Vibegron for the treatment of overactive bladder

Abstract

The present disclosure is directed to a method of treating overactive bladder, comprising orally administering to a subject in need thereof an amount of vibegron from about 50 mg to about 100 mg (e.g., about 75 mg) per day. The present disclosure also provides a method of treating overactive bladder, comprising orally administering to a subject in need thereof a first dosage of vibegron per day for a first period of time, followed by a second dosage of vibegron per day.

Description

[Background technology]

[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 and periodically release urine. This requires the coordinated integration of storage and micturition reflexes involving the regulation of central and peripheral neuroeffector mechanisms and the resulting coordinated control of the sympathetic and parasympathetic components of the autonomic nervous system and somatic motor pathways. These control the contractile smooth muscle of the bladder (detrusor) and urethra, and proximally the striated muscle of the urethral sphincter.

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

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

[0004] β3-adrenergic receptor (β3-AR) activation is an effective way to relax the detrusor muscle in normal and pathological conditions. Functional evidence supporting the important role of β3-AR in urine accumulation comes from in vivo studies. β3-AR agonists have shown efficacy in relieving symptoms of OAB. To date, only one β3-AR agonist, mirabegron (Astellas Pharma Global Development, Inc.), has received marketing approval in the United States and Japan for the treatment of OAB. Mirabegron activates β3-AR in the detrusor muscle in the bladder, which results in muscle relaxation and increased bladder capacity. With mirabegron, a decrease in urination frequency, urinary incontinence, and urgency episodes, as well as an increase in the average 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 beta3-adrenergic receptor (β3-AR) agonist that exhibits >9,000-fold selectivity for activation of the beta3-AR compared to the beta2-AR and beta1-AR in cell-based in vitro assays. See Edmondson et al., J. Med. Chem. 59:609-623 (2016). [ka]

[0006] Vibegron is disclosed as a β3-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 cited publications are incorporated herein by reference in their entirety. [Brief description of the drawings]

[0007] [Figure 1] 1 shows an overlay of density plots of exposure at 100 mg and 75 mg of vibegron estimated in special populations. [Diagram 2] 1 shows the chemical structures of metabolites of vibegron. Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides a method of treating overactive bladder, comprising orally administering to a subject in need thereof a first dosage of vibegron per day for a first period of time followed by a second dosage of vibegron per day, where the second dosage is greater than the first dosage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] So that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly defined herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0010] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The term "a" (or "an"), as well as the terms "one or more" and "at least one," may be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0011] Furthermore, "and / or" as used herein should be considered as a separate disclosure of each of the two specified features or components, with or without the other. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass 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 (single); B (single); and C (single).

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0013] The term "about" as used in reference to numerical values ​​throughout this specification and claims refers to a margin of accuracy familiar and acceptable to those of ordinary skill in the art. Such margin of accuracy is ±10%.

[0014] The term "overactive bladder" generally refers to a clinical syndrome characterized by urgency to urinate, possibly accompanied by frequency and nocturia, with or without urge incontinence.

[0015] As used herein, the term "urge urinary incontinence" (UUI) means urinary incontinence accompanied by a sudden, strong need to urinate, and may be used interchangeably with "urge incontinence" or "urge incontinence." UUI is distinct from stress urinary incontinence, which is urinary incontinence during exertion or physical activity (e.g., sports activity) or when sneezing or coughing.

[0016] The term "impairment" as used herein refers to an acute or chronic impairment of function. 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 metabolic products in the blood.

[0017] As used herein, the term "urgency" means a sudden, irresistible need to urinate that is difficult to postpone.

[0018] As used herein, the term "urinary frequency" refers to the need to empty the bladder frequently.

[0019] The term "free base" as used herein 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.

[0020] As used herein, the term "OAB wet" refers to overactive bladder defined by urinary frequency and urgency accompanied by incontinence.

[0021] As used herein, the term "OAB dry" refers to overactive bladder defined by urinary frequency and urgency without incontinence.

[0022] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is safe and effective for use in a subject and that possesses the desired biological activity.

[0023] The pharma- ceutically acceptable salt of a basic compound may be a salt of an organic or inorganic acid. In some embodiments, the 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), the entirety of which is incorporated herein by reference.

[0024] As used herein, the term "C max " refers to the maximum plasma concentration of a drug after it is administered.

[0025] As used herein, the term "T max " refers to the time after administration of a drug when the maximum plasma concentration is reached.

[0026] As used herein, the term "AUC" refers to the area under the curve of a plot of plasma concentration of a drug versus time after administration.

[0027] The term "steady state" means that the amount of drug that reaches the entire body is approximately the same as the amount of drug that leaves the system. Thus, at "steady state," the patient's body eliminates the drug at approximately the same rate as the drug becomes available to the patient's entire body through absorption into the bloodstream.

[0028] The term "treatment period" refers to the period during which a drug is administered to a 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 efficacy of a drug can be evaluated by measuring certain parameters and calculating the change from baseline throughout the treatment period. Efficacy parameters include, but are not limited to, urination, urge incontinence episodes, total incontinence episodes, and urge episodes.

[0029] Treatment methods The present disclosure relates to a method for treating overactive bladder, comprising orally administering to a subject in need thereof a dosage of vibegron that maintains the desired efficacy while minimizing undesirable side effects. Unexpectedly, the choice of dosage of vibegron results in a C max The side effects associated with the increase can be disproportionally reduced.

[0030] The disclosed method can maximize the therapeutic effect of vibegron for treating overactive bladder while minimizing side effects. A physician can determine the appropriate dosage of the drug, which can vary depending on age, sex, renal function, concurrently administered drugs, and other characteristics of an individual patient. A physician can initiate treatment with a low dose, e.g., less than the optimal dose of the drug, and increase the dose by a fixed amount until the optimal effect is achieved under the circumstances.

[0031] The present disclosure provides a method of treating overactive bladder comprising orally administering to a subject a first dosage of vibegron per day for a first period of time followed by a second dosage of vibegron per day. The treatment period for assessing efficacy of vibegron may include part or all of the first period of time, may include the first period of time and a portion of the period during which the second dosage of vibegron is administered, or may include the first period of time and a second period during which vibegron is administered.

[0032] The disclosure also provides a method of increasing bladder smooth muscle relaxation comprising orally administering to a subject a first dosage of vibegron per day for a first period of time followed by a second dosage of vibegron per day. The treatment period for assessing efficacy of vibegron may include part or all of the first period of time, may include the first period of time and a portion of the period during which the second dosage of vibegron is administered, or may include the first period of time and a second period during which vibegron is administered.

[0033] In some embodiments, the second dosage of vibegron is administered per day more than the first dosage of vibegron is administered per day.

[0034] In some embodiments, the first dosage of vibegron administered per day is about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg. In some embodiments, the first dosage of vibegron administered per day is 50 mg to 75 mg per day.

[0035] In some embodiments, the first dosage 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.

[0036] In some embodiments, the first dosage of vibegron administered per day is about 50 mg. In some embodiments, the first dosage of vibegron administered per day is about 50 mg.

[0037] In some embodiments, the first dosage of vibegron administered per day is about 75 mg. In some embodiments, the first dosage of vibegron administered per day is about 75 mg.

[0038] In some embodiments, the second dosage of vibegron administered per day is about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 100 mg. In some embodiments, the second dosage of vibegron administered per day is 75 mg to 100 mg.

[0039] In some embodiments, the second dosage 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, about 95 mg, or about 100 mg.

