.

[0148] At baseline, the subject must have an average number of urinations per day of ≥8 in the urination diary. Furthermore, subjects in the OAB wet stratum must have an average number of urge incontinence episodes of ≥1 per day in the diary. Subjects in the OAB dry stratum must have an average number of urgency episodes of ≥3 per day in the diary and an average of <1 urge incontinence episode per day in the diary. For all subjects, the total number of urge incontinence episodes must not exceed the total number of stress incontinence episodes.

[0149] The primary objectives of this study were to evaluate the safety and tolerability of treatment with selected vibegron doses (alone or in combination with tolterodine) and to examine the dose-related decrease in the average number of urinations per day compared to placebo at Week 8.

[0150] In Part 1, a statistically significant decrease in the average number of urinations per day was observed at Week 8 in the vibegron 100 mg and 50 mg treatment groups compared to the placebo group. Statistically significant decreases from baseline compared to placebo were also observed in the vibegron 100 mg and 50 mg treatment groups for secondary evaluation items that included urge incontinence and total urinary incontinence (in subjects with OAB wet), and urgency episodes in all subjects. Statistically significant increases from baseline compared to placebo were also observed for the secondary evaluation item: single voided volume, in the vibegron 15, 50, and 100 mg treatment groups. (Tables 12 and 13).

[0151]

Table 12

[0152]

Table 13

[0153] A double-blind, randomized, placebo-controlled, multi-center, Phase 3 study designed to evaluate the safety and efficacy of vibegron in men and women with OAB was completed. At the end of the placebo run-in period, 1,232 patients were randomized to receive 12 weeks of blinded study treatment with vibegron 50 mg (N = 370), vibegron 100 mg (N = 369), placebo (N = 369), or imidaphenacine 0.2 mg (comparator; N = 117). These results indicate that once-daily vibegron resulted in a statistically significant reduction in efficacy parameters, including micturition, UUI episodes, total incontinence episodes, and urgency episodes (Table 14).

[0154]

Table 14

[0155] Example 5 Safety data 5.1 Phase I safety data Safety data from 16 Phase I studies, including 15 completed Phase I studies and 1 study that was terminated early (this study was terminated for reasons unrelated to efficacy or safety), were collected. In the Phase I 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 repeated doses ranging from 25 to 400 mg for up to 28 days. Over the Phase I program, vibegron generally demonstrated good tolerability. No treatment-emergent serious adverse events (SAEs) or deaths were reported, and most adverse events (AEs) were transient and mild or moderate in intensity.

[0156] In the first-phase study, the occurrence of orthostatic hypotension (a decrease in systolic blood pressure > 20 mmHg and / or a decrease in diastolic blood pressure > 10 mmHg) was observed, with or without symptoms (such as dizziness, vertigo, pre-syncope). 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 these AEs after administration of vibegron or tolterodine alone. At doses up to 100 mg in the first-phase repeat-dose study, AEs such as orthostatic vertigo, vertigo, pre-syncope, or syncope did not exhibit an obvious dose-response relationship. However, orthostatic vertigo appeared to increase at doses of 100 mg and above, and the incidence of the AE "orthostatic hypotension with symptoms" tended to be higher at vibegron doses > 200 mg. When vibegron 100 mg was co-administered to subjects with essential hypertension in a stable regimen with either metoprolol (a typical β-blocker) or amlodipine (a typical vasodilator), no orthostatic AEs occurred.

[0157] Evaluation of preliminary first-phase safety data showed no clinically significant changes in laboratory safety parameters (chemistry, hematology, and urine analysis) or ECG parameters (including PR, QRS, and QTc intervals). A thorough QT study was completed, and no clinically significant effects on QTc or blood pressure were seen.

[0158] 5.2 Phase II safety data Phase 2 safety data were collected from a single completed Phase 2B study in which 933 subjects received at least one dose of vibegron. Subjects received vibegron (alone or in combination with turtelazin) at doses ranging from 3 to 100 mg for up to 8 weeks during the main study. Of those who completed the parent study, 605 subjects received vibegron 50 mg (alone) or vibegron 100 mg (alone or in combination with 4 mg turtelazin) for up to 52 weeks during the extension study. The main study included a placebo group, and the main study and extension included groups receiving turtelazin monotherapy. No deaths were reported during the study. Vibegron generally showed good tolerability. No significant differences in the overall incidence or severity of AEs or drug-related AEs were observed between the treatment groups compared to placebo.

