Use of vibegron to treat overactive bladder

Abstract

To provide a method of treating overactive bladder in a treatment-experienced subject in need thereof.SOLUTION: The present invention provides a method comprising orally administering to a subject about 75 mg of vibegron per day as a therapeutically effective amount, wherein following administration of vibegron to the subject over a treatment period: a. the decrease in the average number of micturitions in a 24-hour period in the subject is from about 1.5 to about 10 more than the decrease in the average number of micturitions in a subject who receives a placebo; or b. the average number of urge urinary incontinence (UUI) episodes per 24 hours by the subject decreases by from about 1.7 to about 6 times the decrease as that of a subject treated with placebo.SELECTED DRAWING: None

Description

Background Art

[0001] Overactive bladder (OAB) is a chronic and sometimes debilitating lower urinary tract condition. The function of the lower urinary tract is to store and periodically release urine. This requires coordinated integration of the storage and micturition reflexes, involving various afferent and efferent neural pathways, modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of the sympathetic and parasympathetic components of the autonomic nervous system and the somatic motor pathway. Proximally, these regulate the contractile state of the bladder (detrusor), urethral smooth muscle, and the urethral sphincter striated muscle. From a pathophysiological perspective, overactive bladder is associated with detrusor overactivity. OAB is typically characterized by symptoms of urinary urgency, with or without urge incontinence, often associated with frequency and nocturia. The prevalence of OAB in Europe and the United States has been estimated to be between 16% and 17% in both women and men over 18 years of age. Overactive bladder is often classified as idiopathic, but can be secondary to neurological conditions, bladder outlet obstruction (bladder outlet obstruction, infravesical obstruction), and other causes.

[0002]

Summary of the Invention

Problems to be Solved by the Invention

[0003] Currently, the main class of drugs used in the treatment of OAB is antimuscarinics. The clinical use of antimuscarinics is limited by the potential for dry mouth, constipation, and CNS adverse effects (e.g., cognitive impairment). Limited by moderate efficacy and low tolerability due to side effects based on the mechanism, including . In both clinical trials and real-world settings, high discontinuation rates were observed for both tolterodine and oxybutynin, two commonly prescribed antimuscarinic drugs. . Additionally, recent observational studies have suggested an association between higher cumulative use of anticholinergics and an increased risk of dementia. See Gray SL et al, JAMA Intern Med 2015;175(3): 401-407.

[0004] Activation of the beta-3 adrenergic receptor (β 3 -AR) is an effective way to relax the detrusor in both normal and pathogenic states. Functional evidence supporting an important role for β 3 - AR in urine storage has emerged from in vivo studies. The effectiveness of β 3 -AR agonists in alleviating OAB symptoms has been demonstrated. To date, mirabegron (Astellas Pharma Global Development, Inc) is the only β -AR agonist approved for the treatment of OAB in the United States (US) and Japan. Mirabegron activates β 3 -AR in the detrusor muscle of the bladder, which leads to muscle relaxation and an increase in bladder capacity. With mirabegron, there is a decrease in micturition frequency, urinary incontinence, and urgency episodes, and an increase in the average volume voided per micturition 3 -AR, which leads to muscle relaxation and an increase in bladder capacity. With mirabegron, there is a decrease in micturition frequency, urinary incontinence, and urgency episodes, and an increase in the average volume voided per micturition ​ An increase in mean volume voided per micturition was observed.

[0005] Vibegron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine ( pyrrolidin-)2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrrolidin Myidine-6-carboxamide is a potent and highly selective beta-3 adrenergic receptor antagonist. Body (β 3 -AR) agonist and in cell-based in vitro assays 2 -AR and β 1 -β rather than AR 3 The study demonstrated >9,000-fold selectivity for activating the -AR. Song et al., J. Med. Chem. (Journal of Medicinal Chemistry) 59:609-62 3 (2016).

[0006] [ka]

[0007] Vibegron is disclosed in U.S. Patent Nos. 8,399,480 and 8,247,415, and International Publication WO2018 / 2 In issue 24989, 3 Synthesis of Vibegron as an -AR agonist. The methods are described in U.S. Patent Application Publication Nos. US2017 / 0145014, US2015 / 0087832, US2016 / 0176884, and No. 2014 / 0242645. All publications cited are incorporated by reference in their entirety. More incorporated here. [Brief description of the drawings]

[0008]

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[0009] "Means for Solving the Problems" The present disclosure provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once a day. The present disclosure further provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once a day, wherein the treatment achieves at least one of the following changes (1) to (5) from baseline over the treatment period:

[0010] The present disclosure further provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once a day, wherein the treatment achieves at least one of the following changes (1) to (5) from baseline over the treatment period: The present disclosure further provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once a day, wherein the treatment achieves at least one of the following changes (1) to (5) from baseline over the treatment period: The present disclosure further provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once a day, wherein the treatment achieves at least one of the following changes (1) to (5) from baseline over the treatment period: (1) A change in the average number of urinations per 24 hours from about -1.3 to about -2.3; (2) When the subject is an OAB wet patient, the change in the average number of UUI episodes per 24 hours; (3) The change in the average number of urgency episodes per 24 hours from about -2.2 to about -3.2; (4) The change in the average number of total incontinence episodes per 24 hours from about -1.7 to about -2.7 ; and (5) The change in the average voided volume per void from about 18 mL to about 30 mL.

[0011] In some embodiments, the treatment achieves a statistically significant change compared to placebo in at least one of the following: the average number of voids per 24 hours; the average number of UUI episodes per 24 hours; the average number of urgency episodes per 24 hours; the average number of total incontinence episodes; and the average voided volume per void.

[0012] The present disclosure also provides a method of treating overactive bladder in a subject who has experience with the treatment needed, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once daily, wherein the therapeutically effective amount is about 75 mg, and wherein after administration of vibegron to the subject over a treatment period: a. the decrease in the average number of voids in the subject over a 24 - hour period is greater than the decrease in the average number of voids in a subject receiving placebo by an amount from about 1.5 to about 10; or b. the average number of urgency urinary incontinence (UUI) episodes per 24 hours by the subject is decreased by a reduction from about 1.7 to about 6 - fold less than that of a subject treated with placebo.

[0013] The present disclosure further improves the health - related quality of life (HRQL) of a subject suffering from symptoms of overactive bladder to provide a method, the method comprising orally administering a therapeutically effective amount of vibegron to a subject in need thereof over a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is compared to the HRQL of subjects receiving a placebo.

[0014] The present disclosure also provides a method of treating overactive bladder in a subject in need thereof while improving the health-related quality of life (HRQL), the method comprising orally administering a therapeutically effective amount of vibegron to a subject in need thereof over a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is compared to the HRQL of subjects receiving a placebo.

[0015] In some embodiments, the HRQL comprises one or more subscales selected from coping, worry, sleep, social interaction, and combinations thereof.

[0016] The present disclosure further provides a method of reducing coping behavior in a subject suffering from symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vibegron to a subject in need thereof over a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the coping behavior in the subject is reduced compared to subjects receiving a placebo.

[0017] The present disclosure further provides a method of treating overactive bladder in a subject in need thereof while reducing coping behavior, the method comprising orally administering a therapeutically effective amount of vibegron to a subject in need thereof over a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the coping behavior in the subject is reduced compared to subjects receiving a placebo.

[0018] ​​​​​​​​ The present disclosure further provides a method for maintaining ambulatory blood pressure and / or ambulatory heart rate, while The present invention provides a method for treating overactive bladder in a subject in need thereof, the method being therapeutically effective. and administering orally to a subject an amount of vibegron per day, where the therapeutically effective amount is about 7 It is 5mg.

[0019] The present disclosure also provides a method for treating overactive bladder in a subject in need thereof while allowing free movement. A method for maintaining arterial blood pressure and / or ambulatory heart rate is provided, the method being therapeutically effective. and administering orally to a subject an amount of vibegron per day, where the therapeutically effective amount is about 7 It is 5mg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In order that this disclosure may be more readily understood, certain terms are first defined. As used herein, each of the following is a trademark of its respective owner, unless expressly provided otherwise herein. The following terms shall have the meanings set forth below. Additional definitions may be found throughout the specification. is.

[0021] In this specification and the appended claims, the singular forms "a," "an," and "the" are used interchangeably. Unless the context clearly indicates otherwise, the term "a" (or "an") includes plural references. ), as well as the terms “one or more” and “at least "A" or "an" may be used interchangeably herein. In certain embodiments, the terms "a" or "an" may be used interchangeably. In other embodiments, the terms "a" or "an" refer to two or more. or "plural."

[0022] Furthermore, the "and / or" used herein is considered to specifically disclose each of two specified features or configurations either with or without other elements. Therefore 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" (alone), and "B" (alone). Similarly the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following scenarios: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone); and C (alone).

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (also referred to as a person skilled in the art) to which this disclosure pertains.

[0024] The term "about" as used throughout this specification and the claims in connection with numerical values indicates an interval of accuracy well known and accepted by persons skilled in the art (also referred to as a person skilled in the art). In some embodiments, such an interval of accuracy is ±10%. In other embodiments such an interval of accuracy is ±5%.

[0025] The term "overactive bladder" generally refers to a sense of urinary urgency, with or without urge urinary incontinence, usually accompanied by frequency and nocturia, in the absence of a urinary tract infection or other obvious pathology ​ refers to urinary urgency. The term "overactive bladder" is defined as follows by the International Continence Society (ICS): Overactive bladder (OAB) is a symptom complex consisting of urge incontinence, usually with frequency and nocturia, in the absence of local pathological or hormonal factors (Abrams P et al. Urology 2003, 61(1): 37-49; Abrams P et al. Urology 2003, 62(Supplement 5B): 28-37 and 40-42). Synonyms for overactive bladder (OAB) include "urge syndrome" and "urge frequency syndrome". The term "urge incontinence" refers to the complaint of involuntary loss of urine. The term "urge urinary incontinence" (UUI) refers to the complaint of involuntary loss of urine related to urgency and can be used interchangeably with "urge incontinence". UUI is distinguished from stress urinary incontinence, which is involuntary loss of urine during effort or physical exertion (also referred to as exercise), such as during sports activities, or when sneezing or coughing.

[0026] The term "impairment" as used herein refers to an acute or chronic decrease in function.

[0027]

[0028] Means. For example, kidney impairment refers to a medical condition where the kidneys fail to maintain their normal functions, resulting in the accumulation of waste products and metabolites in the blood.

[0029] As used herein, the term "urgency" refers to an overwhelming, sudden, and irresistible urge to void that is difficult to delay.

[0030] As used herein, the term "urinary frequency" (also referred to as "frequency of micturition" or "frequency of urinary urge") refers to a complaint by a patient (a person, in the context of people) who feels the need to void too frequently during the day.

[0031] As used herein, the term "health-related quality of life" or "health-related QoL" (HRQL) refers to a multi-domain concept that represents a patient's general perception of the impact of illness and treatment on the physical, psychological, and social aspects of life. OAB is mainly defined by symptoms, as opposed to objective measurements, and has been shown to have a significant impact on HRQL. Therefore, the evaluation of treatment effects usually includes an assessment of patient perception. The Overactive Bladder Questionnaire (OAB-q) was developed to evaluate a patient's perception of symptom bother and impact on HRQL. The OAB-q consists of an 8-item symptom bother scale and 25 HRQL items grouped into 4 subscales: coping, concern, sleep, and social interaction. : coping, concern, sleep, and social interaction comprising those that form (social interaction) and provide a total score of HRQL For items of symptom distress, patients are evaluated on a 6 - point scale from "not at all bothered" to "very much bothered". The sub - scales are totaled and converted to a score ranging from 0 to 100. The higher the symptom distress score, the more the symptom distress increases, while on the other hand, the higher the HRQL score, the better the health - related quality of life is indicated. Also, an improvement in HRQL over the treatment period, or HRQL improvement, for example, indicates that overall, how the subject feels or functions as a result of the targeted disease and its treatment has improved, and mentions that there has been no decline in any domain (area).

[0032] As used herein, the term "coping" refers to the OAB - q sub - scale directed at the behaviors that OAB subjects use to manage the demands of OAB. For example, coping behaviors or tasks include, but are not limited to, planning avoidance routes to the toilet, carefully planning commutes, more carefully planning activities, reducing physical activity, finding the nearest toilet upon arrival at a new location, adjusting travel plans, avoiding activities away from the toilet, and feeling discomfort traveling with others. Therefore, for example, a decrease in coping behavior refers to a decrease in overall coping behavior or a decrease in the number of examples of experiencing any one or more of these coping behaviors such as the subject planning escape routes to the toilet over the treatment period. Similarly, an improvement in the coping domain score is the treatment Refers to a decrease or other change in the case of coping behaviors observed over a period of time.

[0033] As used herein, the terms "concern" and "worry" refer to the OAB-q subscore directed at characterizing how the subject is troubled by his / her OAB. For example, an OAB subject may be distressed by his / her OAB symptoms and feel anxious about possible odors or hygiene conditions, and / or feel embarrassed. A decrease in the concern / worry subscore indicates, for example, a decrease in the amount of concern / worry the subject has regarding the OAB symptoms. For example, an OAB subject may be troubled by his / her OAB symptoms and feel anxious about possible odors or hygiene conditions, and / or feel embarrassed. A decrease in the concern / worry subscore indicates, for example, a decrease in the amount of concern / worry the subject has regarding the OAB symptoms. For example, an OAB subject may be distressed by his / her OAB symptoms and feel anxious about possible odors or hygiene conditions, and / or feel embarrassed. A decrease in the concern / worry subscore indicates, for example, a decrease in the amount of concern / worry the subject has regarding the OAB symptoms. For example, an OAB subject may be distressed by his / her OAB symptoms and feel anxious about possible odors or hygiene conditions, and / or feel embarrassed. A decrease in the concern / worry subscore indicates, for example, a decrease in the amount of concern / worry the subject has regarding the OAB symptoms. For example, an OAB subject may be distressed by his / her OAB symptoms and feel anxious about possible odors or hygiene conditions, and / or feel embarrassed. A decrease in the concern / worry subscore indicates, for example, a decrease in the amount of concern / worry the subject has regarding the OAB symptoms.

[0034] As used herein, the term "sleep" refers to the OAB-q subscore directed at the subject's perception of the quality of sleep. For example, an OAB subject may be tired / sleepy during the day and / or may wake up due to a need to urinate at night and not feel fully rested. An improvement in the sleep score indicates, for example, an increase in the subject's perception of the quality of sleep related to his / her OAB. As used herein, the term "sleep" refers to the OAB-q subscore directed at the subject's perception of the quality of sleep. For example, an OAB subject may be tired / sleepy during the day and / or may wake up due to a need to urinate at night and not feel fully rested. An improvement in the sleep score indicates, for example, an increase in the subject's perception of the quality of sleep related to his / her OAB. As used herein, the term "sleep" refers to the OAB-q subscore directed at the subject's perception of the quality of sleep. For example, an OAB subject may be tired / sleepy during the day and / or may wake up due to a need to urinate at night and not feel fully rested. An improvement in the sleep score indicates, for example, an increase in the subject's perception of the quality of sleep related to his / her OAB. As used herein, the term "sleep" refers to the OAB-q subscore directed at the subject's perception of the quality of sleep. For example, an OAB subject may be tired / sleepy during the day and / or may wake up due to a need to urinate at night and not feel fully rested. An improvement in the sleep score indicates, for example, an increase in the subject's perception of the quality of sleep related to his / her OAB.

[0035] As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits. As used herein, the term "social interaction" refers to the OAB-q subscore directed at the impact of the subject's OAB symptoms on his / her socialization habits. For example, an OAB subject may feel that his / her symptoms are affecting his / her relationships with family / friends, may be causing problems with his / her partner, may be keeping him / her at home more than desired, and / or may be leading to a decrease in participation in social gatherings. An improvement in the social interaction score indicates, for example, a decrease in the subject's perception of the impact of OAB on his / her social habits.

[0036] As used herein, the term "symptom bother" refers to the OAB-q subscale that includes eight items related to frequency of urgency, nocturia, and symptoms of incontinence. As described below in Example 6, the items of the Symptom Bother Scale are scored from 1 (none at all) to 6 (very much), and the higher the score on the Symptom Bother Scale, the higher the severity of the symptoms. Therefore, for example, a decrease in symptom bother in a subject or a decreased annoyance of symptoms in a subject over a treatment period refers to the general perception of improvement in the annoyance related to OAB symptoms.

[0037] As used herein, the term "free base" refers to the basic chemical compound itself, rather than in salt form. 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.

[0038] As used herein, the term "OAB wet" means overactive bladder as defined by urinary frequency and urgency and is accompanied by incontinence.

[0039] As used herein, the term "OAB dry" means overactive bladder as defined by urinary frequency and urgency and is not accompanied by incontinence.

[0040] The term "pharmaceutically acceptable salt" is safe and effective for use in a subject and has desirable biological It means a salt of a compound having academic activity.

[0041] Pharmaceutically acceptable salts of basic compounds can be salts of organic acids or inorganic acids. Some embodiments, the organic acids and inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, ma leic acid, mandelic acid, succinic acid and methanesulfonic acid. Generally, refer to Journal of Pharmaceutical Science, 66, 2 (1977), which is hereby incorporated by reference in its entirety. Here, the term "Cmax" means the maximum plasma concentration after the drug is administered.

[0042] Here, the term "Tmax" means the time to reach the maximum plasma concentration after administration of the drug.

[0043]

[0044] Here, the term "AUC" means the area under the curve of the plasma concentration versus time plot after drug administration.

[0045] The term "steady state" means that the amount of drug reaching the system is approximately the same as the amount of drug leaving the system. Thus, in the "steady state", the patient's body eliminates the drug at approximately the same rate at which the drug is absorbed into the bloodstream and becomes available to the patient's system.

[0046] Here, the terms "treated", "treating", or "treatment" or "therapy" mean partially or fully alleviating, improving, ameliorating, reducing, delaying the onset of, suppressing the progression of, decreasing the severity of, decreasing the incidence of, one or more symptoms or characteristics of a disease, or​​​​​​​​ refers to any combination thereof.

[0047] Generally, the term "treatment" refers to counteracting an effect caused as a result of a disease or pathological condition of interest in a subject, and includes the following: (i) suppressing the progression of a disease or pathological condition, i.e., delaying or arresting its onset or progression, or one or more symptoms of such a disorder or condition; (ii) alleviating a disease or pathological condition, i.e., causing regression of the disease or pathological condition, or its symptoms; (iii) stabilizing one or more symptoms of a disease or pathological condition, or such a disorder or condition; (iv) returning one or more symptoms of a disease or pathological condition, or such a disorder or condition, to a normal state; (v) preventing one or more symptoms of a disease or pathological condition, or such a disorder or condition; and (vi) any combination thereof. (v) preventing one or more symptoms of a disease or pathological condition, or such a disorder or condition; and (vi) any combination thereof. is a combination thereof.

[0048] The term "treatment period" means the period during which the agent is administered to the subject. For example, the treatment period can be from about 2 weeks to about 2 years. In some embodiments, the treatment period can be about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 24, about 52, about 76 or about 104 weeks. The efficacy of the drug can be evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, 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 the drug can be evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, 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 evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, 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 the drug can be evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, 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 the drug can be evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, 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 the drug can be evaluated by measuring a parameter and calculating the change from a baseline over the treatment period. Efficacy parameters include, but are not limited to, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, urinary frequency, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, The safety of a drug can be evaluated by measuring certain parameters and calculating the changes from the baselines during the treatment period. Safety parameters include, but are not limited to, systolic blood pressure, diastolic blood pressure, and heart rate. The term "treatment-experienced" refers to OAB subjects who have previously received treatment for OAB or are currently receiving treatment for OAB with a treatment other than vibegron. In certain aspects, the current or previous treatment is the administration of an anticholinergic (also referred to as an anticholinergic agent). Examples of anticholinergics include, but are not limited to, atropine,

[0049] belladonna alkaloids, benztropine mesylate, clidinium, cyclopentolate, darifenacin, dicyclomine, fesoterodine, flavoxate, glycopyrrolate, homatropine hydrobromide, hyoscyamine, ipratropium, orphenadrine, oxybutynin, propantheline, scopolamine, methscopolamine, solifenacin, tiotropium, tolterodine, trihexyphenidyl, trospium, and salts thereof. In some embodiments, the subject has previously been treated with an anticholinergic that is tolterodine. In some aspects, the current or previous treatment is the administration of a beta3 agonist. Examples of beta3 agonists include, but are not limited to, mirabegron, and solabegron. In some embodiments, the subject has previously been treated with a beta3 agonist that is mirabegron. Additional definitions related to urological conditions are provided, for example, by Chapple et al. (2018) "Ter"

[0050] ​​​​​​​​​Terminology report from the International Continence Society(ICS)(International Continence Society(ICS) terminology explanation) Working Group on Underactive Bladder(UAB)(Working Group on Underactive Bladder(UAB) related to the underactive bladder) can be found in Neurology and Urodynamics 37: 2928 - 2931. The additional discussions related to HRQL and OAB - q can be found, for example, in Coyne et al. (2005) "The responsiveness of the Overactive Bladder Questionnaire (OAB - q)" in Quality of Life Research 14: 849 - 855; and Coyne et al. (2002) "Psychometric validation of an overactive bladder symptom and health - related quality of life questionnaire: The OAB - q" in Quality of Life Research 11: 563 - 574, and each of them is incorporated by reference in its entirety. Method of treatment This disclosure includes orally administering vibegron at a dosage that maintains desirable efficacy while minimizing undesirable side effects to a subject in need thereof for treating overactive bladder.

[0051] HRQL and additional discussions related to OAB - q are, for example, Coyne (Coyne) et al. (2005) "The responsiveness of the Overactive Bladder Questionnaire (OAB - q)(Responsiveness of the Overactive Bladder Questionnaire (OAB - q))", Quality of Life Research (Quality of Life Research) 14: 849 - 855; and Coyne et al. (2002) "Psychometric validation of an overactive bladder symptom and health - related quality of life questionnaire: The OAB - q(Psychometric validation of a questionnaire related to overactive bladder symptoms and health - related quality of life: OAB - q)" can be found in Quality of Life Research 11: 563 - 574, and each of them is incorporated by reference in its entirety. bladder symptom and health - related quality of life questionnaire: The OAB - q(Overactive bladder symptoms and psychometric validation of a questionnaire related to health - related quality of life: OAB - q)" can be found in Quality of Life Research 11: 563 - 574, and each of them is incorporated by reference in its entirety. They are incorporated by reference in their entirety. Method of treatment

[0052] This disclosure includes orally administering vibegron at a dosage that maintains desirable efficacy while minimizing undesirable side effects to a subject in need thereof for treating overactive bladder. to a subject in need thereof for treating overactive bladder. Relates to a method of placement.

[0053] The present disclosure provides a method of treating an overactive bladder, the method comprising orally administering to a subject in need thereof vibegron in an amount of 75 mg per day. The present disclosure provides a method of treating an overactive bladder, the method comprising orally administering to a subject in need thereof vibegron in an amount of 75 mg per day, wherein the treatment achieves at least one of (1) to (5) a change from baseline over a treatment period:

[0054] The present disclosure provides a method of treating an overactive bladder, the method comprising orally administering to a subject in need thereof vibegron in an amount of 75 mg per day, wherein the treatment achieves at least one of (1) to (5) a change from baseline over a treatment period: The present disclosure provides a method of treating an overactive bladder, the method comprising orally administering to a subject in need thereof vibegron in an amount of 75 mg per day, wherein the treatment achieves at least one of (1) to (5) a change from baseline over a treatment period: (1) A change in the average number of urinations per 24 hours from about -1.3 to about -2.3; (1) A change in the average number of urinations per 24 hours from about -1.3 to about -2.3; (2) When the subject is an OAB Wet patient, a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5; (2) When the subject is an OAB Wet patient, a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5; (3) A change in the average number of urgency episodes per 24 hours from about -2.2 to about -3.2; (4) A change in the average number of total incontinence episodes per 24 hours from about -1.7 to about -2.7; and (4) A change in the average number of total incontinence episodes per 24 hours from about -1.7 to about -2.7; and (5) A change in the average excretion volume per urination from about 18 mL to about 30 mL.

[0055] In some embodiments, the treatment achieves at least two, at least three, at least four, or all five of (1) to (5) a change from baseline over a treatment period. (5) a change from baseline over a treatment period. In some embodiments, the treatment achieves at least two, at least three, at least four, or all five of (1) to (5) a change from baseline over a treatment period.

[0056] In some embodiments, the treatment is a change from baseline over a treatment period (1) and (2), i.e., when the subject is an OAB Wet patient (1) a change in the average number of urinations per 24 hours from about -1.3 to about -2.3, and (2) a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5. In some embodiments, the treatment is a change from baseline over a treatment period (1) and (2), i.e., when the subject is an OAB Wet patient (1) a change in the average number of urinations per 24 hours from about -1.3 to about -2.3, and (2) a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5. (1) A change in the average number of urinations per 24 hours from about -1.3 to about -2.3, and (2) a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5. Achieve change in the average number of episodes.