[0040] In some embodiments, the second dosage of vibegron administered per day is about 75 mg. In some embodiments, the second dosage of vibegron administered per day is about 75 mg.

[0041] In some embodiments, the second dosage of vibegron administered per day is about 100 mg. In some embodiments, the second dosage of vibegron administered per day is about 100 mg.

[0042] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 50 mg vibegron / day for a first period of time, followed by a second dosage of about 75 mg vibegron / day.In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of 50 mg vibegron / day for a first period of time, followed by a second dosage of 75 mg vibegron / day.

[0043] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 50 mg vibegron / day for a first period of time, followed by a second dosage of about 100 mg vibegron / day. In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of 50 mg vibegron / day for a first period of time, followed by a second dosage of 100 mg vibegron / day.

[0044] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 75 mg vibegron / day for a first period of time, followed by a second dosage of about 100 mg vibegron / day. In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of 75 mg vibegron / day for a first period of time, followed by a second dosage of 100 mg vibegron / day.

[0045] In some embodiments, the first period of time is about 1 week to about 52 weeks, about 1 week to about 24 weeks, about 1 week to about 16 weeks, about 1 week to about 12 weeks, about 1 week to about 10 weeks, about 1 week to about 8 weeks, about 1 week to about 7 weeks, about 1 week to about 6 weeks, about 1 week to about 5 weeks, about 1 week to about 4 weeks, about 1 week to about 3 weeks, about 1 week to about 2 weeks. In some embodiments, the first period of time is about 52 weeks. In some embodiments, the first period of time is about 24 weeks. In some embodiments, the first period of time is about 16 weeks. In some embodiments, the first period of time is about 12 weeks. In some embodiments, the first period of time is about 8 weeks. In some embodiments, the first period of time is about 4 weeks. In some embodiments, the first period of time is about 3 weeks. In some embodiments, the first period of time is about 2 weeks. In some embodiments, the first period of time is about 1 week.

[0046] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 50 mg of vibegron / day for about 8 weeks, followed by about 75 mg of vibegron / day.

[0047] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 50 mg of vibegron / day for about 8 weeks, followed by about 100 mg of vibegron / day.

[0048] In some embodiments, the method of treating overactive bladder comprises orally administering to a subject a first dosage of about 75 mg of vibegron / day for about 8 weeks, followed by about 100 mg of vibegron / day.

[0049] In some embodiments, the subject has symptoms of urge incontinence, urgency, and frequency.

[0050] In some embodiments, the subject has one or more symptoms of urge incontinence (or urge incontinence), urgency, frequency, and nocturia.

[0051] 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.

[0052] In some embodiments, the subject is over 18 years old. In some embodiments, the subject is under about 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.

[0053] In some embodiments, the method comprises milling a unit dose pharmaceutical composition comprising vibegron prior to administration to the subject, hi some embodiments, the subject is orally administered the milled pharmaceutical unit dose comprising vibegron.

[0054] In some embodiments, the subject suffers from or is at risk of suffering from renal impairment, hi some embodiments, the subject suffers from mild renal impairment, moderate renal impairment, or severe renal impairment.

[0055] In some embodiments, the subject has had prior OAB therapy. In some embodiments, the subject has not had prior OAB therapy.

[0056] In some embodiments, the first dosage or the second dosage has a steady-state C of about 0 ng / mL to about 313 ng / mL of vibegron.max to provide.

[0057] In some embodiments, the first dosage or the second dosage provides a steady state AUC of vibegron of about 331 ng·hr / mL to about 3613 ng·hr / mL.

[0058] In some embodiments, the first dosage or the second dosage has a T of vibegron of about 0.5 hours to about 6.0 hours. max to provide.

[0059] In some embodiments, the first dosage or the second dosage has a steady-state C of about 0 ng / mL to about 313 ng / mL of vibegron. max , a steady-state AUC of vibegron of about 331 ng·hr / mL to about 3613 ng·hr / mL, and / or a T of vibegron of about 0.5 hours to about 6.0 hours. max to provide.

[0060] In some embodiments, vibegron is administered together with a second pharmaceutical agent, including, for example, any of those listed in this application. In some embodiments, vibegron is administered simultaneously with the second pharmaceutical agent. In some embodiments, vibegron is administered sequentially with the second pharmaceutical agent. In some embodiments, vibegron is administered before and / or after the second pharmaceutical agent. The embodiments described below include such sequential administration.

[0061] In some embodiments, the subject is receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor, such as a CYP3A inhibitor, concurrently with a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

[0062] In some embodiments, the subject is simultaneously receiving, taking, or otherwise exposed to a P-glycoprotein inhibitor.

[0063] 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.

[0064] In some embodiments, the subject is simultaneously receiving, taking, or otherwise exposed to a muscarinic receptor antagonist.

[0065] Muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, cyclopentolate, atropine methyl nitrate, trihexyphenidyl / benzhexol, tolterodine, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, and aclidinium bromide.

[0066] In some embodiments, the subject is administered a first dosage of vibegron / day for a first period of time followed by a second dosage of vibegron / day and is simultaneously receiving, taking, or otherwise exposed to a muscarinic receptor antagonist.

[0067] In some embodiments, the subject is administered a first dosage of vibegron / day for a first period of time followed by a second dosage of vibegron / day and is concurrently receiving, taking, or otherwise exposed to a CYP3A inhibitor.

[0068] In some embodiments, the subject is administered a first dosage of vibegron / day for a first period of time followed by a second dosage of vibegron / day and is concurrently receiving, taking, or otherwise exposed to a P-glycoprotein inhibitor.

[0069] In some embodiments, the subject is not concurrently receiving, taking, or otherwise exposed to a beta-blocker.

[0070] In some embodiments, the subject is not concurrently receiving, ingesting, or otherwise exposed to amlodipine.

[0071] In some embodiments, vibegron is administered with a meal, within 60 minutes after a meal, or within 2 hours after a meal, hi some embodiments, vibegron is administered regardless of whether the subject has eaten or not.

[0072] In some embodiments, vibegron is administered without food or before a meal, hi some embodiments, vibegron is administered more than 2 hours before a meal.

[0073] In some embodiments, vibegron is administered once a day, twice a day, or three times a day, hi some embodiments, vibegron is administered once a day.

[0074] The change from baseline in blood pressure (BP) and heart rate (HR) for subjects taking vibegron is not substantially different from subjects taking a placebo. In some embodiments, subjects experience a mean maximum change in systolic blood pressure (SBP) from baseline throughout the treatment period (e.g., 8 weeks or 12 weeks) that is less than 2.0 mm / Hg, less than 1.9 mm / Hg, less than 1.8 mm / Hg, less than 1.7 mm / Hg, less than 1.6 mm / Hg, less than 1.5 mm / Hg, less than 1.4 mm / Hg, less than 1.3 mm / Hg, less than 1.2 mm / Hg, less than 1.1 mm / Hg, less than 1.0 mm / Hg, less than 0.9 mm / Hg, less than 0.8 mm / Hg, less than 0.7 mm / Hg, less than 0.6 mm / Hg, or less than 0.5 mm / Hg from subjects taking a placebo.

[0075] In some embodiments, a subject is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from a subject taking a placebo. In some embodiments, a subject is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from a subject taking a placebo.

