Application of vibeglone in treatment of overactive bladder

Abstract

The invention relates to application of vibeglone to treatment of overactive bladder. The present disclosure relates to a method of treating overactive bladder, the method comprising orally administering to a subject in need thereof 75 mg of vibeglone per day, and wherein after administration of vibeglone to the subject during a treatment period: a. A reduction in the average number of urination of the subject over a period of 24 hours is about 1.5 to about 10 times more than a reduction in the average number of urination of a subject receiving a placebo; or b. A reduction in the average number of urgent urinary incontinence (UUI) onset per 24 hours in the subject is from about 1.7 to about 6 times a reduction in the average number of urgent urinary incontinence (UUI) onset in the subject treated with the placebo.

Description

[0001] This application is a divisional application of the application filed on March 18, 2020, with application number 202080036713.7 and invention title "Use of Vibergren in the treatment of overactive bladder". background

[0002] 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 the coordination of the storage and micturition reflexes involving multiple afferent and efferent neural pathways, resulting in the regulation of central and peripheral nerve effector mechanisms, and consequently, the coordinated regulation of the sympathetic and parasympathetic components of the autonomic nervous system and somatic motor pathways. These locally regulate the contractile state of the bladder (detrusor muscle), urethral smooth muscle, and urethral sphincter striated muscle.

[0003] From a pathophysiological perspective, overactive bladder (OAB) is associated with excessive detrusor muscle activity. OAB is characterized by urinary urgency, with or without urge incontinence, and is typically associated with urinary frequency and nocturia. The prevalence of OAB is estimated to be 16% to 17% in both men and women over 18 years of age in the United States and Europe. OAB is most commonly classified as idiopathic, but it can also be secondary to neurological conditions, bladder outlet obstruction, and other causes.

[0004] Currently, the main class of drugs used to treat OAB is the antimuscarinic class. Clinical use of antimuscarinic drugs is limited by moderate potency and poor tolerability due to mechanism-based side effects, including dry mouth, constipation, and potential CNS side effects (e.g., cognitive impairment). High discontinuation rates have been observed in both clinical trials and real-world settings for two commonly prescribed antimuscarinic drugs, tolterodine and oxybutynin. Furthermore, recent evidence from observational studies suggests that higher cumulative anticholinergic drug use is associated with an increased risk of dementia. See Gray SL et al., JAMA Intern Med 2015;175(3): 401-407.

[0005] β3-adrenergic receptor (β3-AR) activation is an effective way to relax the detrusor muscle in both normal and pathological states. Functional evidence supporting the important role of β3-AR in urine storage is demonstrated by in vivo studies. β3-AR agonists have been shown to be effective in reducing OAB symptoms. To date, only one β3-AR agonist, mirabegron (Astellas Pharma Global Development, Inc.), has been approved for marketing in the US and Japan for the treatment of OAB. Mirabecron activates β3-AR in the bladder detrusor muscle, which leads to muscle relaxation and increased bladder capacity. A reduction in voiding frequency, urinary incontinence, and urgency episodes, as well as an increase in the average volume of each voiding, has been observed in cases of mirabegron.

[0006] Vibergron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide, is a potent and highly selective β-3-adrenergic receptor (β3-AR) agonist that, in cell-based in vitro assays, exhibits relative efficacy compared to... 2-AR and 1-AR targets Activation of 3-AR showed >9,000-fold selectivity. See Edmondson et al., J. Med. Chem. 59:609-623 (2016).

[0007]

[0008] Vibergron is disclosed as a β3-AR agonist in U.S. Patents 8,399,480 and 8,247,415, and WO2018 / 224989. Synthetic methods for preparing vilbergron are disclosed in U.S. Publications 2017 / 0145014, 2015 / 0087832, 2016 / 0176884, and 2014 / 0242645. All cited publications are incorporated herein by reference in their entirety. Brief description of the attached diagram

[0009] Figure 1 A superimposed plot depicting density maps of exposure to vebegliflozin at 100 mg and 75 mg, as estimated in specific populations.

[0010] Figure 2 The average (+SD) plasma concentrations of tolterodine, both alone and in the presence of veberberine, are presented as a percentage of time.

