Use of vibegron to treat overactive bladder

Abstract

To provide a method of treating overactive bladder.SOLUTION: Provided is a method comprising orally administering to a subject in need thereof an amount of from about 60 mg to about 90 mg (e.g., about 75 mg) of vibegron per day.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] Overactive bladder (OAB) is a chronic and sometimes debilitating condition of the lower urinary tract. The function of the urinary tract is to store and periodically release urine. This is achieved through central and peripheral nervous effects. Regulation of organ mechanisms and the resulting sympathetic and neurological functions of the autonomic nervous system and somatic motor pathways. The accumulation of neuronal stores, including various afferent and efferent pathways, provides coordinated control of the sympathetic and parasympathetic components of the nervous system. These require a harmonious integration of the bladder (detrusor) and the micturition reflex. and proximally controls the smooth muscle of the urethra and the striated muscle of the urethral sphincter.

[0002] From a pathophysiological point of view, overactive bladder is associated with detrusor overactivity. Characterized by symptoms of urgency, usually accompanied by frequency and nocturia, with or without urge incontinence. The prevalence of OAB in the United States and Europe is The prevalence of overactive bladder is estimated at 16 to 17% in the United States. However, it may 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. Functional side effects, including dry mouth, constipation, and possible CNS adverse effects (e.g., cognitive impairment), may be considered. Anti-muscarinic acid is limited by its modest efficacy and poor tolerability due to side effects related to its mechanism. The clinical use of antidepressants is limited. They are commonly prescribed in both clinical trials and in real life. Two antimuscarinic drugs, tolterodine and oxybutynin, both had high discontinuation rates. The rate is being seen.

[0004] β3-adrenergic receptor (β3-AR) activation relaxes the detrusor muscle in normal and pathological conditions This is an effective method to promote urinary accumulation. Most of the functional evidence comes from in vivo studies. β3-AR agonists have been shown to improve symptoms of OAB. To date, the β3-AR agonist mirabegron has shown efficacy in alleviating the symptoms of rheumatoid arthritis. (Astellas Pharma Global Development, Inc.) Only one has received marketing approval in the United States and Japan for the treatment of OAB. Rabegron activates β3-AR in the detrusor muscle of the bladder, which induces muscle relaxation and bladder Mirabegron has been used to reduce urination frequency, urinary incontinence, and urgency episodes. A decrease in mean voided volume and an increase in mean voided volume were 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 cell-based In vitro assays for β3-AR activation, β2-AR and β1-AR activation A potent and highly selective β3-adrenergic receptor agonist, showing >9,000-fold selectivity compared to It is a β3-AR agonist. Edmondson et al., J.Med. See Chem. 59:609-623 (2016). [ka]

[0006] Vibegron is disclosed in U.S. Patent Nos. 8,399,480 and 8,247,415. The compound is disclosed in the specification as a β3-AR agonist. The synthesis method is described in U.S. Patent Application Publication No. 2017 / 0145014 and U.S. Patent Application Publication No. 2015 / 00 No. 87832, No. 2016 / 0176884, and No. 2014 / 02 No. 42645. All cited publications are incorporated by reference in their entirety. and is hereby incorporated by reference in its 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 for treating overactive bladder, comprising administering to the patient an amount of 60 mg to 90 mg per day. The method includes orally administering vibegron of formula (I) to a subject in need thereof.

[0009] The present disclosure provides a unit dosage pharmaceutical composition comprising 60 mg to 90 mg of vibegron, Further provided is a unit dosage composition suitable for oral administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless expressly defined otherwise herein, the following terms Each shall have the meaning set forth below. Additional definitions are provided throughout this application. Describe the following.

[0011] As used in this specification and the appended claims, the singular forms "a," "an," and "the" The term "a" includes plural referents unless the context clearly dictates otherwise. The terms "one or more" and "at least one" are used throughout this specification. In certain embodiments, the terms "a" or "an" refer to In other embodiments, the terms "a" or "an" can mean "two or more" or includes "multiple".

[0012] Furthermore, as used herein, "and / or" may or may not include the other. , should be considered a separate disclosure of each of the two specified features or components. Thus, the term "and / or" as used herein in expressions such as "A and / or B" includes "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and" used in phrases such as "A, B, and / or C" is intended to mean "or" is intended to include each of the following embodiments: A, B, and C; 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 otherwise defined, all technical and scientific terms used herein are within the meaning of this disclosure. have the same meaning as commonly understood by those of ordinary skill in the relevant art.

[0014] The term "about" as used throughout this specification and claims in reference to numerical values ​​means any number that is within the skill of the art. This represents the range of accuracy that is familiar to and acceptable to those skilled in the art. Such a range of accuracy is ±10%. do.

[0015] The term "overactive bladder" generally refers to a condition that is accompanied by urge incontinence, possibly accompanied by frequency and nocturia. It refers to a clinical syndrome characterized by urgency, with or without urinary urgency.

[0016] As used herein, the term "urge urinary incontinence" (UUI) refers to the sudden, forceful need to urinate. Urinary incontinence means urinary incontinence accompanied by urgency and can be used interchangeably with "urgency incontinence" or "urgency incontinence" UUI occurs during exertion or physical activity (e.g., sports activities) or by sneezing or It is distinguished from stress urinary incontinence, which is urinary incontinence during coughing.

[0017] The term "disorder" as used herein means an acute or chronic impairment of function. For example, Renal dysfunction occurs when the kidneys are unable to maintain their normal function, resulting in the release of waste products and metabolic products into the blood. Refers to a medical condition in which things accumulate.

[0018] As used herein, the term "urgency" refers to a sudden, urge to urinate that is difficult to postpone. It means an uncontrollable urge to urinate.

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

[0020] As used herein, the term "free base" refers to a basic compound per se, not in the form of a salt. For example, vibegron free base is (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-carbo This refers to oxamide.

[0021] As used herein, the term "OAB wet" refers to urinary frequency and urgency accompanied by incontinence. Overactive bladder (OC) is defined as:

[0022] As used herein, the term "OAB dry" refers to urination frequency and urge to urinate without incontinence. It refers to overactive bladder defined by urgency.

[0023] The term "pharmaceutically acceptable salt" refers to a compound that is safe and effective for use in a subject and By salts of compounds is meant those which possess the desired biological activity.

[0024] The pharma- ceutically acceptable salts of basic compounds can be salts of organic or inorganic acids. In embodiments, organic and inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Acids include citric acid, maleic acid, mandelic acid, succinic acid, and methanesulfonic acid. Generally, the Journal of Pharmacology, the entire contents of which are incorporated herein by reference. See, Mechanical Science, 66, 2 (1977).

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

[0026] As used herein, the term "T max " is the dose of the drug at which the maximum plasma concentration is reached Refers to a later time.

[0027] As used herein, the term "AUC" refers to the profile of plasma concentration of a drug versus time after administration. This refers to the area under the curve of a lot.

[0028] The term "steady state" refers to a state in which the amount of drug reaching the system is approximately equal to the amount of drug leaving the system. Thus, at "steady state," the patient's body is The drug is excreted at approximately the same rate as it becomes available to the patient's system through absorption.

[0029] The term "treatment period" refers to the period during which a drug is administered to a subject. For example, a treatment period can include: The treatment period may be from about 2 weeks to about 2 years. In some embodiments, the treatment period is from 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 the drug can be assessed by measuring certain parameters and prolonging the duration of treatment. Efficacy measures can be assessed by calculating the change from baseline throughout the study. Parameters include, but are not limited to, urination, urge incontinence episodes, total incontinence episodes, and threatened episodes.

[0030] Treatment methods The present disclosure provides a method for treating overactive bladder while minimizing undesirable side effects. and administering vibegron to a subject in need thereof at a dosage such that the desired efficacy is maintained. Unexpectedly, the choice of dosage of vibegron provides So, C max Disproportionately increase the side effects of It can be lowered.

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

[0032] The present disclosure also provides a method of increasing bladder smooth muscle relaxation, comprising administering 50 mg to 10 mg of urea per day. 200 mg of vibegron orally to a subject in need thereof. to provide.

[0033] In some embodiments, the amount of vibegron administered per day is from about 55 mg to about 100 mg. 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 It is.

[0034] In some embodiments, the amount of vibegron administered per day is from 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 80mg, about 50mg to about 75mg, about 50mg to about 70mg, about 50mg to about 6 5 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg.