[0159] Adverse events were reported in 607 (43.6%) of 1393 assigned subjects 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). Higher proportions of subjects reported one or more AEs in the vibegron 15 mg and vibegron 50 mg + 4 mg turtelazin treatment groups compared to placebo. The most frequently reported AEs were dry mouth, headache, urinary tract infection (UTI), and nasopharyngitis. The incidence of dry mouth was higher in groups receiving turtelazin (alone or with vibegron) compared to the placebo or vibegron monotherapy groups.

[0160] There were 221 subjects with drug-related AEs, and the lowest incidence of drug-related AEs was reported in the vibegron 100 mg treatment group. The proportion of subjects with drug-related AEs was approximately the same in the vibegron monotherapy groups compared to placebo, and slightly higher in the combination treatment groups compared to placebo or either monotherapy. The proportion of subjects discontinued due to drug-related AEs was low and similar across all treatment groups.

[0161] In 8 subjects, a total of 9 SAEs occurred across the treatment groups (2 in placebo; 1 in vibegron 3 mg; 1 in vibegron 50 mg; 3 in tolterodine 4 mg; 1 in vibegron 50 mg + tolterodine 4 mg). The reported SAEs were atrial fibrillation, anaphylactic reaction, lung adenocarcinoma (stage IV), chronic obstructive pulmonary disease, hypertension, overdose, and foot fracture. In one subject, both gastroesophageal reflux disease and dizziness occurred after an endoscopic pancreatic procedure, prolonging hospitalization. No specific AE terms were reported in more than one subject. All SAEs were considered by the investigator to be unrelated to the study drug.

[0162] During the 52-week extension, no significant differences in the overall incidence of adverse events or serious adverse events were observed between the treatment groups.

[0163] Adverse events were reported in 531 of 845 subjects (62.8%). The proportion of subjects with one or more AEs was approximately the same across all treatment groups. The most frequently reported adverse events were 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 to the other treatment groups. The incidence of constipation was higher in the combination treatment group compared to the monotherapy treatment groups.

[0164] The proportion of subjects with drug-related AEs was slightly higher for tolterodine ER 4 mg and the combination arm compared to the vibegron 50 mg and 100 mg treatment arms. The proportion of subjects discontinued due to an AE or drug-related AE was slightly higher for tolterodine ER 4 mg compared to the other treatment groups. In 41 subjects during the extension, a total of 46 SAEs were reported. Higher overall incidences were reported in the tolterodine ER 4 mg and vibegron 50 mg treatment groups compared to the vibegron 100 mg treatment group. One drug-related SAE of paralytic ileus was reported in the tolterodine ER 4 mg treatment group; the subject discontinued due to this AE.

[0165] Table 15 below summarizes the adverse events commonly seen in the second-phase program of vibegron in patients with overactive bladder.

[0166] [Table 15]

[0167] Serious adverse events observed during the first 12 weeks of treatment with vibegron monotherapy included adenocarcinoma of the lung (stage IV) (n = 1) and chronic obstructive pulmonary disease (n = 1); in the vibegron-toltrazine combination arm, a SAE of overdose was reported. During the second-phase extension study, SAEs reported by two or more subjects receiving monotherapy included cerebrovascular attack (n = 2) and osteoarthritis (n = 2). The only SAE reported in the vibegron-toltrazine combination arm was Borrelia infection. SAEs potentially related to changes in heart rate or blood pressure (at any point during treatment) included loss of consciousness 8 weeks after vibegron (which did not recur upon re-dosing) (n = 1), as well as atrial fibrillation (n = 1) and dizziness (n = 1) in the toltrazine monotherapy arm. The frequency of injuries was numerically higher in the toltrazine arm than with vibegron (2.1%, n = 5 vs. 0.9%, n = 4). Considering the low incidence and lack of pattern of SAEs, serious events are not considered to be predicted for vibegron.

[0168] Based on non-clinical data and available data on similar compounds, the potential risks that may be associated with vibegron treatment include orthostatic hypotension and increased exposure (about two-fold) in patients taking a potent P-gp inducer concomitantly.

[0169] 5.3 Cardiovascular safety The cardiovascular safety of vibegron was evaluated in patients with OAB and healthy volunteers. In a two-part efficacy and safety study with randomization, placebo control, and comparator (tolterodine) active control with a 52-week extension, 7 orthostatic-related AEs (including the adverse event terms postural dizziness, pre-syncope, and orthostatic hypotension) occurred in 6 subjects (0.4%). These events occurred in 1 subject each in the placebo group (0.5%), the vibegron 15 mg group (0.3%), and the vibegron 50 mg + tolterodine ER / vibegron 50 mg treatment group (0.8%), and in 3 subjects in the vibegron 100 mg group (1.1%). These events occurred sporadically throughout the study and were judged by the investigator to be of mild severity. None caused discontinuation. The overall incidence of orthostatic symptoms was low.