[0057] In some embodiments, the change from baseline is placebo adjusted (plac When placebo adjusted, the change during the treatment period was at least one of the following: Can be: (1) a change in the average number of urinations per 24 hours from about -0.1 to about -1.0; (2) When the subject is an OAB wet patient, the UUI per 24 hours is between about -0.1 and about -1.1 change in the average number of episodes; (3) a change in the mean number of urgency episodes per 24 hours from approximately −0.2 to approximately −1.2; (4) A change in the mean number of total incontinent episodes per 24 hours from approximately -0.2 to approximately -1.2 ; and (5) The change in average volume produced per urination from approximately 15 mL to approximately 26 mL.

[0058] In some embodiments, the treatment changes ( 1) and (2), i.e., (1) an average urination rate per 24 hours of about -0.1 to about -1.0; and (2) a change in the mean value from about -0.1 to about -1.1 when the subject was an OAB wet patient. Change in the average number of UUI episodes per 24 hours.

[0059] In some embodiments, the present disclosure provides for maintaining daytime ambulatory blood pressure and Meanwhile, a method for treating overactive bladder in a subject in need thereof is provided, the method comprising the steps of: and administering orally to a subject a therapeutically effective amount of vibegron per day, The amount is about 75 mg. In some embodiments, the present disclosure provides for the treatment of overactive bladder in a patient in need thereof. A method is provided for performing in a subject and, on the other hand, maintaining daytime ambulatory blood pressure, the method including orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences an average change in daytime ambulatory blood pressure from baseline over the treatment period of less than about 2.0 mmHg. For example, Tables 101 and 102 show that the average increase in ambulatory systolic blood pressure from baseline over a 4-week treatment period is 0.89 mmHg and 0.19 mmHg, respectively (full analysis set and per protocol set, respectively), while Table 103 shows that the average increase in ambulatory diastolic blood pressure from baseline over a 4-week treatment period is 0.5 mmHg (full analysis set). In some embodiments, the subject experiences an average change in daytime ambulatory systolic blood pressure from baseline during the treatment period, wherein the average change from the change in subjects taking placebo has an upper bound of the 90% confidence interval of less than about 3.5 mmHg. In some embodiments, the upper bound of the 90% confidence interval is less than about 2.5 mmHg. In some embodiments, the upper bound of the 90% confidence interval is about 2.0 mmHg. For example, Tables 101 and 102 show that the upper bounds of the average daytime ambulatory systolic 90% confidence intervals are 2.49 and 2.00, respectively (full analysis set and per protocol set, respectively), while Table 103 shows that the upper bound of the average daytime ambulatory systolic 90% confidence interval is 1.11 (full analysis set). including orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences an average change in daytime ambulatory blood pressure from baseline over the treatment period of less than about 2.0 mmHg. For example, Tables 101 and 102 show that the average increase in ambulatory systolic blood pressure from baseline over a 4-week treatment period is 0.89 mmHg and 0.19 mmHg, respectively (full analysis set and per protocol set, respectively), while Table 103 shows that the average increase in ambulatory diastolic blood pressure from baseline over a 4-week treatment period is 0.5 mmHg (full analysis set). (respectively, full analysis set and per protocol set), while Table 103 shows that the average increase in ambulatory diastolic blood pressure from baseline over a 4-week treatment period is 0.5 mmHg (full analysis set). In some embodiments, the subject experiences an average change in daytime ambulatory systolic blood pressure from baseline during the treatment period, wherein the average change from the change in subjects taking placebo has an upper bound of the 90% confidence interval of less than about 3.5 mmHg. In some embodiments, the upper bound of the 90% confidence interval is less than about 2.5 mmHg. In some embodiments, the upper bound of the 90% confidence interval is about 2.0 mmHg. For example, Tables 101 and 102 show that the upper bounds of the average daytime ambulatory systolic 90% confidence intervals are 2.49 and 2.00, respectively (full analysis set and per protocol set, respectively), while Table 103 shows that the upper bound of the average daytime ambulatory systolic 90% confidence interval is 1.11 (full analysis set). For example, Tables 101 and 102 show that the upper bounds of the average daytime ambulatory systolic 90% confidence intervals are 2.49 and 2.00, respectively (full analysis set and per protocol set, respectively), (respectively, full analysis set and per protocol set), while Table 103 shows that the upper bound of the average daytime ambulatory systolic 90% confidence interval is 1.11 (full analysis set). For example, Tables 101 and 102 show that the upper bounds of the average daytime ambulatory systolic 90% confidence intervals are 2.49 and 2.00, respectively (full analysis set and per protocol set, respectively), while Table 103 shows that the upper bound of the average daytime ambulatory systolic 90% confidence interval is 1.11 (full analysis set).

[0060] In some embodiments, the subject measures daytime ambulatory activity gain from baseline during the treatment period. experienced a mean change in systolic blood pressure, where the mean change was from that of subjects taking a placebo Less than about 1.0 mmHg, for example, about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0.4 mmHg, 0.5 mmHg, 0.6 mmHg, 0.7mmHg, 0.8mmHg, 0.9mmHg, or the range between any two of the preceding values. In some embodiments, the subject is assessed for daytime ambulatory systolic blood pressure (BP) from baseline during the treatment period. subjects experienced a mean change of about 0.5 m from the change in subjects taking a placebo. mHg, e.g., about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0.4 mmHg, or any two of the preceding values. For example, as shown in Tables 101 and 102, the 4-week treatment period The mean change from baseline in daytime ambulatory systolic blood pressure was 0.81 mmHg and 0.41 mmHg higher than those in the full analysis set and per-sample protocol set).

[0061] In some embodiments, the subject's daytime free activity from baseline over the treatment period The mean change in lower systolic blood pressure is less than about 1.0 mmHg, e.g., about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0. 4mmHg, 0.5mmHg, 0.6mmHg, 0.7mmHg, 0.8mmHg, 0.9mmHg, or any two of the above values In some embodiments, subjects experience a range between 0.01 to 0.1% improvement from baseline during the treatment period. The mean change in ambulatory systolic blood pressure during the day is less than about 0.25 mmHg, e.g., about 0.1 mmHg, 0.11 mmHg mHg, 0.12 mmHg, 0.13 mmHg, 0.14 mmHg, 0.15 mmHg, 0.16 mmHg, 0.17 mmHg, 0.18 mmHg, 0.19 m mHg, 0.20 mmHg, 0.21 mmHg, 0.22 mmHg, 0.23 mmHg, 0.24 mmHg, or any two of the foregoing values experience a range between. As shown in Table 102, for example, the subject experiences an average change in systolic blood pressure during daytime ambulatory activity from a baseline of about 0.19 mmHg over a four-week treatment period.

[0062] In some embodiments, the subject does not experience a greater average change in diastolic blood pressure during daytime ambulatory activity from baseline during the treatment period than subjects taking a placebo. For example, Table 103 shows that the average change in diastolic blood pressure during daytime ambulatory activity from baseline over a four-week treatment period is 0.04 mmHg lower than that of subjects taking a placebo.

[0063] In some embodiments, the subject experiences an average change in diastolic blood pressure during daytime ambulatory activity from baseline during the treatment period that is less than about 0.75 mmHg, for example, about 0.1 mmHg, 1.5 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.6 mmHg, 0.65 m mHg, 0.7 mmHg, or in a range between any two of the preceding values. As shown in Table 103, for example, the subject experiences an average change in diastolic blood pressure during daytime ambulatory activity from baseline over a four-week treatment period of about 0.5 mmHg.

[0064] In some embodiments, the present disclosure treats overactive bladder in subjects in need thereof ​​​​​​A method for maintaining the heart rate during daytime free activity is provided, the method comprising orally administering to a subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the present disclosure provides a method for treating overactive bladder in a subject while maintaining the heart rate during daytime free activity, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences an average change in heart rate during daytime free activity from baseline over the treatment period of less than about 1.25 bpm, e.g., about 1.0 bpm, 1.01 bpm, 1.02 bpm, 1.03 bpm, 1.04 bpm, 1.0 5 bpm, 1.06 bpm, 1.07 bpm, 1.08 bpm, 1.09 bpm, 1.10 bpm, 1.11 bpm, 1.12 bpm, 1.13 bpm, 1. 14 bpm, 1.15 bpm, 1.16 bpm, 1.17 bpm, 1.18 bpm, 1.19 bpm, 1.20 bpm, 1.21 bpm, 1.22 bpm, 1 .23 bpm, 1.24 bpm, or a range between any two of the preceding values. As shown in Table 103, for example, the subject experiences an average change in heart rate during daytime free activity from baseline of about 1.08 bpm over a 4-week treatment period.

[0065] In some embodiments, the subject experiences an average change in heart rate during daytime free activity from baseline over the treatment period, and the average change from that of a subject taking a placebo is less than about 1.0 bpm, e.g., about 0.1 bpm, 0.2 bpm, 0.3 bpm, 0.4, bpm, 0.5 bpm, 0.6 bpm , 0.7 bpm, 0.8 bpm, 0.9 bpm, or a range between any two of the preceding values. For example , Table 103 shows that the average change from the baseline of the daytime ambulatory heart rate during the 4-week treatment period is 0.88 bpm higher than that of the subjects taking placebo. This indicates that the average change from the baseline of the daytime ambulatory heart rate during the 4-week treatment period is 0.88 bpm higher than that of the subjects taking placebo.

[0066] In some embodiments, the present disclosure provides a method for maintaining 24-hour ambulatory blood pressure while treating an overactive bladder in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day. In some embodiments, the present disclosure provides a method for treating an overactive bladder in a subject in need thereof while maintaining 24-hour ambulatory blood pressure, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day. In some embodiments, the present disclosure provides a method for maintaining 24-hour ambulatory blood pressure while treating an overactive bladder in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day. In some embodiments, the present disclosure provides a method for treating an overactive bladder in a subject in need thereof while maintaining 24-hour ambulatory blood pressure, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory blood pressure from baseline during the treatment period of less than about 2.0 mmHg. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg.

[0067] In some embodiments, the subject experiences an average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and the average change from that of the subjects taking placebo is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the preceding values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and the average change from that of the subjects taking placebo is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the preceding values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and the average change from that of the subjects taking placebo is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the preceding values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and the average change from that of the subjects taking placebo is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the preceding values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. In some embodiments, the subject experiences an average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and the average change from that of the subjects taking placebo is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the preceding values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during the 4-week treatment period is 0.61 mmHg, and the average increase in 24-hour ambulatory diastolic blood pressure from baseline during the 4-week treatment period is 0.51 mmHg. The average change from baseline in 24-hour ambulatory systolic blood pressure during free activity is 0.57 mmHg higher than that of subjects taking placebo and is shown.

[0068] In some embodiments, the average change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period for the subject is less than about 0.75 mmHg, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0 .25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0 .65 mmHg, 0.70 mmHg, or in the range between any two of the foregoing values. For example, Table 103 shows that the average increase in 24-hour ambulatory systolic blood pressure from baseline during a 4 -week treatment period is 0.60 mmHg.

[0069] In some embodiments, the subject does not experience an average change in 24-hour ambulatory diastolic blood pressure from baseline during the treatment period that is greater than that of subjects taking placebo. For example, Table 103 shows that the average change in 24-hour ambulatory diastolic blood pressure from baseline during a 4-week treatment period is only 0.19 mmHg lower than that of subjects taking placebo. .

[0070] In some embodiments, the average change in 24-hour ambulatory diastolic blood pressure from baseline over the treatment period for the subject is less than 0.75 mmHg, for example, 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg, or in the range between any two of the foregoing values. ​​​​experience a range between any two of mmHg, 0.70 mmHg, or a preceding value. For example, Table 103 shows that the average increase in 24-hour ambulatory diastolic blood pressure from baseline during a 4-week treatment period is 0.51 mmHg.

[0071] In some embodiments, the present disclosure provides a method of treating overactive bladder in a subject in need thereof while maintaining the 24-hour ambulatory heart rate, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once daily, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the present disclosure provides a method of treating overactive bladder in a subject in need thereof while maintaining the 24-hour ambulatory heart rate, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once daily, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences an average change in 24-hour ambulatory heart rate from baseline during the treatment period of less than about 1.0 bpm, for example, about 0.1 bpm, 0.2 bpm, 0.3 bpm, 0.4 bpm, 0.5 bpm, 0.6 bpm, 0.7 bpm, 0.8 bpm, 0.9 bpm, or a range between any two of the preceding values. As shown in Table 103, for example, the subject experiences an average change in 24-hour ambulatory heart rate from baseline during a 4-week treatment period of about 0.80.

[0072] In some embodiments, the subject experiences an average change in 24-hour ambulatory heart rate from baseline over the treatment period, and the average change from the change in a subject taking a placebo is less than about 1.0 bpm, for example, about 0.1 bpm, 0.2 bpm, 0.3 bpm, 0.4 bpm, 0.5 bpm, 0.6 bpm, 0. 7 bpm, 0.8 bpm, 0.9 bpm, or a range between any two of the preceding values. 7 bpm, 0.8 bpm, 0.9 bpm, or in the range between any two of the preceding values. For example, Table 1 03 shows that the mean change from the baseline of the 24-hour ambulatory heart rate during the 4-week treatment period is 0.96 bpm higher than that of the subjects taking the placebo.

[0073] In some embodiments, the present disclosure provides a method for maintaining one or more of the following: daytime ambulatory blood pressure, daytime ambulatory systolic blood pressure, daytime ambulatory diastolic blood pressure, daytime ambulatory heart rate, 24-hour ambulatory blood pressure, 24-hour ambulatory systolic blood pressure, 24-hour ambulatory diastolic blood pressure, and / or 24-hour ambulatory heart rate, while treating overactive bladder in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. In some embodiments, / or 24-hour ambulatory heart rate, while treating overactive bladder in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg. The present disclosure provides a method for treating overactive bladder while maintaining one or more of the following: daytime ambulatory blood pressure, daytime ambulatory systolic blood pressure, daytime ambulatory diastolic blood pressure, daytime ambulatory heart rate, 24-hour ambulatory blood pressure, 24-hour ambulatory systolic blood pressure, 24-hour ambulatory diastolic blood pressure, and / or 24-hour ambulatory heart rate, the method comprising orally administering to the subject a therapeutically effective amount of vibegron once a day, wherein the therapeutically effective amount is about 75 mg.

[0074] In some embodiments, the subject has an average change in systolic blood pressure at C max of less than about 0.50 mmHg , for example, about 0.05 bpm, 0.1 bpm, 0.15 bpm, 0.2 bpm, 0.25 bpm, 0.3 bpm, 0.35 bpm, 0.4 bpm, Experience a range between 0.45 bpm or any two of the preceding values. Some In embodiments, the subject experiences an average change in systolic blood pressure over 24 hours of less than about 0.50 mmHg, such as, for example, about 0.05 bpm, 0.1 bpm, 0.15 bpm, 0.2 bpm, 0.25 bpm, 0.3 bpm, 0.35 bpm, 0.4 bpm, 0.45 bpm, or a range between any two of the preceding values. In some embodiments, the subject experiences a maximum average change in blood pressure from baseline over 6.5 hours from 0.5 hours after administration of less than about 2.0 mmHg. In some embodiments

[0075] In some embodiments, the subject experiences a maximum average change in systolic blood pressure from baseline over 6.5 hours from 0.5 hours after administration, and there the maximum average change is less than about 1.75 mmHg from that of a subject taking a placebo, such as, for example, about 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg, 1.25 mmHg, 1.30 mmHg, 1.35 mmHg, 1.40 mmHg, 1.45 mmHg, 1.50 mmHg, 1.55 mmHg, 1.60 mmHg, 1.65 mmHg, 1.70 mmHg, or a range between any two of the preceding values. In some embodiments the subject experiences a maximum average change in systolic blood pressure from baseline over 6.5 hours from 0.5 hours after administration of less than about 2.0 mmHg, such as, for example, about 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg 1.25 mmHg, 1.30 mmHg, 1.35 mmHg, 1.40 mmHg, 1.45 mmHg, 1.50 mmHg, 1.55 mmHg, 1.60 mmHg 1.65 mmHg, 1.70 mmHg, 1.75 mmHg, 1.80 mmHg, 1.85 mmHg, 1.90 mmHg, 1.95 mmHg, or a range between any two of the preceding values. In some embodiments the subject experiences a maximum average change in systolic blood pressure from baseline over 6.5 hours from 0.5 hours after administration of less than about 2.0 mmHg, such as, for example, about 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg 1.25 mmHg, 1.30 mmHg, 1.35 mmHg, 1.40 mmHg, 1.45 mmHg, 1.50 mmHg, 1.55 mmHg, 1.60 mmHg 1.65 mmHg, 1.70 mmHg, 1.75 mmHg, 1.80 mmHg, 1.85 mmHg, 1.90 mmHg, 1.95 mmHg, or a range between any two of the preceding values. In some embodiments, the subject experiences a maximum average change in systolic blood pressure from baseline over 6.5 hours from 0.5 hours after administration of less than about 2.0 mmHg, such as, for example, about 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg Experience a range between any two of the values to be performed. In some embodiments, the pair The subject experiences a maximum average change in diastolic blood pressure from baseline over a period of 0.5 hours to 6.5 hours after administration And there the maximum average change is less than about 1.25 mmHg from subjects taking placebo, for example About 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg, or a range between any two of the preceding values In some embodiments, the subject experiences a maximum average change in diastolic blood pressure from baseline over a period of 0.5 hours to 6.5 hours after administration The maximum average change in diastolic blood pressure from baseline is less than 0.75 mmHg over a period of 0.5 hours to 6.5 hours after administration, for example, about 0.10 mmHg, 0.15 mmHg, 0.20 mmHg, 0.25 mmHg, 0.30 mmHg, 0.35 mmHg, 0.40 mmHg, 0.45 mmHg, 0.50 mmHg, 0.55 mmHg, 0.60 mmHg, 0.65 mmHg, 0.70 mmHg or a range between any two of the preceding values Experience.

[0076] In some embodiments, the subject experiences a maximum average change in heart rate from baseline over a period of 0.5 hours to 6.5 hours after administration Is less than about 2.0 bpm. In some embodiments The subject experiences a maximum average change in heart rate from baseline over a period of 0.5 hours to 6.5 hours after administration And there the maximum average change is less than about 1.50 bpm from the heart rate of subjects taking placebo, for example About 1.0 bpm, 1.05 bpm, 1.10 bpm, 1.15 bpm, 1.20 bpm, 1.25 bpm, 1.30 bpm, 1.35 bpm, 1 .40 bpm, 1.45 bpm, or a range between any two of the preceding values.

[0077] In some embodiments, the present disclosure provides a method of treating overactive bladder, the method comprising about 75 mg orally administering to a subject in need thereof an amount of vibegron from about 75 mg to about 400 mg per day such that the subject experiences a maximum mean change in systolic blood pressure that is less than that of a subject receiving a therapeutically effective amount of mirabegron In some embodiments, the subject receiving vibegron experiences an increase in maximum mean change in systolic blood pressure of from about 1.5 mmHg to about 4.0 mmHg that is less than that of a subject receiving a therapeutically effective amount of mirabegron

[0078] In some embodiments, the present disclosure provides a method of treating overactive bladder, the method comprising orally administering to a subject in need thereof an amount of vibegron from about 75 mg to about 400 mg per day, such that the subject experiences a smaller mean 24 - hour change in systolic blood pressure than a subject receiving a therapeutically effective amount of mirabegron In some embodiments, the subject receiving vibegron experiences an increase in mean 24 - hour change in systolic blood pressure of from about 1.0 mmHg to about 10.0 mmHg that is less than that of a subject receiving a therapeutically effective amount of mirabegron

[0079] In some embodiments, the present disclosure provides a method of treating overactive bladder, the method comprising orally administering to a subject in need thereof an amount of vibegron from about 75 mg to about 400 mg per day, such that the subject experiences a smaller maximum mean increase in heart rate than a subject receiving a therapeutically effective amount of mirabegron In some embodiments, the subject receiving vibegron experiences an increase in maximum mean heart rate of from about 2 bpm to about 14 bpm that is less than that of a subject receiving a therapeutically effective amount of mirabegron

[0080] In some embodiments, the amount of vibegron per day is from about 75 mg to about 200 mg ​​​​​​​​. In some embodiments, the amount of vibegron per day is less than about 400 mg or less than about 200 mg. In some embodiments, the amount of vibegron per day is more than about 75 mg.

[0081] In some embodiments, a therapeutically effective amount of mirabegron is an amount from about 50 mg to about 200 mg. In some embodiments, a therapeutically effective amount of mirabegron is 50 mg, 100 mg, or 200 mg.

[0082] In some embodiments, the present disclosure provides a method of treating overactive bladder, the method comprising orally administering 75 mg of vibegron per day to a subject in need thereof, wherein the subject has a body weight greater than about 65 kg, and wherein the subject experiences a similar average change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0083] In some embodiments, the present disclosure provides a method of treating overactive bladder, the method comprising orally administering 75 mg of vibegron per day to a subject in need thereof, wherein the subject is about 67 years old or older, and wherein the subject experiences a similar average change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0084] In some embodiments, the present disclosure provides a method of treating overactive bladder in a subject having bladder outlet obstruction (bladder outlet obstruction, bladder lower urinary tract obstruction) (BOO), the method comprising orally administering an amount of 75 mg of vibegron per day to a subject in need thereof. In some aspects, the subject does not experience urinary retention. In some aspects, the subject experiences urinary retention. ​ In some embodiments, the method includes monitoring a subject for signs and / or symptoms of urinary retention.

[0085] In various embodiments related to ambulatory blood pressure and heart rate, the subject is a human. In some embodiments, the human is male. In some embodiments, the human is female. In some embodiments, the human has a weight greater than about 65 kg. In some embodiments, the human has a weight less than about 65 kg. In some embodiments, the human is about 67 years old or older. In some embodiments, the human is about 67 to about 75 years old. In some embodiments, the human is less than about 67 years old.

[0086] In various embodiments related to ambulatory blood pressure and heart rate, the human is hypertensive or at risk of becoming hypertensive. In various other embodiments related to ambulatory blood pressure and heart rate, the human has hypertension or is at risk of developing hypertension. As used herein, the terms "hypertensive" or "hypertension" refer to a subject having high blood pressure or taking an antihypertensive agent. Hypertension generally means a systolic blood pressure (SBP) of about 139 mmHg or higher, a diastolic blood pressure (DBP) of about 89 mmHg or higher, or both.

[0087] In some embodiments, the human has chronic kidney disease. In some embodiments, the chronic kidney disease is stage 1, stage 2, stage 3a, or stage 3b. In some embodiments, the human has a glomerular filtration rate of about 30 mL / min / 1.73m 2has an estimated glomerular filtration rate (eGFR) greater than In some embodiments, the eGFR is from about 30 to about 44 mL / min / 1.73 m 2 up to, greater than about 45 to about 59 mL / min / 1.73 m 2 , greater than about 60 to about 89 mL / min / 1.73 m 2 , or greater than about 90 mL / min / 1.73 m Selected from. In some embodiments, the eGFR is greater than about 72 mL / min / 1.73 m 2 and the eGFR is less than about 72 mL / min / 1.73 m 2 .

[0088] The present disclosure also provides a method of reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg per day over a treatment period.

[0089]

[0090] The present disclosure also provides a method of treating overactive bladder while reducing the average number of urinations per 24 hours in a subject in need thereof, the method comprising orally administering to the subject an amount of vibegron of 75 mg per day over a treatment period.

[0091] The present disclosure also provides a method of reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of 75 mg of vibegron per day over a treatment period.

[0091] The present disclosure also provides a method of treating overactive bladder while reducing the average number of UUI episodes per 24 hours in a subject in need thereof, the method comprising orally administering to the subject 75 mg of amount of vibegron per day over a treatment period The study involves administering a daily oral dose of vibegron to subjects.

[0092] The present disclosure also provides a method for determining the average number of urgency episodes per 24 hours in subjects with overactive bladder. The method provides a method for reducing the number of patients with rheumatoid arthritis who need to administer 75 mg of vibegron over the treatment period. The method includes administering the compound orally to a subject in need thereof once daily.

[0093] The present disclosure also provides a method for treating overactive bladder while reducing the average number of urge episodes per 24 hours. The present invention provides a method for reducing the average daily intake of a subject in need thereof, the method comprising the steps of: The study included oral administration of vibegron to 10,000 patients per day.

[0094] The present disclosure also provides a method for determining the average total incontinence episodes per 24 hours in subjects with overactive bladder. The present invention provides a method for reducing the average number of patients receiving vibegron per day, the method comprising administering an amount of vibegron per day of 75 mg over a treatment period. It includes administering orally once a day to a subject in need thereof.