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

[0036] In some embodiments, the amount of vibegron administered per day is about 55 mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg or about 95 mg. In some embodiments, the amount of vibegron administered per day is In some embodiments, the amount of Vibegro administered per day is about 75 mg. The amount of nicotine is 75 mg.

[0037] In some embodiments, the amount of vibegron administered per day is about 50 mg. In some embodiments, the amount of vibegron administered per day is about 100 ml. In some embodiments, the amount of vibegron administered per day is 50 g. In some embodiments, the amount of vibegron administered per day is not 1 mg. Not 00mg.

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

[0039] In some embodiments, the subject is diagnosed with urge urinary incontinence (or urge urinary incontinence), urgency, urge to urinate, Patients have one or more of the following symptoms: frequent urination, frequent urination at night, and nocturia.

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

[0041] In some embodiments, the subject is over 18 years of age. The elephant is under about 18 years of age. In some embodiments, the subject is about 6 to about 18 years of age, about 6 to about 12 years of age, or about 12 to about 18 years of age. In some embodiments, the subject is In some embodiments, the subject is greater than about 25 years of age. In some embodiments, the subject is over about 30 years of age. In some embodiments, the subject is over 35 years of age. In some embodiments, the subject is over 40 years of age. In some embodiments, the subject is over 45 years of age. In some embodiments, the subject is over 55 years of age. In embodiments, the subject is over 60 years of age. In some embodiments, the subject is over 65 years of age. In some embodiments, the subject is over 70 years old. In this case, the subjects were over 75 years old.

[0042] In some embodiments, the method further comprises administering to the subject a unit dose comprising vibegron. In some embodiments, the subject is administered a dose of vibegron. The powder is administered orally in a crushed pharmaceutical unit dose.

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

[0044] In some embodiments, the subject has had prior OAB therapy. In this condition, subjects have not received any prior OAB therapy.

[0045] In some embodiments, the subject suffers from impaired renal function and is receiving about 75 mg of bilirubin per day. He was given Begron.

[0046] In some embodiments, vibegron can be administered as a medicament, including, for example, any of those listed in this application. In some embodiments, vibegron is administered in combination with a second pharmaceutical agent, such as In some embodiments, vibegron is administered in conjunction with a second pharmaceutical agent. In some embodiments, vibegron is administered prior to and / or subsequent to the second pharmaceutical agent. is administered later. The embodiments described below include such sequential administration.

[0047] In some embodiments, the subject is taking a cytochrome P450 inhibitor, such as a CYP3A inhibitor. The following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A Concurrently receiving, ingesting, or otherwise being exposed to drugs that are substrates of is.

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

[0049] CYP3A / P-glycoprotein inhibitors include, but are not limited to, amiodarone, Bezilol, clarithromycin, dronedarone, itraconazole, lapatinib, ropinib Navirin and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil, curcumin, Closporin A, eltrombopag, atazanavir and ritonavir, clarithromycin, Cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, ampicillin (e.g., single dose), simeprevir, p-aminohippuric acid (PAH)(b), provir Robencid, teriflunomide, cimetidine, dolutegravir, isavuconazole, ranolavir These include aztreonam, trimethoprim, and vandetanib.

[0050] In some embodiments, the subject is receiving a muscarinic receptor antagonist concurrently. have been taking or otherwise exposed to muscarinic receptor antagonists.

[0051] Muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, Droxizine, 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.

[0052] In some embodiments, the subject is administered about 75 mg of vibegron per day, and Are you concurrently receiving, taking, or otherwise using a muscarinic receptor antagonist? Being exposed to phospholipid receptor antagonists.

[0053] In some embodiments, the subject is administered about 75 mg of vibegron per day, and If you are concurrently taking, or are taking, or are otherwise inhibiting CYP3A have been exposed to harmful agents.

[0054] In some embodiments, the subject is administered about 75 mg of vibegron per day, and Are you concurrently receiving, taking, or otherwise administering a P-glycoprotein inhibitor? are exposed to protein inhibitors.

[0055] In some embodiments, the subject is not concurrently receiving or taking a beta-blocker. nor are they otherwise exposed to beta-blockers.

[0056] In some embodiments, the subject is not concurrently receiving or taking amlodipine. These patients are not or would otherwise be exposed to amlodipine.

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

[0058] In some embodiments, vibegron is administered without food 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 is fasting or fasting. is administered.

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

[0060] Baseline blood pressure (BP) and heart rate (HR) data for subjects taking vibegron The change from baseline is not substantially different from subjects taking a placebo. In embodiments, subjects are assessed for a decrease in schizophrenia from baseline over the course of a treatment period (e.g., 8 weeks or 12 weeks). Received the mean maximum change in systolic blood pressure (SBP) and the mean maximum change from subjects taking placebo Major changes were less than 2.0mm / Hg, less than 1.9mm / Hg, less than 1.8mm / Hg, and 1. Less than 7mm / Hg, Less than 1.6mm / Hg, Less than 1.5mm / Hg, Less than 1.4mm / Hg Over, Less than 1.3mm / Hg, Less than 1.2mm / Hg, Less than 1.1mm / Hg, 1.0mm / Hg, less than 0.9mm / Hg, less than 0.8mm / Hg, less than 0.7mm / Hg, 0 Less than .6mm / Hg, or less than 0.5mm / Hg.

[0061] In some embodiments, the subject is administered about 75 mg of vibegron per day and Subjects receiving placebo had a mean mean of less than 2 mm / Hg over the course of treatment (e.g., 8 weeks or 1 The mean maximum change in SBP from baseline over the course of 2 weeks is then measured. In the study, subjects were given approximately 75 mg of vibegron per day and a placebo. Subjects reported a baseline blood glucose level of less than 1 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) Receive the mean maximum change in SBP from the line.

[0062] In some embodiments, the subject is over 65 years of age and receives about 75 mg of bevacizumab per day. Treatment duration <2 mm / Hg from subjects receiving Glon and taking placebo Receive the mean maximum change in SBP from baseline over the course of 8 or 12 weeks (e.g., week 8 or week 12) In some embodiments, the subject is over 65 years of age and receives about 75 mg of bevacizumab per day. Treatment duration <1 mm / Hg from subjects receiving Glon and taking placebo Receive the mean maximum change in SBP from baseline over the course of 8 or 12 weeks (e.g., week 8 or week 12) .

[0063] In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. From subjects receiving GLON and taking placebo, the duration of treatment (e.g., 8 weeks or 1 A mean maximum change in SBP from baseline of less than 2 mm / Hg over the course of 2 weeks In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. From subjects receiving GLON and taking placebo, the duration of treatment (e.g., 8 weeks or 1 A mean maximum change in SBP from baseline of less than 1 mm / Hg over the course of 2 weeks .

[0064] In some embodiments, the subject is administered vegetative therapy throughout the treatment period (e.g., 8 weeks or 12 weeks). The mean maximum change in diastolic blood pressure (DBP) from baseline was compared with placebo. The mean maximum change from control was less than 2.0 mm / Hg, less than 1.9 mm / Hg, and less than 1.8 mm / Hg, less than 1.7mm / Hg, less than 1.6mm / Hg, less than 1.5mm / Hg, 1 Less than .4mm / Hg, Less than 1.3mm / Hg, Less than 1.2mm / Hg, 1.1mm / Hg Less than, 1.0mm / Hg, less than 0.9mm / Hg, less than 0.8mm / Hg, 0.7m m / Hg, less than 0.6 mm / Hg, or less than 0.5 mm / Hg.

[0065] In some embodiments, the subject is administered about 75 mg of vibegron per day and Subjects receiving placebo had a mean mean of less than 2 mm / Hg over the course of treatment (e.g., 8 weeks or 1 The mean maximum change in DBP from baseline over the course of 2 weeks is then measured. In the study, subjects were given approximately 75 mg of vibegron per day and a placebo. Subjects reported a baseline blood glucose level of less than 1 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) Average maximum change in DBP from the line undergoing.

[0066] In some embodiments, the subject is over 65 years of age and receives about 75 mg of bevacizumab per day. From subjects receiving GLON and taking placebo, the duration of treatment (e.g., 8 weeks or 1 A mean maximum change in DBP from baseline of less than 1 mm / Hg over the course of 2 weeks .