[0170] Changes from baseline in BP and HR across treatment groups are shown in Table 16. For systolic blood pressure (SBP) and diastolic blood pressure (DBP), the mean change at week 1 and mean maximum change over 8 weeks for 50 mg and 100 mg were equivalent between placebo and vibegron, with differences <1 mmHg. The absolute changes in SBP and DBP were also similar between placebo and vibegron, with the percentage of vibegron subjects increasing slightly at 100 mg, with a change from baseline of DBP >15 mmHg (1.3% for 100 mg vs 0.5% for placebo). For HR, no dose-dependent pattern was detected as the mean maximum change over 8 weeks was comparable to placebo (<2 bpm). The slight differences in the percentage of subjects exceeding the absolute heart rate and blood pressure thresholds for vibegron were similar to the tolterodine arm.

[0171]

Table 16

[0172] A more thorough evaluation of heart rate and blood pressure was conducted in several Phase 1 studies in healthy volunteers. A six-part, double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, and repeated-dose PK of vibegron in healthy subjects included a specific analysis of heart rate. 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 interval of the maximum change from baseline in the moving average of heart rate over 4 hours post-dose (MA4 HR) are shown in Table 17. The effect on heart rate was dose-dependent, and the 100 mg dose showed a <1 bpm difference from placebo.

[0173]

Table 17

[0174] Cardiovascular safety was also evaluated in healthy volunteers in a detailed QT study after single doses of 200 and 400 mg, approximating the steady-state exposure of vibegron at 100 mg and 200 mg, respectively. The mean of the maximum effects on blood pressure and RR interval decreased at lower doses, as shown in Table 18. Using log-log regression analysis from repeated-dose vibegron exposure (from three Phase 1 studies), the calculated mean ± standard deviation C max and AUC from the 75 mg dose were 120 ± 74.7 ng / mL and 1140 ± 476 ng·h / mL, respectively. These estimates were approximately 3.3-fold and 2-fold lower than after a single 200 mg dose and 9.2-fold and 6-fold lower than after a single 400 mg dose, respectively, for C max and AUC.

[0175]

Table 18

[0176] Example 6 Dose Selection 6.1 Dose-Comparative Efficacy As shown in Table 19, the second-phase study discussed in Example 4 demonstrated a dose-dependent effect on urination. Conversely, no dose-dependent effect on urge incontinence or total urinary incontinence was observed. These data reveal a relatively shallow dose-response relationship between 50 mg and 100 mg (once daily). Since vibegron efficacy begins to reach a plateau at 50 to 100 mg, at 75 mg, most of the efficacy obtained at 100 mg is achieved.

[0177]

Table 19

[0178] 6.2 Reduction of Side Effects Vibegron shows an increase in exposure greater than proportional to the dose. Surprisingly, an increase in dose from 50 to 100 mg results in an approximately three-fold increase in the PK parameter C, which is considered to be most closely related to cardiovascular effects. To explain the PK parameters of the 75 mg dose, data from the first-phase study were used to create dose-C max and dose-AUC models. Based on simulations, administration of 75 mg of vibegron was found to prevent approximately 29% of the exposure observed at the 100 mg dose and subsequently reduce the upper limit of the exposure range that could be obtained at the 100 mg dose. This unexpected decrease in C max values reduces the likelihood of clinically relevant cardiovascular effects. max

[0179] In the first-phase repeated-dose study at doses up to 100 mg maximum, adverse events such as orthostatic dizziness, dizziness, pre-syncope, and syncope did not exhibit a clear dose-response relationship. However, orthostatic dizziness appeared to increase at doses ≥ 100 mg, and the incidence of the adverse event "orthostatic hypotension with symptoms" was higher at vibegron doses exceeding 150 mg. The risk of these dose-related adverse events can be disproportionately reduced by decreasing the dose from 100 mg to 75 mg. Because a 25% decrease in dose results in a decrease in C maxThis is because it results in an approximate 40% decrease (from 206 ng / mL at 100 mg to 120 ng / mL at 75 mg). Although it is not desirable to be restricted by theory, the increase in bioavailability that is greater than proportional to the dose with the increase in dose may be due to the efflux mediated by saturable P-glycoprotein (P-gp) in the intestine.