[0095] The present disclosure also provides a method for treating overactive bladder while reducing the total incontinent episodes per 24 hours. The present invention provides a method for reducing the mean number of The study involves oral administration of 10 mg of vibegron per day to subjects.

[0096] The present disclosure also provides a method for increasing the average output per micturition in a subject suffering from overactive bladder. The method comprises administering vibegron in an amount of 75 mg per day to a subject in need thereof for a treatment period. This includes administering the drug orally.

[0097] The present disclosure also provides a method for treating overactive bladder while increasing the average output per micturition. Provide a method for performing on a subject in need, the method comprising orally administering an amount of vibegron of 75 mg over a treatment period to the subject once daily.

[0098] The present disclosure provides a method for treating overactive bladder, the method comprising orally administering an amount of 75 mg of vibegron to a subject in need thereof once daily, wherein the treatment is over a 12-week treatment period and achieves at least one of the following changes (1) to (5): (1) A greater or equivalent decrease in the mean number of micturitions per 24 hours compared to that achieved with tolterodine extended release (ER) 4 mg; (2) When the subject is an OAB wet patient, a greater or equivalent decrease in the mean number of micturitions per 24 hours compared to that achieved with tolterodine ER 4 mg; (3) A greater or equivalent decrease in the mean number of urgency episodes per 24 hours compared to that achieved with tolterodine ER 4 mg ; (4) A greater or equivalent decrease in the mean number of total incontinence episodes per 24 hours compared to that achieved with tolterodine ER 4 mg ; and (5) A greater or equivalent increase in the mean volume voided per micturition compared to that achieved with tolterodine ER 4 mg.

[0099] In some embodiments, the treatment achieves a greater change than that achieved with tolterodine ER 4 mg in at least one of changes (1) to (5). In some embodiments the treatment achieves a change equivalent to that achieved with tolterodine ER 4 mg in at least one of changes (1) to (5). In some embodiments the treatment achieves a change equivalent to that achieved with tolterodine ER 4 mg in at least one of changes (1) to (5).

[0100] ​In some embodiments, the treatment achieves a greater change than that achieved with tolterodine ER 4 mg in changes (2) and (4), and a greater change than that achieved with vibegron 50 mg or 100 mg. In some embodiments, the treatment achieves a change that is greater than that achieved with tolterodine ER 4 mg in change (1), but less than that achieved with 50 mg or 100 mg of vibegron. In some embodiments, the treatment achieves a change that is greater than that achieved with tolterodine ER 4 mg in change (5), but less than that achieved with 50 mg or 100 mg of vibegron. In some embodiments, the treatment achieves a change that is greater than that achieved with tolterodine ER 4 mg in change (1), but less than that achieved with 50 mg or 100 mg of vibegron. In some embodiments, the treatment achieves a change that is greater than that achieved with tolterodine ER 4 mg in change (5), but less than that achieved with 50 mg or 100 mg of vibegron. In some embodiments, the treatment achieves a change that is greater than that achieved with tolterodine ER 4 mg in change (5), but less than that achieved with 50 mg or 100 mg of vibegron. In some embodiments, the treatment achieves at least one of changes (1) through (5) over a 12-week treatment period:

[0101] In some embodiments, the treatment achieves at least one of changes (1) through (5) over a 12-week treatment period: (1) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urinations per 24 hours; (2) When the subject is an OAB wet patient, a greater decrease than that achieved with an equivalent dose of mirabegron in the average number of UUI episodes per 24 hours; (3) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urgency episodes per 24 hours; (4) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of total incontinence episodes per 24 hours; and (5) An increase greater than that achieved with an equivalent dose of mirabegron in the average volume of urine voided per urination. (1) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urinations per 24 hours; (2) When the subject is an OAB wet patient, a greater decrease than that achieved with an equivalent dose of mirabegron in the average number of UUI episodes per 24 hours; (3) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urgency episodes per 24 hours; (4) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of total incontinence episodes per 24 hours; and (5) An increase greater than that achieved with an equivalent dose of mirabegron in the average volume of urine voided per urination. (1) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urinations per 24 hours;

[0102] In some embodiments, the treatment achieves at least one of changes (1) through (5) over a 12-week treatment period: (1) A greater decrease than that achieved with an equivalent dose of mirabegron in the average number of urinations per 24 hours; (1) A reduction achieved with 50 mg or 100 mg of vibegron in terms of the average number of urinations per 24 hours that is greater than or equal to the reduction; (2) When the subject is an OAB wet patient, a reduction that is greater than or equal to the reduction achieved with 50 mg or 100 mg of vibegron in terms of the average number of urinations per 24 hours ; (3) A reduction achieved with 50 mg or 100 mg of vibegron in terms of the average number of urgency episodes per 24 hours that is greater than or equal to the reduction; (4) A reduction that is greater than or equal to the reduction achieved with 50 mg or 100 mg of vibegron in terms of the average number of total incontinence episodes per 24 hours; and (5) An increase that is greater than or equal to the increase achieved with 50 mg or 100 mg of vibegron in terms of the average volume of urine excreted per urination.

[0103] In some embodiments, the treatment achieves a greater change in changes (2) and (4) than that achieved with 50 mg or 100 mg of vibegron.

[0104] In some embodiments, the treatment achieves at least one of changes (1) or (5) over a 12-week treatment period: (1) A reduction less than the value achieved with 50 mg or 100 mg of vibegron in terms of the average number of urinations per 24 hours; or (5) An increase less than that achieved with 50 mg or 100 mg of vibegron in terms of the average volume of urine excreted per urination.

[0105] The present disclosure also provides a method of treating overactive bladder while reducing the average number of urinations per 24 hours in a subject in which it is needed, the method comprising administering 75 mg of vibegron over a 12-week treatment period Comprising oral administration once a day to a subject, wherein the reduction is greater than or equal to the amount achieved with 4 mg of tolterodine sustained release (ER). (ER) is greater than or equal to the amount achieved with 4 mg.

[0106] The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, the method comprising oral administration once a day to a subject in need thereof of 75 mg of vibegron over a 12-week treatment period, wherein the reduction is greater than or equal to the amount achieved with 4 mg of tolterodine sustained release (ER). Comprising oral administration once a day to a subject in need thereof of 75 mg of vibegron over a 12-week treatment period, wherein the reduction is greater than or equal to the amount achieved with 4 mg of tolterodine sustained release (ER). Comprising oral administration once a day to a subject in need thereof of 75 mg of vibegron over a 12-week treatment period, wherein the reduction is greater than or equal to the amount achieved with 4 mg of tolterodine sustained release (ER). (ER) is greater than or equal to the amount achieved with 4 mg.

[0107] In some embodiments, the subject is a human 65 years of age or older. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.0 and about 2.5 times, for example, about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.5 and about 2.0 times. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.0 and about 2.5 times, for example, about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.5 and about 2.0 times. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.5 and about 2.0 times. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours for the subject is greater than that achieved with placebo by between about 1.5 and about 2.0 times. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. In some embodiments, the reduction or decrease in the average number of urinations over 24 hours is between about 0.5 times and about 2.0 times greater than the value achieved with 4 mg of tolterodine sustained release (ER), for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any range between any two of the preceding values. It is 1.5 times.

[0108] In some embodiments, the present disclosure provides a method for effecting a decrease of from about -2.2 to about -3.5 in the average number of urgency episodes per 24 hours in subjects 65 years of age and older in whom such decrease is needed, the method comprising orally administering to the subject a therapeutically effective amount of vibegron or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 75 mg per day. In some embodiments, the present disclosure provides a method for treating overactive bladder while effecting a decrease of from about -2.2 to about -3.5 in the average number of urgency episodes per 24 hours in subjects 65 years of age and older in whom such decrease is needed, the method comprising orally administering to the subject a therapeutically effective amount of vibegron or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 75 mg per day. In some embodiments, when the subject is an OAB wet patient, the change in the average number of voids per 24 hours is from about -1.3 to about - 2.5; and / or the change in the average number of UUI episodes per 24 hours is from about -1.5 to about - 2.5. In some embodiments, the human is older than 75 years. In some embodiments, the subject has received an anticholinergic agent up to 12 months prior to vibegron administration. In some embodiments, the decrease or reduction in the average number of voids over a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1.0, 1.1, 1.2, 1 .3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the preceding values.

[0109] In some embodiments, the decrease or reduction in the average number of voids over a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1.0, 1.1, 1.2, 1 .3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of voids over a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1.0, 1.1, 1.2, 1 .3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the preceding values. In some embodiments, the decrease in the average number of voids over a 24-hour period is The decrease or reduction in the average number is about 1.5 and about 2.0 times greater than that achieved with the placebo. There is a range between. In some embodiments, the decrease or reduction in the average number of urinations in 24 hours is between about 0.5 and about 2.0 times greater than that achieved with tolterodine extended release (ER) 4 mg, for example, about 0.5, 0. 6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1. 9, 2.0, or in the range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of urinations in a 2 4-hour period is between about 1.0 and about 1.5 times greater than that achieved with tolterodine extended release (ER) 4 mg.

[0110] In some embodiments, the subject received a beta-3 agonist other than vibegron up to 12 months prior to vibegron administration. In some embodiments, the decrease or reduction in the average number of urinations in a 24-hour period is about 1 and less than about 10 times less than the average number of urinations of subjects receiving placebo, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or in the range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of urinations in a 24-hour period is about 1 and about 4 times less than the average number of urinations of subjects receiving placebo. In some embodiments, the decrease or reduction in the average number of urinations in a 24-hour period is between about 1.0 and about 3.0 times greater than that achieved with tolterodine extended release (ER) 4 mg, for example, about 1.0, 1.1, 1 .2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2 .8, 2.9, 3.0, or in the range between any two of the preceding values. In some embodiments ​ In this case, the decrease or reduction in the average number of urinations over a 24-hour period is between 2.0 and 2.5 times greater than that achieved with tolterodine extended release (ER) 4 mg.

[0111] The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering 75 mg of vibegron per day to the subject in need thereof over a 12-week treatment period, wherein the reduction is greater than or equivalent to that achieved with tolterodine extended release (ER 4 mg. In some embodiments, the subject is a human 65 years of age or older. In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24 hours of the aforementioned subject is between about 0.5 and about 2.0 times greater than that achieved with placebo, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 , 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any two of the preceding values

[0112] In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24-hour period for the aforementioned subject is between about 1.25 and about 1.75 times greater than that achieved with placebo. In some embodiments, the subject has received an anticholinergic agent up to 12 months prior to vibegron administration. In some embodiments, the decrease or reduction in the average number of UUI episodes in a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1. In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24-hour period for the aforementioned subject is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1. , 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or any two of the preceding values In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24-hour period for the aforementioned subject is between about 1.25 and about 1.75 times greater than that achieved with placebo. In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24-hour period for the aforementioned subject is between about 1.25 and about 1.75 times greater than that achieved with placebo. In some embodiments, the decrease or reduction in the average number of UUI episodes in the 24-hour period for the aforementioned subject is between about 1.25 and about 1.75 times greater than that achieved with placebo.

[0113] In some embodiments, the subject has received an anticholinergic agent up to 12 months prior to vibegron administration. In some embodiments, the decrease or reduction in the average number of UUI episodes in a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1. In some embodiments, the decrease or reduction in the average number of UUI episodes in a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1. In some embodiments, the decrease or reduction in the average number of UUI episodes in a 24-hour period is between about 1.0 and about 2.5 times greater than that achieved with placebo, e.g., about 1. 0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 1.5 and about 2.0 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 1.5 and about 2.0 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 1.5 and about 2.0 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, .

[0114] In some embodiments, the subject received a beta-3 agonist other than vibegron up to 12 months prior to vibegron administration. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 2 and about 10 times, for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 4 and about 6 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 2 and about 10 times, for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 4 and about 6 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with placebo by about 4 and about 6 times. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 0.5 and about 2.0 times, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or a range between any two of the preceding values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is greater than that achieved with 4 mg of tolterodine extended release (ER) by about 1.25 and about 1.75 times. Between about 0.5 and about 3.5 times greater than that achieved with 4 mg of tolterodine extended release (ER), for example, about 0.5 , 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, or within the range between any two of the foregoing values. In some embodiments, the decrease or reduction in the average number of UUI episodes over a 24-hour period is between about 1.5 and about 3.0 times greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than or equivalent to that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER).

[0115] The present disclosure also provides a method of reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than or equivalent to that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than or equivalent to that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER).

[0116] The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). The present disclosure also provides a method of reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or of treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron once daily to a subject in need thereof over a 12-week treatment period, where the reduction is greater than that achieved with 4 mg of tolterodine extended release (ER). ​​or equivalent. The present disclosure also provides a method of increasing the average voided volume per micturition in a subject suffering from overactive bladder, or a method of treating overactive bladder in a subject in need thereof, the method comprising orally administering 75 mg of vibegron per day to a subject in need thereof over a 12-week treatment period, wherein the increase is greater than or equivalent to that achieved

[0117] by 4 mg of tolterodine extended release (ER). In some embodiments, the decrease in the average number of micturitions per 24 hours, the average number of UUI episodes per 24 hours, the average number of urgency episodes per 24 hours, or the average total incontinence episodes per 24 hours is greater than the decrease achieved by 4 mg of tolterodine ER. In some embodiments, the decrease in the average number of micturitions per 24 hours, the average number of UUI episodes per 24 hours, the

[0118] average number of urgency episodes per 24 hours, or the average total incontinence episodes per 24 hours is equivalent to the decrease achieved by 4 mg of tolterodine ER. In some embodiments, the present disclosure provides a method of treating overactive bladder and, on the other hand, decreasing the average number of UUI

[0119] episodes in a female subject. In some embodiments, the decrease in UUI episodes in female subjects is greater than that achieved in male subjects. In some embodiments, the increase in the average voided volume per micturition is greater than the increase

[0120] The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urinations per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urinations per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urinations per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urinations per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urinations per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron.

[0121] The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron.

[0122] The present disclosure also provides a method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron.

[0123] The present disclosure also provides a method for reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. The present disclosure also provides a method for reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of vibegron in an amount of 75 mg per day over a treatment period of 12 weeks, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron. Provided is a method for reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vibegron per day to subjects in need thereof over a 12-week treatment period, wherein the reduction is greater than that achieved with an equivalent dose of mirabegron.

[0124] The present disclosure also provides a method for increasing the average urine volume per void in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while increasing the average urine volume per void, the method comprising orally administering 75 mg of vibegron per day to subjects in need thereof over a 12-week treatment period, wherein the increase is greater than that achieved with an equivalent dose of mirabegron.

[0125] The present disclosure also provides a method for reducing the average number of voids per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of voids per 24 hours, the method comprising orally administering 75 mg of vibegron per day to subjects in need thereof over a 12-week treatment period, wherein the reduction is greater than or equal to that achieved with 50 mg or 100 mg of vibegron.

[0126] The present disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, or for treating overactive bladder in a subject in need thereof, while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering 75 mg of vibegron per day to subjects in need thereof over a 12-week treatment period. ​​​​​​​​​​​​​comprises a decrease that is greater than or equivalent to that achieved with 50 mg or 100 mg of vibegron or equivalent.

[0127] The present disclosure also provides a method of reducing the mean number of urgency episodes per 24 hours in a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof, while reducing the mean number of urgency episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of 75 mg of vibegron per day over a treatment period of 12 weeks wherein the decrease is greater than or equivalent to that achieved with 50 mg or 100 mg of vibegron. or equivalent.

[0128] The present disclosure also provides a method of reducing the mean number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof, while reducing the mean number of total incontinence episodes per 24 hours, the method comprising orally administering to a subject in need thereof a quantity of 75 mg of vibegron per day over a treatment period of 12 weeks wherein the decrease is greater than the amount achieved with 50 mg or 100 mg of vibegron or equivalent. or equivalent.

[0129] The present disclosure also provides a method of increasing the average volume of urine voided per micturition in a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof, while increasing the average volume of urine voided per micturition, the method comprising orally administering to a subject in need thereof a quantity of 75 mg of vibegron per day over a treatment period of 12 weeks wherein the increase is greater than or equivalent to that achieved with 50 mg or 100 mg of vibegron. or equivalent.​​​​

[0130] In some embodiments, the subject is treated with vibegron for a treatment period, or the subject is treated with vibegron over a treatment period, where the treatment period is about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, and also selected from the group consisting of 52 weeks. In some embodiments, the treatment period is within the range between any of these weeks. In some embodiments, the treatment period is selected from about 2 weeks, about 4 weeks, about 8 weeks weeks, about 12 weeks, or about 52 weeks. In some embodiments, the treatment period is about 12 weeks. In some embodiments, the treatment period is about 52 weeks.

[0131] The present disclosure provides a method of reducing coping behavior in a subject suffering from overactive bladder symptoms, or improving the coping domain score of a subject based on the OAB-q LF (OAB-q long form). The present disclosure also provides a method of treating overactive bladder in a subject in need thereof, while reducing coping behavior on the one hand, or improving the coping domain score of the subject based on the OAB-q LF (OAB-q long form) on the other hand. The method includes orally administering a therapeutically effective amount of vibegron to a subject in need thereof once a day over a treatment period, where the therapeutically effective amount is about 75 mg, and where the coping behavior of the subject is reduced as compared to a subject receiving a placebo. The coping domain score of the OAB-q LF assesses certain aspects of OAB that are measurable tasks and important to the patient. In certain embodiments, the coping behavior or Tasks include planning a route to avoid the toilet, paying attention to your commute planning in depth, planning activities even more carefully, reducing physical activity, new finding the nearest toilet when arriving at a new location, adjusting travel plans, toilet avoiding activities in places far from the toilet, and feeling discomfort traveling with others including, but not limited to, these. In some embodiments, the subject's coping behavior is reduced compared to before the subject starts treatment with vibegron (i.e., baseline), or compared to the coping behavior in subjects who received a placebo, tolterodine extended release (ER) 4 mg for the treatment of OAB, or other compounds In some embodiments, the subject's coping domain score is improved compared to before the subject starts treatment with vibegron In some embodiments, the subject's coping domain score is improved compared to subjects who received a placebo, tolterodine extended release (ER) 4 mg for the treatment of OAB, or other compounds In certain embodiments, the present disclosure provides a method of improving the coping domain score in a subject suffering from overactive bladder The method includes orally administering to the subject in need thereof an amount of vibegron of 75 mg per day over a treatment period In some embodiments, the improvement in the coping domain score is greater than that achieved with tolterodine extended release (ER) 4 mg In some embodiments, the improvement in the coping domain score is greater than the score achieved with a placebo In some embodiments, the improvement is measured from baseline In some embodiments, the coping domain score of a subject receiving vibegron is at least about 3.2 points higher compared to a subject receiving a placebo In some embodiments, the improvement in the score of the coping domain is greater than the score achieved with a placebo In some embodiments, the improvement is measured from baseline In some embodiments, the coping domain score of a subject receiving vibegron is at least about 3.2 points higher compared to a subject receiving a placebo It is improved in the core. For example, as shown in Table 59, over a 12-week treatment period with vibegron the coping doman score of the subjects treated therewith experiences an improvement of 3.6, which is greater than that of the subjects who received the placebo.

[0132] The present disclosure also provides a method of improving sleep in a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof, while providing a method of improving sleep, the method comprising orally administering to the subject in need thereof an amount of 75 mg of vibegron per day over a treatment period. In some embodiments, the improvement in sleep is greater than that achieved with tolterodine extended release (ER) 4 mg. In some embodiments, the improvement in sleep is greater than that achieved with a placebo. In some embodiments, the improvement is measured from the baseline. In some embodiments, the sleep of the subjects who received vibegron is improved by at least about 2.6 scores compared to the subjects who received the placebo. For example, as shown in Table 60, over a 12-week treatment period, the sleep score of the subjects treated with vibegron experiences an improvement of 4.5, which is greater than that of the subjects who received the placebo.

[0133] The present disclosure also provides a method of improving health-related quality of life (HRQL) in a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof, while providing a method of improving health-related quality of life (HRQL), the method comprising orally administering to the subject in need thereof an amount of 75 mg of vibegron per day over a treatment period. In some embodiments, the improvement in HRQL is greater than that achieved with tolterodine extended release (ER) 4 mg. In form, the improvement in HRQL is greater than that achieved with placebo. In some embodiments HRQL includes one or more subscales selected from coping, worry, sleep, or social interaction. In some embodiments, the improvement in HRQL is measured from baseline. In some embodiments subjects receiving vibegron are improved by at least about 3.8 total score compared to subjects receiving placebo. For example, as shown in Table 60, the total HRQL score of subjects receiving vibegron over a 12-week treatment period experiences a score improvement of 3.8 greater than that of subjects receiving placebo.

[0134] The present disclosure also provides a method of reducing the symptom distress of a subject suffering from overactive bladder, or treating overactive bladder in a subject in need thereof while reducing the symptom distress, the method comprising orally administering to a subject in need thereof an amount of 75 mg of vibegron per day over a treatment period. In some embodiments, the reduction in symptom distress is greater than that achieved with tolterodine extended release (ER) 4 mg. In some embodiments the reduction in symptom distress is greater than that achieved with placebo. In some embodiments, the reduction is measured from baseline. In some embodiments, the symptom distress of subjects receiving vibegron is reduced by at least about -5.0 score compared to subjects receiving placebo. For example, as shown in Table 60, the symptom distress score of subjects treated with vibegron over a 12-week treatment period is reduced by up to 6.9 more than that of subjects receiving placebo.

[0135] In some embodiments, the subject has symptoms of urge incontinence, urinary urgency, and frequency.

[0136] In some embodiments, the subject has one or more symptoms of urgency urinary incontinence (also known as urge urinary incontinence), urinary urgency, frequency of urination, and nocturia.

[0137] 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.

[0138] In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is between about 6 years of age and about 18 years of age, between about 6 years of age and about 12 years of age, or between about 12 years of age and about 18 years of age. In some embodiments, the subject is greater than about 20 years of age. In some embodiments, the subject is greater than about 25 years of age. In some embodiments, the subject is greater than about 30 years of age. In some embodiments, the subject is greater than about 35 years of age. In some embodiments, the subject is greater than 40 years of age. In some embodiments, the subject is greater than 45 years of age. In some embodiments, the subject is greater than 50 years of age and older. In some embodiments, the subject is greater than 55 years of age. In some embodiments the subject is greater than 60 years of age. In some embodiments, the subject is greater than 65 years of age. In some embodiments, the subject is greater than 70 years of age. In some embodiments, the subject is greater than 75 years of age.

[0139] In some embodiments, the method is a pharmaceutical unit containing vibegron before administration to the subject It includes pulverizing the dosage composition. In some embodiments, the subject is orally administered a pulverized unit dosage on a dosage form containing vibegron.

[0140] In some embodiments, the subject has or is at risk of having kidney impairment. In some embodiments, the subject has mild, moderate, or severe kidney impairment.

[0141] In some embodiments, the subject has previously received OAB therapy. In some embodiments, the subject has not received prior OAB therapy.

[0142] In some embodiments, vibegron is co-administered with a pharmaceutical agent on a second dosage form, including any of those listed herein. In some embodiments, vibegron is administered concomitantly with a pharmaceutical agent on a second dosage form. In some embodiments, vibegron is administered sequentially with a pharmaceutical agent on a second dosage form. In some embodiments, vibegron is administered before and / or after a pharmaceutical agent on a second dosage form. The embodiments described below include such sequential administration.

[0143] In some embodiments, the subject has received, taken, or otherwise been previously exposed to a β-AR agonist, such as mirabegron or solabegron. 3

[0144] In some embodiments, the subject has received, taken, or otherwise been previously exposed to an anticholinergic agent.

[0145] In some embodiments, the present disclosure is in subjects with a history of treatment experience who need it for overactivity The present invention provides a method for treating bladder dysfunction, the method comprising administering to a subject a therapeutically effective amount of vibegron per day. orally, where the therapeutically effective amount is about 75 mg, and over the course of treatment After administration of vibegron to subjects: a. The reduction in the mean number of urinations in a 24-hour period in subjects was greater than or equal to the number of urinations in subjects receiving a placebo. a decrease in the average number of urine samples of more than about 1.5 to about 10; or b. The mean number of urge urinary incontinence (UUI) episodes per 24 hours by subjects was by about a 1.7 to about a 6-fold reduction in those in treated subjects.

[0146] In some embodiments, the reduction in the average number of urinations per 24 hour period in a subject is Approximately 1.5 and 2.5 times higher than the average number of urinations in a 24-hour period in subjects receiving placebo Approximately 9 bays, approximately 1.5 and approximately 8 bays, approximately 1.5 and approximately 7 bays, approximately 1.5 and approximately 6 bays, approximately 1.5 and approximately 5 bays, Between about 1.5 and about 4, or between about 1.5 and about 3. In some embodiments, the 24 The reduction in the mean number of urinations over the time period was greater than the mean number of urinations in subjects receiving placebo. In some embodiments, the decrease in the 24 hour period in a subject is from about 2 to about 4 times greater than the decrease in the 24 hour period in a subject. The reduction in the mean number of urinations during the study period was greater than the reduction in the mean number of urinations in subjects receiving placebo. The most common range is between about 2 and about 3.