[0067] In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. From subjects receiving GLON and taking placebo, the duration of treatment (e.g., 8 weeks or 1 A mean maximum change in DBP from baseline of less than 2 mm / Hg over the course of 2 weeks In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. From subjects receiving GLON and taking placebo, the duration of treatment (e.g., 8 weeks or 1 A mean maximum change in DBP from baseline of less than 1 mm / Hg over the course of 2 weeks .

[0068] In some embodiments, the subject is over 45 years of age and receives about 75 mg of vibegron per day. Treatment duration <1 mm / Hg from subjects taking placebo, administered once daily The mean maximum change in DBP from baseline over the course of the study (e.g., 8 or 12 weeks) and the progression Subjects receiving placebo had a mean mean of less than 1 mm / Hg over the course of treatment (e.g., 8 weeks or 1 The mean maximum change in SBP from baseline over the course of 2 weeks will be received.

[0069] In some embodiments, the subject is over 65 years of age and receives about 75 mg of vibegron per day. Treatment duration <1 mm / Hg from subjects taking placebo, administered once daily The mean maximum change in DBP from baseline over the course of the study (e.g., 8 or 12 weeks) and the progression Subjects receiving placebo had a mean mean of less than 1 mm / Hg over the course of treatment (e.g., 8 weeks or 1 The mean maximum change in SBP from baseline over the course of 2 weeks will be received.

[0070] In some embodiments, the subject is assessed for baseline schizophrenia throughout the treatment period (e.g., 8 weeks or 12 weeks). Systolic blood pressure (SBP) from the line: less than 10mm / Hg, less than 9.5mm / Hg , less than 9mm / Hg, less than 8.5mm / Hg, less than 8mm / Hg, less than 7.5mm / Hg , less than 7mm / Hg, less than 6.5mm / Hg, less than 6mm / Hg, less than 5.5mm / Hg , or undergoes a mean maximum change of less than 5 mm / Hg.

[0071] In some embodiments, the subject is administered about 75 mg of vibegron per day and <0 mm / Hg from baseline throughout the treatment period (e.g., 8 or 12 weeks) Receive the mean maximum change in SBP.

[0072] In some embodiments, the subject is over 65 years of age and receives about 75 mg of bevacizumab per day. Patients were administered GLON and maintained a blood glucose level of less than 10 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks). The mean maximum change in SBP from baseline was received.

[0073] In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. Patients were administered 100 mg / kg / day of ... treatment and had a mean S score of 100 mg / kg / day from baseline over the treatment period (e.g., 8 or 12 weeks). undergo a mean maximum change in BP of less than 10 mm / Hg.

[0074] In some embodiments, the subject is assessed for baseline schizophrenia throughout the treatment period (e.g., 8 weeks or 12 weeks). Diastolic blood pressure (DBP) from Sline: less than 7mm / Hg, less than 6.5mm / Hg, Less than 6mm / Hg, less than 5.5mm / Hg, less than 5mm / Hg, less than 4.5mm / Hg, Less than 4mm / Hg, less than 3.5mm / Hg, less than 3mm / Hg, less than 2.5mm / Hg, or undergoes a mean maximum change of less than 2 mm / Hg.

[0075] In some embodiments, the subject is administered about 75 mg of vibegron per day to treat DBP < 7 mm / Hg from baseline throughout the treatment period (e.g., 8 or 12 weeks) The average maximum change is 100%.

[0076] In some embodiments, the subject is administered about 75 mg of vibegron per day to treat Baseline mean number of urinations per 24 hours over the treatment period (e.g., 8 or 12 weeks) The change from the line is shown here for subjects taking a placebo. The difference from placebo is 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 preceding values be.

[0077] In some embodiments, the subject is administered about 75 mg of vibegron per day to treat Approximately -1% reduction in the average number of urinations per 24 hours over the treatment period (e.g., 8 or 12 weeks) .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 any of the preceding values The change from baseline ranges between either of the two.

[0078] In some embodiments, the subject has ≥ 1 urge urinary incontinence (UUI) episode per day prior to treatment. had an average of 10 episodes, were receiving approximately 75 mg of vibegron per day, and had UUI The mean number of episodes from baseline through the treatment period (e.g., 8 or 12 weeks) These changes were compared here with those seen in 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 any two of the preceding values The range is between .

[0079] In some embodiments, the subject is administered about 75 mg of vibegron per day, and The mean number of UUI episodes over the treatment period (e.g., 8 or 12 weeks) was approximately 1.3 to about -2.5, for example, 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 change from baseline between any two of the preceding values .

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

[0081] In some embodiments, the subject has ≥ 1 urge urinary incontinence (UUI) episode per day prior to treatment. had an average of 10 episodes, were receiving approximately 75 mg of vibegron per day, and had a treatment duration of 10 days. A small reduction in the average number of UUI episodes per day over a period (e.g., 8 or 12 weeks) at least 50%, at least 55%, at least 60%, at least 65%, at least 7 A reduction of 0%, at least 75%, at least 80%, or at least 85% is experienced.

[0082] In some embodiments, the subject has an average of ≧1 urgency episode per day prior to treatment. and receiving approximately 75 mg of vibegron per day and for a treatment period (e.g., 8 weeks or A reduction of at least 30% of the average number of urgency episodes per day over the first 12 weeks of treatment at least 40%, at least 45%, at least 50%, at least 55%, at least 6 A decrease of 0%, at least 65%, at least 70%, or at least 75% is experienced.

[0083] In some embodiments, the subject is over 65 years of age and receives about 75 mg of bevacizumab per day. Patients receiving GLON and had a blood glucose level of less than 7 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) Receive the mean maximum change in DBP from baseline.

[0084] In some embodiments, the subject is over 45 years of age and receives about 75 mg of bevacizumab per day. Patients receiving GLON and had a blood glucose level of less than 7 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) Receive the mean maximum change in DBP from baseline.

[0085] In some embodiments, a subject over 45 years of age receives about 75 mg of vibegron daily. A baseline blood glucose level of less than 7 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) was administered once. Mean maximum change in DBP from baseline and less than 10 mm / Hg over the course of treatment (e.g. The mean maximum change in SBP from baseline through the end of study (week 1, week 8 or week 12) will be received.

[0086] In some embodiments, a subject over 65 years of age receives about 75 mg of vibegron daily. A baseline blood glucose level of less than 7 mm / Hg throughout the treatment period (e.g., 8 or 12 weeks) was administered once. Mean maximum change in DBP from baseline and less than 10 mm / Hg over the course of treatment (e.g. The mean maximum change in SBP from baseline through the end of study (week 1, week 8 or week 12) will be received.

[0087] In some embodiments, vibegron has an onset of action of about 4 weeks. In some embodiments, vibegron provides an onset of action in about 3 weeks. Begron has an onset of action of about 2 weeks. "Onset of action" as used herein means This refers to the time it takes for a drug's effects to become noticeable after administration.

[0088] Unit Dose Pharmaceutical Composition The present disclosure provides a unit dose pharmaceutical composition comprising a dosage amount of vibegron as disclosed herein. The present invention provides a unit dosage composition suitable for oral administration. Oral dosage forms include, for example, liquid This includes dosage forms such as tablets, capsules, and gelcaps. It is recognized by those skilled in the art that the unit dose composition may be in the form of a tablet. In some embodiments, the unit dose composition is a solid dosage form such as a tablet, It is.

[0089] Pharmaceutically acceptable excipients include lactose, microcrystalline cellulose, starch, calcium carbonate, and the like. , Magnesium Stearate, Stearic Acid, Talc, Colloidal Silicon Dioxide, stabilizing agents such as glycerol, croscarmellose sodium, and hydroxypropyl cellulose In some embodiments, the excipients disclosed herein are generally recognized as being safe. The unit dose pharmaceutical composition comprises a diluent, a disintegrant, a binder, and a lubricant. Remington's Pharmacy, the contents of which are incorporated herein by reference. tical Sciences,20th ed.,Mack Publishing, See Easton PA (2000).

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

[0091] Oral dosage forms can be prepared by standard pharmaceutical manufacturing techniques. For example, wet granulation, wet milling, fluid bed drying, dry milling, lubrication, tabletting, and aqueous filling. Includes film coating.