[0076] In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0077] In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in SBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0078] In some embodiments, subjects experience a mean maximum change in diastolic blood pressure (DBP) from baseline throughout the treatment period (e.g., 8 weeks or 12 weeks) that is a mean maximum change from subjects receiving a placebo of less than 2.0 mm / Hg, less than 1.9 mm / Hg, less than 1.8 mm / Hg, less than 1.7 mm / Hg, less than 1.6 mm / Hg, less than 1.5 mm / Hg, less than 1.4 mm / Hg, less than 1.3 mm / Hg, less than 1.2 mm / Hg, less than 1.1 mm / Hg, less than 1.0 mm / Hg, less than 0.9 mm / Hg, less than 0.8 mm / Hg, less than 0.7 mm / Hg, less than 0.6 mm / Hg, or less than 0.5 mm / Hg.

[0079] In some embodiments, a subject is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from a subject taking a placebo. In some embodiments, a subject is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from a subject taking a placebo.

[0080] In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0081] In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 2 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo. In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a mean maximum change in DBP from baseline of less than 1 mm / Hg over the treatment period (e.g., 8 weeks or 12 weeks) from subjects taking a placebo.

[0082] In some embodiments, the subject is over 45 years of age, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 1 mm / Hg from subjects taking a placebo, and a mean maximum change in SBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 1 mm / Hg from subjects taking a placebo.

[0083] In some embodiments, the subject is over 65 years of age, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 1 mm / Hg, and a mean maximum change in SBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 1 mm / Hg from subjects taking a placebo.

[0084] In some embodiments, subjects experience a mean maximum change in systolic blood pressure (SBP) from baseline throughout the treatment period (e.g., 8 weeks or 12 weeks) 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.

[0085] In some embodiments, subjects are administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experience a mean maximum change in SBP from baseline of less than 10 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0086] In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in SBP from baseline of less than 10 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0087] In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in SBP from baseline of less than 10 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0088] In some embodiments, subjects experience a mean maximum change in diastolic blood pressure (DBP) from baseline throughout the treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mm / Hg, less than 6.5 mm / Hg, less than 6 mm / Hg, less than 5.5 mm / Hg, less than 5 mm / Hg, less than 4.5 mm / Hg, less than 4 mm / Hg, less than 3.5 mm / Hg, less than 3 mm / Hg, less than 2.5 mm / Hg, or less than 2 mm / Hg.

[0089] In some embodiments, subjects are administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experience a mean maximum change in DBP from baseline of less than 7 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0090] In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline of less than 7 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0091] In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline of less than 7 mm / Hg throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0092] In some embodiments, the subject is over 45 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mm / Hg, and a mean maximum change in SBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 10 mm / Hg.

[0093] In some embodiments, the subject is over 65 years of age and is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a mean maximum change in DBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mm / Hg, and a mean maximum change in SBP from baseline over the treatment period (e.g., 8 weeks or 12 weeks) of less than 10 mm / Hg.

[0094] In some embodiments, subjects are administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experience a change from baseline in the average number of urinations per 24 hours over the treatment period (e.g., 8 weeks or 12 weeks), where the change is greater than the change for subjects taking a placebo, the difference from placebo being 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 a range between any two of the foregoing values.

[0095] In some embodiments, a subject is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experiences a change from baseline in average number of urinations per 24 hours over the treatment period (e.g., 8 weeks or 12 weeks) of 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 a range between any two of the foregoing values.

[0096] In some embodiments, a subject has an average of ≥ 1 urgency urinary incontinence (UUI) episode per day prior to treatment, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a change from baseline in the average number of UUI episodes over the treatment period (e.g., 8 weeks or 12 weeks), where the change is greater than the change for subjects taking a placebo. The difference from placebo is 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 a range between any two of the preceding values.

[0097] In some embodiments, a subject has an average of ≧1 urge urinary incontinence (UUI) episodes per day prior to treatment, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences a change from baseline in the average number of UUI episodes over the treatment period (e.g., 8 weeks or 12 weeks) of about -1.3 to about -2.5, e.g., 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.

[0098] In some embodiments, subjects are administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day and experience a change from baseline over the treatment period (e.g., 8 weeks or 12 weeks) in volume voided per micturition (mL), where the change is greater than the change for subjects taking a placebo. The difference from placebo is about 20 mL to about 35 mL, e.g., 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.

[0099] In some embodiments, a subject had an average of ≧1 urge urinary incontinence (UUI) episodes per day prior to treatment, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences at least a 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 UUI episodes per day throughout the treatment period (e.g., 8 weeks or 12 weeks).

[0100] In some embodiments, a subject had an average of ≧1 urgency episodes per day pre-treatment, is administered a first dosage of vibegron / day for a first period followed by a second dosage of vibegron / day, and experiences 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% reduction in the average number of urgency episodes per day over the treatment period (e.g., 8 weeks or 12 weeks).

[0101] In some embodiments, vibegron has an onset of action of about 4 weeks. In some embodiments, vibegron has an onset of action of about 3 weeks. In some embodiments, vibegron has an onset of action of about 2 weeks. "Onset of action," as used herein, refers to the time it takes for the effects of a drug to become noticeable after administration.

[0102] Unit Dose Pharmaceutical Composition The present disclosure provides a unit dose pharmaceutical composition comprising a dosage amount of vibegron as disclosed herein, the unit dose composition being suitable for oral administration. Oral dosage forms include, for example, liquid formulations, tablets, capsules, and gelcaps, as recognized by those skilled in the art. In some embodiments, the unit dose composition is a solid dosage form, such as a tablet and capsule. In some embodiments, the unit dose composition is a tablet.

[0103] Pharmaceutically acceptable excipients are those 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 compositions disclosed herein include diluents, disintegrants, binders, and lubricants. See generally Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000), the entire contents of which are incorporated herein by reference.

[0104] In one embodiment, the unit dose pharmaceutical composition disclosed herein comprises mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0105] Oral dosage forms can be prepared by standard pharmaceutical manufacturing techniques, including, for example, wet granulation, wet milling, fluid bed drying, dry milling, lubrication, tabletting, and aqueous film coating.

[0106] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from about 50 mg to about 100 mg of vibegron.

[0107] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises about 55 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 100 mg of vibegron.

[0108] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg of vibegron.

[0109] 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.

[0110] 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.

[0111] In some embodiments, the unit dose pharmaceutical compositions of the present disclosure can be milled. In some embodiments, the unit dose pharmaceutical compositions of the present disclosure can be milled prior to oral administration.

[0112] In vitro assays Vibegron was tested in several in vitro assays to determine its agonist potency at the human β3-AR, its selectivity over other human β-AR subtypes, and its potency at β3-ARs from other species.

[0113] Vibegron activity was measured in a functional assay measuring the increase in cellular adenylyl cyclase activity in Chinese Hamster Ovary (CHO) cells stably expressing the human β3-AR. The extent of activation to a proven full agonist (isoproterenol) was measured using a compound EC 50 was measured together.

[0114] Vibegron has an EC 50It is a potent and selective agonist of the β3-AR, with 84% activation relative to isoproterenol. In the presence of 40% human serum, small serum changes are observed (EC 50 = 1.7 nM, 102% activation).

[0115] Additionally, the selectivity of vibegron for the β3-AR compared to the β1- and β2-AR subtypes was determined by testing in CHO cells expressing β1-AR or β2-AR. Vibegron is highly selective for the β3-AR over the β1-AR and β2-AR, demonstrating >9000-fold selectivity for activating the β3-AR compared to the β1-AR or β2-AR in a cell-based in vitro functional assay.