[0011] Figure 3 The average (+SD) plasma concentrations of metoprolol, both alone and in the presence of vebeguron, are plotted over time.

[0012] Figure 4 The reduction in urge urinary incontinence (UUI) over time was described. A statistically significant effect was achieved after 2 weeks of vebergellon treatment.

[0013] Figure 5 The decrease in urination over time was described. Vibergone treatment achieved a statistically significant effect after 2 weeks.

[0014] Figure 6 The decrease in urinary urgency over time was described. Statistically significant efficacy was achieved after 2 weeks of vebergellon treatment.

[0015] Figure 7 The response rate for urge incontinence was plotted over time. Vibeglaron achieved statistically significant efficacy after 2 weeks of treatment.

[0016] Figure 8 The percentage of respondents who experienced a 75% and 100% reduction in UUI episodes and a 50% reduction in urinary urgency episodes at week 12 is depicted.

[0017] Figure 9 The reduction in total incontinence episodes over time was described. Statistically significant efficacy was achieved after 2 weeks of vebergellon treatment.

[0018] Figure 10 The improvement in displacement over time was depicted. Vibergren achieved statistically significant efficacy after 2 weeks of treatment.

[0019] Figure 11 The time and events of the ABPM study are shown.

[0020] Figure 12 The 90% confidence interval for the change in ABPM systolic blood pressure from baseline at day 28 is shown.

[0021] Figure 13 The 90% confidence interval for the change in ABPM diastolic blood pressure from baseline at day 28 is shown.

[0022] Figure 14 The 90% confidence interval for the change in ABPM heart rate from baseline at day 28 is shown.

[0023] Figure 15 This indicates a decrease in urination over 52 weeks.

[0024] Figure 16It showed a reduction in urge incontinence (UUI) episodes within 52 weeks.

[0025] Figure 17 This showed a reduction in urinary urgency episodes within 52 weeks.

[0026] Figure 18 It shows a reduction in total incontinence episodes within 52 weeks.

[0027] Figure 19 Kaplan Meier plot showing the time of urge incontinence (UUI) and a 75% reduction.

[0028] Figure 20 The Kaplan-Meier graph shows the time to urinary urgency and a 50% reduction.

[0029] Figure 21 A graph showing the mean LS value of the change in urinary urgency from baseline over time in the dry OAB population. Overview

[0030] This disclosure provides a method for treating overactive bladder, comprising orally administering 75 mg of vebergellon daily to a subject with the corresponding need.

[0031] This disclosure also provides a method for treating overactive bladder, comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the treatment achieves at least one of (1) to (5) a change from baseline during the treatment period: (1) The average number of urinations per 24 hours changed from approximately -1.3 times to approximately -2.3 times; (2) When the subject was a wet OAB patient, the average number of UUI attacks per 24 hours varied from about -1.5 times to about -2.5 times; (3) The average number of urinary urgency episodes per 24 hours changed from approximately -2.2 times to approximately -3.2 times; (4) The average number of episodes of complete incontinence per 24 hours varied from approximately -1.7 to approximately -2.7; and (5) The average volume of urine per urination varied from about 18 mL to about 30 mL.

[0032] In some implementations, the treatment achieves a statistically significant change compared to placebo in at least one of the following: the average number of urinations per 24 hours; the average number of UUI episodes per 24 hours; the average number of urinary urgency episodes per 24 hours; the average number of total incontinence episodes; and the average volume of urine per urination.

[0033] This disclosure also provides a method for treating overactive bladder in a treated subject with appropriate need, the method comprising administering orally to the subject daily a therapeutically effective dose of vilbeganol, wherein the therapeutically effective dose is approximately 75 mg, and wherein after administering vilbeganol to the subject during the treatment period: a. The subjects experienced a decrease in the average number of urinations over a 24-hour period that was approximately 1.5 to 10 times greater than the decrease in the average number of urinations among subjects receiving a placebo; or b. The reduction in the average number of urge incontinence (UUI) episodes per 24 hours was approximately 1.7 to approximately 6 times that of the placebo-treated subjects.