[0180] Compared with the 100 mg dose, the lower exposure at the 75 mg dose also proportionally reduces the risk of adverse events in special populations. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared with subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Assuming a two-fold increase in C max at the 75 mg dose, the probability that these special populations will achieve a C of vibegron that exceeds that observed at 100 mg is 15% (see Figure 1). Minimizing and reducing the exposure of subjects to the limit is important for the elderly and women, who show approximately 50-70% higher C max than healthy young men. max

[0181] Example 7 Pharmacokinetic data for the 75 mg dose A pharmacokinetic study was completed to evaluate the drug interaction between vibegron and rifampin. All subjects were healthy adults. An overview of the preliminary results is shown in Table 20. Subjects received a single dose of 75 mg of vibegron on Day 1, 600 mg of rifampin QD from Day 10 to Day 23, and a single dose of 75 mg of vibegron on Day 17 simultaneously with the administration of rifampin. The administration of vibegron and rifampin showed good tolerance in healthy male and female subjects. No severe TEAEs, SAEs, or deaths were reported during the study. Three out of 20 subjects (15%) experienced AEs related to the study drug, namely 2 cases of headache and 1 case of constipation, all of which were mild. No clinically significant changes or results were observed in the evaluation by vital signs, ECG, or clinical tests.

[0182] ​

Table 20

[0183] Now, the present invention has been fully described, and it will be understood by those skilled in the art that the same can be practiced within a wide range of equivalent conditions, formulations, and other parameters without affecting the scope of the present invention or any of its embodiments.

[0184] Other embodiments of the present invention will be apparent to those skilled in the art from a consideration of this specification and the practice of the invention disclosed herein. This specification and the examples are to be considered as illustrative only, and it is intended that the true scope and spirit of the present invention be indicated by the following claims.

[0185] The entire contents of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety.

Claims

**Claim 1**: A pharmaceutical composition for oral administration for treating overactive bladder by administering to a human in need of treatment for overactive bladder, comprising vibegron or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition contains 75 mg ± 10% of vibegron or a pharmaceutically acceptable salt thereof, said pharmaceutical composition. **Claim 2**: The pharmaceutical composition according to claim 1, wherein the human has one or more symptoms selected from urge urinary incontinence (UUI), urinary urgency, frequency of urination, or combinations thereof. **Claim 3**: The pharmaceutical composition according to claim 2, wherein the human has symptoms of urge urinary incontinence (UUI), urinary urgency, and frequency of urination. **Claim 4**: The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is for once-daily administration. **Claim 5**: The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is for administration with food. **Claim 6**: The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is for administration without food. **Claim 7**: The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is a tablet. **Claim 8**: The pharmaceutical composition according to claim 7, wherein the tablet is crushed. **Claim 9**: The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is effective for treating overactive bladder in 4 weeks, 3 weeks, or 2 weeks. **Claim 10**: The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition is effective for treating overactive bladder in 2 weeks. **Claim 11**: The pharmaceutical composition according to claim 1, wherein the human is female. **Claim 12**: The pharmaceutical composition according to claim 1, wherein the human is male. **Claim 13**: The pharmaceutical composition according to any one of claims 1 to 12, wherein the human suffers from severe renal impairment. **Claim 14**: The pharmaceutical composition according to any one of claims 1 to 12, wherein the human suffers from moderate renal impairment. **Claim 15**: The pharmaceutical composition according to any one of claims 1 to 14, wherein the human is co-administered a CYP3A / P-glycoprotein inhibitor. **Claim 16**: The pharmaceutical composition according to any one of claims 1 to 15, wherein the human is simultaneously receiving a CYP2D6 substrate, a CYP2C9 substrate, a CYP3A inhibitor, a P-glycoprotein inhibitor, an oral contraceptive, or combinations thereof.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition comprises a pharmaceutically acceptable salt of vibegron.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the composition produces, in the human, an average change in systolic blood pressure from baseline over a treatment period, and the average change in the human is less than 1 mmHg from the average change in a human taking a placebo.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the percentage of humans in whom the composition experiences an average change in systolic blood pressure of 15 mmHg or more from baseline over a treatment period is 1.3%.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the composition produces, in the human, an average change in diastolic blood pressure from baseline over a treatment period, and the average change in the human is less than 1 mmHg from the average change in a human taking a placebo.

21. The pharmaceutical composition according to any one of claims 1 to 19, wherein the composition produces, in the human, an average change in diastolic blood pressure from baseline over a treatment period, and the average change is less than 5 mmHg.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the composition produces, in the human, a change of -1.5 to -2.1 in the average number of urinations per 24 hours from baseline over a treatment period.