[0147] In some embodiments, the number of urge urinary incontinence (UUI) episodes per 24 hours by a subject. The mean number of decreases was about 1 to about 2, and about 1.1 to about 2.0, respectively, as compared to placebo-treated subjects. Up to about 1.9, from about 1.3 to about 1.8, from about 1.4 to about 1.8, or from about 1.5 to about 1.8 times Decrease. In some embodiments, the urgency urinary incontinence (UUI) episodes per 24 hours by the subject The average number of pisode decreases by a decrease of about 1.7 times that of the subjects treated with placebo.

[0148] In some embodiments, the urgency urinary incontinence (UUI) episodes per 24 hours by the subject The average number of is reduced from about 5 to about 6.5, from about 5.1 to About 6.4, from about 5.2 to about 6.3, from about 5.3 to about 6.4, from about 5.4 to about 6.1, or about 5 .5 to about 6.2 times that of the subjects treated with placebo. In some embodiments, the average number of urgency urinary incontinence (UUI) episodes per 24 hours by the subject Is reduced by a reduction of about 6 times that of the subjects treated with placebo.

[0149] In some embodiments, the average number of urinations per 24 hours by the subject is from about -2.0 to about -4.0 Up to, from about -1.9 to -3.9, from about -1.8 to about -3.8, from about -1.7 to about -3.7, from about -1.6 To about -3.6, from about -1.5 to about -3.5, from about -1.4 to about -3.4, from about -1.3 to about -3.3, about -1.2 to about -3.2, from about -1.1 to about -3.1, or from about -1.0 to about -3.0. In some embodiments, the average number of urinations per 24 hours is reduced from about -1.3 to about -2.5 by Decrease.

[0150] In some embodiments, the urgency urinary incontinence (UUI) episodes per 24 hours by the subject The average number of is from about -2.0 to about -4.0, from about -1.9 to about -3.9, from about -1.8 to about -3.8, about -1 .7 to about -3.8, from about -1.7 to about -3.7, from about -1.6 to about -3.6, from about -1.5 to about -3.5 and decreases by from about -1.4 to about -3.4, from about -1.3 to about -3.3, from about -1.2 to about -3.2, from about -1.1 to about -3.1, or from about -1.0 to about -3.0.

[0151] In some embodiments, after administration of vibegron to a subject over a treatment period, the average number of urinations in the subject over a 24-hour period is about -1.0, -1.1, -1.2, 1.3, -1.4, -1.5, -1.6, -1. 7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, 2.5, -2.6, -2.7, -2.8, -2.9, or -3.0, and the average number of UUI episodes per 24 hours by the subject is about -1. 0, -1.1, -1.2, 1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, 2.5, -2.6, -2.7, -2.8, -2.9, or -3.0. In some embodiments, the average number of urinations decreases by from about -1.3 to about -2.5, and the average number of UUI episodes decreases by from about -1.5 to about -2.5.

[0152] In some embodiments, after administration of vibegron to a subject over a treatment period, the average number of urinations in the subject over a 24-hour period is reduced by between about 1.5 and about 10 compared to the average number of urinations in subjects receiving a placebo, and the average number of UUI episodes per 24 hours by the subject decreases by from about -1.5 to about -2.5.

[0153] In some embodiments, after administration of vibegron to a subject over a treatment period, per 24 hours The average number of urgency episodes ranges from about -1.5 to about -4.2, from about -1.6 to about -4.1, from about -1.7 to about -4.0, from about -1.8 to about -3.9, from about -1.9 to about -3.8, from about -2.0 to about -3.7 and decreases by from about -2.1 to about -3.6 or from about -2.2 to about -3.5.

[0154] In some embodiments, after administration of vibegron to a subject over a treatment period, the total incontinence e pisode average ranges from about -1.0 to about -3.0, from about -1.1 to about -2.9, from about -1.2 to about -2.8 and, at about -1.3 to about -2.7, at about -1.4 to about -2.6, at about -1.5 to about -2.7, at about -1.7 to about -2.7, at about -1.6 to about -2.6, or at about -1.5 to about -2.5. In some embodiments, the total incontinence e pisode average decreases by from about -1.7 to about -2.7.

[0155] In some embodiments, after administration of vibegron to a subject over a treatment period, the average volume excreted per micturition ranges from about 10 mL to about 40 mL, from about 11 mL to about 39 mL, from about 12 mL to about 38 mL, from about 13 mL to about 37 mL, from about 14 mL to about 36 mL, from about 15 mL to about 35 mL, from about 16 mL to about 34 mL, from about 17 mL to about 33 mL, from about 18 mL to about 30 mL, from about 19 mL to about 29 mL, from about 20 mL to about 28 mL, or from about 21 mL to about 27 mL. In some embodiments, the average volume of excreted urinary volume per micturition increases by from about 18 mL to about 30 mL.

[0156] In some embodiments, subjects with treatment experience have been previously treated with an anticholinergic. ​In some embodiments, a subject with treatment experience has received treatment with an anticholinergic agent within 12 months prior to treatment with vibegron. In some embodiments, a subject with treatment experience has received treatment with an anticholinergic agent more than 12 months prior to treatment with vibegron. In some embodiments, a subject with treatment experience is concomitantly treated with an anticholinergic agent and receives treatment with vibegron. In some embodiments, a subject with treatment experience has previously been treated with a beta-3 agonist other than vibegron. In some embodiments, a subject with treatment experience has received treatment with a beta-3 agonist other than vibegron within 12 months prior to treatment with vibegron. In some embodiments, a subject with treatment experience has received treatment with a beta-3 agonist other than vibegron more than 12 months prior to treatment with vibegron. In some embodiments, a subject with treatment experience is concomitantly treated with a beta-3 agonist other than vibegron and

[0157] receives treatment with vibegron. In some embodiments, the beta-3 agonist is mirabegron. In some embodiments, the beta-3 agonist is solabegron. In some embodiments, a subject is concurrently receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor (inhibitor) such as a CYP3A inhibitor and a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2 C9, 2C19, 2D6, and 3A4. In some embodiments, a subject is concurrently receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor (inhibitor) such as a CYP3A inhibitor and a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2 C9, 2C19, 2D6, and 3A4. In some embodiments, a subject is concomitantly treated with a beta-3 agonist other than vibegron and receives treatment with vibegron. In some embodiments, the beta-3 agonist is mirabegron. In some embodiments, the beta-3 agonist is solabegron. In some embodiments, the beta-3 agonist is mirabegron. In some embodiments, the beta-3 agonist is solabegron. In some embodiments, a subject is concurrently receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor (inhibitor) such as a CYP3A inhibitor and a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2

[0158] C9, 2C19, 2D6, and 3A4. In some embodiments, a subject is concurrently receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor (inhibitor) such as a CYP3A inhibitor and a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2 C9, 2C19, 2D6, and 3A4. In some embodiments, a subject is concurrently receiving, taking, or otherwise exposed to a cytochrome P450 inhibitor (inhibitor) such as a CYP3A inhibitor and a drug that is a substrate of the following CYPs: CYP1A2, 2B6, 2C8, 2

[0159] In some embodiments, the subject is concomitantly receiving, taking, or administering a CYP2D6 substrate. It is exposed to the wind.

[0160] CYP 2D6 substrates include, but are not limited to, imipramine, amitriptyline, and fluoxetine. paroxetine, fluvoxamine, venlafaxine, duloxetine, mianserin , mirtazapine, opioids, codeine, morphine, tramadol, O-desmethyltramadol Dhol, N,O-didesmethyltramadol, oxycodone, hydrocodone, hydromorphone , tapentadol, haloperidol, risperidone, perphenazine, thioridazine, Zuclopenthixol, Iloperidone, Aripiprazole, Chlorpromazine, Levomeprazole Lomazin, remoxipride, minaprine, tamoxifen, hydroxytamoxifen, Beta-blockers, metoprolol, timolol, Luprenolol, Carvedilol, Bufuralol, Nebivolol, Propranolol, Dextran Brixoquine, flecainide, propafenone, encainide, mexiletine, lidocaine , sparteine, ondansetron, donepezil, phenformin, tropisetron, a Amphetamine, methoxyamphetamine, dextromethamphetamine, atomoxetine , chlorphenamine, dexfenfluramine, dextromethorphan Phenacetin, dextrorphan, metoclopramide, perhexiline, phenacetin, prothrombin These include methazine, m-tyramine, warfarin, tolterodine, and p-tyramine.

[0161] In some embodiments, the subject is concomitantly receiving a P-glycoprotein inhibitor. or otherwise exposed.

[0162] CYP3A / 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 ri tonavir, rifampin (e.g., single dose),simeprevir, p-aminohippuric acid (PAH)(b) , probenecid, teriflunomide, cimetidine, dolutegravir, isavuconazole, la norazine, trimethoprim, and vandetanib.

[0163] In some embodiments, the subject is concomitantly receiving, taking, or otherwise exposed to a muscarinic receptor antagonist .

[0164] Muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine , doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutyn in, tiotropium, cyclopentolate, methylatropine nitrate, trihexyphenidyl / benzhexol, tolterodine, solifenacin, darifenacin, benztropine , mebeverine, procyclidine, and acridine bromide. .

[0165] In some embodiments, the subject is administered about 75 mg of vibegron per day and subsequently receives, takes, or is otherwise exposed to a muscarinic receptor antagonist.

[0166] In some embodiments, the subject is administered about 75 mg of vibegron per day and subsequently receives, takes, or is otherwise exposed to a CYP3A inhibitor.

[0167] In some embodiments, the subject is administered about 75 mg of vibegron per day and subsequently receives, takes, or is otherwise exposed to a P-glycoprotein inhibitor.

[0168] In some embodiments, the subject does not receive, take, or is otherwise exposed to a beta blocker.

[0169] In some embodiments, the subject does not receive, take, or is otherwise exposed to amlodipine.

[0170] In some embodiments, vibegron is administered with food, within 60 minutes after a meal, or within 2 hours after a meal.

[0171] In some embodiments, vibegron is administered without food or before a meal. In some embodiments, vibegron is administered more than two hours before food. In some embodiments, vibegron is administered regardless of whether the subject has eaten or not. ​​​​​​

[0172] In some embodiments, vibegron is administered once, twice, or three times a day In some embodiments, vibegron is administered once a day

[0173] Changes from baseline in blood pressure (BP) and heart rate (HR) in subjects taking vibegron are not substantially different from those in subjects taking placebo. In some embodiments, the subject experiences an average maximum change in systolic blood pressure (SBP) from baseline over a treatment period (e.g., 8 weeks or 12 weeks), and the average maximum change is less than 2.0 mmHg, less than 1.9 mmHg, less than 1.8 mmHg, less than 1.7 mmHg, less than 1.6 mmHg, less than 1.5 mmHg, less than 1.4 mmHg, less than 1.3 mmHg, less than 1.2 mmHg, less than 1.1 mmHg, less than 1.0 mmHg, less than 0.9 mmHg, less than 0.8 mmHg, less than 0.7 mmHg, less than 0.6 mmHg, or less than 0.5 mmHg from that of subjects taking placebo In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 2 mmHg from that of subjects taking placebo. In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) that is less than 1 mmHg from that of subjects taking placebo

[0174] In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron per day

[0175] ​​​​​​​​​​​administered to and experiences an average maximum change in SBP from baseline over a treatment period of less than 2 mmHg from that of subjects taking a placebo ( e.g., 8 weeks or 12 weeks). In some embodiments, the subject is over 65 years of age and about 75 mg of vibegron is administered per day to and experiences an average maximum change in SBP from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo ( e.g., 8 weeks or 12 weeks).

[0176] In some embodiments, the subject is over 45 years of age and about 75 mg of vibegron is administered per day to and experiences an average maximum change in SBP from baseline over a treatment period of less than 2 mmHg from that of subjects taking a placebo ( e.g., 8 weeks or 12 weeks). In some embodiments, the subject is over 45 years of age and about 75 mg of vibegron is administered per day to and experiences an average maximum change in SBP from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo ( e.g., 8 weeks or 12 weeks).

[0177] In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks). The average maximum change is less than 2.0 mmHg, less than 1.9 mmHg, less than 1.8 mmHg, less than 1.7 mmHg, less than 1.6 mmHg, less than 1.5 mmHg, less than 1.4 mmHg from that of subjects taking a placebo, less than 1.3 mmHg, less than 1.2 mmHg, less than 1.1 mmHg, less than 1.0 mmHg, less than 0.9 mmHg, less than 0.8 mmHg from that of subjects taking a placebo, less than 0.7 mmHg, less than 0.6 mmHg, less than 0.5 mmHg, less than 0.4 mmHg, less than 0.3 mmHg, less than 0.2 mmHg, less than 0.1 mmHg from that of subjects taking a placebo, less than 0.05 mmHg, less than 0.04 mmHg, less than 0.03 mmHg, less than 0.02 mmHg, less than 0.01 mmHg is less than 0.7 mmHg, less than 0.6 mmHg, or less than 0.5 mmHg.

[0178] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 2 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks ). In some embodiments the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks).

[0179] In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 2 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks). In some embodiments the subject is over 65 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks).

[0180] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 2 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks). In some embodiments the subject is over 45 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg from that of subjects taking a placebo (e.g., 8 weeks or 12 weeks). Subjects who are administered and taking placebo experience an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg (e.g., 8 weeks or 12 weeks).

[0181] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron once daily and experiences an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg (e.g., 8 weeks or 12 weeks) from that of subjects who are administered and taking placebo, and an average maximum change in SBP from baseline over a treatment period of less than 1 mmHg (e.g., 8 weeks or 12 weeks) from that of subjects who are taking placebo. In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron once daily and experiences an average maximum change in DBP from baseline over a treatment period of less than 1 mmHg (e.g., 8 weeks or 12 weeks) from that of subjects who are administered and taking placebo, and an average maximum change in SBP from baseline over a treatment period of less than 1 mmHg (e.g., 8 weeks or 12 weeks) from that of subjects who are taking placebo.

[0182] In some embodiments, the subject experiences an average maximum change in systolic blood pressure (SBP) from baseline over a treatment period of less than 10 mmHg, less than 9.5 mmHg, less than 9 mmHg, less than 8.5 mmHg, less than 8 mmHg, less than 7.5 mmHg, less than 7 mmHg, less than 6.5 mmHg, less than 6 mmHg, less than 5.5 mmHg, or less than 5 mmHg (e.g., 8 weeks or 12 weeks).

[0183]

[0184] ​​​​​​​In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period of less than 10 mmHg (e.g., 8 weeks or 12 weeks). In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period of less than 10 mmHg (e.g., 8 weeks or 12 weeks).

[0185] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period of less than 10 mmHg (e.g., 8 weeks or 12 weeks). In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron per day and experiences an average maximum change in SBP from baseline over a treatment period of less than 10 mmHg (e.g., 8 weeks or 12 weeks).

[0186] In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline over a treatment period of less than 7 mmHg, less than 6.5 mmHg, less than 6 mmHg, less than 5.5 mmHg, less than 5 mmHg, less than 4.5 mmHg, less than 4 mmHg, less than 3.5 mmHg, less than 3 mmHg, less than 2.5 mmHg, or less than 2 mmHg (e.g., 8 weeks or 12 weeks). In some embodiments, the subject experiences an average maximum change in diastolic blood pressure (DBP) from baseline over a treatment period of less than 7 mmHg, less than 6.5 mmHg, less than 6 mmHg, less than 5.5 mmHg, less than 5 mmHg, less than 4.5 mmHg, less than 4 mmHg, less than 3.5 mmHg, less than 3 mmHg, less than 2.5 mmHg, or less than 2 mmHg (e.g., 8 weeks or 12 weeks).

[0187] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 7 mmHg (e.g., 8 weeks or 12 weeks). In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 7 mmHg (e.g., 8 weeks or 12 weeks).

[0188] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 7 mmHg (e.g., 8 weeks or 12 weeks). In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences an average maximum change in DBP from baseline over a treatment period of less than 7 mmHg (e.g., 8 weeks or 12 weeks).

[0189] In some embodiments, the subject is administered about 75 mg of vibegron per day and ​​​​​​The change from baseline over a treatment period (e.g., 8 or 12 weeks) in the average number of urinations per hour is experienced from the baseline, where the change is greater than that for subjects taking a placebo. The difference from placebo (i.e., placebo-adjusted change) is from about -0.1 to about -1.5 and can be, for example, about -0.1, -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1 , -1.2, -1.3, -1.4, or -1.5, or in the range between any two of the preceding values . In some embodiments, the placebo-adjusted change is from about -1.0 to about -0.1, or about -0.8 to about -0.2. In some embodiments, the placebo-adjusted change is about -0.5 .

[0190] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline in the average number of urinations per 24 hours over a treatment period (e.g., 8 or 12 weeks) in the range from about -1.3 to about -2.5, such as about -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1 , -2.2, -2.3, -2.4, or -2.5, or in the range between any two of the preceding values. In some embodiments, the change from baseline in the average number of urinations per 24 hours is from about -1.3 to about -2.3, from about -1.5 to about -2.1, or from about -1.6 to about -2.0. In some embodiments, the change from baseline in the average number of urinations per 24 hours is about -1.8.

[0191] In some embodiments, the subject has experienced on average ≥ 1 urgency urinary incontinence (UUI) episode prior to treatment have one episode per day and administer about 75 mg of vibegron per day, and UUI e experience a change from baseline over a treatment period (e.g., 8 or 12 weeks) at the mean number of episodes where the change is greater than that for subjects taking placebo The difference from placebo (i.e., placebo-adjusted change) ranges from about -0.1 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. In some embodiments, the placebo-adjusted change ranges from about -1.1 to about -0.1, or from about -0.9 to about -0.3 In some embodiments, the placebo-adjusted change is about -0.6 In some embodiments, the placebo-adjusted change is about -0.6

[0192] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline over a treatment period (e.g., 8 or 12 weeks) at the mean number of UUI episodes from 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 preceding values In some embodiments, the subject experiences a change from baseline over a treatment period (e.g., 8 or 12 weeks) at the mean number of UUI episodes from about -1.5 to about -2.5, about -1.7 to about -2.3, or from about -1.8 to about -2.2. In some embodiments, the change from baseline at the mean number of UUI episodes is about -2.0 In some embodiments, the change from baseline at the mean number of UUI episodes is about -2.0 In some embodiments, the change from baseline at the mean number of UUI episodes is about -2.0 In some embodiments, the change from baseline at the mean number of UUI episodes is about -2.0

[0193] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline over a treatment period (e.g., 8 weeks or 12 weeks) in the mean number of urgency episodes per 24 hours, where the change is greater than the change in subjects taking placebo. The difference from placebo (i.e., the placebo-adjusted change) is from about -0.4 to about -1.5 and, for example, about -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or in the range between any two of the preceding values. In some embodiments the placebo-adjusted change is from about -1.2 to about -0.2, or from about -0.9 to about -0.4 . In some embodiments, the placebo-adjusted change is about -0.7.

[0194] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline over a treatment period (e.g., 8 weeks or 12 weeks) in the mean number of urgency episodes per 24 hours of from about - 2.2 to about -3.2, for example, about -2.2, -2.3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9, -3. 0, -3.1, or -3.2, or in the range between any two of the preceding values. In some embodiments the change from baseline in the mean number of urgency episodes per 24 hours is from about -2.2 to about -3.2, from about -2.4 to about -3.0 , or, if possible, from about -2.5 to about -2.9. In some embodiments, the change from baseline in the mean number of urgency episodes per 24 hours is about -2.7.

[0195] ​​​​​In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline over the treatment period (e.g., 8 or 12 weeks ) in the mean number of total incontinence episodes per 24 hours, where the change is greater than the change in subjects taking placebo. The difference from placebo (i.e., the placebo-adjusted change) is from about -0.4 to about -1.5, e.g., about -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1 .3, -1.4, or -1.5, or in the range between any two of the preceding values. In some embodiments, the placebo-adjusted change is from about -1.2 to about -0.2, or from about -1.0 to about -0.4. In some embodiments, the placebo-adjusted change is about -0.7.

[0196] In some embodiments, the subject is administered about 75 mg of vibegron per day and experiences a change from baseline in the range from about -1.8 to about -2.8, e.g., about -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7, or -2.8, or in the range between any two of the preceding values, over the treatment period (e.g., 8 or 12 weeks). In some embodiments, the change from baseline in the mean number of total incontinence episodes per 24 hours is from about -1.8 to about -2.8, from about -2.0 to about -2.6, or from about -2.1 to about -2.5. In some embodiments, the change from baseline in the mean number of total incontinence episodes per 24 hours is from about -1.8 to about -2.8, from about -2.0 to about -2.6, or from about -2.1 to about -2.5. In some embodiments, the change from baseline in the mean number of total incontinence episodes per 24 hours is about -2.3.

[0197] ​In some embodiments, the subject is administered about 75 mg of vibegron per day, and experiences a change in the volume excreted per micturition (mL), where the change is greater than that for a subject taking a placebo. The difference from placebo (i.e., the placebo-adjusted change) is from about 20 mL to about 35 mL, for example, 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 any value in between or in the range between two such preceding values. In some embodiments, the placebo-adjusted change is from about 15.0 to about 26, from about 18.0 to about 23.0. In some embodiments, the placebo-adjusted change is about 21.2.

[0198] In some embodiments, the subject is administered about 75 mg of vibegron per day, and experiences a change from baseline in the volume excreted per micturition (mL) over a treatment period (e.g., 8 weeks or 12 weeks), from about 18 mL to about 30 mL, from about 20 mL to about 28 mL, or from about 22 mL to about 26 mL. In some embodiments, the change from baseline in the volume excreted per micturition (mL) is about 23 mL or about 24 mL.

[0199] In some embodiments, the subject has at least an average of 1 urgency urinary incontinence (UUI) episode per day prior to treatment, and is administered about 75 mg of vibegron per day, and there is at least a 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% reduction in the average number of UUI episodes per day over a treatment period (e.g., 8 weeks or 12 weeks). 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% reduction in the average number of UUI episodes per day over a treatment period (e.g., 8 weeks or 12 weeks). also experience a decrease of at least 75%, at least 80%, or at least 85%.

[0200] In some embodiments, the subject has an average of ≧1 urgent episode per day prior to treatment, and is administered about 75 mg of vibegron per day, and experiences a decrease of at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% in the average number of urgent episodes per day over a treatment period (e.g., 8 weeks or 12 weeks). also experience a decrease of at least 75%, at least 80%, or at least 85%.

[0201] In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron per day, and experiences an average maximum change in DBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mmHg.

[0202] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron per day, and experiences an average maximum change in DBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mmHg.

[0203] In some embodiments, a subject over 45 years of age is administered about 75 mg of vibegron once daily and experiences an average maximum change in DBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) of less than 7 mmHg, and an average maximum change in SBP from baseline over a treatment period (e.g., 8 weeks or 12 weeks) of less than 10 mmHg.

[0204] In some embodiments, a subject over 65 years of age is administered about 75 mg of vibegron once daily​​​​​​ and an average maximum change in DBP from baseline over a treatment period of less than 7 mmHg (examples are 8 weeks or 12 weeks), and an average maximum change in SBP from baseline over a treatment period of less than 10 mmHg (examples are 8 weeks or 12 weeks). experience

[0205] In some embodiments, vibegron has an onset of action in about 4 weeks. In some embodiments, vibegron has an onset of action in 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 period until the effect of the drug becomes prominent upon administration.

[0206] As disclosed herein, the method of treating OAB patients with vibegron is well tolerated and adverse events that exceed 2% or are greater than placebo are very few, and these adverse events include headache, nasopharyngitis, diarrhea, and nausea (such as nausea, vomiting and queasiness, etc.).

[0207] Vibegron has a similar incidence for other adverse events compared to placebo, such as hypertension, blood pressure increase, tachycardia, hypotension dizziness, urinary tract infection, urinary retention, thirst, constipation, and fatigue, etc. In some embodiments, treatment with vibegron does not cause any increased risk in hypertension compared to placebo. In some embodiments, treatment with vibegron does not cause an increased risk in blood pressure increase. In some embodiments, treatment with vibegron does not cause an increased risk in tachycardia. In some embodiments, treatment with vibegron does not cause an increased risk in hypotension. In some embodiments, treatment with vibegron ​The treatment does not cause any increased risk in one or more of hypertension, blood pressure, tachycardia, or hypotension. It does not occur.