[0034] This disclosure also provides a method for improving the health-related quality of life (HRQL) of subjects with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to the subject in need daily during the treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is compared to the HRQL of the subject receiving placebo.

[0035] This disclosure also provides a method for treating overactive bladder in subjects with appropriate needs while improving health-related quality of life (HRQL), the method comprising orally administering a therapeutically effective amount of vilbegaron to the subject with appropriate needs daily during the treatment period, wherein the therapeutically effective amount is approximately 75 mg, and wherein the improvement is compared to the HRQL of a subject receiving a placebo.

[0036] In some implementations, HRQL includes one or more subscales selected from coping, anxiety, sleep, social interaction, and combinations thereof.

[0037] This disclosure also provides a method for reducing coping behaviors in subjects with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective dose of vebergellon to a subject in need daily during the treatment period, wherein the therapeutically effective dose is approximately 75 mg, and wherein the subject's coping behaviors are reduced compared to subjects receiving a placebo.

[0038] This disclosure also provides a method for treating overactive bladder in subjects with appropriate needs while reducing coping behaviors, the method comprising orally administering a therapeutically effective dose of vebergellon to the subjects with appropriate needs daily during the treatment period, wherein the therapeutically effective dose is approximately 75 mg, and wherein the subjects' coping behaviors are reduced compared to subjects receiving a placebo.

[0039] This disclosure also provides a method for maintaining ambulatory blood pressure and / or ambulatory heart rate in subjects with appropriate need, while treating overactive bladder, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is approximately 75 mg.

[0040] This disclosure also provides a method for treating overactive bladder in subjects with appropriate needs while maintaining ambulatory blood pressure and / or ambulatory heart rate, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is approximately 75 mg.

[0041] This disclosure also provides the following items: 1. A method for treating overactive bladder in a treated subject with corresponding need, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is about 75 mg, and wherein after administering vilbeganol to the subject during the treatment period: a. The subjects reported a reduction in the average number of urinations over a 24-hour period that was approximately 1.5 to 10 times greater than the reduction in the average number of urinations among the placebo-receiving subjects; or b. The reduction in the average number of urge incontinence (UUI) episodes per 24 hours in the subjects was approximately 1.7 to approximately 6 times the reduction in the average number of urge incontinence (UUI) episodes in subjects treated with placebo.

[0042] 2. According to the method of Project 1, the subject experienced a reduction in the average number of urinations over a 24-hour period of approximately 2 to approximately 4 times greater than the subject receiving a placebo experienced a reduction in the average number of urinations.

[0043] 3. The method according to Project 1 or 2, wherein after administration of vilbegon to the subject during the treatment period, the average number of times the subject urinates per 24 hours decreases from about 1.3 times to about 2.5 times, and the average number of times the subject experiences UUI episodes per 24 hours decreases from about -1.5 times to about -2.5 times.

[0044] 4. The method according to any one of items 1-3, wherein after administration of vebergellon to the subject during the treatment period, the average number of urinations of the subject within a 24-hour period is reduced by between about 1.5 and about 10 times compared to the average number of urinations of the subject receiving a placebo, and the average number of UUI episodes of the subject per 24 hours is reduced from about -1.5 times to about -2.5 times.

[0045] 5. The method according to any one of items 1 to 4, wherein after administration of vebergellon to the subject during the treatment period, the average number of urinary urgency episodes per 24 hours is reduced from about -2.2 times to about -3.5 times.

[0046] 6. The method according to any one of items 1 to 5, wherein after administration of vilbegon to the subject during the treatment period, the average number of episodes of complete incontinence is reduced from about -1.7 to about -2.7.

[0047] 7. The method according to any one of items 1 to 6, wherein after administration of vebergellon to the subject during the treatment period, the average volume of each urination increases by about 18 mL to about 30 mL.

[0048] 8. The method according to any one of items 1-7, wherein the treated subject has previously been treated with an anticholinergic drug.

[0049] 9. The method according to Project 8, wherein the treated subject had been treated with an anticholinergic drug within 12 months prior to treatment with vebergellon.

[0050] 10. The method according to Project 8, wherein the treated subject had been treated with an anticholinergic drug for more than 12 months prior to treatment with vebergellon.