[0116] Bibegron IC 50 was determined in a standard competitive binding assay using membranes prepared from cells expressing recombinant β1, β2, or β3-AR. Vibegron inhibited the binding of a nonspecific β-AR radiolabeled antagonist in the filter binding assay. 125 Regarding I-CYP competition, β3-AR IC 50 =193nM (86ng / mL). The relative lack of binding affinity of vibegron to the potent in vitro agonist activity at human β3-AR is related to the relative ability of the compound to compete for unbound versus bound receptors, both of which will be measured by antagonist binding assays. Furthermore, the compound does not bind to either β1-AR or β2-AR, as shown in binding competition assays, confirming that the compound is neither an agonist nor an antagonist of these receptors.

[0117] Absorption, Distribution, Metabolism, and Excretion Vibegron achieved maximum plasma concentrations (C) approximately 1 to 3 hours after oral administration in healthy subjects. max ) is reached. maxand AUC increased more than dose proportionally up to 400 mg. Steady-state concentrations were achieved within 7 days of once-daily dosing of vibegron. The geometric mean accumulation ratios of steady-state AUC were approximately 2 in young male subjects and approximately 2.8 in elderly subjects (male and female). Vibegron exposure in young Japanese male subjects was moderately (<2-fold) increased after single-dose administration compared to exposure in non-Japanese young male subjects.

[0118] In healthy middle-aged and elderly women, repeated oral doses of 150 mg vibegron administered with food increased mean AUC levels by approximately 42% and 59% on day 1 and by approximately 20% and 43% on day 14 compared to the same dose administered in the fasted state. 0-24 and C max brought value.

[0119] In a two-part, open-label, single-dose study to investigate the pharmacokinetics of vibegron in patients with hepatic insufficiency, the apparent volume of distribution (Vd / F) of vibegron was approximately 9120 L. Vibegron is bound (approximately 49%) to human plasma proteins.

[0120] Vibegron is excreted by various routes, including urinary excretion, biliary excretion, and hepatic metabolism. CYP3A4 is the main CYP responsible for in vitro metabolism, but metabolism appears to play only a minor role in the excretion of vibegron. In a mass balance study in healthy subjects, the majority of the recovered dose was excreted as unchanged vibegron. The average total recovery of radioactivity in excreta was 79%, with approximately 59% and 20% of this dose being recovered in feces and urine, respectively.

[0121] The majority of the vibegron dose was found to be excreted as the unchanged parent drug. Seven trace 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. [ 14 The concentration of radioactivity derived from [C]vibegron was 0.3 μM on average maxand T of 2.5 hours max The radioactivity profiles of plasma samples at 2 and 4 hours showed that approximately 78% and 73% of the plasma radioactivity was accounted for by unchanged vibegron, respectively, and that the O-glucuronide (M7) was the predominant circulating metabolite (approximately 12-14% of total circulating drug-related substances). Two additional minor oxidative metabolites, M4 (4-6%) and M17 (6-7%), were also detected in human plasma. At other time points beyond 4 hours post-dose, radioactivity in plasma samples was too low to be profiled. Due to sufficient data from subsequent time points to allow half-life estimation, a possible accumulation of circulating metabolites in plasma was not assumed.

[0122] Vibegron has a terminal half-life of 59 to 94 hours in young and elderly subjects. 1 / 2 At steady state, mean renal clearance (CLR) in young men ranged from 150 to 187 mL / min across all dose levels, whereas the CLR in elderly subjects (males and females) was somewhat lower at 127 mL / min. 0-24hr There is a trend for an increasing proportion of the dose excreted in the fetal bovine serum (fBS), reflecting increased bioavailability with increasing dose. 0-24hr The mean fe in young Japanese subjects was similar to that in older subjects, being approximately 14% at 100 and 150 mg in young men and approximately 17% at 100 mg in older subjects. 0-24hr and C.L. R was similar to that observed in non-Japanese subjects. EXAMPLES

[0123] Example 1 Vibegron tablet formulation The composition of vibegron tablets (50 mg, 75 mg, and 100 mg) is shown in Table 1.

[0124] [Table 1]

[0125] 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 ascending-dose oral Phase 1 studies. All subjects were healthy adults. The results are summarized in Table 2. After single oral doses of vibegron ranging from 2 to 600 mg, the mean t max Terminal elimination half-life t 1 / 2 averaged 43 to 75 hours for all doses from 10 to 600 mg in healthy young male subjects. Systemic exposure was greater than proportional to dose up to 600 mg.

[0126] Vibegron exposure in young Japanese men was moderately increased compared to exposure in young non-Japanese men. Vibegron AUC 0-inf The geometric mean ratio (GMR; Japanese / non-Japanese) and corresponding 90% CI for vibegron C decreased with increasing dose from 1.75 (1.38, 2.23) at 10 mg to 1.17 (0.99, 1.40) at 300 mg. max The GMR (Japanese / non-Japanese) and 90% CI for T did not appear to be affected by dose and was 1.75 (1.35, 2.26) (pooled) across all doses. max Median values ​​(1 to 3 hours) and harmonic mean apparent terminal half-life t 1 / 2 The estimates (58 to 71 hours) were similar to those in non-Japanese subjects. 0-inf and C max appeared to increase more than proportionally with dose up to 300 mg.

[0127] The single-dose pharmacokinetics of 50 mg vibegron in non-Japanese elderly male and female subjects are also shown in Table 2. In elderly male and female subjects, the mean AUC0-inf and C max were approximately 70% and 60% higher, respectively, than the corresponding values ​​after 50 mg in young men. max was similar to that observed in young men (T max Median = 1.0 hours) is the apparent terminal half-life t 1 / 2 was slightly longer in older people than in younger people (harmonic mean t 1 / 2 = 52 hours versus 92 hours). Vibegron exposure in elderly women was somewhat higher than in elderly men.

[0128] [Table 2]

[0129] 2.2 Repeated-dose pharmacokinetics The multiple-dose pharmacokinetics of vibegron was investigated in two randomized, double-blind, placebo-controlled, multiple-ascending dose Phase 1 studies in healthy non-Japanese young male, middle-aged male and female, and elderly male and female subjects, and in healthy Japanese young male, elderly male and female subjects. Japanese subjects received multiple doses ranging from 50 to 200 mg for 14 days, whereas non-Japanese subjects received multiple doses ranging from 25 to 400 mg for 7 to 28 days. Pharmacokinetic results after 14 days of dosing are summarized in Table 3.

[0130] On average, women tend to receive 50% higher exposure (AUC) compared to men, regardless of age. Steady-state AUC and C after QD administration of 100 mg vibegron in elderly subjects max The values ​​were approximately 1.7- and 1.3-fold higher, respectively, compared with younger men.

[0131] GMC max The AUC and CUC accumulation ratios were 1.78 and 1.84 for Japanese subjects at the 200 mg dose level. On average, steady-state exposure in young Japanese male subjects was approximately 30% higher than in young male non-Japanese subjects; the difference in exposure was statistically significant.max The GMR (Japanese / non-Japanese) (pooled across doses) and corresponding 90% CI were 1.27 (1.09, 1.48) and 1.33 (1.06, 1.67), respectively.

[0132] On average, steady-state exposure at day 14 in elderly male and female Japanese subjects was 35% higher than in elderly male and female non-Japanese subjects; the difference in exposure was statistically significant. 0-24 and C max The GMR (Japanese / non-Japanese) on day 14 and the corresponding 90% CI were 1.35 (1.09, 1.68) and 1.82 (1.32, 2.51), respectively.