[0208] For systolic blood pressure (SBP) and diastolic blood pressure (DBP), monitor the changes from the baseline. Category - specific changes in SBP and DBP are measured, for example, changes of ≧5 mmHg, ≧10 mmHg, ≧15 mmHg, or ≧20 mmHg. Pharmaceutically unit - dose compositions

[0209] The present disclosure provides pharmaceutically unit - dose compositions comprising the dosages of vibegron disclosed herein, wherein the unit - dose compositions are suitable for oral administration. Oral dosage forms include, for example, forms such as liquid preparations, tablets, capsules, and gelcaps, which are recognized by those skilled in the art. In some embodiments, the unit - dose composition is a solid dosage form, such as tablets and capsule formulations. In some embodiments, the unit - dose composition is a tablet.

[0210] Pharmaceutically acceptable excipients are generally recognized as safe excipients, such as lactose, microcrystalline cellulose, starch, calcium carbonate, magnesium stearate, stearic acid, talc, colloidal silicon dioxide, mannitol, croscarmellose sodium, hydroxypropylcellulose, and the like. In some embodiments, the pharmaceutically unit - dose compositions disclosed herein comprise diluents, disintegrants, binders, and lubricants. Generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton P ​​​​A (2000)(Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton, Pennsylvania (2000 year)) is incorporated herein by reference in its entirety.

[0211] In some embodiments, the pharmaceutical unit dosage compositions of the present disclosure can be pulverized. In some embodiments, the pharmaceutical unit dosage compositions of the present disclosure are pulverized prior to oral administration .

Examples

[0212] Example 1 Formulation of vibegron tablets The compositions of vibegron tablets (50 mg, 75 mg, and 100 mg) are shown in Table 1.

[0213]

Table 1

[0214] In men and women with OAB (stratified by OAB wet and OAB dry), a randomized, double-blind, placebo and active control, parallel-group two-part phase 2b study of vibegron was completed. Part 1 was a dose-range study to evaluate the safety, tolerability, and efficacy of vibegron, and a proof-of-concept study regarding the efficacy of vibegron and the concomitant dosing of vibegron with tolterodine ER 4 mg. . Approximately 980 subjects in Part 1 were in seven treatment arms (an "arm" can also be referred to as a group): vibegron 3 mg, 15 mg, 50 mg, or 100 mg once daily for 8 weeks; tolterodine ER 4 mg once Once daily for 8 weeks; placebo once daily for 8 weeks; or take vibegron 50 mg and tolterodine ER 4 mg After 4 weeks of both, vibegron 50 mg was equally allocated at random in any of the 4 weeks in a double-blind manner Part 2 was designed to continue to evaluate the safety and efficacy of the concomitant medication In Part 2, 408 subjects were randomly assigned in a double-blind manner to one of four treatment arms of vibegron 100 mg, tolterodine ER 4 mg, tolterodine ER 4 mg together with vibegron 100 mg, or placebo once daily for 4 weeks in a ratio of 2:2:2:1 Subjects in both Part 1 and Part 2 had the option to enroll in a 1-year extension study Participants were required to keep a voiding diary and record the occurrence of each episode of strong urgency, total incontinence, and urge urinary incontinence The efficacy data from Part 1 and Part 2 are summarized here

[0215] At baseline, subjects must have had an average of ≥8 voids per day in the voiding diary Furthermore, subjects in the OAB wet stratum must have had an average number of urge incontinence episodes per diary day of ≥1 Subjects in the OAB dry stratum must have had an average number of urgency episodes per diary day of ≥3 and an average number of urge incontinence episodes per diary day of <1 The total number of urge incontinence episodes must have exceeded the total number of stress incontinence episodes for all subjects

[0216] The primary objective of this study was to evaluate the safety and tolerability of treatment with the selected doses of vibegron (alone or in combination with tolterodine), and the number of voids per day compared to placebo at week 8​​​​​​ The objective of this study was to investigate the dose-related decrease in the mean number of

[0217] In part 1, treatment with vibegron 100 mg and 50 mg was compared with placebo at week 8 The average number of urinations per day in the treatment groups A statistically significant reduction in the secondary endpoints was observed. Including urge incontinence and total incontinence (in subjects with OAB wetness) The incidence of urgency episodes in all subjects was also significantly higher in the 100 mg and 50 mg vibegron treatment groups. A statistically significant reduction from baseline was observed with the loop compared to placebo. The secondary endpoint of single voided voided volume was also significantly higher in the vibegron 15, 50, and 100 mg treatment groups. A statistically significant increase from baseline was observed in the 10-mg / kg / day group compared with placebo (Table 2 and Table 3). and 3).

[0218] [Table 2]

[0219] [Table 3-1] [Table 3-2]

[0220] To evaluate the safety and efficacy of vibegron in males and females with OAB A double-blind, randomized, placebo-controlled, multicenter, phase 3 study was designed to The study was completed. After the placebo administration period ended, 1,232 patients were randomly assigned to the following: vibegron 50 mg (N = 370), vibegron 100 mg (N = 369), placebo (N = 369), or imidafenacin 0.2 mg (comparator, N = 117) and received a 12-week blinded study treatment. The results demonstrated that once-daily vibegron produced a statistically significant decrease in efficacy parameters, including micturition frequency, UUI episodes, total incontinence episodes, and urgency episodes (Table 4). The following: vibegron 50 mg (N = 370), vibegron 100 mg (N = 369), placebo (N = 369), or imidafenacin 0.2 mg (comparator, N = 117) and received a 12-week blinded study treatment. The results demonstrated that once-daily vibegron produced a statistically significant decrease in efficacy parameters, including micturition frequency, UUI episodes, total incontinence episodes, and urgency episodes (Table 4). imidafenacin 0.2 mg (comparator, N = 117) and received a 12-week blinded study treatment. The results demonstrated that once-daily vibegron produced a statistically significant decrease in efficacy parameters, including micturition frequency, UUI episodes, total incontinence episodes, and urgency episodes (Table 4). Results demonstrated that once-daily vibegron produced a statistically significant decrease in efficacy parameters, including micturition frequency, UUI episodes, total incontinence episodes, and urgency episodes (Table 4). episodes (Table 4). (Table 4).

Table 4

[0221] In the Phase 1 studies, orthostatic hypotension (a decrease in systolic blood pressure >2 orthostatic hypotension (a decrease in systolic blood pressure >2 The occurrence of <0 mmHg and / or a decrease in diastolic blood pressure > 10 mmHg) was separated. After co - administration of vibegron 100 mg or 150 mg and tordusin ER 4 mg, the incidence of orthostatic AEs was similar to the incidence of these AEs after administration of vibegron or tordusin alone. In the multiple - dosing phase 1 study, at doses up to 100 mg, AEs such as postural dizziness, dizziness, pre - syncope, syncope, etc. did not show a clear dose - response relationship. However, postural dizziness showed an increase at doses of 100 mg and above, and the AE "orthostatic hypotension with symptoms" tended to have an even higher incidence at vibegron doses > 200 mg. When 100 mg of vibegron was co - administered to subjects with essential hypertension who were stably receiving either metoprolol (a representative beta - blocker) or amlodipine (a representative vasodilator), there was no manifestation of orthostatic AEs. After co - administration of vibegron 100 mg or 150 mg and tordusin ER 4 mg, the incidence of orthostatic AEs was similar to the incidence of these AEs after administration of vibegron or tordusin alone. In the multiple - dosing phase 1 study, at doses up to 100 mg, AEs such as postural dizziness, dizziness, pre - syncope, syncope, etc. did not show a clear dose - response relationship. However, postural dizziness showed an increase at doses of 100 mg and above, and the AE "orthostatic hypotension with symptoms" tended to have an even higher incidence at vibegron doses > 200 mg. When 100 mg of vibegron was co - administered to subjects with essential hypertension who were stably receiving either metoprolol (a representative beta - blocker) or amlodipine (a representative vasodilator), there was no manifestation of orthostatic AEs. The examination of phase 1 safety preliminary data did not suggest clinically meaningful changes in laboratory safety parameters (chemical, hematological and urine tests) or ECG parameters, including PR, QRS and QTc intervals. A thorough QT study has been completed and it has not found clinically meaningful effects on QTc or blood pressure. 3.2 Phase II safety data Phase 2 safety data were collected from a single 2B - phase study in which 933 subjects completed at least one dose of vibegron. Subjects received vibegron doses in the range of 3 to 100 mg for up to 8 weeks during the main study (either alone or in combination with tordusin). The parent trial was terminated.

[0222] The examination of phase 1 safety preliminary data did not suggest clinically meaningful changes in laboratory safety parameters (chemical, hematological and urine tests) or ECG parameters, including PR, QRS and QTc intervals. A thorough QT study has been completed and it has not found clinically meaningful effects on QTc or blood pressure. 3.2 Phase II safety data

[0223] Phase 2 safety data were collected from a single 2B - phase study in which 933 subjects completed at least one dose of vibegron. Subjects received vibegron doses in the range of 3 to 100 mg for up to 8 weeks during the main study (either alone or in combination with tordusin). The parent trial was terminated. ​​​​Of those who did, 605 subjects received dosing with vibegron 50 mg (alone) or vibegron 1 00 mg (alone or in combination with 4 mg of tolterodine) for up to 52 weeks during the extension study. The primary studies included a placebo group and groups that received tolterodine monotherapy in the primary study and its extension. There were no reported deaths during the study. The tolerability of vibegron was generally good. There was no significant difference in the overall incidence or severity of AEs or drug-related AEs between the treatment groups compared to placebo .

[0224] In the primary study, adverse events were reported in 607 (43.6%) of the 1393 subjects assigned. In the vibegron 50 mg and vibegron 100 mg treatment groups, the proportion of subjects reporting one or more AEs was similar to placebo (see Table 14). In the vibegron 15 mg and vibegron 50 mg + 4 mg tolterodine treatment groups, the proportion of subjects reporting one or more AEs was higher compared to placebo . The most frequently reported AEs were dry mouth, headache, urinary tract infection (UTI), and nasopharyngitis. The incidence of dry mouth was higher in the groups that received tolterodine (alone or in combination with vibegron) compared to the placebo or vibegron monotherapy groups .

[0225] There were 221 subjects with drug-related AEs, and the lowest incidence of drug-related AEs was reported in the vibegron 100 mg treatment group. The proportion of subjects with drug-related AEs was similar in the vibegron monotherapy groups compared to placebo and ​​​​​​It was only slightly higher in the concomitant treatment group compared to drug administration. Due to drug-related AEs The proportion of subjects who discontinued was low and was similar across all treatment groups.

[0226] A total of 9 SAEs were reported in 8 subjects and occurred across treatment groups (2 in placebo; 1 in vibegron 3 mg; 1 in vibegron 50 mg; 3 in tolterodine 4 mg; 1 in vibegron 50 mg + tolterodine 4 mg). The reported SAEs were atrial fibrillation, anaphylactic reaction, stage IV lung adenocarcinoma, chronic obstructive pulmonary disease, hypertension, overdose, foot fracture, and in 1 subject both gastroesophageal reflux and dizziness occurred after a prolonged hospitalization for a pan endoscopic procedure. No specific AE term was reported in more than 1 subject. All SAEs were judged by the investigator to be unrelated to the study drug. During the 52-week extension period, no significant differences were observed in the overall incidence of adverse events and the incidence of serious adverse events between treatment groups.

[0227] Adverse events were reported in 531 (62.8%) of 845 subjects. The proportion of subjects with 1 or more AEs was similar across all treatment groups. The most frequently reported adverse events were urinary tract infection, nasopharyngitis, upper respiratory tract infection, and dry mouth. The incidence of dry mouth was higher in the tolterodine ER 4 mg treatment group compared to the other treatment groups. The incidence of constipation was even higher in the concomitant treatment group compared to the monotherapy

[0228] treatment groups. treatment groups. The proportion of subjects with drug-related AEs was for tolterodine ER 4 mg and the concomitant dosing arm

[0229] ​​​​​ It was slightly higher compared to the vibegron 50 mg and 100 mg treatment arms. Also, AE or The proportion of subjects discontinued due to drug-related AE was higher in the tolterodine ER 4 mg group compared to other treatment groups. A total of 46 SAEs were reported from 41 subjects during the extension period. In the tolterodine ER 4 mg and vibegron 50 mg treatment groups, a higher overall incidence was reported compared to the vibegron 100 mg treatment group. One drug-related SAE of ileus paralysis was reported in the tolterodine ER 4 mg treatment group; the subject was discontinued due to this AE.

[0230] Table 5 below summarizes the adverse events commonly seen in the second-phase program of vibegron in patients with overactive bladder.

[0231]

Table 5

[0232] accompanied by a potent P-gp inducer. 3.3 Cardiovascular safety The cardiovascular safety of vibegron was evaluated in patients with OAB and healthy volunteers. In a randomized, placebo- and active comparator (tolterodine)-controlled, 2-part, 52-week

[0233] extension efficacy and safety study, 7 orthostatic-related AEs (including presyncope, near syncope, and orthostatic hypotension in the adverse event terms) occurred in 6 subjects (0.4% ). One subject each in the placebo group (0.5%), the vibegron 15 mg group (0.3%), and the vibegron 50 mg + tolterodine ER / vibegron 50 mg treatment group (0.8%), and 3 subjects in the vibegron 100 mg group (1.1%) experienced events. These events occurred at random times during the study period and the investigators judged them to be of mild severity. None led to interruption. The overall incidence of orthostatic symptoms was low.

[0234] ​​​Table 6 shows the changes from baseline in BP and HR across treatment groups. For systolic blood pressure (SBP) and diastolic blood pressure (DBP), the mean change at week 1 and the mean maximum change over 8 weeks for 50 mg and 100 mg were equivalent between placebo and vibegron, with a difference of <1 mmHg. The category-specific changes in SBP and DBP were also similar between placebo and vibegron, although the percentage of vibegron subjects with a change from baseline in DBP >15 mmHg increased slightly at 100 mg (1.3% for 100 mg vs 0.5% for placebo). Since the mean of the maximum change over 8 weeks for HR was similar to placebo (<2 bpm), a dose-dependent pattern was not observed. The small differences in the percentage of subjects exceeding the

[0235] category-specific heart rate and blood pressure thresholds for vibegron were similar

[0236] to those in the torterodine arm. In several Phase 1 studies, a more detailed evaluation of heart rate and blood pressure was performed in healthy volunteers. Six sub-studies were double-blind, randomized, and placebo-controlled to evaluate the safety, tolerability, and PK of multiple-dose vibegron in healthy subjects with a specific analysis regarding heart rate. Doses ranged from 25 to 400 mg once daily for 7 to 28 days across cohorts. Table 7 presents the least-squares mean and 90% confidence interval of the It was.

[0237]

Table 7

[0238] Cardiovascular safety was evaluated following a thorough QT study in healthy volunteers and after single doses of 200 mg and 400 mg, which were close to the steady-state exposure levels of vibegron at 100 mg and 200 mg, respectively. As shown in Table 8, the mean maximum effects on blood pressure and RR interval decreased with even lower doses. Using log-log regression analysis from multiple-dose exposure of vibegron (three Phase 1 studies), the calculated mean ± standard deviation C and AUC were 120 ± 74.7 ng / mL and 1140 ± 476 ng·h / mL, respectively max These estimates represent C and AUC, which were approximately 3.3-fold and 2-fold lower than those of a single 200 mg dose, respectively, and approximately 9.2-fold and 6-fold max lower than those of a single 400 mg dose, respectively.

[0239]

Table 8

[0240] Example 4 Dose Selection 4.1 Dose-Comparative Efficacy

[0240] The Phase 2 study examined in Example 2 demonstrated a dose-dependent effect on urination, as seen in Table 9. Conversely, no dose-dependent effect was observed on urge incontinence or total incontinence. From these data, a relatively shallow dose-response relationship was revealed between 50 and 100 mg once daily. It plateaued from 50 to 100 mg, so 75 mg achieved most of the efficacy achieved by 100 mg.

[0241]

Table 9

[0242] Unexpectedly, when measured at week 8, the reduction in UUI episodes and urination was not dose-proportional. For UUI episodes, comparing the change data from the baseline at week 8 of 50 mg in the Phase 2 trial (Table 3) with the change data from the baseline at week 8 of 75 mg in the Phase 3 trial (Table 15), it was unexpected that the 75 mg dose used in the Phase 3 trial resulted in a lower reduction compared to the 50 mg dose used in the Phase 2. Similarly, the reduction in urination was lower with 75 mg administration (Table 16) than with 50 mg administration (Table 3). 4.2 Reduction of side effects

[0243] Vibegron demonstrated an increase greater than dose-proportionality in exposure. Unexpectedly, the increase at doses from 50 mg to 100 mg resulted in an approximately three-fold increase in the PK parameter most closely related to the cardiovascular effects, max C. To apply the PK parameters of the 75 mg dose to the situation, dose-C and dose-AUC models were created using the data from the Phase 1 study. Based on the simulation, at a 75 mg dose of vibegron, approximately 29% of the exposure observed at a 100 mg dose was avoided, and it was found that the upper limit of exposure achieved later at a 100 mg dose decreased. Thus, with the reduction of the outlier of C the clinically important cardiovascular max max adverse events are reduced.​​​​​​​ The potential for systemic effects is reduced.

[0244] In multiple-dose studies of the first phase, up to a dose of 100 mg, adverse events such as postural dizziness , dizziness, pre-syncope, syncope, etc. did not show a clear dose-response relationship. However, postural dizziness appears to increase at a dose of ≧100 mg, and the incidence of the adverse event "orthostatic hypotension with symptoms" was higher at doses of vibegron more than 150 mg. The risk of these dose-related adverse events can be reduced to imbalance by reducing the dose from 100 mg to 75 mg, which is because a 25% reduction in dose results in approximately a 40% reduction in C (120 ng / mL at 75 mg vs 206 ng / mL at 100 mg). Although it is not desirable to be bound by theory, an increase in bioavailability with increasing dose that is more than proportional to the dose may be due to saturation of efflux via P-glycoprotein (P-gp) in the digestive tract. At a dose of 75 mg, since the exposure is less than at a dose of 100 mg, the risk of adverse events in special populations also proportionally decreases. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Assuming that the C at 75 mg doubles, the probability that these special populations achieve a higher C max of vibegron than that observed at 100 mg is 15% (see Figure 1). The elderly showed a C approximately 50 - 70% higher than that of healthy young males. Although it is not desirable to be bound by theory, an increase in bioavailability with increasing dose that is more than proportional to the dose may be due to saturation of efflux via P-glycoprotein (P-gp) in the digestive tract. At a dose of 75 mg, since the exposure is less than at a dose of 100 mg, the risk of adverse events in special populations also proportionally decreases. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Assuming that the C

[0245] At a dose of 75 mg, since the exposure is less than at a dose of 100 mg, the risk of adverse events in special populations also proportionally decreases. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. Subjects with moderate renal impairment had an average 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving a strong CYP3A / P-gp inhibitor had approximately twice the exposure. max If we assume that the C at 75 mg doubles, the probability that these special populations achieve a higher C max of vibegron than that observed at 100 mg is 15% (see Figure 1). The elderly showed a C max approximately 50 - 70% higher than that of healthy young males. For both males and females, it is important to minimize exposure to extreme targets. Example 5 Pharmacokinetic data for 75 mg and 100 mg doses

[0246] A pharmacokinetic study was completed to evaluate the drug interaction between vibegron and rifampin. All subjects were healthy adults. An overview of the preliminary results is shown in Table 10. Subjects received a single dose of vibegron 75 mg on day 1, rifampin 600 mg QD from day 10 to 23, and a single dose of vibegron 75 mg on day 17 concomitantly with the administration of rifampin. The administration of vibegron and rifampin to healthy male and female subjects showed good tolerance. No serious TEAEs, SAEs or deaths were reported during the study. Three (15%) out of 20 subjects experienced AEs related to the study drug, two headaches and one constipation, all of which were mild. No clinically significant changes or findings were observed in vital signs, ECGs or clinical laboratory evaluations.

[0247]

Table 10

[0248] A two - way crossover, double - dummy randomized and placebo - controlled study was completed to evaluate the drug interaction between vibegron and tortrazine, a sensitive CYP2D6 substrate. All subjects were healthy adults. An overview of the preliminary results is shown in Table 11 and Figure 2. Subjects received either the concomitant administration of vibegron 100 mg QD and tortrazine 4 mg QD, or the concomitant administration of vibegron 100 mg QD and tortrazine placebo, from day 1 - 7. ​​​​​​​​​​Subjects who received a placebo of tolterodine were administered vibegron 100 mg QD and tolterodine 4 mg QD on days 29 - 35. Subjects who initially received tolterodine 4 mg QD were administered vibegron 100 mg QD and a placebo of tolterodine on days 29 - 35. The tolerance of the study treatment was good, and there was no evidence of an increase in adverse events during concomitant administration with vibegron. As shown in Table 11, concomitant administration of vibegron did not alter the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of tolterodine. The elimination half-life of tolterodine was equivalent in the presence of single administration and the steady state of vibegron. In addition, the change in plasma concentration over time with tolterodine alone was similar to the profiles seen with tolterodine and vibegron (Figure 2). From these results, it was demonstrated that vibegron does not inhibit CYP2D6 and has a favorable drug - drug interaction profile in the use in patients with OAB. Subjects who initially received tolterodine 4 mg QD were administered vibegron 100 mg QD and a placebo of tolterodine on days 29 - 35. The tolerance of the study treatment was good, and there was no evidence of an increase in adverse events during concomitant administration with vibegron. As shown in Table 11, concomitant administration of vibegron did not alter the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of tolterodine. The elimination half-life of tolterodine was equivalent in the presence of single administration and the steady state of vibegron. In addition, the change in plasma concentration over time with tolterodine alone was similar to the profiles seen with tolterodine and vibegron (Figure 2). From these results, it was demonstrated that vibegron does not inhibit CYP2D6 and has a favorable drug - drug interaction profile in the use in patients with OAB.

Table 11

[0249]

[0250] A pharmacokinetic study to evaluate the drug interaction of vibegron and metoprolol succinate, a CYP2D6 substrate with moderate sensitivity, was also completed. All subjects were healthy adults. An overview of the preliminary results is shown in Table 12 and Figure 3. Subjects received a single dose of metoprolol succinate 100 mg with warfarin 10 mg on day 1, vibegron 75 mg QD on days 8 - 16, a dose of vibegron 75 mg with metoprolol succinate 100 mg and warfarin 10 mg on day 17, and A pharmacokinetic study to evaluate the drug interaction of vibegron and metoprolol succinate, a CYP2D6 substrate with moderate sensitivity, was also completed. All subjects were healthy adults. An overview of the preliminary results is shown in Table 12 and Figure 3. Subjects received a single dose of metoprolol succinate 100 mg with warfarin 10 mg on day 1, vibegron 75 mg QD on days 8 - 16, a dose of vibegron 75 mg with metoprolol succinate 100 mg and warfarin 10 mg on day 17, and a dose of vibegron 75 mg on days 18 - 23 without concomitant metoprolol succinate and warfarin. Received vibegron 75 mg QD in the eyes. The tolerability of the study treatment was good, and there was no evidence of an increase in adverse events during combination administration with vibegron. The geometric mean Cmax and AUC values of metoprolol increased slightly in the presence of vibegron. However, the elimination half-life of metoprolol was similar with single administration and in combination with vibegron, suggesting that CYP2D6 was not likely to be inhibited. The time-course plasma concentration for metoprolol alone was similar to the profile seen with the combination of metoprolol and vibegron (Figure 3).

[0251]

Table 12

[0252] International, Phase 3, randomized, double-blind, with placebo control and active control (tolterodine), parallel-group, multi-center study was conducted in men and women with overactive bladder. For patient enrollment, patients with OAB wet (with UUI, involuntary urinary incontinence with urgency) and OAB dry (Dry, dry) (without UUI) were included. A total of 1,518 patients were randomly assigned to one of three groups for a 12-week treatment period through 215 study sites.

[0253] The study consisted of a screening period (up to 5 weeks from 1), a single-blind run-in period (2 weeks), a randomized double-blind treatment period (12 weeks), and a follow-up ​The study consisted of a four-week training period.

[0254] The study evaluated the safety, tolerability, and efficacy of 75 mg vibegron compared with placebo. Tolterodine ER 4 mg was the active control. Patients were randomized to one of three treatments in a double-blind study. Placement arm: randomized 5:5:4 to vibegron 75 mg, placebo, or tolterodine ER 4 mg. All were randomized to receive once-daily treatment for 12 weeks. Interim, patients had study evaluations at 4 and 8 weeks. 6.1. Eligibility Criteria

[0255] To participate in this study, patients must meet all of the following inclusion criteria prior to enrollment: Patients must meet the following exclusion criteria: 6.1.1 Inclusion Criteria

[0256] 1. Willing and able to provide written informed consent.

[0257] 2. Male or female, ≥ 18 years of age. Note: Up to 15% of patients can be male.