[0051] 11. The method according to Project 8, wherein the treated subject is concurrently receiving an anticholinergic drug.

[0052] 12. The method according to any one of items 1-8, wherein the treated subject has previously been treated with a β-3 agonist other than vebergellon.

[0053] 13. The method according to item 12, wherein the β-3 agonist is miraberione.

[0054] 14. The method according to item 12 or 13, wherein the treated subject had been treated with a β-3 agonist other than vilbegaron within 12 months prior to treatment with vilbegaron.

[0055] 15. The method according to item 12 or 13, wherein the treated subject had been treated with a β-3 agonist other than vilbegan for more than 12 months prior to treatment with vilbegan.

[0056] 16. The method according to item 12 or 13, wherein the treated subject is concurrently receiving a β-3 agonist other than vebergellon.

[0057] 17. A method for treating overactive bladder in a subject with appropriate need while improving health-related quality of life (HRQL), the method comprising orally administering a therapeutically effective amount of vebergellon to the subject with appropriate need daily during the treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is compared with the HRQL of a subject receiving a placebo.

[0058] 18. The method according to Item 17, wherein the HRQL includes one or more subscales selected from coping, anxiety, sleep, or social interaction.

[0059] 19. The method according to item 17 or 18, wherein the improvement in HRQL is greater than the improvement with tolterodine extended-release (ER) 4 mg.

[0060] 20. The method according to any one of items 17 to 19, wherein the HRQL of the subject receiving vebergelone was improved by at least about 3.8 points compared with the subject receiving placebo.

[0061] 21. A method for reducing coping behaviors in subjects with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject with appropriate need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the coping behaviors of the subject are reduced compared to those of a subject receiving a placebo.

[0062] 22. A method for improving the coping domain score of a subject with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject with appropriate need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is defined as a comparison of the coping domain score of a subject receiving a placebo.

[0063] 23. The method described in Project 22, wherein the improvement in response area score is greater than the improvement with tolterodine extended-release (ER) 4 mg.

[0064] 24. The method according to item 22 or 23, wherein the subject receiving vebergerone showed an improvement of at least approximately 3.2 points in the coping domain score compared to the subject receiving placebo.

[0065] 25. A method for improving sleep in a subject suffering from symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject with appropriate need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is compared to sleep in a subject receiving a placebo.

[0066] 26. The method described in Project 25, wherein the improvement in sleep is greater than the improvement achieved with tolterodine extended-release (ER) 4 mg.

[0067] 27. The method described in Item 25 or 26, wherein the sleep scores of the subjects receiving vebergerone were improved by at least approximately 2.6 points compared to those receiving a placebo.

[0068] 28. A method for reducing symptom distress in a subject suffering from symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject in need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the reduction is compared to symptom distress in a subject receiving a placebo.

[0069] 29. The method described in Project 28, wherein the reduction in symptom distress is greater than the reduction with 4 mg of tolterodine extended-release (ER).

[0070] 30. The method according to item 28 or 29, wherein the subject receiving vebegenol had a lower score of at least approximately -5.0 points for symptom distress compared to the subject receiving placebo.

[0071] 31. A method for maintaining daytime ambulatory blood pressure and treating overactive bladder in subjects with appropriate need, the method comprising administering a therapeutically effective amount of vilbeganol orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences a mean change in daytime ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

[0072] 32. The method according to item 31, wherein the subject experiences a mean change in diurnal ambulatory systolic blood pressure during the treatment period, and wherein the mean change has an upper limit of a 90% confidence interval of less than about 3.5 mmHg compared to the mean change in a subject taking a placebo.

[0073] 33. The method according to item 32, wherein the upper limit of the 90% confidence interval is less than about 2.5 mmHg.

[0074] 34. The method according to item 33, wherein the upper limit of the 90% confidence interval is approximately 2.0 mm Hg.

[0075] 35. The method according to any one of items 31 to 34, wherein the subject experiences a mean change in diurnal dynamic systolic blood pressure during the treatment period, and wherein the mean change is less than about 1.0 mmHg compared to the mean change in a subject taking a placebo.