23. The pharmaceutical composition according to any one of claims 1 to 21, wherein the composition produces a difference of -0.4 to -0.8 from placebo in the average number of urinations per 24 hours in the human over a treatment period.

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the human has at least one urgency urinary incontinence (UUI) episode per day before treatment, and the composition produces, in the human, a change of -1.8 to -2.3 in the average number of UUI episodes from baseline over a treatment period. **Claim 25**: The pharmaceutical composition according to any one of claims 1 to 24, wherein the human has at least one urgency urinary incontinence (UUI) episode per day on average before treatment, and the composition causes a difference of -0.3 to -0.9 from placebo in the average number of UUI episodes in the human over the treatment period. **Claim 26** The pharmaceutical composition according to any one of claims 1 to 25, wherein the composition causes a change of -2.0 to -2.3 from baseline in the average number of total incontinence episodes in the human over the treatment period. **Claim 27** The pharmaceutical composition according to any one of claims 1 to 26, wherein the composition causes a difference of 20 mL to 28 mL from placebo in the increase in urine volume per micturition in the human over the treatment period. **Claim 28**: The pharmaceutical composition according to any one of claims 1 to 27, wherein the composition is for a treatment period selected from the group consisting of 2, 4, 6, 8, 12, and 52 weeks. **Claim 29** An oral pharmaceutical composition for treating overactive bladder by administering to a human in need of treatment for overactive bladder, comprising vibegron at 75 mg ± 10% as an active ingredient, which provides an area under the curve (AUC) of 1140 ng-hr / mL ± 476 ng·h / mL in the human after a single administration. **Claim 30** An oral pharmaceutical composition for treating overactive bladder by administering to a human in need of treatment for overactive bladder, comprising vibegron at 75 mg ± 10% as an active ingredient, which provides a Cmax of 120 ng / mL ± 74.7 ng / mL in the human after a single administration. **Claim 31**: The pharmaceutical composition according to claim 1, wherein the composition comprises vibegron at 75 mg ± 10% as an active ingredient and reduces the average number of micturitions per 24 hours in the human. **Claim 32**: The pharmaceutical composition according to claim 31, wherein the composition reduces the average number of micturitions per 24 hours in the human by -1.5 to -2.1 from baseline over the treatment period. **Claim 33**: The pharmaceutical composition according to claim 31 or 32, wherein the composition results in a difference in the average number of urinations per 24 hours from placebo in the human subject of from -0.4 to -0.8 over the treatment period. **Claim 34**: The pharmaceutical composition according to claim 1, wherein the composition comprises 75 mg ± 10% vibegron as an active ingredient and reduces the average number of UUI episodes per day in the human subject. **Claim 35**: The pharmaceutical composition according to claim 34, wherein the composition reduces the average number of UUI episodes per day in the human subject by from -1.8 to -2.3 from baseline over the treatment period. **Claim 36**: The pharmaceutical composition according to claim 34 or 35, wherein the composition results in a difference in the average number of UUI episodes from placebo in the human subject of from -0.3 to -0.9 over the treatment period. **Claim 37**: The pharmaceutical composition according to claim 1, wherein the composition comprises 75 mg ± 10% vibegron as an active ingredient and reduces the average number of total incontinence episodes per day in the human subject. **Claim 38**: The pharmaceutical composition according to claim 37, wherein the composition reduces the average number of total incontinence episodes per day in the human subject by from -2.0 to -2.3 from baseline over the treatment period. **Claim 39**: The pharmaceutical composition according to claim 1, wherein the composition comprises 75 mg ± 10% vibegron as an active ingredient and increases the urine volume (mL) per urination in the human subject. **Claim 40**: The pharmaceutical composition according to claim 39, wherein the composition increases the increase in urine volume (mL) per urination in the human subject from placebo by from 20 mL to 28 mL over the treatment period. **Claim 41**: The pharmaceutical composition according to claim 1, wherein the composition is an oral dosage unit form comprising 75 mg ± 10% vibegron. **Claim 42**: The pharmaceutical composition according to claim 41, wherein the composition in the form of the pharmaceutical unit dosage form is in the form of a tablet. **Claim 43**: The pharmaceutical composition according to claim 42, wherein the composition in the form of the pharmaceutical unit dosage form is crushed. **Claim 44**: The pharmaceutical composition according to any one of claims 41 to 43, wherein the composition in the form of the pharmaceutical unit dosage form comprises a pharmaceutically acceptable excipient.

45. The pharmaceutical composition according to claim 1, wherein the composition contains vibegron at 75 mg ± 10% as an active ingredient and is for treating nocturia in the human.

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