[0258] 3. Have had OAB (physician-diagnosed) for at least 3 months prior to the screening visit Note: OAB is usually associated with frequency and nocturia, and a sense of urgency, not urgency loss. It is defined as having or not having uncontrolled intravenous incontinence (UUI). Urodynamic evaluation is not required.

[0259] 4. Run-in Visit and Baseline Visit Based on the Patient Voiding Diary returned at both the outpatient and outpatient visits, Meets either the OAB wet criteria or the OAB dry criteria listed above (all criteria are included in the eligibility criteria). (All complete diary days must be used.) Diaries returned at the Visit must contain a minimum of 5 complete diary days (not necessarily consecutive). The diaries returned at the baseline visit should have 4 complete diary days. The average value should not be rounded up to the next integer: a.OAB Wet Criteria: i. The average number of voids per Diary Day is ≥ 8.0; and ii. An average of ≥ 1.0 UUI episodes per diary day; and iii. If stress urinary incontinence is present, the total number of UUI episodes will be recorded from the previous visit diary. The number of stress incontinence episodes must be greater than the total number of stress incontinence episodes reported by all patients. b.OAB Dry Criteria: i. The average number of voids per diary day is ≥ 8.0; and ii. An average of ≥ 3.0 urgency episodes per diary day; and iii. Average of <1.0 UUI episodes per diary day; and iv. If stress urinary incontinence is present, the total number of UUI episodes will be recorded from the previous visit diary. The number of stress incontinence episodes must be greater than the total number of stress incontinence episodes reported by all patients.

[0260] 5. For reproductive potential females: From the screening visit to the completion of the follow-up visit Patients should remain abstinent or use an acceptable form of contraception (see section 5.2.1) whenever they have sex. agree to use (or allow their male sexual partner to use) do.

[0261] 6. Reproductive Females: Study Treatment You agree not to donate eggs until at least one month after your last dose of the vaccine.

[0262] 7. Demonstrate ≥80% compliance with self-administration of study treatment during the run-in period. is.

[0263] 8. Ambulatory and investigator-controlled Be in good general physical and mental health as determined by the

[0264] 9. In the opinion of the investigator, the electronic questionnaire, patient voiding diary, and urinary volume diary Are able and willing to comply with the requirements of the protocol, including completion of the Study Diary. (Graduated urine collection and measurement containers [to be provided by Sponsor if necessary]) The patient must be able to collect, measure, and record her / his voided urine volume using a (Assuming that.) 6.1.2. Exclusion criteria Urological history

[0265] 1. 24-hour urinary volume >3,000 mL in the past 6 months or during the Run-in Period ) has a history of urine volume exceeding 3,000 mL on a day in the daily urine diary.

[0266] 2. Any disease of the lower urinary tract that, in the opinion of the investigator, may cause urgency, frequency, or incontinence. Alterations: including but not limited to urolithiasis, interstitial cystitis, prostate cancer, gastrointestinal (GI) cancer, tuberculosis, Stone disease, urothelial tumors, prostatitis, and clinically relevant prostatic have benign prostatic hyperplasia (BPH) or bladder outlet obstruction Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the investigator have had medication for the treatment of BPH for at least 1 year prior to their screening, have had no change in the dosage of herbal medications, alpha-blockers, or other symptomatic therapies or medications within 3 months prior to screening, and may be included unless there is a change in the dosage of 5-alpha reductase inhibitors within 6 months of screening.

[0267] 3. Have a history of surgery to correct stress urinary incontinence, pelvic organ prolapse, or BPH procedural treatments within 6 months of screening. 3. Have a history of surgery to correct stress urinary incontinence, pelvic organ prolapse, or BPH procedural treatments within 6 months of screening.

[0268] 4. Have a history or evidence of stage 2 or greater pelvic organ prolapse (prolapse beyond the hymenal ring). 4. Have a history or evidence of stage 2 or greater pelvic organ prolapse (prolapse beyond the hymenal ring).

[0269] 5. The patient is currently using a pessary for the treatment of pelvic organ prolapse.

[0270] 6. Have a known history of an increase in post-void residual volume defined as greater than 150 mL. 6. Have a known history of an increase in post-void residual volume defined as greater than 150 mL.

[0271] 7. Have had bladder training or electrical stimulation within 28 days prior to screening or plan to initiate either during the study. 7. Have had bladder training or electrical stimulation within 28 days prior to screening or plan to initiate either during the study.

[0272] 8. Active or recurrent (per year) by clinical symptoms or laboratory criteria (white blood cells (WBC) ≥ 5, or positive urine culture defined as ≥ 105 colony-forming units [CFU] / mL in 1 specimen). >3) has a urinary tract infection. Patients diagnosed with a urinary tract infection (UTI) during a screening visit May receive treatment and undergo rescreening after the infection has resolved.

[0273] 9. There is a need for an indwelling catheter or intermittent catheterization.

[0274] 10. Have received an intradetrusor injection of botulinum toxin within 9 months prior to screening at any time. Other medical history

[0275] 11. Have uncontrolled hyperglycemia (fasting blood glucose > 150 mg / dL or 8.33 mmol / L and / or non - fasting blood glucose > 200 mg / dL or 11.1 mmol / L as defined), or are considered to have uncontrolled hyperglycemia in the opinion of the investigator.

[0276] 12. There is evidence of diabetes insipidus.

[0277] 13. Are pregnant, breastfeeding, or planning a predicted pregnancy during the study period.

[0278] 14. Have a concurrent malignant tumor or a history of malignant tumor within 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.

[0279] 15. Have uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg and / or diastolic blood pressure ≥ 100 mmHg), or a resting heart rate (by pulse) > 100 beats per minute.

[0280] 16. Patients with a systolic blood pressure ≥ 160 mmHg but < 180 mmHg are, in the opinion of the investigator and / or the medical The Medical Monitor is considered safe to proceed with this study and is excluded if it is not considered possible to complete the study according to the protocol; these patients must have been on stable hypertensive medications for at least 90 days.

[0281] 17. Regardless of blood pressure measurement, all patients with signs and symptoms of uncontrolled hypertension are excluded from the study. These include, but are not limited to, neurological symptoms or findings, hematuria, proteinuria, retinopathy, unstable angina, and acute heart failure.

[0282] 18. Having narrow angle glaucoma (primary open angle glaucoma is not excluded).

[0283] 19. Having a history of cerebral vascular accident, transient ischemic attack, unstable angina, myocardial infarction, coronary intervention (examples are coronary artery bypass grafting, percutaneous coronary intervention [examples are angioplasty, stent insertion]), or neurovascular intervention (example is carotid artery stenting) within 6 months prior to the screening visit. Patients with these conditions must have received stable medical treatment for at least 3 months prior to the screening visit.

[0284] 20. Having a known history of liver disease.

[0285] 21. Having a history of injury, surgery, or neurodegenerative disease (examples are multiple sclerosis, Parkinson's disease) that may affect the lower urinary tract or its nerve supply. 6.2 Evaluation and Procedures of the Study

[0286] The investigator or eligible designee may implement any protocol-specified washout requirements. Review previous medication use, including seroconversion, and completion of a screening eDiary. Previous medications taken by patients within 28 days prior to initiation were recorded.

[0287] Record all medications for the treatment of OAB received within 1 year from the screening visit Male patients with a history of mild to moderate BPH were randomly assigned to receive a 2-month trial. Medication history was assessed to ensure appropriate treatment regimens.

[0288] At each study visit between screening and 12 weeks and at any unscheduled visits Concomitant medications were reviewed and recorded at each patient-led visit.

[0289] Male patients with investigator-defined mild to moderate BPH without evidence of bladder obstruction Participants were taking medication to treat BPH for at least 1 year prior to baseline. , herbal therapy, alpha antagonist application or other symptomatic treatment within the 3 months prior to baseline There was no change in the method or dose of medication. To be eligible for the study, Medication(s) must be stable from screening to baseline visit. No.

[0290] Patients with a history of hypertension had stable blood pressure control for 90 days prior to the baseline visit. must be receiving the regimen and the investigator and / or medical monitor It is deemed safe to proceed with this study and that it can be completed according to the protocol. It must be done. 6.2.1 Patient voiding diary

[0291] The patient voiding diary was used for participants to record (via e-diary or paper diary) by selecting in the respective boxes the frequency of daily OAB symptoms, including all voids, urgency, incontinence, and the main reasons for incontinence, that occurred during the given daytime and night periods. The "diary day" was defined as the time until the patient woke up each morning (i.e., the time from when the patient woke up yesterday until when the patient woke up today; approximately 24 hours).

[0292] The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete. The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete.

[0293] The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete. The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete. The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete. The "complete diary day" was defined as the diary day indicating that the patient had recorded all voids and any leakage that occurred during that diary day. Specifically, on the e-diary, the patient entered "Yes" in the corresponding item of the Begin Day Questionnaire, indicating that the data for the previous diary day was complete. 6.2.2 Urine volume diary

[0294] Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. Urine volume data was collected individually by the patient using the urine volume component of the e-diary or a paper urine volume scale. The urine volume chart is a tool used in medical and clinical research to evaluate voiding function over a 24-hour period and is considered a useful means (instrument) in the investigation of patients with voiding symptoms. Urine volume could be collected during any one (1) day of the diary for the 7 days prior to admission, and it was necessary to record for ~24 hours from when the patient woke up on that day until when the patient woke up the next day. 6.2.3 Outcome by patient report

[0295] Patients filled out a paper questionnaire on-site at the start of each required study visit and at study visits Patients were assessed for perceived symptom relief, symptom bother, and health-related quality of life. Recommended guidelines for the use of outcome measures in advocacy are available in the Gui dance for Industry, Patient-Reported Outcome Measures: Use in Medical Product De Development to Support Labeling Claims (Guidance for Industry, Patient-Reported Outcomes "Tocam Measurements: Use in Medical Product Development to Support Labeling Claims," ​​US Department of Health and Human Services, Food and Drug Administration, December 2009 (U.S. Department of Health and Human Services, Food and Drug Administration, December 2009), the contents of which are as follows: All are incorporated by reference. These included the following questionnaires:

[0296] 1. Global Impression (Global Impression) is Patient Global Impression of Severity (PGI-Severity), Control Patient Global Impression of the Control (PGI-Control), Frequency (Frequency, Patient Global Impression (PGI-Frequency), Leakage, Patient Global Impression of Leakage (PGI-Leakage), and Change , change) and Patient Global Impression of Patient's Experience (PGI-Change).

[0297] 2. Overactive Bladder Questionnaire (OAB-q long form [OAB-q LF], 1 week Ricoh The [name removed] is a disease-specific questionnaire for the management of 33 items of patients, which includes a health-related QoL (Health-Related QoL) scale (25 items) and a symptom bother scale (8 items). HRQL is a multi-domain concept that represents the patient's general perception of the impact of illness and treatment on the physical, psychological, and social aspects of life. Claiming a statistically and significantly improved HRQL means the following: (1) all important HRQL domains that are relevant for interpreting any changes in the feeling or functioning of the clinical trial population due to the targeted disease and its treatment are measured; (2) an overall improvement is demonstrated; and (3) no decrease is demonstrated in any domain. In this study, the HRQL scale was divided into four subscales: namely, Coping (which may also be referred to as "coping"), Concern (which may also be referred to as "worry"), Sleep, and Social Interaction. The Coping subscale (which is also referred to as the Coping domain score) is a secondary decision point, and the items are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). lated QoL) scale (25 items) and a symptom bother scale (Symptom Bother Scale) (8 items). HRQL is a multi-domain concept that represents the patient's general perception of the impact of illness and treatment on the physical, psychological, and social aspects of life. HRQL is a multi-domain concept that represents the patient's general perception of the impact of illness and treatment on the physical, psychological, and social aspects of life. HRQL statistically and significantly improved HRQL means the following: (1) all important HRQL domains that are relevant for interpreting any changes in the feeling or functioning of the clinical trial population due to the targeted disease and its treatment are measured; (2) an overall improvement is demonstrated; and (3) no decrease is demonstrated in any domain. In this study, the HRQL scale was divided into four subscales: namely, Coping (which may also be referred to as "coping"), Concern (which may also be referred to as "worry"), Sleep, and Social Interaction. The Coping subscale (which is also referred to as the Coping domain score) is a secondary decision point, and the items are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). study, the HRQL scale was divided into four subscales: namely, Coping (which may also be referred to as "coping"), Concern (which may also be referred to as "worry"), Sleep, and Social Interaction. The Coping subscale (which is also referred to as the Coping domain score) is a secondary decision point, and the items are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). procedure includes both men and women, and is continent (which may also be referred to as "moderate"). procedure includes both men and women, and is continent (which may also be referred to as "moderate"). procedure includes both men and women, and is continent (which may also be referred to as "moderate"). procedure includes both men and women, and is continent (which may also be referred to as "moderate"). The items of the Coping subscale (which is also referred to as the Coping domain score) are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). The items of the Coping subscale (which is also referred to as the Coping domain score) are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). The items of the Coping subscale (which is also referred to as the Coping domain score) are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). The items of the Coping subscale (which is also referred to as the Coping domain score) are scored from 1 (never) to 6 (always), with a higher score indicating a better QoL. The HRQL total score is calculated by summing the scores of the individual HRQL subscales. The items of the symptom bother scale are scored from 1 (none at all) to 6 (very much), with a higher symptom bother score indicating a higher severity of symptoms. This procedure includes both men and women, and is continent (which may also be referred to as "moderate"). Developed and validated in OAB patients with incontinence (also known as overactive bladder).

[0298] 3. Work Productivity and Activity Impairment Questionnaire-Irinary Symptoms (WPAI-US) Version 2.0 is a 6-item questionnaire that assesses health-related work productivity loss due to urinary symptoms over a 1-week recall period. along with a 1-week recall period. Yes.

[0299] 4. The EQ-5D health questionnaire is a standardized means for use in measuring health outcomes. The EQ-5D health questionnaire is a standardized questionnaire for measuring health status and is applicable to a wide range of health states and treatments; it provides a simple descriptive profile and a single index value for the health state. Yes. 6.2.4 Post-void residual

[0300] The risk of acute urinary retention or pathological conditions associated with an increase in post-void residual (PVR) is related to antimuscarinic therapy that promotes smooth muscle relaxation by suppressing acetylcholine-induced smooth muscle contraction. During contraction, if the bladder is unable to generate sufficient pressure to overcome the outlet resistance at the urethra, it is either due to low detrusor contractility or Yes. profound obstruction (most commonly from BPH), and acute urinary retention or incomplete bladder emptying may result. Yes. either Yes.

[0301] The amount of urine remaining in the bladder after urination (PVR) is an objective measurement that serves as a proxy for impaired ability to void. Yes.

[0302] PVR was performed via ultrasound at visits indicated on the activity schedule. 6.3 Pharmacokinetic Sample Collection

[0303] To assess the impact of demographic covariates in population PK analyses, patients at selected sites were PK sampling in a sub-population (approximately 30% of the total study population) was carried out. 6.4 Safety Considerations

[0304] Study evaluations of safety included adverse events, physical examination, vital signs (and weight), and and clinical laboratory tests were included.

[0305] An adverse event is any event occurring in a patient or clinical investigational patient that is temporarily related to the use of a medicinal product. Any untoward medical occurrence believed to be related to a medicinal product. This does not matter whether or not

[0306] Therefore, the adverse event may not be temporally related to the use of a medicinal product or protocol-specified procedure. undesirable and unintended signs (including abnormal laboratory findings), symptoms or diseases (new or worsening) and considered related to medicinal product or protocol-specified procedures. It does not matter whether or not

[0307] The following events meeting the definition of an adverse event are included:

[0308] 1. Aggravation, other than minor fluctuations, in the nature, severity, frequency, or duration of a pre-existing condition;

[0309] 2. Detected or diagnosed after administration of the investigational product, even if it may have been present before the start of the study. new symptoms identified;

[0310] 3. Injury or accident: If the medical condition that caused the injury or accident is known, the medical condition and the accident should be reported as two separate medical events (for example, for a fall secondary to vertigo, both "vertigo" and "fall" should be recorded separately);

[0311] 4. Abnormalities in investigations (for example, laboratory parameters, vital signs, ECG (electrocardiogram)) are limited to those that are clinically important as considered by the investigator based on at least one of the following criteria: a. Cause clinical signs or symptoms; b. Require active intervention; c. Require interruption or discontinuation of the study treatment.

[0312] 5. Signs, symptoms, or clinical sequelae suggesting an interaction.

[0313] 6. Signs, symptoms, or clinical sequelae suggesting overdose of either the investigational product or a concomitant medication.

[0314] Investigators or site staff had the responsibility to detect, document, and report events that met the definition of an adverse event or a serious adverse event.

[0315] Clinically interesting adverse events for this study include:

[0316] 1. Potential major adverse cardiac and cerebrovascular events (Potential Major Adverse Cardiac and C​​​​ Major Adverse Cardiovascular and Cerebrovascular Events)(MACCE), and they were adjudicated by a clinical adjudication committee (CAC), which consisted of independent external experts, according to the definitions in the CAC charter into the following categories: Any event associated with death or a fatal outcome Myocardial infarction / heart attack Cerebrovascular accident / stroke Hospitalization due to unstable angina / chest pain Hospitalization due to heart failure Coronary revascularization / angioplasty / stent

[0317] 2. Hypertension: Adverse events of hypertension were reported and considered as AECI as follows: In patients without hypertension at baseline (mean SBP < 140 mmHg, DBP < 90 mmHg), at three consecutive visits, systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg (or both); in patients without hypertension at baseline, at two consecutive visits; or in patients with hypertension at baseline, at three consecutive visits, an increase in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg compared to baseline; The initiation or increase of drug administration for the treatment of hypertension in any patient.

[0318]

[0319] 3. Adverse events consistent with orthostatic hypotension confirmed by orthostatic vital signs.

[0320] 4. Adverse events suggesting cystitis or urinary tract infection.

[0320] 5. Laboratory values of AST or ALT increased, and the administration of the study drug was temporarily withheld,​ or must be permanently interrupted. 6.5 Statistical Analysis

[0321] Investigational decision points (e xploratory endpoints) that evaluated efficacy, safety, and differences within and / or between treatments are shown below.

[0322] In the description of the following efficacy variables, it was limited to the primary time point of interest at week 12 in the study . However, many variables were measured at additional time points and analyzed at other time points.

[0323] The co-primary efficacy endpoints were as follows:

[0324] 1. Change from baseline (CFB) at week 12 in the mean number of voids per 24 hours in all OAB patients;

[0325] 2. CFB at week 12 in the mean number of UUI episodes per 24 hours in OAB wet patients.

[0326] For the purposes of this study, the number of voids was defined as the number of times the patient voided at the toilet as recorded in the patient voiding diary. The mean number of voids per day was calculated using the daily records in the patient voiding diary entered for the 7 days prior to each study visit. The mean number of voids per day was calculated by dividing the total number of voids that occurred on a full diary day by the number of full diary days in the patient voiding diary. A full diary day required the patient to confirm that all voids and leaks for that day were recorded in the patient excretion diary. Baseline was defined as the mean value of the number of voids that occurred during the last evaluable day in the diary prior to the baseline visit.

[0327] ​​​​​​​The number of UUI episodes was defined as the number of times the patient checked "urgency" as a reason for accidental urine leakage and was calculated in the same manner as the above-mentioned micturition decision points at each study visit. The mean number of UUI episodes per day at each study visit was calculated in the same manner. The UUI endpoint was analyzed using only OAB wet patients.

[0328] The secondary efficacy endpoints were as follows:

[0329] 1. CFB at week 12 in the mean number of urgency episodes over 24 hours in all OAB patients (the need to urinate immediately is required)

[0330] 2. The percentage reduction of 50% from baseline in the number of urgency episodes per 24 hours at week 12 in all OAB patients (the need to urinate immediately is required)

[0331] 3. The percentage of OAB wet patients with a 75% reduction from baseline in UUI episodes per 24 hours at week 12

[0332] 4. CFB at week 4 in the mean number of micturitions per day in all OAB patients

[0333] 5. CFB at week 4 in the mean number of UUI episodes per day in OAB patients

[0334] 6. CFB at week 12 in the coping score of the Overactive Bladder Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB patients

[0335] 7. CFB up to week 2 in the mean number of micturitions per 24 hours in all overactive bladder patients

[0336] 8. CFB up to week 2 in the mean number of UUI episodes per 24 hours in OAB wet patients

[0337] ​ 9. Mean number of total incontinence episodes over 24 hours in OAB wet patients CFB at Week 12

[0338] 10. CFB at Week 12 in mean voided volume per micturition in all OAB patients

[0339] Additional secondary efficacy endpoints were as follows:

[0340] 1. CFB at Week 12 in total HRQL score from OAB-q LF (1-week recall) in all OAB patients at Week 12

[0341] 2. CFB at Week 12 in Symptom Bother Score of OAB-q-LF ( 1-week recall) in all OAB patients

[0342] 3. Percentage of OAB wet patients with zero UUI episodes at Week 12

[0343] 4. Percentage of all OAB patients with mean number of micturitions per 24 hours < 8 at Week 12

[0344] 5. Percentage of OAB wet patients with a 50% reduction from baseline in total number of incontinence episodes per 24 hours at Week 12 at Week 12

[0345] 6. CFB at Week 12 in overall bladder symptoms based on PGI-severity in all OAB patients B

[0346] 7. CFB at Week 12 in overall control of bladder symptoms based on PGI-control in all OAB patients at Week 12

[0347] Investigational endpoints were as follows:

[0348] 1. CFB in the proportion of dry diary days at week 12 and week 4 in OAB wet patients (CFB in the proportion where UUI episodes = zero)

[0349] 2. CFB in the proportion of dry diary days at week 12 in OAB wet patients (total incontinence episodes = zero) in CFB

[0350] 3. Work productivity and activity impairment questionnaires at week 12 and week 4 in all OAB patients - CFB in the total score of the Work Productivity and Activity Impairment Questionnaire - Urinary Symptoms (WAI - US) in CFB

[0351] 4. CFB at week 12 of the EQ - 5D score in all OAB patients

[0352] 5. In all OAB patients with NVU ≥ 1 at baseline, CFB at week 12 in the average number of NVU per 24 hours in CFB

[0353] 6. In all OAB patients, CFB at week 12 in the overall symptom frequency based on PGI - Frequency in CFB

[0354] 7. In all OAB wet patients, CFB at week 12 in the overall urgency - related leakage for bladder symptoms based on PGI - Leakage in CFB

[0355] 8. In all OAB patients, the overall change of bladder symptoms at week 12 based on PGI - Change in CFB

[0356] 9. Concern scores from OAB-q LF (1-week recall) in all OAB patients at week 12 of CFB

[0357] 10. Week 12 of the sleep score of OAB-q LF (1-week recall) in all OAB patients of CFB

[0358] 11. Week 12 of CFB of the social interaction score of OAB-q LF in all OAB patients (1-week recall) (recall)

[0359] 12. Week 52 of CFB in the average number of nocturnal voids in all patients

[0360] 13. Week 52 of CFB in the mean value of the number of nocturnal voids in patients with nocturia at baseline of CFB 6.6 Analysis population

[0361] The Full Analysis Set (FAS) population was treated as the main population for analyzing efficacy data in this study. Since the decision points related to incontinence would only apply to patients who met the definition of incontinence at the start of the study, another FAS definition with additional criteria was needed to define the main analysis population for the decision points of incontinence. In this study, the following FAS populations were defined.

[0362]

[0363] 1. Full Analysis Set (FAS): All randomized OAB patients who received at least one double-blind Study Treatment and had at least one evaluable change from baseline voiding measurements.

[0364] ​​2. Full Analysis Set for Incontinence (FAS-I): All randomized OAB patients who received at least one double-blind study treatment and had at least one evaluable change from baseline UUI measurement. -ment, and at least one evaluable change from the baseline UUI measurement.

[0365] The Per-Protocol population (PP) and the Per-Protocol population for incontinence (PP-I) exclude patients due to major biases from the protocol that could substantially affect the results of the primary efficacy endpoints. Supportive analyses using the Per-Protocol population are performed for co-primary and secondary endpoints.

[0366] Patients were included in the treatment groups to which they were randomly assigned for analysis of efficacy data using the FAS and Per-Protocol populations.

[0367] In this study, a Safety Set (SAF) was used for analysis of safety data. The SAF consisted of all patients who received at least one study treatment.

[0368] The PK population included all subjects in the Safety Set who underwent plasma PK sampling and had results from an evaluable PK assay. 6.7 Statistical Methods

[0369] For the analysis of the co-primary endpoints (change from baseline in the mean number of voids per day at week 12 and change from baseline in the mean number of urgency urinary incontinence episodes per day at week 12, and their respective placebo adjustments), the restricted maximum likelihood estimation method (restricted maximum likelihood estimati on) was used. The mixed model for repeated measures (MMRM) was used for the repeated measurements by on). This model corrects for dropouts and uses all available information on patients within the same set of covariates to derive estimates of treatment effects for the population without dropouts, taking into account the tendency for the long-term measurements of the same patients to be correlated. For each efficacy endpoint, the analysis model includes terms for treatment, visit, OAB type (wet vs. dry), sex (female vs. male), region (United States vs. the rest of the world), baseline score, and the interaction of treatment by visit.