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

[0093] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from about 55 mg to about 100 mg. g, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 10 0 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 Vibegro Includes

[0094] In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises from 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 Contains 50 mg to about 60 mg, or 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 , about 65 mg to about 85 mg, or about 70 mg to about 80 mg of vibegron. In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises 60 mg to 90 mg, 65 mg to 85 mg, or 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 9 5 mg of vibegron. In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises: In some embodiments, the unit dose pharmaceutical composition of the present disclosure comprises about 75 mg of vibegron. contains 75 mg of vibegron.

[0097] 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 may be milled prior to oral administration. can.

[0098] In vitro assays Vibegron was tested in several in vitro assays to demonstrate potent potency at the human β3-AR. Its agonist potency, its selectivity for other human β-AR subtypes, and its potency against other species-derived Its potency at the β3-AR was determined.

[0099] In Chinese hamster ovary (CHO) cells stably expressing human β3-AR, Vibegron activity was significantly increased in a functional assay measuring the increase in cellular adenylyl cyclase activity by The degree of activation in response to a proven full agonist (isoproterenol) was measured. Compound EC 50 was measured together.

[0100] Vibegron has an EC 50 and 84% activation to isoproterenol. It is a potent and selective agonist of the β3-AR, having is small, consistent with the low plasma protein binding of this compound (49% unbound in humans). Significant serum changes were observed (EC 50 = 1.7 nM, 102% activation).

[0101] Furthermore, vibegron was shown to be effective against the β3-AR compared with the β1- and β2-AR subtypes. The selectivity of the β1-AR or β2-AR was tested in CHO cells expressing the β1-AR or β2-AR. Vibegron has a higher effect on β3-AR than on β1-AR and β2-AR. is highly selective for β3-AR activation in cell-based in vitro functional assays. It shows >9000-fold selectivity for β1-AR or β2-AR.

[0102] Bibegron IC 50 were prepared from cells expressing recombinant β1, β2, or β3-AR. The binding activity of vibegron was determined in a standard competitive binding assay using membranes prepared from filters. -Radiolabeled antagonist of nonspecific β-AR in binding assay 125 I- Regarding CYP competition, β3-AR IC 50 = 193 nM (86 ng / mL) Binding parent for potent in vitro agonist activity of vibegron at human β3-AR The relative lack of affinity indicates that the compound binds to the unbound receptor versus the bound receptor. The relative abilities of the antagonists to compete for each other (both of which are measured by antagonist binding assays) In addition, the compound exhibited a binding competition assay As shown, the compound does not bind to either the β1-AR or the β2-AR. This confirms that it is neither an agonist nor an antagonist of the receptor.

[0103] Absorption, Distribution, Metabolism, and Excretion Vibegron reaches maximum plasma concentrations approximately 1 to 3 hours after oral administration in healthy subjects. degree(C max ) is reached. max and AUC were dose-proportional up to 400 mg. Steady-state concentrations were achieved within 7 days of once-daily dosing of vibegron. The geometric mean accumulation ratio of steady-state AUC was approximately 2 in young male subjects and 4.1 in elderly subjects (male and The mean exposure to vibegron in young Japanese male subjects was approximately 2.8 in non-Japanese male subjects. Moderate (<2-fold) increase in exposure after single dose compared with exposure in young male subjects .

[0104] Repeated oral doses of 150 mg vibegron with food in healthy middle-aged and elderly women Administration of 10 mg / kg / day reduced the pulmonary circulation by approximately 42% and 59% on day 1 and 14, respectively, compared to the same dose in the fasted state. Mean AUC of approximately 20% and 43% 0-24 and C max brought value.

[0105] A Two-Part, Open-Label Study to Investigate the Pharmacokinetics of Vibegron in Patients with Hepatic Insufficiency In a single-dose study, 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 via various routes, including urinary excretion, biliary excretion, and hepatic metabolism. CYP3A4 is the main CYP responsible for in vitro metabolism, but metabolism is It appears to play only a minor role in the excretion of ethanol. In the study, the majority of the recovered dose was excreted as unchanged vibegron. The average total recovery of radioactivity in excreta was 79%, approximately 59% and 20% of this dose. % was recovered in feces and urine, respectively.

[0107] The majority of the vibegron dose was found to be excreted as unchanged parent drug. Seven trace metabolites were detected in urine and feces, six of which (M1, M3, M4 Metabolite M7, M8, M9, M10, M11, and M17) were oxidative metabolites (see Figure 2). is the O-glucuronide conjugate of vibegron. 14 C] derived from vibegron The concentration of radioactivity was 0.3 μM with an average C max and T of 2.5 hours max 2 and The radioactivity profiles of plasma samples at 4 and 5 h were approximately 78% and 7% of the plasma radioactivity, respectively. 3% was accounted for by unchanged vibegron and also by the O-glucuronide (M7). was shown to be the major circulating metabolite (approximately 12-14% of all circulating drug-related substances). Two additional minor oxidative metabolites, M4 (4-6%) and M17 (6-7%), were also identified. , was detected in human plasma. Radioactivity was too low to be profiled. Subsequent time points allowed for half-life estimation. Thanks to ample data from the study, a possible accumulation of circulating metabolites in plasma was not expected. It was.

[0108] Vibegron has a terminal half-life of 59 to 94 hours in young and elderly subjects. 1 / 2. At steady state, the mean renal clearance (CLR) in young men is ranged from 150 to 187 mL / min across dose levels in the elderly subjects, The CLR in both men and women was 127 mL / min, which was slightly lower. Both are steady state (fe 0-24hr There is a tendency for the proportion of the dose excreted in the This indicates that bioavailability increases with increasing dose. Reflects. 0-24hr ,ss was similar in young men and older men, The rate was approximately 14% at 100 and 150 mg in elderly subjects and approximately 17% at 100 mg in elderly subjects. The mean fe in young Japanese subjects 0-24hr and C.L. R is for non-Japanese subjects. was similar to that observed. EXAMPLES

[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 evaluated in two double-blind, randomized, placebo-controlled This was a single, ascending-dose, oral Phase 1 study. All subjects were healthy adults. A summary of the results is shown in Table 2. Single oral doses of vibegron ranging from 2 to 600 mg After administration, the mean t max Terminal elimination half-life t 1 / 2 Is Ken In healthy young male subjects, the mean scores ranged from 43 to 700 mg for all doses from 10 to 600 mg. Systemic exposure was greater than proportional to dose up to 600 mg.

[0112] Exposure to vibegron in young Japanese men was higher than that in young non-Japanese men. , moderately increased. Vibegron AUC 0-inf Geometric mean ratio (GMR; Japan The mean mean mean 90% CI for the 10 mg group was 1.75–1.75 for the 10 mg group, and 1.75–1.75 for the 10 mg group. (1.38, 2.23) at 300 mg to 1.17 (0.99, 1.40) at 300 mg. Vibegron C max The GMR (Japanese / non-Japanese) and 90% CI for It appeared to be unaffected by dose, with a mean of 1.75 (1.35, 2 .26) (pooled). max Median of values ​​(1 to 3 time) and the harmonic mean apparent terminal half-life t 1 / 2 The estimates (58 to 71 hours) are The results were similar to those in Japanese subjects. U.C. 0-inf and C max increases more than proportionally with dose up to 300 mg It seemed like it.

[0113] Single-dose pharmacokinetics of 50 mg vibegron in non-Japanese elderly male and female subjects The mean AUC values ​​after administration of 50 mg vibegron in elderly male and female subjects were 0-inf and C max than the corresponding values ​​after 50 mg in young men, respectively. The results were approximately 70% and 60% higher. max was similar to that observed in young men. There was (T max Median = 1.0 hours) is the apparent terminal half-life t 1 / 2 is an elderly person was slightly longer than that of young people (harmonic mean t 1 / 2 = 52 hours vs. 92 hours). Vibegron exposure in women was somewhat higher than in older men.

[0114] [Table 2]

[0115] 2.2 Repeated-dose pharmacokinetics The multiple-dose pharmacokinetics of vibegron were evaluated in two randomized, double-blind, placebo-controlled In a Phase 1 ascending dose multiple dose study, healthy non-Japanese young male subjects, middle-aged men and women in both sexes, as well as in elderly male and female subjects, and in healthy young male Japanese subjects. The study was conducted in male and female subjects and in elderly subjects. The Japanese subjects received repeated doses ranging from 5 to 400 mg for 14 days. The pharmacokinetic results after 14 days of dosing are shown in Table 3. Stop and indicate.