[0133] [Table 3]

[0134] 2.3 Bioavailability and Bioequivalence Five Phase 1 studies were conducted using a capsule formulation of vibegron, whereas seven Phase 1 and one Phase 2b study used the tablet formulation.An open-label, randomized, two-period, crossover PK study in healthy male subjects aged 18 to 45 years compared the single-dose pharmacokinetics of capsule (1 x 150 mg capsule) and tablet (3 x 50 mg tablets) formulations of vibegron.

[0135] The tablet formulation provided comparable exposure to the capsule formulation, as shown in Table 4. max and apparent terminal half-life t 1 / 2 was also similar between the two formulations.

[0136] [Table 4]

[0137] This open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover Phase 1 study evaluated the relative bioequivalence of two tablets with slightly different compositions: an aqueous tablet (test) and a non-aqueous tablet (reference standard).

[0138] [Table 5]

[0139] 2.4 Effect of food on oral absorption The effect of food on the single-dose pharmacokinetics of vibegron 50 mg was evaluated in healthy non-Japanese and Japanese young men in two randomized, double-blind, placebo-controlled, single-ascending-dose Phase 1 studies, whereas the effect of food on the multiple-dose pharmacokinetics of vibegron 150 mg in middle-aged women was evaluated in a randomized, double-blind, placebo-controlled, multiple-ascending-dose Phase 1 study. A summary of the pharmacokinetic results is listed in Table 6.

[0140] Administration of 50 mg vibegron with a high-fat meal in non-Japanese young men significantly increased AUC 0-inf and C max and a 46% and 67% decrease in T max Administration of 50 mg vibegron to young Japanese men with a standard Japanese breakfast resulted in a delayed AUC 0-inf and C max These results led to a 37% and 52% decrease in

[0141] Administration of multiple oral doses of 150 mg vibegron with food in healthy middle-aged women significantly increased the mean AUC 0-24hr and C max This resulted in a 20% and 47% decrease in T max was slower in the fed state compared with the fasted state (6.0 vs. 2.0 h).

[0142] [Table 6]

[0143] 2.5 Pharmacokinetics in target disease populations A randomized, double-blind, placebo- and active-controlled, parallel-group, two-part Phase 2b study in patients with OAB demonstrated that dilute vibegron trough concentrations (C trough ) were measured; mean (±SD) C trough The mean (±SD) Cs of vibegron 50 mg in healthy young men were 27.4 (±18.3) ng / mL and 73.6 (±65.5) ng / mL, respectively. trough The mean (±SD) C of vibegron 100 mg was 15.2 (±5.07) ng / mL. trough Values ​​ranged from 31.9 (±11.5) in healthy young men to 54.2 (±15.3) in healthy older adults.

[0144] Example 3 Pharmacokinetics in Special Populations 3.1 Effect of age Vibegron exposure was evaluated in young (18-45 years), middle-aged (46-64 years), and elderly (65-85 years) men and women. Exposure was similar in middle-aged men compared with young men, but plasma concentrations were higher in elderly compared with 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 elderly subjects compared with young subjects. 1 / 2 was longer in elderly subjects at 92 hours compared with 52 hours in younger subjects in a randomized, double-blind, placebo-controlled, dose-escalating, single-dose study. 0-24h and C maxThe values ​​were approximately 1.7-fold and 1.3-fold greater in elderly subjects compared with young men in a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Furthermore, the geometric mean accumulation ratios of steady-state AUC were approximately 2 in young men and 2.8 in elderly subjects. In elderly Japanese subjects, AUC 0-24 and C max were increased by approximately 35% and 82%, respectively, compared with elderly non-Japanese subjects.

[0145] 3.2 Gender influence 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, multiple-ascending dose study. Vibegron plasma concentrations were similar in middle-aged men compared with younger men; however, exposure was slightly higher in middle-aged women compared with middle-aged men (approximately 1.5-fold higher steady-state AUC in middle-aged women), which was also seen when exposure in older women was compared with exposure in older men.

[0146] 3.3 Effects of renal dysfunction The pharmacokinetics of a single dose of vibegron 100 mg 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 PK study. A summary of the pharmacokinetic parameters and statistical comparisons between patients with various degrees of renal impairment and their healthy counterparts are shown in Table 7.

[0147] 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 Vibegron AUC in patients with renal impairment (but not undergoing dialysis) 0-inf were 49%, 106%, and 83% higher, respectively, compared with healthy matched control subjects. maxwere 96%, 68%, and 42%, respectively, higher compared to healthy matched control subjects. In summary, increasing degrees of renal impairment were associated with increased vibegron AUC 0-inf was associated with an increase in C max No clear trends were observed. 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 significantly greater than 1 mL / min / 1.73 m of eGFR. 2 It was found that the CL / F ratio increased by approximately 0.8% per increase in AUC. Based on this linear relationship, the CL / F ratios for the mild, moderate, and severe populations relative to 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. Modeling the relationship between CL / F and creatinine clearance produced similar results. Renal clearance (CLR) and the fraction of the dose excreted in urine over a 48-hour collection interval (fe[urine]48hr) decreased with increasing degrees of renal impairment. Patients with mild, moderate, and severe renal impairment had reduced CLRs of 39%, 65%, and 82%, respectively, compared to healthy matched control subjects. Fe[urine]48hr was similar in patients with mild renal impairment (8.5%) and healthy matched control subjects (7.9%), and was 5.5% and 2.1% in patients with moderate and severe renal impairment, respectively.

[0148] [Table 7]

[0149] 3.4 Effects of liver damage The pharmacokinetics of a single dose of vibegron 100 mg was evaluated in eight patients with moderate hepatic impairment (Child-Pugh Score of 7 to 9) and eight age-, sex-, and BMI-matched healthy subjects in a two-part, open-label, single-dose Phase 1 study. Statistical comparison of vibegron pharmacokinetic parameters is shown in Table 8. AUC for patients with moderate hepatic impairment and healthy control subjects0-inf and C max The GMR (90% CI) was 1.27 (0.96, 1.67) and 1.35 (0.88, 2.06), respectively, suggesting that moderate hepatic impairment was not associated with a clinically important effect on vibegron exposure.

[0150] [Table 8]

[0151] 3.5 Drug interaction studies Four drug interaction studies were conducted evaluating 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.

[0152] Repeated doses of ketoconazole 200 mg, a strong CYP3A4 / P-gp inhibitor, and diltiazem 240 mg, a moderate CYP3A4 / P-gp inhibitor, were evaluated in combination with a single dose of vibegron 100 mg. GM vibegron AUC 0-inf and C max were increased by 2.08-fold and 2.22-fold, respectively, in the presence of repeated doses of 200 mg ketoconazole. 0-inf and C max was increased by 63% and 68% in the presence of multiple doses of 240 mg or 180 mg diltiazem, respectively. 1 / 2 The mean time to onset was 75, 75.4, and 80.2 hours when vibegron was administered alone, with diltiazem, or with ketoconazole, respectively. 1 / 2 The lack of an increase in the pharmacokinetics of vibegron suggests that interactions occurred primarily during the absorption phase. However, these interactions are not considered to be clinically significant. Tolterodine ER 4 mg had no effect on the pharmacokinetics of vibegron.