[0370] The main inference was drawn from the differences in treatment methods for the changes from baseline derived from the MMRM model at week 12. As part of the secondary objectives, the treatment differences for each visit after baseline were also derived using the same MMRM model. The estimated treatment differences at each visit were presented in the summary of the statistical analysis together with the 95% confidence intervals and the associated P-values.

[0371] An unstructured covariance matrix was used to model the correlations between repeated measurements. Statistical inference was performed using the Kenward- Roger adjustment with restricted (or residual) maximum likelihood (REML). If the unstructured covariance model does not converge using the default Newton-Raphson algorithm, the initial values of the covariance parameters can be provided using the Fisher scoring algorithm or other appropriate methods. If neither of the above methods results in convergence, structured covariance is used to model the correlations between repeated measurements.

[0372] ​​​​​​The change from the baseline of the efficacy determination point is the same MM as that described for the co-primary determination point and was analyzed using the RM model.

[0373] The proportion of patients with at least a 75% decrease in the average number of UUI episodes per day at week 12, and the proportion of patients with a 50% decrease in the average number of urgency episodes per day at week 12 were analyzed at the efficacy determination point using the Cochran-Mantel-Haenszel risk difference estimator. Missing data at week 12 were analyzed using multiple imputation. Using the weights proposed by Greenland and Robins, the Cochran-Mantel-Haenszel risk difference estimators stratified by OAB type (wet vs. dry) and sex (female vs. male) were used to calculate the estimated difference in the proportion of responders and the 95% confidence interval for that difference. The same statistical methods used to analyze the co-primary and secondary determination points were used for the diagnostic analysis. The diagnostic responder analysis was analyzed using the same Cochran-Mantel-Haenszel model as described above for the secondary determination point. The safety analysis was performed using the SAF and summarized by treatment group treated.

[0374] The treatment start period was defined as the period from the first dosing day of the study treatment by double-blind method to 28 days after the last dosing of the study treatment, or the start date of another investigational drug or surgical intervention, or the rollover date to the extension study, whichever occurs first. Safety was the summary of adverse events, adverse

[0375] events, and was summarized by treatment group treated. The treatment start period was defined as the period from the first dosing day of the study treatment by double-blind method to 28 days after the last dosing of the study treatment, or the start date of another investigational drug or surgical intervention, or the rollover date to the extension study, whichever occurs first. Safety was the summary of adverse events, adverse events, and was summarized by treatment group treated. The treatment start period was defined as the period from the first dosing day of the study treatment by double-blind method to 28 days after the last dosing of the study treatment, or Frequency of treatment interruption due to events, and assessment by clinical laboratory evaluation was performed. 6.8 Subgroup analysis and influence of baseline factors

[0376] To determine whether the treatment effect is consistent across various subgroups, the estimated treatment effect between groups for the primary decision point (with nominal 95% confidence interval [CI]) was estimated and plotted within each category of the following classification variables. 1. Region (United States vs. the rest of the world) 2.2. Age group (<40, ≥40 and <55, ≥55 and <65, ≥65 and <75, ≥75) 3. Age group (<65, ≥65) 4. Race (White vs. others) 5. Gender (Female vs. male) 6. OAB treatment history (Native and non-native) 7. OAB type (OAB wet vs. OAB dry)

[0377] For each subgroup, the primary MMRM model was applied, including the subgroup by treatment interaction term, and the model results were presented. The consistency of the treatment effect was descriptively evaluated by summary statistics by category of the above classification variables. 6.9 Clinical trial data and results

[0378] The demographics of the patients in this trial are shown in Table 13, and the subject disposition is shown in Table 14.

[0379]

Table 13

[0380]

Table 14

[0381] Vibegron achieved the co-primary endpoints demonstrating a statistically significant reduction in daily urination and daily urgency urinary incontinence (UUI) compared to placebo (p < 0.001 and p < 0.0001, respectively). The co-primary efficacy results are shown in Tables 15 and 16. Figures 4 and 5 show that vibegron achieved a statistically significant onset of action in 2 weeks for both UUI and reduction in urination, and the benefit persisted until week 12.

[0382]

Table 15-1

Table 15-2

[0383]

Table 16-1

Table 16-2

[0384] Changes in daily urgency urinary incontinence (UUI) within some subgroups are shown in Tables 17-21.

[0385]

Table 17

[0386] ​​Unexpectedly, females showed a greater decrease in the UUI episode than males.

[0387]

Table 18

[0388]

Table 19-1

Table 19-2

[0389]

Table 20-1

Table 20-2

[0390]

Table 21-1

Table 21-2

[0391]

Table 22-1

Table 22-2

[0392] Subjects with or without BPH, subjects with or without prior (ACH) use, and previous beta-3 (B3) ago Table 23 shows the changes in daily urge urinary incontinence (UUI) within the subjects with or without nist use. Past Subjects who had used either ACH or a B3 agonist within the past 12 months had a greater reduction in UUI after taking vibegron compared to subjects who had taken a placebo

[0393] [Table 23]

[0394] As shown in Table 23, the average number of UUI episodes in the 24-hour period for subjects with prior ACH use was reduced by approximately 1.75 times that of subjects treated with placebo, while the average number of UUI episodes in the 24-hour period for subjects with prior B3 use was reduced by approximately 5 and approximately 6 times that of subjects treated with placebo

[0395] Table 24 and Figure 19 show the overall time to the first occurrence of a 75% reduction in UUI episodes (epidoses). Table 25 shows the estimated values at 2, 4, 8, and 12 weeks to the first occurrence of a 75% reduction in UUI episodes, and Table 26 shows a 75% UUI responder analysis up to 12 weeks categorized by baseline UUI severity

[0396] [Table 24]

[0397] [Table 25] ​​​​​​

[0398]

Table 26

[0399] Table 27 shows the overall time until the first occurrence of a 100% decrease in UUI. Table 28 shows the estimated times at weeks 2, 4, 8, and 12 until the first occurrence of a 100% decrease in UUI episodes, and Table 29 shows a 12-week 100% UUI responder analysis classified by baseline UUI severity.

[0400]

Table 27

[0401]

Table 28

[0402]

Table 29

[0403] Tables 30 and Figure 20 show the overall time until the first occurrence of a 50% decrease in urgent episodes. Table 31 shows the estimated values at weeks 2, 4, 8, and 12 until the first occurrence of a 50% decrease in urgent episodes.

[0404]

Table 30

[0405]

Table 31

[0406] Changes in the daily urine output within several subgroups are shown in Tables 32 - 38. The subjects aged 65 years and over who received vibegron showed a statistically significant decrease in the frequency of urination compared to the subjects in the same age group who received tolterodine. Unexpectedly, the subjects aged ≥65 years had a greater decrease in urination compared to the subjects aged <65 years.

[0407] [Table 32]

[0408] Unexpectedly, the subjects aged ≥65 years had a greater decrease in urination compared to the subjects aged <65 years.

[0409] [Table 33]

[0410] [Table 34]

[0411] [Table 35 - 1] [Table 35 - 2]

[0412] [Table 36]

[0413] [Table 37 - 1] [Table 37 - 2]

[0414]

Table 38

[0415] The results for a certain subgroup are shown in Table 39. Subpopulations dosed with vibegron had a further greater decrease in urination and also in UUI episodes compared to the group dosed with tolterodine or placebo.

[0416]

Table 39-1

Table 39-2

[0417] As shown in Table 39, the decrease in the average number of urinations within 24 hours in subjects with prior ACH use was about 0.7 times more than the decrease in the number of urination episodes in subjects treated with placebo, while the decrease in the average number of urinations within 24 hours for subjects with prior B3 use was about 2.9 times more than the decrease in the number of urination episodes in subjects treated with placebo.

[0418] Unexpectedly, subjects with treatment experience (subjects previously treated with an ACH or B3 agonist ) had an improved decrease in urination and / or UUI episodes compared to subjects without treatment experience. This represents an unexpected benefit for patients who have sought other treatment methods without success and thus still have unmet needs.

[0419] Also unexpectedly, subjects aged ≥65 treated with vibegron had a ​​​​​​​showed improvement in comparison in terms of decreases in urination, urgency episodes, and UUI episodes. This is important because a large number of patients experiencing OAB symptoms are present in this demographic.

[0420] Vibegron achieved statistical significance at all seven secondary endpoints compared to placebo: (1) decrease in daily urgency episodes; (2) 75% and 100% decreases in UUI; (3) 50% decrease in daily urgency; (4) decrease in daily total incontinence; (5) OAB-q coping score; and (5) average volume voided per urination. For example, data regarding the decrease in urgency episodes are shown in Table 40, as well as in Figures 6 and 7. For example, data regarding the decrease in urgency episodes are shown in Table 40, as well as in Figures 6 and 7. For example, data regarding the decrease in urgency episodes are shown in Table 40, as well as in Figures 6 and 7.

[0421]

Table 40-1

Table 40-2

Table 40-3

[0422] Data regarding the decrease in urgency episodes in the dry group are shown in Tables 41 and 42, as well as in Figure 21.

[0423]

Table 41-1

Table 41-2

Table 41-3

[0424] The decrease in urgency in the dry group classified by age group is shown in Table 42.

[0425]

Table 42-1

Table 42-2

[0426] Data for 50% responders in terms of urgency in OAB dry patients are shown in Table 43.

[0427]

Table 43-1

Table 43-2

[0428] Data regarding the reduction of urgent episodes in 75% UUI responders are shown in Table 44.

[0429]

Table 44-1

Table 44-2

[0430] Changes in mean excretion volume in 75% UUI responders from baseline to week 12 are shown in Table 4 5.

[0431]

Table 45-1

Table 45-2

[0432] Changes in PGI-control in 75% UUI responders are shown in Table 46, while in 75% U Table 47 shows the changes in the 12-week OAB-q management in the UI responder. The changes in the bother of OAB-q symptoms at week 12 in 75% of the UUI responders - are shown in Table 48.

[0433]

Table 46-1

Table 46-2

[0434]

Table 47

[0435]

Table 48

[0436] Data on the reduction of urgency episodes for a certain subpopulation are shown in Tables 49 and 50.

[0437]

Table 49

[0438]

Table 50

[0439] Data on total incontinence are shown in Tables 51 and Figure 9. The mean change in the amount from the baseline for daily total incontinence decreased to 2.3 episodes in the vibegron 75 mg group after 12 weeks of treatment. The mean of the daily total incontinence episodes after placebo adjustment was significantly reduced to -0.7 episodes (SE, 0.16; P < 0.0001 vs placebo) at week 12 in the vibegron 7 5 mg group. 5 mg group at week 12. 5 mg group at week 12 to -0.7 episodes (SE, 0.16; P < 0.0001 vs placebo). decreased, and it was numerically greater compared to -0.5 (SE, 0.17; P = 0.0074 vs placebo) in the tolterodine arm (Table 35). A rapid and statistically significant improvement in the total incontinence volume per day was observed in the vibegron group at week 2 (after placebo adjustment, -0. 7), and statistical significance was maintained throughout all time points including week 12. For the mean voided volume (mL), the mean change from baseline after placebo adjustment was significantly

[0440] improved (increased) to 21.2 mL (SD, 3.52; P < 0.0001 vs placebo) in the vibegron 75 mg group at week 12, and it was also numerically greater compared to the tolterodine group, 13.3 mL (SD, 3.76; P < 0.001 vs placebo) (Table 36).

[0441]

Table 51-1

Table 51-2

[0442] Table 52 shows the analysis results of all-incontinence 75% responders, while Tables 54-57 show the data for 50% responders.

[0443]

Table 52-1

Table 52-2

[0444]

Table 53-1

Table 53-2

[0445]

Table 54-1

Table 54-2

[0446]

Table 55

[0447]

Table 56-1

Table 56-2

[0448] The changes in the number of dry days in the dry diary in 50% of total incontinence responders are shown in Table 57.

[0449]

Table 57-1

Table 57-2

[0450] Table 58 and Figure 10 show the changes in the average volume voided per micturition.

[0451]

Table 58-1

Table 58-2

[0452] Patients treated with vibegron also showed improvement in OAB-q coping scores (see Table 59). 。By week 12, vibegron demonstrated statistically significant improvements compared to placebo in bother (p<0.0001), concern (p<0.0001), sleep (p<0.001), and coping (p = 0.0038) scales and the total HRQL score (p<0.001) (see Table 60). The difference in LS means between vibegron and placebo numerically improved for the social interaction subscale of HRQL but did not reach statistical significance (P = 0.1116). For all OAB-q scales, the results for vibegron were numerically better than those for tolterodine. These patients reported improvements in QoL seen after treatment with vibegron, which paralleled the significant improvements compared to placebo seen at the co-primary efficacy endpoints of mean number of voids and change from baseline in UUI episodes.

[0453]

Table 59

[0454]

Table 60-1

Table 60-2

Table 60-3

Table 60-4

[0455] Table 61 shows the proportion of OAB-q responders at week 12. Except for the bother symptom score, the re A responder was defined as having a change from a baseline of ≥10 in the bothersome symptom score. For the responder, a change from a baseline of ≤10 was defined. A higher percentage of patients showed a good response.

[0456] As shown in the table, the odds ratios were statistically significant in the comparison of vibegron to placebo for bothersome symptoms and the coping subscale.

[0457] [Table 61-1] [Table 61-2] [Table 61-3]

[0458] Figure 8 shows a comparison of the percentages of responders with a 75% and 100% decrease in UUI episodes and a 50% decrease in urgency episodes. The percentage of patients who achieved a clinically meaningful (≥75% decrease) reduction in daily UUI episodes (UUI responders) was highest in the vibegron 75 mg group (49.3%) compared to placebo (32.8%) and tolterodine (42.2%) at week 12 (p<0.001). Vibegron showed a rapid onset of effect, with significantly more UUI responders compared to placebo by week 2 (p<0.01).

[0459] The tolerability of vibegron was good, with few adverse events >2% compared to placebo. A summary of treatment-emergent adverse events is shown in Table 62. More than 2%, and ​​​​​​​Adverse events that were more frequent than placebo were headache, nasopharyngitis, diarrhea, and nausea (see Table 63). Others data on adverse events are listed in Table 64. Adverse events in subjects aged ≥ 75 years are shown in Table 65. Shown.

[0460]

Table 62

[0461]

Table 63

[0462]

Table 64-1

Table 64-2

Table 64-3

[0463]

Table 65

[0464] No difference was observed between placebo and adverse events regarding hypertension, elevated blood pressure, and urinary tract infections. The dropout rate due to AEs was 1.1% for placebo, 1.5% for vibegron, and 3.0 % for tortelopide. Patients with at least 1 severe AE were placebo (1.1%), vibegron (1.5 %), and tortelopide (2.3%). A tachycardia rate of 0.2% was reported only in the tortelopide treatment group pro. Reported.

[0465] Data on the vital signs of subjects including heart rate and blood pressure are shown in Tables 66 - 74.

[0466]

Table 66

[0467]

Table 67

[0468]

Table 68-1

Table 68-2

[0469]

Table 69

[0470]

Table 70-1

Table 70-2

[0471]

Table 71

[0472]

Table 72

[0473]

Table 73-1

Table 73-2

[0474]

Table 74

[0475] Data on post-void residual urine volume (PVR) in all subjects and subgroups are shown in Tables 75 - 77.

[0476]

Table 75 - 1

Table 75 - 2

[0477]

Table 76

[0478]

Table 77

[0479]

Table 78

[0480] Overall, vibegron demonstrated strong efficacy at all OAB endpoints. (See Table 79)

[0481]

Table 79

[0482] Once-daily 75 mg vibegron demonstrated significantly superior efficacy compared to placebo across three secondary endpoints (as well as two co-primary endpoints), demonstrating further benefit of vibegron in patients with UUI. 75 mg vibegron reduced total incontinence episodes by week 2 compared to placebo and showed further benefit of vibegron in patients with UUI. 75 mg vibegron reduced total incontinence episodes by week 2 compared to placebo and showed further benefit of vibegron in patients with UUI. 75 mg vibegron reduced total incontinence episodes by week 2 demonstrated a statistically significant decrease in the -d and maintained this significance during the 12-week treatment period. Vibergo 75 mg demonstrated a clear increase in the volume of urine discharged per micturition, a relatively objective indicator of increased bladder capacity. Total incontinence episodes decreased by up to half in the Vibergo-glu -p versus baseline, and almost half of the Vibergo-treated patients with UUI had at least a 75% decrease in UUI episodes after 12 weeks of Vibergo therapy. The tolerability of Vibergo was favorable, with >2% and more of adverse events

[0483] being only slightly less than that of placebo. In addition, once-daily Vibergo 75 mg demonstrated statistically significant improvements in the OAB-q coping, worry, sleep, and symptom bother scales and total HRQL score compared to placebo at week 12. Example 7 A double-blind, active-controlled, multi-center, 40-week extension study from a 12-week parent study to evaluate the safety, tolerability, and efficacy of Vibergo 75 mg in men and women with overactive bladder (OAB)

[0484] As an extension of the study described in Example 6 (the "parent study"), a Phase 3, double-blind, active-controlled, multi-center study was conducted in men and women with overactive bladder. Approximately 500 men and women with overactive bladder were enrolled at approximately 110 study sites in the United States after they

[0485] All subjects randomized to vibegron or tolterodine ER 4 mg in the parent study continued on the same treatment. Subjects randomized to placebo in the parent study were randomized 1:1 to vibegron or tolterodine, stratified by sex and base line OAB type.

[0486] The primary endpoint was to evaluate the safety and tolerability of vibegron for up to 52 weeks in patients with OAB symptoms. The secondary endpoints were the mean number of micturitions, the number of urge urinary incontinence ( UUI) episodes, the number of urgency episodes, and the assessment of CFB at week 52 in total incontinence episodes. All CFB calculations used the baseline values of the parent study.

[0487] Table 80 shows the demographics of the overall group, while Table 81 shows the demographics for the vibegron and tolterodine arms.

[0488]

Table 80

[0489]

Table 81

[0490] Table 82 shows the temperament of the overall group of subjects, while Table 83 shows the temperament of the subjects for the vibegron and tolterodine arms.

[0491]

Table 82

[0492] ​

Table 83

[0493] Tables 84 to 87 show the adverse events that occurred during the study. As shown in these tables, there was no difference related to hypertension between vibegron and tolterodine.

[0494]

Table 84

[0495]

Table 85

[0496]

Table 86

[0497]

Table 87-1

Table 87-2

[0498] As shown in Figures 15-18 and Table 88, the changes after baseline adjustment were maintained over 52 weeks at all four efficacy decision points (urination, UUI, urgency, and total incontinence). In addition, numerically better effects were seen for vibegron compared to tolterodine in all four categories.

[0499]

Table 88-1

Table 88-2

[0500]

Table 89

[0501]

Table 90

[0502]

Table 91-1

Table 91-2

[0503]

Table 92

[0504]

Table 93

[0505]

Table 94-1

Table 94-2

[0506]

Table 95

[0507] Table 96 shows the urgency of the 52nd week and the decision points of UUI responders.

[0508]

Table 96

[0509] As shown in Table 97, vibegron demonstrated strong efficacy against all OAB endpoints at week 52. This was demonstrated.

[0510]

Table 97-1

Table 97-2

[0511] Table 98 shows the week 52 responder scores from the Quality-of-Life Long Form (OABq-LF). This indicates the responder scores.

[0512]

Table 98-1

Table 98-2

[0513] A Phase 1, double-blind, placebo-controlled, multi-site study was conducted in men and women with overactive bladder. A total of 214 patients were randomized to one of two study groups (108 receiving placebo and 106 receiving 75 mg of vibegron) over approximately 10 study sites for a 28-day treatment period. This was randomly assigned to either of the two study groups. This was randomly assigned.

[0514] The study evaluated the effect of vibegron on blood pressure and heart rate. The objectives and endpoints were as follows. The "mean daytime" ABPM endpoint was calculated as the mean of all valid ABPM measurements during the 24-hour monitoring session while the subject was awake. The "24-hour mean" AB This was calculated as the mean of all valid ABPM measurements while the subject was awake during the 24-hour monitoring session. This was calculated as the mean of all valid ABPM measurements while the subject was awake during the 24-hour monitoring session. The PM decision point is defined as the average of all valid ABPM readings during a 24-hour monitoring session and is calculated. The "maximum average" ABPM decision point is the maximum of the hourly averages in the Tmax window (from 0.5 to 6.5 hours after cuff-fitting at baseline and from 0.5 to 6.5 hours on and after the 28th day). It is calculated as the maximum value of the hourly averages in the Tmax window (from 0.5 to 6.5 hours after cuff-fitting at baseline

[0515]

Chemical formula

Chemical formula

[0516] To be eligible for participation in this study, patients must meet all of the following inclusion criteria prior to enrollment and not meet any of the following exclusion criteria . 8.1.1 Inclusion Criteria

[0517] 1. Be able to give written informed consent, which includes compliance with the requirements and restrictions listed in the consent form .

[0518] 2. Males and females between 40 and 75 years of age at screening (Visit 1). Note: Up to 30% of the subjects can be male

[0519] 3. Subjects with a history of OAB. Note: OAB is defined as the presence or absence of urgency and urge urinary incontinence (UUI) and is usually associated with frequency and nocturia

[0520] 4. The post-void residual urine volume (PVR) must be 100 mL or less at bladder scan or ultrasound-based screening (Visit 1 ).

[0521] 5. Female subjects are eligible to participate if: - Documented infertility due to bilateral tubal ligation and bilateral oophorectomy (oophorectomy) defined as premenopausal females with hysteroscopic sterilization; or postmenopausal, defined as 12 months of spontaneous amenorrhea. A record is also acceptable. - Possible pregnancy and for an appropriate period (as specified on the product label or by the investigator) before initiating treatment Any of the contraceptive methods listed in Section 5.6.1 for agree to use the drug and be able to adequately minimize the risk of pregnancy at that time Female subjects must agree to use contraception until the follow-up visit.

[0522] 6. For females of childbearing potential: Eggs may be produced for at least 1 month after the last dose of study treatment. Agree not to donate offspring (eggs).

[0523] 7. Weight at screening (Visit 1) was ≥ 50 kg for men and ≥ 45 kg for women, and body mass index ( Body Mass Index: 18.5-35.0 kg / m 2 Within the scope of (including).

[0524] 8. Mid-arm circumference must be ≦45cm to accommodate the maximum size of the ABPM cuff. 8.1.2 Exclusion Criteria

[0525] 1. Subject has a positive drug test at Screening (Visit 1) but the drug is not prescribed to the subject. Unless it is a prohibited substance.

[0526] 2. At screening (Visit 1), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is > 2.0 times the upper limit of normal (ULN), or bilirubin (total bilirubin) > 1.5 × ULN (or > 2.0 × ULN in the case of secondary due to Gilbert's syndrome or a pattern consistent with Gilbert's syndrome).

[0527] 3. At screening (Visit 1), the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study (MDRD) equation is > 3 0 mL / min / 1.73m 2 .

[0528] 4. The regular alcohol intake history within 6 months from screening (Clinic Visit 1) is defined as follows:

[0529] · The average intake per week is > 14 drinks / week for men or > 7 drinks / week for women. One drink is equivalent to (12 g of alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80-proof distilled spirits.

[0530] 5. The subject has received the investigational product or device (including placebo) within the following period prior to the first dosing date in the current study: 30 days, 5 half-lives, or a period 2 times the biological effect of the investigational product, whichever is longer.

[0531] 6. The subject is currently participating in or has participated in a study using vibegron.

[0532] 7. Use of any of the following prohibited drugs (appropriate washout periods from these drugs are also provided): anticholinergics; smooth muscle relaxants, beta2-adrenergic agonists for the treatment of stress urinary incontinence ; beta2-adrenergic agonists; synthetic antidiuretic hormone; beta 3-adrenergic agonists; intravesical botulinum toxin; CNS stimulants; cannabis products ; alpha1-agonists (oral); NSAIDs; herbal supplements.

[0533] 8. Have changed the dose of certain medications (examples are tricyclic antidepressants alone or in combination; serotonin and / or norepinephrine reuptake inhibitors; inhaled anticholinergics ; antihypertensive drugs not listed as prohibited; alpha1-antagonists; 5 alpha reductase inhibitors; phosphodiesterase type 5 inhibitors) within 4 weeks prior to screening (Visit 1), or intend to start or change any administration of these medications during the study.

[0534] 9. A history of hypersensitivity to any study treatment or excipient, or their components, or a history of drugs or other allergies that are contraindications to their participation in the opinion of the investigator.