[0116] On average, women received 50% higher exposure (AUC) compared to men, regardless of age. Steady-state AUC after QD administration of 100 mg vibegron in elderly subjects and C max The values ​​were approximately 1.7- and 1.3-fold higher, respectively, compared with younger men.

[0117] GMC max The AUC accumulation ratio was 1.0 for Japanese subjects at the 200 mg dose level. On average, the steady-state exposures in young Japanese male subjects were .78 and 1.84. was approximately 30% higher in young male non-Japanese subjects than in non-Japanese subjects; the difference in exposure was statistically significant. Vibegron AUC and C max (pooled across doses) GMR (Japanese / (non-Japanese) and the corresponding 90% CI were 1.27 (1.09, 1.48) and 1.29 (1.13, 1.26), respectively. and 1.33 (1.06, 1.67).

[0118] On average, the steady-state exposure at day 14 in elderly male and female Japanese subjects was 35% higher than in older male and female non-Japanese subjects; the difference in exposure was not statistically significant. Vibegron AUC in the elderly panel 0-24 and C max The 14th day of G The MR (Japanese / non-Japanese) and the corresponding 90% CI were 1.35 (1.09 , 1.68) and 1.82 (1.32, 2.51).

[0119] [Table 3]

[0120] 2.3 Bioavailability and Bioequivalence Five Phase 1 studies were conducted using a capsule formulation of vibegron, whereas seven One Phase 1 study and one Phase 2b study used a tablet formulation. An open-label, randomized, two-period, crossover PK study in male subjects , Vibegron capsule (1 x 150 mg capsule) and tablet (3 x 50 mg tablets) formulations Single-dose pharmacokinetics were compared.

[0121] 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.

[0122] [Table 4]

[0123] Open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover - Phase 1 studies have demonstrated that two tablets with slightly different compositions are available: an aqueous tablet (test) and The relative bioequivalence of the non-aqueous tablet (reference standard) was evaluated.

[0124] [Table 5]

[0125] 2.4 Effect of food on oral absorption The effect of food on the pharmacokinetics of a single dose of vibegron 50 mg was evaluated in two randomized controlled trials. In a double-blind, placebo-controlled, single-ascending dose phase 1 study, The study was conducted in young Japanese men, whereas the efficacy of vibegron 150 mg in middle-aged women was evaluated. The effect of food on the repeated-dose pharmacokinetics of 100 mg of 10 ... The pharmacokinetic results were evaluated in a controlled, multiple-ascending dose Phase 1 study. A summary of the pharmacokinetic results is listed in Table 6. do.

[0126] Administration of 50 mg vibegron with a high-fat meal in non-Japanese young men showed no significant difference in fasting Compared with administration in the non-steroidal anti-inflammatory state, AUC 0-inf and C max 46% and 67% respectively A decrease in T max This resulted in a delay in the standard Japanese Administration of 50 mg of vibegron with breakfast was comparable to non-meal-treated subjects receiving the same dose with a high-fat meal. The AUC was almost the same as the results for Japanese male subjects. 0-inf and C max 3 of each This resulted in a 7% and 52% decrease.

[0127] Administration of multiple oral doses of 150 mg vibegron with food in healthy middle-aged women Mean AUC on Day 14 compared to the same dose in the fasted state 0-24hr and C ma x This resulted in a 20% and 47% decrease in T max is the fasting state and In comparison, it was slower in the fed state (6.0 vs. 2.0 h).

[0128] [Table 6]

[0129] 2.5 Pharmacokinetics in target disease populations Randomized, double-blind, placebo- and active-controlled study in patients with OAB A parallel-group, two-part Phase 2b study of tro ugh ) were measured; mean (±SD) C trough were 27.4 (±18.3) ng / mL and 73.6 (±65.5), respectively. )ng / mL. The mean (±SD) C trough The mean mean serum creatinine concentration was 15.2 (±5.07) ng / mL. Mean (±SD)C trough The values ​​were 31.9 (±11.5) in healthy young men. ranged from 54.2 (±15.3) in healthy older adults.

[0130] Example 3 Pharmacokinetics in Special Populations 3.1 Effect of age Vibegron exposure was assessed in young (18 to 45 years), middle-aged (46 to 64 years), and elderly Exposure was assessed in middle-aged men and in young men (65 to 85 years old) and women. whereas plasma concentrations were similar in elderly compared with middle-aged and younger subjects. After a single 50 mg dose, vibegron AUC 0-inf and C max High The elimination half-life t 1 / 2 was a randomized, double-blind, placebo-controlled, dose-escalating, single-dose study. At 92 hours, this was longer in older subjects compared with 52 hours in younger subjects. Vibegron AUC 0-24h and C max Values ​​are randomized, double-blind, placebo In a controlled, multiple-ascending dose study, older adults had approximately 10% more vasodilatory cerebrospinal fluid (CCE) than younger adults, respectively. In addition, the geometric mean accumulation ratios of steady-state AUC were approximately 0.7 and 1.3 times greater in young men. The AUC was approximately 2 in the male and 2.8 in the elderly. 0-24 and C m ax were increased by approximately 35% and 82%, respectively, compared with elderly non-Japanese subjects.

[0131] 3.2 Gender influence The effect of gender on steady-state vibegron exposure following administration of 100 or 150 mg was assessed in a randomized controlled trial. The efficacy and safety of bisphosphonates was evaluated in a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Glon plasma concentrations were similar in middle-aged men compared with younger men; however, Exposure was somewhat higher in middle-aged women (approximately 1.5% in middle-aged women) compared with middle-aged men. 2-fold higher steady-state AUC), which is consistent with the exposure in older women compared with the exposure in older men. This was also observed when comparing

[0132] 3.3 Effects of renal dysfunction Single-agent analysis in 24 patients with renal dysfunction (severe 8, moderate 8, and mild 8) The pharmacokinetics of vibegron 100 mg administered once were evaluated in an open-label, single-dose PK study in eight subjects. The pharmacokinetic parameters and the efficacy and safety of cyclophosphamide were compared with those of healthy control subjects with varying degrees of renal impairment. A summary of the statistical comparisons between patients with and their healthy counterparts is shown in Table 7.

[0133] Mild (eGFR ≥ 60 to < 90 mL / min / 1.73 m 2 ), moderate (eGFR≧30 to <60mL / min / 1.73m 2 ), and severe (eGFR < 30 mL / min / 1.73 m 2 Vibegron AUC in patients with renal impairment (but not undergoing dialysis) 0-in f were 49%, 106%, and 83% higher, respectively, compared with healthy matched control subjects. Vibegron C in patients with mild, moderate, and severe renal impairment max A healthy response These were 96%, 68%, and 42% higher, respectively, than control subjects. The degree of functional impairment increased with increasing vibegron AUC 0-inf was associated with an increase in C ma x No clear trends were observed. Reduced 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 is 1 mL / min / 1.73 m of eGFR. 2 Increasing Based on this linear relationship, the mean increase in the mean for healthy subjects was approximately 0.8%. The CL / F ratios for the mild, moderate, and severe populations were 0.81, 0.64, and 0.87, respectively. The corresponding predicted ratios for AUC were 1.24, 1.5 7 and 2.00. Modeling the relationship between CL / F and creatinine clearance Similar results were obtained by administering the same amount of The proportion of the dose excreted in urine throughout the sampling interval (fe[urine]48hr) was Patients with mild, moderate, and severe renal impairment had a significantly higher mean ... Compared with matched control subjects, these reduced CLR by 39%, 65%, and 82%, respectively. Fe[urine]48hr was significantly higher in patients with mild renal dysfunction (8.5%) and in matched healthy controls ( 7.9%) in patients with moderate and severe renal impairment, and 5.5 and 5.9%, respectively. % and 2.1%.

[0134] [Table 7]

[0135] 3.4 Effects of liver damage The pharmacokinetics of a single dose of vibegron 100 mg was evaluated in a two-part, open-label, single-dose Phase 1 study. In a phase 2 study, moderate liver impairment (Child-Pugh scale 7 to 9) was Eight patients with 100% CI, 0.01 to 0.25 were randomly assigned to receive a randomized controlled trial. Statistical comparison of the pharmacokinetic parameters of vibegron is shown in Table 8. AUC for patients with moderate hepatic impairment and healthy control subjects 0-inf and C max G The MR (90% CI) was 1.27 (0.96, 1.67) and 1.35 (0. 88, 2.06), which indicates that moderate liver injury is a clinically relevant response to vibegron exposure. This suggests that there was no significant impact.