[0153] Repeated doses of vibegron were evaluated in combination with the p-gp substrate, digoxin. AUC of digoxin when coadministered with vibegron 0-inf The 90% CI for GMR was within the 80-125% bioequivalence range, suggesting that vibegron does 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 vibegron. The AUC and C of EE max The 90% CI for GMR (EE / LNG + vibegron vs. EE / LNG alone) was within 0.8 and 1.25. max increased by 18 to 21% in the presence of multiple doses of vibegron, but these increases were not considered clinically significant. No clinically significant pharmacokinetic interactions occur when vibegron 100 mg or 150 mg is coadministered with tolterodine ER 4 mg.

[0154] [Table 9]

[0155] [Table 10]

[0156] 3.6 Effect on QT interval prolongation The effect of vibegron on the QTc interval was evaluated in a single oral dose study. Fifty-two healthy subjects received a single dose of 400 mg vibegron, a single dose of 200 mg vibegron, a single dose of 400 mg moxifloxacin, and a single dose of vibegron and matching placebo.

[0157] The 400 mg dose of vibegron produced a maximum LS mean difference (90% CI) from placebo in QTcF of 4.60 (2.71, 6.48) ms at 1 hour after dosing. Similar results were recorded for QTcF after a single 200 mg dose, where the maximum LS mean difference (90% CI) from placebo was 4.98 (3.07, 6.88) ms at 1 hour after dosing. The upper end of the 90% CI for all mean differences was below the target of 10 ms (Table 11). A statistically significant effect of moxifloxacin on QTcF was observed.

[0158] GM(CV%)C obtained after a single 200mg dose max and AUC 0-23.5hr The mean plasma concentrations were 366 (50.4) ng / mL and 2270 (37.3) ng·h / mL, respectively. max was 1.63-fold higher than that obtained in elderly subjects receiving multiple doses of 100 mg in a double-blind, randomized, placebo-controlled, alternating (Panels A and B), multiperiod, single ascending-dose oral Phase 1 study, but the AUC was similar. max and AUC 0-23.5hr The C max and AUC 0-23.5hr These values ​​are 4.55- and 2.89-fold those obtained in elderly subjects receiving multiple doses of vibegron 100 mg.

[0159] Target PK exposures were achieved at both the 200 mg and 400 mg dose levels. Steady-state C values ​​obtained in elderly female subjects at the maximum clinical dose of 100 mg were max and AUC 0-24hr The values ​​were 278 ng / mL and 2620 ng·h / mL, respectively.

[0160] [Table 11]

[0161] Example 4 Clinical Efficacy Data A randomized, double-blind, placebo- 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 of co-administration of vibegron with tolterodine ER 4 mg. 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 the co-administration. In part 2, 408 subjects were randomized in a double-blind fashion in a 2:2:2:1 ratio to one of four treatment arms: 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 parts 1 and 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 urge incontinence episode. Efficacy data for parts 1 and 2 are summarized here.

[0162] At baseline, subjects must have a voiding diary with a mean number of voids per diary day of ≥8. Additionally, subjects in the OAB wet stratum must have a mean number of urge incontinence episodes per diary day of ≥1. Subjects in the OAB dry stratum must have a mean number of urge episodes per diary day of ≥3 and a mean of <1 urge incontinence episode per diary day. For all subjects, the total number of urge incontinence episodes must exceed the total number of stress incontinence episodes.

[0163] 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 the dose-related reduction in the mean number of urinations per day compared with placebo at week 8.

[0164] In part 1, a statistically significant reduction in the mean number of voids per day was observed in the vibegron 100 mg and 50 mg treatment groups compared to placebo at week 8. There were also statistically significant reductions from baseline in the vibegron 100 mg and 50 mg treatment groups compared to placebo for secondary endpoints including urge incontinence and total urinary incontinence (in subjects with OAB wet), and urge episodes in all subjects. There were also statistically significant increases from baseline in the vibegron 15, 50, and 100 mg treatment groups compared to placebo for the secondary endpoint: voided volume. (Tables 12 and 13).

[0165] [Table 12]

[0166] [Table 13]

[0167] A double-blind, randomized, placebo-controlled, multicenter, Phase 3 study designed to evaluate the safety and efficacy of vibegron in men and women with OAB was completed. Upon completion of the placebo run-in period, 1,232 patients were randomized to receive 12 weeks of blinded study treatment, including vibegron 50 mg (N=370), vibegron 100 mg (N=369), placebo (N=369), or imidafenacin 0.2 mg (comparator; N=117). These results show that once-daily vibegron resulted in a statistically significant reduction in efficacy parameters, including voiding, UUI episodes, total incontinence episodes, and urgency episodes (Table 14). Another open-label, uncontrolled, multicenter, Phase 3 study designed to evaluate the long-term (52-week) safety and efficacy of vibegron with OAB was completed. Upon completion of the 1-week observation period, 169 patients were initiated on vibegron 50 mg once daily. After 8 weeks, this dose could be increased to 100 mg once daily if clinically indicated. Patients continued on vibegron at 50 mg or 100 mg doses through week 52. Once-daily vibegron reduced voiding episodes, UUI episodes, total urinary incontinence episodes, and urgency episodes throughout the 52-week treatment period.

[0168] [Table 14]

[0169] Example 5 Safety Data 5.1 Phase I Safety Data Safety data were collected from 16 Phase 1 studies, including 15 completed Phase 1 studies and one study that was terminated early (the study was terminated for reasons unrelated to efficacy or safety). A total of 466 subjects received at least one dose of vibegron in the Phase 1 program; 238 subjects received a single dose ranging from 2 to 600 mg, and 238 subjects received multiple doses ranging from 25 to 400 mg for up to 28 days. Across the Phase 1 program, vibegron was generally well tolerated. No treatment-emergent serious adverse events (SAEs) or deaths were reported, and the majority of adverse events (AEs) were transient and mild or moderate in intensity.

[0170] In the Phase 1 study, isolated incidences of orthostatic hypotension (decrease in systolic blood pressure >20 mmHg and / or decrease in diastolic blood pressure >10 mmHg) with or without symptoms (e.g., lightheadedness, dizziness, presyncope) were seen. The incidence of orthostatic AEs after coadministration of vibegron 100 mg or 150 mg with 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 Phase 1 multiple-dose study, AEs such as positional dizziness, dizziness, presyncope, or syncope did not show a clear dose-response relationship. However, positional dizziness appeared to increase with doses ≥100 mg, and the incidence of the AE "orthostatic hypotension with symptoms" tended to be higher at vibegron doses >200 mg. When vibegron 100 mg was coadministered with a stable regimen of either metoprolol (a typical beta-blocker) or amlodipine (a typical vasodilator) to subjects with essential hypertension, no orthostatic AEs occurred.

[0171] Evaluation of the preliminary Phase 1 safety data did not indicate any clinically meaningful changes in laboratory safety parameters (chemistry, hematology, and urinalysis) or ECG parameters (including PR, QRS, and QTc intervals). A thorough QT study was completed and showed no clinically meaningful effects on QTc or blood pressure.

[0172] 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 doses ranging from 3 to 100 mg of vibegron (alone or in combination with tolterodine) for up to 8 weeks during the main study. Of those completing the parent study, 605 subjects received vibegron 50 mg (alone) or vibegron 100 mg (alone or in combination with tolterodine 4 mg) 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 tolterodine monotherapy. No deaths were reported during the study. Vibegron was generally well tolerated. There were no meaningful differences in the overall incidence or severity of AEs or drug-related AEs between treatment groups compared with placebo.

[0173] Adverse events were reported in 607 of 1393 assigned subjects (43.6%) 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 subjects reported one or more AEs in the vibegron 15 mg and vibegron 50 mg + tolterodine 4 mg treatment groups compared with 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 tolterodine (alone or with vibegron) compared with placebo or vibegron monotherapy groups.