[0535] 10. If heparin is used during PK sampling (for those subjects who have consented to PK sampling), subjects with a history of hypersensitivity to heparin or heparin-induced thrombocytopenia shall not be enrolled.

[0536] 11. Pregnant females determined by a positive serum (Screening Visit 1) or urine (Day 1) human chorionic gonadotropin test at screening or prior to dosing.

[0537] 12. Lactating, and the female is actively breastfeeding.

[0538] 13. Subjects with uncontrolled hypertension (systolic blood pressure > 160 mmHg and / or diastolic blood pressure > 95 mmHg), or with a resting heart rate (by pulse) > 100 beats per minute at screening (Visit 1).

[0539] 14. Subjects with existing conditions that could interfere with normal gastrointestinal anatomy, function, or motility (including gastric bypass), absorption, metabolism, and / or excretion of the study treatment, and that cause impairment of liver and / or kidney function.

[0540] 15. Subjects with active urinary tract infection on Day 1 (Visit 2)

[0541] 16. History of significant psychiatric or neurological disorders.

[0542] 17. History of asthma or chronic obstructive pulmonary disease that requires the use of inhaled beta2 agonists.

[0543] 18. History of uncontrolled diabetes (HbA1c > 9%) at screening (Visit 1).

[0544] 19. History of cerebrovascular accident, transient ischemic attack, unstable angina, myocardial infarction, coronary artery intervention (examples are coronary artery bypass grafting or percutaneous coronary intervention [examples are angioplasty, stent placement]), or neurovascular intervention (examples are carotid stenting) within 6 months prior to the screening visit. Subjects with these conditions must have received stable medical therapy for at least 3 months prior to the screening visit.

[0545] 20. Subjects who engage in occupational or recreational activities involving lifting heavy objects and cannot refrain from participating in these activities on the study days when ABPM measurements are collected. 21. Subjects who require at least 8 consecutive hours of sleep between 0700 and 2300 for their occupation (i.e., night shift workers) or recreational activities. 22. Exclusion criteria for screening ECG (single repetition is allowed for eligibility determination):

[0546] 23. Post-void residual urine (PVR) > 100 mL at screening (visit 1) 24. Subjects who are disqualified from the ABPM device trial based on the pass / fail criteria located in the study reference manual

[0547] 25. History of chronic pain or chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain treatment; however, low-dose aspirin therapy is excluded and is allowed. Chronic pain is defined as daily pain that interferes with daily life and requires specific daily treatment (examples are daily analgesics, or regular acupuncture, electrostimulation treatment, etc.).

[0548]

Chemical

[0549] 27. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject.

[0550] 28. Subjects who are disqualified from the ABPM device trial based on the pass / fail criteria located in the study reference manual 29. History of chronic pain or chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain treatment; however, low-dose aspirin therapy is excluded and is allowed. Chronic pain is defined as daily pain that interferes with daily life and requires specific daily treatment (examples are daily analgesics, or regular acupuncture, electrostimulation treatment, etc.).

[0551] 30. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject. 31. History of chronic pain or chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain treatment; however, low-dose aspirin therapy is excluded and is allowed. Chronic pain is defined as daily pain that interferes with daily life and requires specific daily treatment (examples are daily analgesics, or regular acupuncture, electrostimulation treatment, etc.). 32. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject. 33. History of chronic pain or chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain treatment; however, low-dose aspirin therapy is excluded and is allowed. Chronic pain is defined as daily pain that interferes with daily life and requires specific daily treatment (examples are daily analgesics, or regular acupuncture, electrostimulation treatment, etc.). 34. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject.

[0552] 35. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject. 36. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject. 37. Any other condition, treatment, laboratory abnormality or investigator's opinion where the subject's ability to comply with the study procedures is impaired or participation in the study is not in the best interest of the subject. 8.2 Research Evaluation and Procedures 8.2.1. Investigational Products and Other Research Procedures

[0553] The term 'Research Procedures' is used throughout the protocol to describe single - dose vibegron or placebo. for explanatory purposes.

[0554]

Chem.

[0555] Subjects were randomly assigned to receive either of two treatment methods in a 1:1 ratio. - Vibegron 75 mg - Placebo matching Vibegron 75 mg

[0556] Randomization was stratified based on age (≤55 years or >55 years), sex (male or female), and existing hypertension (yes or no).

[0557] Enrollment was capped using the following restrictions: - Up to 30% of the enrolled subjects may be male - The proportion of subjects with an existing history of hypertension and / or hypertension at baseline may be capped at 55 %. 8.2.3. Time and Event Table

[0558] Figure 11 shows the time and event table of the study. 8.4 Safety Considerations

[0559] Safety was evaluated by clinical laboratory tests, physical examinations, and vital sign measurements from clinic visits at various times during the study, and by documentation of AEs. 8.5 Statistical Analysis

[0560] The primary hypothesis was to test whether the change in the mean of daytime systolic BP during free activity from baseline (CFB) to day 29 for the vibegron arm was less than 3.5 mmHg CFB by day 29 for the placebo arm. The null and alternative statistical hypotheses are as follows: For the placebo arm, the change in the mean of daytime systolic BP during free activity from baseline (CFB) to day 29 was less than 3.5 mmHg CFB by day 29. The null and alternative statistical hypotheses are as follows: H 0 : μ v - μ p ≧ 3.5 : μ v - μ p < 3.5

[0561] Therefore, μ v = the mean of CFB during the day up to day 29 for the vibegron arm, and μ p = the mean of CFB during the day up to day 29 for the placebo arm. 8.6 Analysis population

[0562] Safety set (SAF): All subjects who received at least one treatment in the double-blind study were included in the SAF and were included in the treatment group corresponding to the study treatment they actually received. This is the population used to summarize safety analyses collected during clinic visits and interactions with the facility staff; a summary of baseline / demographic characteristics was also presented for the SAF.

[0563] Full analysis set (FAS): All subjects who were randomly assigned, received at least one double-blind study treatment and had valid baseline ambulatory blood pressure monitoring (ABPM) measurements and valid day 29 ABPM measurements were included in the FAS. According to the intent-to-treat principle subjects were included regardless of the treatment they actually received, as long as they were randomly assigned ​was included in the treatment group. This group was used for all analyses of ABPM measurements. FAS When FAS differed from SAF, baseline / demographic characteristics were also presented for FAS.

[0564] Pharmacokinetic population: The PK population included all subjects who had blood PK sampling and had evaluable concentration-time data for analysis. 8.7 Final analysis

[0565] The final analysis was performed after the end of the study and approval of the final dataset was obtained.

[0566] Data were listed and summarized. Treatments were assigned based on the dosing schedule and included in the data list. The list was sorted by subject, day, and time; the summary was presented by treatment, day, and time.

[0567] Data were analyzed using SAS System version 9.2 or later to create tables, figures, and lists. 8.71 Analysis of ABPM

[0568] Analysis of ABPM endpoints (systolic and diastolic blood pressure, and CFB up to Day 29 of heart rate) used the generalized linear model (GLM). FAS was used to analyze these endpoints; by definition, FAS has no missing data, so imputation of missing data was not necessary. The analysis model for each efficacy endpoint included terms for treatment, age group (≤55 vs > 55 years), gender (male vs female), and existing hypertension (yes vs no), and the baseline score.

[0569] ​Primary inferences were drawn from the treatment differences for the 29th day CFB from GLM. The estimated treatment differences were presented in the summary of the statistical analysis along with the two-sided 90% confidence intervals and the associated p-values. To test the primary hypothesis at section 85, the upper limit of the two-sided 90% confidence interval was compared with 3.5, and the null hypothesis was rejected if the upper limit was strictly less than 3.5.

[0570] The 24-hour mean ambulatory baseline for systolic and diastolic blood pressure, and heart rate was the arithmetic mean of all valid measurements from the time the cuff was applied on day 1 until the cuff was removed on day 1. The 24-hour mean on the 29th day was the arithmetic mean of all valid measurements from the time the cuff was applied on day 28 until the cuff was removed on day 29.

[0571] The maximum SBP, DBP, and HR in the tmax window at baseline were the maximum of the hourly averages of valid measurements from 0.5 to 6.5 hours after the time of cuff application on day 1. On day 28, the maximum of SBP, DBP, and HR in the tmax window was the maximum of the hourly averages of valid measurements from 0.5 to 6.5 hours after dosing.

[0572] The mean of the daytime ambulatory baseline for systolic and diastolic blood pressure, and heart rate was the arithmetic mean of all measurements taken during the time intervals when the subject was awake. The same definition was applied to the measurements on the 29th day. 8.8 Clinical trial data and results

[0573] The patient demographics in this trial are shown in Table 99, and the temperament of the subjects is shown in Table 100.

[0574]

Table 99-1

[0575] [Table 100]

[0576] Vibegron met its primary decision point: Daytime ambulatory systolic blood pressure over the treatment period The mean change from baseline was less than approximately 1 mmHg above that of subjects receiving placebo. The 90% confidence interval for the limit was less than 3.5 mmHg. The results are shown in Table 101 (full analysis set) and Table 102. 102 (Pell Protocol Set).

[0577] [Table 101]

[0578] [Table 102]

[0579] Full analysis population and per-protocol set describing changes to blood pressure and heart rate Secondary decision points are shown in Tables 103 and 104. Figure 12 shows baseline results for ABPM systolic blood pressure. Figure 13 shows the 90% confidence intervals for treatment differences in the change from baseline to day 28. 90% confidence interval for treatment differences in day 28 change from baseline in mean blood pressure Figure 14 shows the treatment-dependent change from baseline to day 28 for ABPM heart rate. The 90% confidence intervals for the differences in position are shown.

[0580] [Table 103]

[0581]

Table 104

[0582] Changes from the baseline on day 28 for the study decision points, grouped by category are shown in Table 105.

[0583]

Table 105-1

Table 105-2

[0584] Tables 106, 107, and 108 show the changes in systolic blood pressure, diastolic blood pressure, and heart rate relative to in-clinic measurements over the treatment period.

[0585]

Table 106

[0586]

Table 107

[0587]

Table 108-1

Table 108-2

[0588] Changes in subgroup in-clinic vital signs are shown in Tables 109 to 114 。For subjects with a weight of at least about 65.4 kg, the number of subjects with systolic blood pressure increased by ≧5, ≧10, or 15 mmHg was not different between treatment and placebo. The same was true for subjects over 66 years old.

[0589]

Table 109-1

Table 109-2

[0590]

Table 110-1

Table 110-2

[0591]

Table 111

[0592]

Table 112

[0593]

Table 113-1

Table 113-2

[0594]

Table 114-1

Table 114-2

[0595] ​​Adverse events are summarized in Tables 115, 116, and 117.

[0596] [Table 115-1] [Table 115-2]

[0597] [Table 116-1] [Table 116-2]

[0598] [Table 117]

[0599] Table 118 shows a comparison of QTc studies between mirabegron and vibegron.

[0600] [Table 118-1] [Table 118-2]

[0601] The safety profile was similar to the Phase 3 study described in Example 6, with no significant difference in efficacy compared to placebo. Hypertension was more prevalent in the group with 1 AE. This study does not provide any clinically relevant evidence for hypertension. There were no effects and the overall safety profile of vibegron was confirmed.

[0602] The following are examples of certain embodiments of the present invention:

[0603] Embodiment 1: A method of treating overactive bladder, the method comprising administering vibegron in an amount of 75 mg to said Comprising oral administration to a subject in need thereof once a day, wherein the treatment is over a treatment period at least one of (1) to (5) a change from baseline: (1) a change in the average number of urinations per 24 hours from about -1.3 to about -2.5; (2) when the subject is an OAB wet patient, a change in the average number of UUI episodes per 24 hours from about -1.5 to about -2.5; (3) a change in the average number of urgency episodes per 24 hours from about -2.2 to about -3.5; change; (4) a change in the average number of total incontinence episodes per 24 hours from about -1.7 to about -2.7; and and (5) a change in the average voided volume per urination from about 18 mL to about 30 mL is achieved.

[0604] Embodiment 2: The method of Embodiment 1, wherein the treatment achieves at least two of (1) to (5) a change from baseline over a treatment period.

[0605] Embodiment 3: The method of Embodiment 2, wherein the treatment achieves a change from baseline of (1) and (2) over a treatment period.

[0606] Embodiment 4: The method according to any one of Embodiments 1 to 3, wherein the change in the average number of urinations per 24 hours is from about -1.5 to about -2.1, or preferably from about -1.6 to about -2.0.

[0607] Embodiment 5: The method according to any one of Embodiments 1 to 4, wherein the change in the average number of UUI episodes per 24 hours is from about -1.7 to about -2.3, or preferably from about -1.8 to about -2.2.

[0608] Embodiment 6: The change in the average number of urgency episodes per 24 hours is from about -2.4 to about - 3.0, or preferably from about -2.5 to -2.9, any one of the methods from 5 to 1 of Embodiment 1. way.

[0609] Embodiment 7: The change in the average number of total incontinence episodes per 24 hours is from about -1.9 to about -2.5, or preferably from about -2.0 to -2.4, any one of the methods from 6 to 1 of Embodiment 1. way.

[0610] Embodiment 8: The change in the average voided volume per void is from about 20 mL to about 28 mL, and or preferably from about 22 mL to about 26 mL, any one of the methods from 7 to 1 of Embodiment 1.

[0611] Embodiment 9: The subject has symptoms selected from the group consisting of urge urinary incontinence, urinary urgency, frequent urination, or combinations thereof, any one of the methods from 8 to 1 of Embodiment 1. way.

[0612] Embodiment 10: The subject has symptoms of urge urinary incontinence, urinary urgency, and frequent urination, Embodiment 9 method.

[0613] Embodiment 11: A method of reducing the average number of voids per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of 75 mg of vibegron once daily over a treatment period. way.

[0614] Embodiment 12: A method of reducing the average number of UUI episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of 75 mg of vibegron once daily over a treatment period. way.

[0615] Embodiment 13: A method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg once daily over a treatment period. A method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg once daily over a treatment period. A method for reducing the average number of urgency episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg once daily over a treatment period.

[0616] Embodiment 14: A method for reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg once daily over a treatment period. A method for reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of vibegron of 75 mg once daily over a treatment period. A method for reducing the average number of total incontinence episodes per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering to the subject in need thereof an amount of ...

Claims

1. A method of treating overactive bladder in a treatment-experienced subject in need thereof, comprising the steps of: and administering orally to a subject a therapeutically effective amount of vibegron per day, The amount is about 75 mg, and after administration of vibegron to a subject over the treatment period: a. The reduction in the mean number of urinations in a 24-hour period in subjects receiving placebo A decrease in the average number of urinations in subjects with ;or b. The mean number of episodes of urgency urinary incontinence (UUI) per 24 hours by subjects was significantly greater than that by placebo. by about 1.7 to about 6-fold reduction in those treated with method.

2. Reduction in the mean number of urinations in a 24-hour period in subjects receiving placebo 2. The method of claim 1, wherein the reduction in the average number of urinations in a subject is from about 2 to about 4. method.

3. Average voiding per 24 hours by subjects after administration of vibegron over the treatment period The number of UUI episodes per 24 hours by subjects decreased from about -1.3 to about -2.

5.

3. The method of claim 1 or 2, wherein the average number is decreased by about -1.5 to about -2.

5.

4. Voiding by subjects in a 24-hour period following administration of vibegron to the subjects over the treatment period The mean number of urinations was between about 1.5 and about 10 compared to the mean number of urinations in subjects receiving placebo. and the mean number of UUI episodes per 24 hours by subjects decreased from approximately -1.5 to approximately -2.5 The method of any one of claims 1-3, wherein the concentration of

5. The average number of urgency episodes per 24 hours after subjects received vibegron over the treatment period 5. The method of any one of claims 1 to 4, wherein the average number is reduced by about -2.2 to about -3.

5. 。

6. After subjects received vibegron over the treatment period, the mean number of total incontinence episodes was approximately -1.7 6. The method of claim 1, wherein the β-amino acid salt is reduced by about -2.

7.

7. After subjects received vibegron over the treatment period, the average volume voided per void was approximately 18 7. The method of any one of claims 1 to 6, wherein the amount of blood flow is increased by from about 1 mL to about 30 mL.

8. A treatment-experienced subject is one who has been previously treated with an anticholinergic agent, How to.

9. Treatment-experienced subjects were randomly assigned to receive vibegron after treatment with an anticholinergic agent within 12 months of vibegron administration. The method of claim 8,

10. Treatment-experienced subjects were randomly assigned to receive anticholinergic medication for >12 months prior to treatment with vibegron. Treated according to claim 8.

11. 10. The method of claim 8, wherein the treatment-experienced subject is concomitantly receiving an anticholinergic agent.

12. Treatment-experienced subjects were previously treated with a beta-3 agonist other than vibegron.

9. The method of any one of claims 1-8.

13. 13. The method of claim 12, wherein the beta 3 agonist is mirabegron.

14. Treatment-experienced subjects were those who had received any other beta-blocker other than vibegron within 12 months prior to treatment with vibegron. The method of claim 12 or 13, wherein the patient is treated with a data set 3 agonist.

15. Treatment-experienced subjects were required to have received any medication other than vibegron >12 months prior to treatment with vibegron.

14. The method of claim 12 or 13, wherein the patient is treated with a beta 3 agonist.

16. Treatment-experienced subjects are receiving concomitant beta-3 agonists other than vibegron. The method of claim 12 or 13.

17. Treating overactive bladder in subjects in need thereof while improving health-related quality of life A method for improving human heart rate quality of life (HRQL) comprising administering a therapeutically effective amount of vibegron to a subject in need thereof. orally administered daily for a period of time, where the therapeutically effective amount is about 75 mg. and where improvement is compared to the HRQL of subjects receiving a placebo.

18. HRQL includes one or more subscales selected from coping, worry, sleep, or social interaction.

20. The method of claim 17.

19. The improvement in HRQL is greater than that with tolterodine extended release (ER) 4 mg. There are 18 ways.

20. Subjects receiving vibegron had at least the same HRQL as subjects receiving placebo 20. The method of any one of claims 17 to 19, improved by a combined score of about 3.

8.

21. A method for reducing coping behaviors in a subject suffering from symptoms of overactive bladder, comprising administering to said subject a therapeutically effective amount of orally administering to a subject in need thereof a daily dose of vibegron for the treatment period. wherein the therapeutically effective amount is about 75 mg, and wherein the coping behavior in the subject is is reduced compared to subjects receiving a placebo.

22. 1. A method for improving a coping domain score in a subject suffering from overactive bladder symptoms, comprising: A therapeutically effective amount of vibegron is orally administered daily to a subject in need thereof for the duration of treatment. wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is greater than or equal to placebo. The method is compared with the coping domain scores of the subjects receiving it.

23. Improvement in coping domain scores was greater with tolterodine ER 4 mg 23. The method of claim 22.

24. Coping domain scores in subjects receiving vibegron compared with subjects receiving placebo 24. The method of claim 22 or 23, wherein the method is improved by a score of at least about 3.

2.

25. A method for improving sleep in a subject suffering from symptoms of overactive bladder, comprising administering a therapeutically effective amount of bladder supplement to a subject. and orally administering Begron to a subject in need thereof daily for a treatment period. , where the therapeutically effective amount is about 75 mg, and where the improvement is greater than that of subjects receiving a placebo. A method that is compared to sleep.

26. The improvement in sleep is greater than that achieved with 4 mg of tolterodine extended release (ER). Law.

27. Subjects receiving vibegron had at least 10% better sleep than subjects receiving placebo 27. The method of claim 25 or 26, improved by a score of about 2.

6.

28. A method for reducing symptom burden in a subject suffering from overactive bladder symptoms, comprising administering to said subject a therapeutically effective amount of orally administering to a subject in need thereof a daily dose of vibegron for the treatment period. wherein the therapeutically effective amount is about 75 mg, and wherein the relief is in response to a placebo. A method in which the symptoms of interest are compared to the bother of the subject.

29. The relief in symptom burden is greater than with tolterodine extended release (ER) 4 mg. 8 ways.

30. Subjects receiving vibegron reported less symptom bother than subjects receiving placebo.

30. The method of claim 28 or 29, wherein the symptom is reduced by a score of at least about -5.

0.

31. Maintain daytime ambulatory blood pressure while treating overactive bladder in those who need it The method comprises orally administering a therapeutically effective amount of vibegron to a subject per day. wherein the therapeutically effective amount is about 75 mg, and wherein the subject has a blood pressure of less than about 2.0 mmHg. The method involves the mean change in daytime ambulatory blood pressure over the treatment period.

32. Subjects will experience a mean change in daytime ambulatory systolic blood pressure over the treatment period and there The mean change from that of subjects taking placebo was less than about 3.5 mmHg (90% confidence interval).

32. The method of claim 31 , having an upper bound of:

33. 33. The method of claim 32, wherein the upper bound of the 90% confidence interval is less than about 2.5 mmHg.

34. 34. The method of claim 33, wherein the upper bound of the 90% confidence interval is about 2.0 mmHg.

35. Subjects will experience a mean change in daytime ambulatory systolic blood pressure over the treatment period and there 31. The mean change from subjects taking a placebo at 0.5 mg / kg or less is less than about 1.0 mmHg.

34. The method according to any one of claims 1 to 34.

36. Claim 35: The mean change from that of subjects taking a placebo is less than about 0.5 mmHg. How to.

37. Subjects experienced a mean change in daytime ambulatory systolic blood pressure over the treatment period of less than approximately 1.0 mmHg.

37. The method of any one of claims 31 to 36, wherein

38. 38. The method of claim 37, wherein the average change is less than about 0.25 mmHg.

39. Subjects had greater daytime free activity over the treatment period than subjects taking placebo.

39. The method of any one of claims 31 to 38, wherein the method does not experience a mean change in active diastolic blood pressure.

40. Subjects experienced a mean change in daytime ambulatory diastolic blood pressure over the treatment period of less than approximately 0.75 mmHg.

40. The method of any one of claims 31 to 39, further comprising:

41. Subjects who need to maintain daytime ambulatory heart rate while treating overactive bladder The method comprises orally administering a therapeutically effective amount of vibegron to a subject per day. wherein the therapeutically effective amount is about 75 mg, and wherein the subject is receiving a blood glucose level of less than about 1.25 bpm. and experiencing a mean change in daytime ambulatory heart rate over the treatment period.

42. Subjects will experience mean changes in daytime ambulatory heart rate over the treatment period and will then 42. The method of claim 41, wherein the mean change from that of subjects taking a placebo is less than about 1.0 bpm. 。

43. Subjects who need to maintain 24-hour ambulatory blood pressure while treating overactive bladder The method comprises orally administering a therapeutically effective amount of vibegron to a subject per day. wherein the therapeutically effective amount is about 75 mg, and wherein the subject has a blood glucose level of less than about 2.0 mmHg. The method comprises the steps of: (a) determining the mean change in 24-hour ambulatory blood pressure over the treatment period;

44. Subjects will experience a mean change in 24-hour ambulatory systolic blood pressure over the treatment period, and wherein the mean change from subjects taking a placebo is less than about 0.75 mmHg. 43 ways.

45. Subjects will achieve a mean change in 24-hour ambulatory systolic blood pressure over the treatment period of less than approximately 0.75 mmHg.

44. The method of claim 43, wherein the

46. Subjects will receive a greater 24-hour freedom from the treatment period than subjects receiving placebo.

46. ​​The method of any one of claims 43 to 45, wherein the method does not experience a mean change in ambulatory diastolic blood pressure.

47. Subjects experienced a mean change in 24-hour ambulatory diastolic blood pressure over the treatment period of less than 0.75 mmHg.

47. The method of any one of claims 43 to 46, further comprising:

48. Maintain 24-hour ambulatory heart rate while treating overactive bladder for those who need it The method comprises administering orally to the subject a therapeutically effective amount of vibegron per day. wherein the therapeutically effective amount is about 75 mg, and wherein the subject is receiving a blood glucose level of less than about 1.0 bpm. and experiencing a mean change in 24-hour ambulatory heart rate over the treatment period.

49. 49. The method of claim 48, wherein the mean change from that of subjects taking a placebo is less than about 1.0 bpm. method.

50. Any one of claims 31 to 49, wherein the subject receiving vibegron has hypertension. How to.

51. The method of any one of claims 1-50, wherein vibegron is administered once daily.

52. The method of any one of claims 1-51, wherein vibegron is administered as a free base.

53. The method of any one of claims 1-51, wherein vibegron is administered as a pharma- ceutically acceptable salt thereof. method.

54. Treatment duration is approximately 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 54, 55, 56, 57, 58, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 11 Either one of the methods.

55. The method of any one of claims 1-53, wherein the treatment period is selected from about 2, 4, 8, 12, and 52 weeks. method.

56. 56. The method of claim 55, wherein the treatment period is about 12 weeks.

57. 56. The method of claim 55, wherein the treatment period is about 52 weeks.

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