[0136] [Table 8]

[0137] 3.5 Drug interaction studies Conducted four drug interaction studies evaluating vibegron in combination with six compounds Table 9 shows the effect of ketoconazole, diltiazem, or tol- The effects of Terodine are summarized in Table 10. Digoxin, ethinyl estradiol, and levothyroxine are also shown. Summarize the effects of vibegron on the pharmacokinetics of bonorgestrel or tolterodine. show.

[0138] Strong CYP3A4 / P-gp inhibitor, ketoconazole 200 mg, and moderate CY Repeated administration of P3A4 / P-gp inhibitor, diltiazem 240mg, and vibegron 100mg g. GM vibegron AUC 0-inf and C max teeth , 2.08-fold and 2.22-fold, respectively, in the presence of repeated doses of 200 mg ketoconazole. Increased. GM vibegron AUC 0-inf and C max 240mg or 180mg In the presence of repeated doses of diltiazem, the increases were 63% and 68%, respectively. 1 / 2 were administered with vibegron alone, with diltiazem, or with ketoconazole. The mean time to death was 75, 75.4, and 80.2 hours for the ketoconazole and Vibegron t in the presence of diltiazem 1 / 2 The fact that there was no increase in However, these interactions were not clinically significant. Tolterodine ER 4 mg is not believed to have any adverse effect on the pharmacokinetics of vibegron. It had no effect.

[0139] Repeated doses of vibegron were evaluated in combination with the p-gp substrate, digoxin. AUC of digoxin when coadministered with ronate 0-inf 90% about GMR The CIs were within the range of 80-125% bioequivalence, which is consistent with the results for vibegron. However, these results suggested that it did not affect digoxin pharmacokinetics to a clinically significant extent. Ethinylestradiol (EE) and levonorgestrel (LNG), i.e. oral contraceptives The pharmacokinetics of two common components of pregnancy-related drugs was not altered by repeated administration of vibegron. The AUC and C of EE max GMR for EE / LNG alone The 90% CI for NG + vibegron were within 0.8 and 1.25. AUC and C of LNG max increased by 18 to 21% in the presence of repeated doses of vibegron. Although the increases were significant, these increases were not considered clinically significant. When coadministered with tolterodine ER 4 mg, 0 mg or 150 mg, no clinically significant No significant pharmacokinetic interactions occur.

[0140] [Table 9]

[0141] [Table 10]

[0142] 3.6 Effect on QT interval prolongation The effect of vibegron on the QTc interval was evaluated in a single oral dose study. of healthy subjects received a single dose of 400 mg of vibegron, a single dose of 200 mg of vibegron, A single dose of moxifloxacin 400 mg and a single dose of vibegron and matching placebo was given.

[0143] The 400 mg dose of vibegron resulted in a 4.60 (2.71, 6.48) millisecond increase in pulmonary function at 1 hour after administration. The maximum mean difference from placebo in QTcF was 0.5–1.5 seconds (90% CI). Similar results were noted in QTcF after a single dose of 200 mg, where placebo The maximum LS mean difference (90% CI) between the 8) milliseconds. The upper ends of the 90% CIs for all mean differences were below the 10 millisecond target. A statistically significant effect of moxifloxacin on QTcF was observed (Table 11). Ta.

[0144] GM(CV%)C obtained after a single 200mg dose max and AUC 0-23.5h r were 366 (50.4) ng / mL and 2270 (37.3) ng h / mL, respectively. Vibegron C max is a double-blind, randomized, placebo-controlled, alternating (Panels A and B) In a multiperiod, single-dose, oral, ascending-dose Phase 1 study, This was 1.63 times the value obtained in elderly subjects receiving repeated doses of 0 mg, but UC was almost the same. GM (CV%) obtained after a single dose of 400 mg max and AUC 0-23.5hr were 1020 (39.9) ng / mL and 6450 (34.0) ng·h / mL. max and AUC 0-23.5hr value was 4.5 times the value obtained in elderly subjects receiving multiple doses of vibegron 100 mg. 5 times and 2.89 times.

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

[0146] [Table 11]

[0147] Example 4 Clinical Efficacy Data Men with OAB (stratified as OAB wet and OAB dry) A randomized, double-blind, placebo- and active-controlled study of vibegron in men and women Part 1 evaluated the safety, tolerability and safety of vibegron in patients with refractory bronchitis. A dose ranging study to evaluate the tolerability and efficacy of vibegron and tolterodine This was a proof of concept study of coadministration with ER 4 mg. 980 subjects were randomized equally to one of seven treatment arms in a double-blind fashion. 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 Part 2 will continue to evaluate the safety and efficacy of coadministration. In part 2, 408 subjects were randomized in a double-blind fashion to one of four treatment arms. Patients were randomized in a 2:2:2:1 ratio to one of two treatments: vibegron 100 mg, tolte Rosin ER 4mg, Tolterodine ER 4mg with Vibegron 100mg, or Pla Sebo (once daily for 4 weeks). Subjects in both Part 1 and Part 2 were treated with a 1-year extension. Participants had the option to enroll in the study for each of the following: strong urgency, total incontinence, and urge incontinence. They were asked to keep a voiding diary to record the occurrence of episodes. Part 1 and Part 2 Efficacy data for are summarized here.

[0148] At baseline, subjects were required to have a voiding diary with an average of ≥8 voids per diary day. In addition, subjects in the OAB wet layer must have Patients must have a mean number of urge incontinence episodes of ≥ 1 per 100 patients. Subjects in this stratum had a mean number of ≥ 3 urgency episodes per diary day and All subjects must have an average of <1 urge incontinence episode per 100 subjects. In this case, the total number of urge incontinence episodes must not exceed the total number of stress incontinence episodes. It won't happen.

[0149] The primary objective of this study was to evaluate the efficacy and safety of the selected vibegron dose (alone or in combination with tolterodine) To evaluate the safety and tolerability of treatment at week 8 compared with placebo The aim of the study was to determine the dose-related reduction in the mean number of voids per day.

[0150] In part 1, placebo was compared in the vibegron 100 mg and 50 mg treatment groups at week 8. There was a statistically significant reduction in the mean number of urinations per day compared with the sebo group. Urge incontinence and total incontinence (in subjects with OAB wet), and all subjects The secondary endpoints, including urgency episodes, were compared between vibegron 100 mg and Statistically significant improvement from baseline in the 50 mg treatment group compared with placebo Secondary endpoints in the vibegron 15, 50, and 100 mg treatment groups were Statistically significant improvement from baseline in single voided volume compared to placebo An increase was also observed (Tables 12 and 13).

[0151] [Table 12]

[0152] [Table 13]

[0153] To evaluate the safety and efficacy of vibegron in men and women with OAB The study was completed in a double-blind, randomized, placebo-controlled, multicenter, Phase 3 study. Upon completion of the placebo run-in period, 1,232 patients were randomized to receive vibegron 50 mg ( N=370), vibegron 100 mg (N=369), placebo (N=369), or infusion One study included midafenacin 0.2 mg (comparator; N=117). Patients were randomized to receive blinded study treatment for 2 weeks. These results were Vibegron reduced voiding, UUI episodes, total urinary incontinence episodes, and urgency episodes The results show that both treatments resulted in statistically significant reductions in the efficacy parameters included (Table 14).

[0154] [Table 14]

[0155] Example 5 Safety Data 5.1 Phase I Safety Data Fifteen completed phase 1 studies and one early terminated study (which did not provide efficacy or Safety data from 16 Phase 1 studies, including one that was terminated for reasons unrelated to safety In the Phase 1 study, a total of 466 subjects received at least one dose of vibegron. 238 subjects received single doses ranging from 2 to 600 mg; 238 Human subjects received multiple doses ranging from 25 to 400 mg for up to 28 days. Across the program, vibegron was generally well tolerated. Treatment-emergent adverse events No serious adverse events (SAEs) or deaths were reported, and the majority of adverse events (AEs) were transient. , the intensity was light or moderate.