[0076] 36. The method according to item 35, wherein the mean change is less than about 0.5 mmHg compared to the mean change in subjects taking placebo.

[0077] 37. The method according to any one of items 31 to 36, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure of less than about 1.0 mmHg during the treatment period.

[0078] 38. The method according to item 37, wherein the average variation is less than about 0.25 mmHg.

[0079] 39. The method according to any one of items 31 to 38, wherein the subject did not experience a greater mean change in daytime dynamic diastolic blood pressure during the treatment period than the subject taking placebo.

[0080] 40. The method according to any one of items 31 to 39, wherein the subject experiences a mean change in diurnal dynamic diastolic blood pressure of less than about 0.75 mmHg during the treatment period.

[0081] 41. A method for maintaining daytime dynamic heart rate and treating overactive bladder in subjects with appropriate need, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences a mean change in daytime dynamic heart rate of less than about 1.25 bpm during the treatment period.

[0082] 42. The method according to item 41, wherein the subject experiences a mean change in daytime dynamic heart rate during the treatment period, and wherein the mean change is less than about 1.0 bpm compared to the mean change in a subject taking a placebo.

[0083] 43. A method for maintaining 24-hour ambulatory blood pressure in a subject with appropriate need while treating overactive bladder, the method comprising administering a therapeutically effective amount of vilbeganol orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences a mean change in 24-hour ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

[0084] 44. The method according to item 43, wherein the subject experiences a 24-hour average change in systolic blood pressure during the treatment period, and wherein the average change is less than about 0.75 mmHg compared to the average change in a subject taking a placebo.

[0085] 45. The method according to item 43, wherein the subject experiences a mean change in 24-hour ambulatory systolic blood pressure of less than about 0.75 mmHg during the treatment period.

[0086] 46. ​​The method according to any one of items 43 to 45, wherein the subject did not experience a greater mean change in 24-hour ambulatory diastolic blood pressure during the treatment period than the subject taking placebo.

[0087] 47. The method according to any one of items 43 to 46, wherein the subject experiences a mean change in 24-hour dynamic diastolic blood pressure of less than 0.75 mmHg during the treatment period.

[0088] 48. A method for maintaining 24-hour ambulatory heart rate in a subject with appropriate need while treating overactive bladder, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences an average 24-hour ambulatory heart rate variation of less than about 1.0 bpm during the treatment period.

[0089] 49. The method according to item 48, wherein the mean change is less than about 1.0 bpm compared to the mean change in subjects taking placebo.

[0090] 50. The method according to any one of items 31 to 49, wherein the subject being administered vebegliflozin has hypertension.

[0091] 51. The method according to any one of items 1-50, wherein vibergron is applied once daily.

[0092] 52. The method according to any one of items 1-51, wherein vibergron is applied as a free base.

[0093] 53. The method according to any one of items 1-51, wherein vibergron is administered as a pharmaceutically acceptable salt.

[0094] 54. The method according to any one of items 1-53, wherein the treatment period is selected from the group consisting of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, and about 52 weeks.

[0095] 55. The method according to any one of items 1-53, wherein the treatment period is selected from about 2 weeks, about 4 weeks, about 8 weeks, about 12 weeks and about 52 weeks.

[0096] 56. The method according to item 55, wherein the treatment period is approximately 12 weeks.

[0097] 57. The method according to item 55, wherein the treatment period is approximately 52 weeks. Detailed description

[0098] To facilitate a clearer understanding of this disclosure, certain terms are first defined. As used herein, each of the following terms shall have the meaning set forth below unless expressly specified herein. Further definitions are set forth throughout this application.

[0099] In this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. The terms “a or an,” “one or more,” and “at least one” are used interchangeably herein. In some aspects, the term “a or an” means “single.” In other aspects, the term “a or an” includes “two or more” or “multiple.”

[0100] Furthermore, when used herein, “and / or” should be considered as a specific disclosure of each of two particular features or components, with or without the other. Therefore, the term “and / or” as used herein in wording 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 wording such as “A, B, and / or C” is intended to include each of the following: 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).

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art relating to this disclosure.