[0174] There were 221 subjects with drug-related AEs, with the lowest incidence of drug-related AEs reported in the vibegron 100 mg treatment group. The proportion of subjects with drug-related AEs was similar in the vibegron monotherapy group compared with placebo and slightly higher in the concurrent treatment groups compared with placebo or either monotherapy. The proportion of subjects who discontinued due to drug-related AEs was low and similar across all treatment groups.

[0175] A total of nine SAEs were reported in eight subjects, occurring across treatment arms (2 placebo; 1 vibegron 3 mg; 1 vibegron 50 mg; 3 tolterodine 4 mg; 1 vibegron 50 mg + tolterodine 4 mg). Reported SAEs were atrial fibrillation, anaphylactic reaction, lung adenocarcinoma (stage IV), chronic obstructive pulmonary disease, hypertension, overdose, foot fracture, and one subject experienced both gastroesophageal reflux and dizziness following a pancreatic endoscopic procedure, prolonging hospitalization. No specific AE terms were reported in more than one subject. All SAEs were considered unrelated to study drug by the investigator.

[0176] No meaningful differences in the overall incidence of adverse events or serious adverse events were observed between treatment groups during the 52-week extension.

[0177] Adverse events were reported in 531 of 845 subjects (62.8%). The proportion of subjects with one or more AEs was similar 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 with the other treatment groups. The incidence of constipation was higher in the concurrent treatment group compared with the monotherapy treatment group.

[0178] The proportion of subjects with drug-related AEs was slightly higher for the tolterodine ER 4 mg and co-medication arms compared with the vibegron 50 mg and 100 mg treatment arms. The proportion of subjects who discontinued due to AEs or drug-related AEs was slightly higher for tolterodine ER 4 mg compared with the other treatment arms. A total of 46 SAEs were reported in 41 subjects during the extension. A higher overall incidence was reported in the tolterodine ER 4 mg and vibegron 50 mg treatment arms compared with the vibegron 100 mg treatment arm. One drug-related SAE, paralytic ileus, was reported in the tolterodine ER 4 mg treatment arm; the subject discontinued due to this AE.

[0179] Table 15 below summarizes adverse events commonly seen in the vibegron Phase 2 program in patients with overactive bladder.

[0180] [Table 15]

[0181] Serious adverse events observed during the first 12 weeks of treatment with vibegron monotherapy included lung adenocarcinoma (stage IV) (n=1) and chronic obstructive pulmonary disease (n=1); an SAE of overdose was reported in the vibegron-tolterodine combination arm. During the Phase 2 extension study, SAEs reported by two or more subjects receiving monotherapy included cerebrovascular accident (n=2) and osteoarthritis (n=2). The only SAE reported in the vibegron-tolterodine combination arm 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 (which did not recur upon rechallenge) (n=1), as well as atrial fibrillation (n=1) and dizziness (n=1) in the tolterodine monotherapy arm. The frequency of injuries was numerically higher in the tolterodine arm than with vibegron (0.9%, n=4 vs. 2.1%, n=5). Given the low incidence and lack of pattern for SAEs, serious events are not considered expected with vibegron.

[0182] Potential risks associated with vibegron treatment, based on nonclinical data and available data on similar compounds, include orthostatic hypotension and increased exposure (approximately 2-fold) in patients taking concomitantly strong P-gp inducers.

[0183] 5.3 Cardiovascular safety The cardiovascular safety of vibegron was evaluated in patients with OAB and in healthy participants. In a randomized, placebo- and comparator (tolterodine)-controlled, two-part efficacy and safety study with 52-week extension, seven orthostatic-related AEs (which included the adverse event terms postural dizziness, presyncope, and orthostatic hypotension) occurred in six (0.4%) subjects. These events occurred in one subject in the placebo (0.5%), vibegron 15 mg (0.3%), and vibegron 50 mg + tolterodine ER / vibegron 50 mg treatment groups (0.8%), respectively, and in three subjects in the vibegron 100 mg group (1.1%). These events occurred irregularly throughout the study and were judged by the investigator to be mild in severity. None caused discontinuation. The overall incidence of orthostatic symptoms was low.

[0184] 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 changes at week 1 and mean maximum changes through 8 weeks for 50 mg and 100 mg were comparable for placebo and vibegron, with differences of <1 mmHg. Absolute changes in SBP and DBP were also similar between placebo and vibegron, with a slight increase in the percentage of vibegron subjects 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 could be detected, as the mean maximum changes through 8 weeks were comparable to placebo (<2 bpm). Small differences in absolute heart rate and the percentage of subjects above blood pressure threshold for vibegron were similar to the tolterodine arm.

[0185] [Table 16]

[0186] More thorough evaluation of heart rate and blood pressure was performed in healthy participants in several Phase 1 studies. A 6-part, double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, and repeat-dose PK of vibegron in healthy subjects included 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 means and 90% confidence intervals of the maximum change from baseline in moving average heart rate through 4 hours post-dose (MA4 HR) are shown in Table 17. The effect on heart rate was dose-dependent, with the 100 mg dose showing a difference of <1 bpm from placebo.

[0187] [Table 17]

[0188] Cardiovascular safety was also evaluated in healthy volunteers in a thorough QT study after single doses of 200 and 400 mg, which approximate vibegron steady-state exposure at 100 and 200 mg, respectively. The mean maximum effects on blood pressure and RR interval decreased at the lower doses, as shown in Table 18. Using log-log regression analysis from repeat-dose vibegron exposure (from three Phase 1 studies), the calculated mean ± standard deviation C from the 75 mg dose max The C and AUC were 120 ± 74.7 ng / mL and 1140 ± 476 ng h / mL, respectively. These estimates are approximately 3.3-fold and 2-fold lower, respectively, than the 200 mg single dose and 9.2-fold and 6-fold lower, respectively, than the 400 mg single dose. max and AUC.

[0189] [Table 18]

[0190] Example 6 Dose escalation 6.1 Dose-comparison efficacy The Phase 2 study discussed in Example 4 demonstrated a dose-dependent effect on micturition, as can be seen in Table 19. 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. Vibegron efficacy begins to reach a plateau between 50 and 100 mg, so that at 75 mg, most of the efficacy obtained at 100 mg is obtained.

[0191] [Table 19]

[0192] 6.2 Reducing side effects Vibegron exhibits a greater than dose-proportional increase in exposure. Surprisingly, an increase in dose from 50 to 100 mg significantly increased C max , which results in an approximately three-fold increase in the PK parameter thought to be most closely related to cardiovascular effects. To describe the PK parameters of the 75 mg dose, data from the Phase 1 study were used to compare dose-C max A dose-AUC model was created. Based on the simulation, it was found that administration of 75 mg of vibegron prevented approximately 29% of the exposure observed with the 100 mg dose, and subsequently reduced the upper limit of the range of exposure that can be obtained with the 100 mg dose. max Lower values ​​reduce the likelihood of clinically relevant cardiovascular effects.