[0156] Phase 1 studies have shown that the drug can be used with or without symptoms (e.g., lightheadedness, dizziness, presyncope). , orthostatic hypotension (decrease in systolic blood pressure >20mmHg and / or decrease in diastolic blood pressure >10mmHg Vibegron 100 mg or 150 mg and tolterodine The incidence of orthostatic AEs following coadministration of vibegron with ER 4 mg was The incidence of these AEs was similar to that following single-dose administration of 100 mg of cefotaxime in a Phase 1 multiple-dose study. At doses up to 100 mg, AEs such as postural dizziness, dizziness, presyncope, or syncope were not observed without obvious use. No dose-response relationship was observed. However, postural dizziness increased at doses of 100 mg or more. The incidence of the AE "symptomatic orthostatic hypotension" was higher at doses of vibegron >200 mg. Vibegron 100mg is more effective than metoprolol (a typical beta-blocking The subjects were on a stable regimen of either thalidomide (a typical vasodilator) or amlodipine (a typical vasodilator). When coadministered to subjects with chronic hypertension, no orthostatic AEs occurred.

[0157] Evaluation of the preliminary Phase 1 safety data included laboratory safety parameters (chemistry, hematology, and Clinical evaluation of urinalysis or ECG parameters (including PR, QRS, and QTc intervals) A thorough QT study was completed and No clinically meaningful effects on cerebrovascular events or blood pressure were seen.

[0158] 5.2 Phase II Safety Data A completed single-phase trial in which 933 subjects received at least one dose of vibegron Phase 2 safety data from the Phase 2B study were collected. Subjects were randomized to receive 100 mg / kg / day for up to 8 weeks and 3 days during the main study. Vibegron doses ranging from 0.01 to 100 mg (alone or in combination with tolterodine) Of those completing the parent study, 605 subjects were enrolled in the extension study. , up to 52 weeks, vibegron 50 mg (alone) or vibegron 100 mg (alone or tol The main study included a placebo group and The study and extension included a group receiving tolterodine monotherapy. No deaths were reported during the study. Vibegron was generally well tolerated. Compared with placebo, No meaningful differences in the overall incidence or severity of AEs or drug-related AEs were observed between the Ta.

[0159] Adverse events occurred in 607 of 1393 assigned subjects in the main study (43 In the vibegron 50 mg and vibegron 100 mg treatment groups, The proportion of subjects with one or more AEs in the placebo group was similar to that in the placebo group (see Table 14). In the vibegron 15 mg and vibegron 50 mg + tolterodine 4 mg treatment groups, Compared with sebo, a higher proportion of subjects reported one or more AEs. The AEs reported were dry mouth, headache, urinary tract infection (UTI), and nasopharyngitis. The incidence of dryness was significantly higher in the groups receiving tolterodine (alone or with vibegron) than in the group receiving placebo. or higher compared with the vibegron monotherapy group.

[0160] There were 221 subjects with drug-related AEs in the vibegron 100 mg treatment group. The lowest incidence of drug-related AEs was reported in the bilirubin group. In the Begron monotherapy group, the results were similar to those of placebo, and in the concomitant treatment group, the results were The incidence of discontinuation due to drug-related AEs was slightly higher than that of placebo or either monotherapy. Subject rates were low and similar across all treatment groups.

[0161] A total of 9 SAEs were reported in 8 subjects across treatment arms (P<0.05). 2 placebo patients; 1 vibegron 3 mg; 1 vibegron 50 mg; 1 tolterodine 4 mg 3 patients; vibegron 50 mg + tolterodine 4 mg 1 patient). Reported SAEs were atrial fibrillation, fibrillation, anaphylactic reaction, lung adenocarcinoma (stage IV), chronic obstructive pulmonary disease, hypertension, hypertension The most common symptoms were overeating, leg fractures, and in one subject, gastroesophageal reflux and dizziness after a pancreatic endoscopy procedure. Both occurred and prolonged hospitalization. No specific AE terms were reported in more than one subject. All SAEs were considered by the investigators to be unrelated to the study drug. .

[0162] There was a meaningful difference in the overall incidence of adverse events or serious adverse events between treatment arms during the 52-week extension. No significant differences were observed.

[0163] Adverse events were reported in 531 of 845 subjects (62.8%). The proportion of subjects with more than one AE was similar across 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 group compared with the other treatment groups. The incidence of constipation was higher in the concurrent treatment group compared with the monotherapy group.

[0164] The proportion of subjects with drug-related AEs was 1.0 in the tolterodine ER 4 mg and concomitant medication arms. The AEs were slightly higher in the vibegron 50 mg and 100 mg treatment arms compared with those in the vibegron 50 mg and 100 mg treatment arms. The proportion of subjects who discontinued due to drug-related AEs was , slightly higher than in the other treatment groups. A total of 46 S AEs were reported in the tolterodine ER 4 mg and vibegron 50 mg treatment groups. A higher overall incidence was reported in the tolterodine ER group compared with the 100 mg Glon treatment group. One drug-related SAE, paralytic ileus, was reported in the 4 mg treatment group; The study was discontinued due to this AE.

[0165] Table 15 below shows the general efficacy and safety profile of vibegron in Phase 2 studies in patients with overactive bladder. Adverse events observed are summarized below.

[0166] [Table 15]

[0167] Serious adverse events observed during the first 12 weeks of treatment with vibegron monotherapy included pulmonary adenocarcinoma. Cancer (stage IV) (n=1) and chronic obstructive pulmonary disease (n=1); An SAE of overdose was reported in the lon-tolterodine combination arm. During the extension study, SAEs reported by ≥2 subjects receiving monotherapy included: These included cerebrovascular accidents (n=2) and osteoarthritis (n=2). The only SAE reported in the Rosin 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 treatment (which did not recur when re-administered) (n=1), as well as Including atrial fibrillation (n=1) and dizziness (n=1) in the luterodine monotherapy arm The incidence of injury was numerically higher in the tolterodine arm than with vibegron. (0.9%, n=4 vs. 2.1%, n=5). Given the lack of a turnaround time, serious events are not expected for vibegron. I can't.

[0168] Potential risks associated with vibegron treatment include those based on non-clinical data and similar Based on the available data for this compound, it is believed to be effective in preventing orthostatic hypotension and, at the same time, potent P- These include increased exposure (approximately 2-fold) in patients taking gp inducers.

[0169] 5.3 Cardiovascular safety The cardiovascular safety of vibegron was evaluated in patients with OAB and healthy controls. A randomized, placebo- and comparator-controlled trial with a 52-week extension. or) (tolterodine) In an active-controlled, two-part efficacy and safety study, 6 patients (0.4 % of subjects experienced 7 orthostatic-related AEs (including postural dizziness, presyncope, and These events were The placebo group (0.5%), the vibegron 15 mg group (0.3%), and the vibegron 50 mg group One subject in the 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 randomly throughout the study and were assessed by the investigators as mild in severity. None were considered to cause discontinuation. The overall incidence of orthostatic symptoms was low or I did.

[0170] The changes from baseline in BP and HR across treatment groups are shown in Table 16. For SBP and DBP, the values ​​for 50 mg and 100 mg were The mean change at week 1 and the mean maximum change through week 8 were similar for placebo and vibegron. The absolute changes in SBP and DBP were also significantly greater with placebo and bevacizumab than with placebo, with the difference being <1 mmHg. The results were similar between vibegron and 100 mg, with the percentage of vibegron subjects increasing slightly at 100 mg. , change from baseline in DBP >15 mmHg (vs. 0.5% for placebo) For HR, the mean maximum change over 8 weeks was comparable to placebo. As previously reported (<2 bpm), no dose-dependent pattern was detectable. The small differences in absolute heart rate and percentage of subjects exceeding blood pressure thresholds for Similar to the tolterodine arm.

[0171] [Table 16]

[0172] More thorough assessment of heart rate and blood pressure has been performed in healthy participants in several Phase 1 studies. To evaluate the safety, tolerability, and multiple-dose PK of vibegron in healthy subjects A six-part, double-blind, randomized, placebo-controlled study of The dose ranged from 25 to 400 mg depending on the cohort. g (once a day for 7 to 28 days). Least squares mean and 90% confidence interval (CI) for maximum change from baseline in moving average (MA4 HR) The intervals are shown in Table 17. The effect on heart rate was dose-dependent, with the 100 mg dose: showed a difference from placebo of <1 bpm.