[0193] In a Phase 1 multiple-dose study at doses up to 100 mg, adverse events such as postural dizziness, vertigo, presyncope, and syncope did not show a clear dose-response relationship. However, postural dizziness appeared to increase at doses ≥100 mg, and the incidence of the adverse event "symptomatic orthostatic hypotension" was higher at doses of vibegron above 150 mg. The risk of these dose-related adverse events could be disproportionately reduced by reducing the dose from 100 mg to 75 mg, because a 25% reduction in dose was associated with a higher C maxThis is because it results in an approximately 40% reduction in bioavailability (206 ng / mL at 100 mg vs. 120 ng / mL at 75 mg). Without wishing to be bound by theory, the greater than dose-proportional increase in bioavailability with increasing dose may be due to saturable P-glycoprotein (P-gp)-mediated efflux in the intestine. Exposure, and therefore risk of adverse events, can be further reduced using the 50 mg dose.

[0194] The lower exposure at the 75 mg dose compared with the 100 mg dose disproportionately reduces the risk of adverse events in special populations as well. Subjects with moderate renal impairment had a mean increase in AUC of 1.6-fold compared with subjects with normal renal function, whereas subjects receiving strong CYP3A / P-gp inhibitors had approximately 2-fold higher exposure. max Assuming a two-fold increase in vibegron C over 100 mg, these special populations may experience max The probability of achieving this is 15% (see Figure 1). By minimizing and reducing the exposure of the subjects to the limit, the subjects will achieve a C max This is important for older people and women who show

[0195] Greater than proportional C between the 50 mg and 100 mg doses of vibegron while limiting exposure max Dose escalation can be used to take advantage of the increased efficacy of the drug. Dose escalation is the process of gradually adjusting the dose of a pharmaceutical until a desired effect is achieved. This is done, in part, to monitor and reduce the occurrence of adverse side effects. In the method of the present invention, a vibegron dosage form is administered to a subject to treat overactive bladder. When a dose escalation regimen is implemented, the dosage over the first treatment period may be less than that administered in subsequent treatments.

[0196] The relatively shallow dose-response relationship between the 50 mg and 100 mg doses of vibegron was compared with the greater than proportional C between the 50 mg and 100 mg doses of vibegron.max Combined with increased doses, this allows for dose escalation that maintains efficacy while disproportionately reducing exposure.

[0197] Example 7 Pharmacokinetic data for the 75mg dose A pharmacokinetic study evaluating the drug interaction between vibegron and rifampin was completed. All subjects were healthy adults. A summary of preliminary results is shown in Table 20. Subjects received a single dose of vibegron 75 mg on day 1, rifampin 600 mg QD on days 10-23, and a single dose of vibegron 75 mg on day 17 concomitant with rifampin administration. Vibegron and rifampin administration was well tolerated in healthy male and female subjects. No severe TEAEs, SAEs, or deaths were reported during the study. Three of the 20 subjects (15%) experienced AEs related to the study drug, namely, two headaches and one constipation, all mild. No clinically significant changes or findings were noted in vital signs, ECGs, or clinical laboratory assessments.

[0198] [Table 20]

[0199] The present invention having now been fully described, it will be understood by those skilled in the art that the same may be practiced within a wide equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any of its embodiments.

[0200] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0201] All patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A pharmaceutical composition for the treatment of overactive bladder comprising vibegron as an active ingredient, for orally administering to a subject in need thereof a first therapeutically effective amount of vibegron / day for a first period of time, followed by a second therapeutically effective amount of vibegron / day thereafter, said first therapeutically effective amount being between 50 mg and 75 mg per day; A pharmaceutical composition wherein said second therapeutically effective amount is between 75 mg and 100 mg per day, and said second therapeutically effective amount is greater than said first therapeutically effective amount.

2. The pharmaceutical composition of claim 1, wherein the subject is a human.

3. 2. The pharmaceutical composition of claim 1, wherein the first therapeutically effective amount is 50 mg / day.

4. 2. The pharmaceutical composition of claim 1, wherein the second therapeutically effective amount is 100 mg / day.

5. 2. The pharmaceutical composition of claim 1, wherein the first therapeutically effective amount is 50 mg / day and the second therapeutically effective amount is 100 mg / day.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the first period is from 1 week to 12 weeks.

7. The pharmaceutical composition of claim 6, wherein the first period is 8 weeks.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the treatment of overactive bladder is treatment of one or more symptoms selected from the group consisting of urge urinary incontinence (UUI), urgency, frequent urination, nocturia, or a combination thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the one or more symptoms are urge urinary incontinence (UUI), urgency or frequency of urination.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the subject is a female human.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the subject is a male human.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the subject is a human being over 65 years of age.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject suffers from severe renal dysfunction.

14. The method according to any one of claims 1 to 12, wherein the subject suffers from moderate renal dysfunction. Pharmaceutical compositions.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the subject is concomitantly receiving a CYP3A / P-glycoprotein inhibitor.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein vibegron is administered once a day.

17. 17. The pharmaceutical composition of claim 16, wherein vibegron is administered with a meal.

18. 17. The pharmaceutical composition of claim 16, wherein vibegron is administered without food.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein vibegron is in the form of a tablet.

20. 20. The pharmaceutical composition of claim 19, wherein the tablet is crushed prior to administration.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein vibegron is administered as a pharma- ceutically acceptable salt thereof.

22. The first therapeutically effective amount and / or the second therapeutically effective amount is a steady-state C ｍａｘ The pharmaceutical composition according to any one of claims 1 to 21, which provides:

23. The pharmaceutical composition according to any one of claims 1 to 21, wherein the first therapeutically effective amount and / or the second therapeutically effective amount provides a steady state AUC of vibegron of 331 ng·hr / mL to 3613 ng·hr / mL.

24. The first therapeutically effective amount and / or the second therapeutically effective amount have a T of vibegron of 0.5 to 6.0 hours. ｍａｘ The pharmaceutical composition according to any one of claims 1 to 21, which provides:

25. The first therapeutically effective amount and / or the second therapeutically effective amount are selected from the group consisting of: (i) Steady-state C of vibegron from 0 ng / mL to 313 ng / mL ｍａｘ ; (ii) a steady-state AUC of vibegron of 331 ng·hr / mL to 3613 ng·hr / mL; or (iii) T of vibegron from 0.5 hours to 6.0 hours ｍａｘ 22. The pharmaceutical composition according to any one of claims 1 to 21, which provides one or more of:

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein vibegron is effective in treating overactive bladder in 4 weeks, 3 weeks, or 2 weeks.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the subject experiences a mean change in systolic blood pressure from baseline of less than 2 mm / Hg following administration of the second therapeutically effective amount of vibegron.

28. 28. The pharmaceutical composition of claim 27, wherein the first therapeutically effective amount is 50 mg and the second therapeutically effective amount is 100 mg.

29. The pharmaceutical composition of any one of claims 1 to 26, wherein the subject experiences a mean change in diastolic blood pressure from baseline of less than 1 mm / Hg following administration of the second therapeutically effective amount of vibegron.

30. 30. The pharmaceutical composition of claim 29, wherein the first therapeutically effective amount is 50 mg and the second therapeutically effective amount is 100 mg.

31. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the subject experiences a lower mean change in systolic blood pressure after administration of a second therapeutically effective amount than the mean change in systolic blood pressure after administration of a first therapeutically effective amount.

32. 32. The pharmaceutical composition of claim 31, wherein the mean change in systolic blood pressure after administration of the second therapeutically effective amount is less than 1 mm / Hg.

33. 32. The pharmaceutical composition of claim 31, wherein the first therapeutically effective amount is 50 mg and the second therapeutically effective amount is 100 mg.

34. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the subject experiences a change in the mean number of urgency urinary incontinence (UUI) episodes from baseline of -1.3 to -2.5 over the treatment period.

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