[0173] [Table 17]

[0174] Cardiovascular safety was also evaluated in patients with vibegron steady-state exposure at 100 mg and 200 mg, respectively. In a thorough QT study following single doses of 200 and 400 mg, which approximate the The mean maximum effects on blood pressure and RR interval were lower, as shown in Table 18. The log-100% reduction in vibegron exposure from repeated doses (from three Phase 1 studies) Using log regression analysis, the calculated mean ± standard deviation C from the 75 mg dose max Reach The mean mean serotonin concentration and AUC were 120 ± 74.7 ng / mL and 1140 ± 476 ng h / mL, respectively. These estimates were approximately 3.3 and 2 times higher than the 200 mg single dose. and 9.2-fold and 6-fold lower C than a single 400 mg dose, respectively. max and AU The answer is C.

[0175] [Table 18]

[0176] Example 6 Dose Selection 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 effects were observed on urge or total urinary incontinence. These data suggest a relatively shallow dose-response between 50 mg and 100 mg once daily. The efficacy of vibegron began to plateau at 50 to 100 mg. Therefore, 75 mg provides most of the efficacy of 100 mg.

[0177] [Table 19]

[0178] 6.2 Reducing side effects Vibegron exhibits a greater than dose-proportional increase in exposure. Surprisingly, Dose escalation from 0.1 mg to 100 mg is max , i.e., those most closely related to cardiovascular effects. The 75 mg dose resulted in an approximately three-fold increase in PK parameters that were considered to be To describe the dose-C parameters, data from a Phase 1 study were used. max And for A dose-AUC model was created. Based on the simulation, the dose of 75 mg of vibegron prevented approximately 29% of exposure seen at the 100 mg dose, followed by This has been shown to lower the upper limit of the range of possible exposures. max Value drop reduces the likelihood of clinically relevant cardiovascular effects.

[0179] In a Phase 1 multiple-dose study at doses up to 100 mg, postural dizziness, vertigo, and premonitory symptoms were reported. Adverse events such as dizziness and syncope did not show a clear dose-response relationship. The incidence of symptomatic orthostatic hypotension appeared to increase at doses ≥ 100 mg. The incidence was higher with vibegron doses above 150 mg. The risk of adverse events was disproportionately reduced by decreasing the dose from 100 mg to 75 mg. Because a 25% reduction in dose is max Approximately 40% lower (206 ng / mL at 100 mg vs. 120 ng / mL at 75 mg) Without wishing to be bound by theory, it is believed that the dose-proportional effect increases with increasing dose. The increased bioavailability was due to the intestinal saturable P-glycoprotein (P- gp)-mediated excretion.

[0180] The lower exposure at the 75 mg dose compared with the 100 mg dose may be of benefit in special populations. The risk of adverse events is similarly disproportionately reduced. Subjects with moderate renal impairment should be treated with had a mean increase in AUC of 1.6-fold compared to subjects with normal renal function, whereas In contrast, subjects receiving strong CYP3A / P-gp inhibitors had approximately two-fold higher exposure. The 75 mg dose of C max If we assume a two-fold increase in the number of cases, these special populations would Vibegron C in excess of that observed at 0.00 mg max The probability of achieving this is 15%. (See Figure 1). Minimizing and lowering the subject's exposure to the extreme is more effective than reducing the risk of developing a chronic condition such as diabetes. Approximately 50-70% higher C max This is important for older people and women who show

[0181] Example 7 Pharmacokinetic data for the 75mg dose A pharmacokinetic study evaluating the drug interaction between vibegron and rifampin has been completed. All subjects were healthy adults. A summary of the preliminary results is shown in Table 20. Vibegron 75 mg single dose on day 1, rifampin 600 mg QD on days 10-23 On day 17, the patient received a single dose of vibegron 75 mg, concurrent with rifampin administration. Begron and rifampin were well tolerated in healthy male and female subjects. No severe TEAEs, SAEs, or deaths were reported during the study. Three of these (15%) had AEs related to the study drug: headache in two and constipation in one. All patients experienced mild symptoms. No clinical signs, ECGs, or laboratory tests were assessed. No significant changes or results were observed.

[0182] [Table 20]

[0183] The present invention has now been fully described, and no limitation or limitation thereon is imposed on the scope of the invention or any of its embodiments. perform the same thing within a broadly equivalent range of conditions, formulations, and other parameters without affecting the It will be understood by those skilled in the art that this is possible.

[0184] Other embodiments of the present invention will become apparent from the discussion of this specification and practice of the present invention disclosed herein. It will be apparent to one skilled in the art that the present specification and examples are to be considered as exemplary only. It is intended that the true scope and spirit of the invention be indicated by the following claims. do.

[0185] All patents, patent applications, and other publications cited herein are incorporated by reference in their entirety. 6,033,363, which is incorporated herein in its entirety.

Claims

1. 1. A method of treating overactive bladder, comprising orally administering vibegron in an amount of about 60 mg to about 90 mg per day to a subject in need thereof.

2. 2. The method of claim 1, wherein the amount of vibegron is from about 65 mg to about 85 mg.

3. 2. The method of claim 1, wherein the amount of vibegron is from about 70 mg to about 80 mg.

4. 2. The method of claim 1, wherein the amount of vibegron is about 75 mg.

5. The method of any one of claims 1 to 4, wherein the subject has a condition selected from the group consisting of urge urinary incontinence, urgency, urinary frequency, or a combination thereof.

6. 6. The method of claim 5, wherein the subject has symptoms of urge incontinence, urgency, and frequency.

7. The method according to any one of claims 1 to 6, wherein the subject is a human.

8. The method of claim 7, wherein the human is a female.

9. The method of claim 7, wherein the human is a male.

10. The method of any one of claims 7 to 9, wherein the human is over 65 years of age.

11. The method according to any one of claims 1 to 10, wherein the subject suffers from severe renal dysfunction.

12. The method according to any one of claims 1 to 10, wherein the subject suffers from moderate renal impairment.

13. The method of any one of claims 1 to 12, wherein the subject is concomitantly receiving a CYP3A / P-glycoprotein inhibitor.

14. The method of any one of claims 1 to 13, wherein vibegron is administered once a day.

15. 15. The method of claim 14, wherein vibegron is administered with a meal.

16. 15. The method of claim 14, wherein vibegron is administered without food.

17. The method of any one of claims 1 to 16, wherein vibegron is administered as a free base.

18. The method according to any one of claims 1 to 16, wherein vibegron is administered as a pharma- ceutically acceptable salt thereof.

19. 19. The method of any one of claims 1-18, wherein the subject experiences a mean maximum change in systolic blood pressure from baseline throughout the treatment period, wherein the mean maximum change from subjects taking a placebo is less than 1 mm / Hg.

20. 19. The method of any one of claims 1-18, wherein the subject experiences a mean maximum change in systolic blood pressure from baseline throughout the treatment period of less than 8 mm / Hg.

21. 19. The method of any one of claims 1-18, wherein the subject experiences a mean maximum change in diastolic blood pressure from baseline throughout the treatment period, wherein the mean maximum change from subjects taking a placebo is less than 1 mm / Hg.

22. 19. The method of any one of claims 1-18, wherein the subject experiences a mean maximum change in diastolic blood pressure from baseline throughout the treatment period of less than 5 mm / Hg.

23. 19. The method of any one of claims 1-18, wherein the subject experiences a change from baseline over the treatment period in average number of urinations per 24 hours of about -1.5 to about -2.

5.

24. 19. The method of any one of claims 1-18, wherein the subject has an average of ≧1 urge urinary incontinence (UUI) episodes per day pre-treatment and experiences a change from baseline over the treatment period in the average number of UUI episodes of about -1.3 to about -2.

5.

25. 25. The method of any one of claims 19 to 24, wherein the treatment period is selected from the group consisting of 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 weeks.

26. 26. The method of any one of claims 1-25, wherein vibegron has an onset of action of about 4 weeks, about 3 weeks, or about 2 weeks.

27. A method of increasing bladder smooth muscle relaxation, comprising orally administering vibegron in an amount of about 60 mg to about 90 mg per day to a subject in need thereof.

28. A unit dosage pharmaceutical composition suitable for oral administration, comprising about 60 mg to about 90 mg of vibegron.

29. 29. The unit dosage pharmaceutical composition of claim 28, comprising about 65 mg to about 85 mg of vibegron.

30. 29. The unit dosage pharmaceutical composition of claim 28, comprising about 70 mg to about 80 mg of vibegron.

31. 29. The unit dosage pharmaceutical composition of claim 28, comprising about 75 mg of vibegron.

Images