[0102] Throughout the specification and claims, the term "about" used in conjunction with numerical values ​​indicates a range of precision familiar and acceptable to those skilled in the art. In some embodiments, such a range of precision is ±10%. In other embodiments, such a range of precision is ±5%.

[0103] The term “overactive bladder” generally refers to urinary urgency, usually accompanied by urinary frequency and nocturia, with or without urge incontinence, and without urinary tract infection or other obvious pathology. The term “overactive bladder” is defined by the International Continence Society (ICS) as follows: Overactive bladder (OAB) is a syndrome consisting of urinary urgency with or without urge incontinence, usually accompanied by urinary frequency and nocturia, without 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”.

[0104] The term "urge incontinence" refers to the discomfort of involuntary urination.

[0105] The term "urgency urinary incontinence" (UUI) refers to the discomfort of involuntary incontinence associated with urinary urgency and can be used interchangeably with "urge urinary incontinence" or "urge incontinence." UUI is distinct from stress urinary incontinence, which is involuntary incontinence that occurs during exertion or physical exertion (e.g., physical activity) or when sneezing or coughing.

[0106] As used in this article, the term "impairment" refers to an acute or chronic decline in function. For example, kidney damage is a medical condition in which the kidneys are unable to maintain their normal function, resulting in the accumulation of waste products and metabolites in the blood.

[0107] As used in this article, the term "urinary urgency" refers to the discomfort of a sudden, intense urge to urinate that is difficult to delay.

[0108] As used in this article, "frequent urination" refers to the discomfort experienced by patients who feel they urinate too frequently during the day.

[0109] As used in this article, “health-related quality of life” or “health-related QoL” (HRQL) is a multi-domain concept representing a patient’s general perception of the physical, psychological, and social impact of illness and treatment on their life. Because the OAB is primarily defined by symptoms rather than objective measurements and has shown a significant impact on HRQL, assessments of treatment effectiveness often include evaluations of patient perceptions. The Overactive Bladder Questionnaire (OAB-q) was developed to assess patient perceptions of symptom distress and its impact on HRQL. The OAB-q consists of an 8-item symptom distress scale and 25 HRQL items, forming four subscales: coping, anxiety, sleep, and social interaction, and provides a total HRQL score. For symptom distress items, patients rate each item on a 6-subscale ranging from “none” to “very many.” The subscales are summarized and converted into scores ranging from 0 to 100. Higher symptom distress scores indicate increased symptom distress, while higher HRQL scores indicate better health-related quality of life. Improvement or enhancement of HRQL during the treatment period refers to, for example, how well a subject feels or functions as a result of the target disease and its treatment, evidence of general improvement, and evidence of no decline in any area.

[0110] As used herein, the term “coping” refers to the OAB-q sub-scores for behaviors that OAB participants use to manage their OAB needs. Coping behaviors or tasks include, for example, planning a route to the restroom, carefully planning a commute, more carefully planning activities, reducing physical activity, locating the nearest restroom upon arrival at a new location, adjusting travel plans, avoiding activities far from the restroom, and discomfort when traveling with others. Therefore, for example, a reduction in coping behavior refers to a decrease in the overall number of coping behaviors or situations during the treatment period in which the participant engages in any or more of these coping behaviors (such as planning a route to the restroom). Similarly, an improvement in the coping domain score refers to an observed decrease or other change in coping behaviors during the treatment period.

[0111] As used in this article, the terms “anxiety” and “concern” refer to the OAB-q sub-scores that characterize how much a subject is troubled by his / her OAB. For example, an OAB subject may be distressed, anxious, and / or embarrassed by possible odors or hygiene issues, and / or embarrassed by his / her OAB symptoms. For example, a decrease in the anxiety / concern sub-score indicates a reduced amount of anxiety / concern that the subject has about his / her OAB symptoms.

[0112] As used in this article, “sleep” refers to the OAB-q sub-score, which reflects an OAB subject’s perception of sleep quality. For example, an OAB subject may feel tired / drowsy and / or unrested during the day due to waking up at night to urinate. For instance, an improvement in the sleep score indicates an increased perception of sleep quality in the subject, as this is associated with his / her OAB.

[0113] As used in this paper, “social interaction” refers to the OAB-q item score assessing the impact of an OAB subject’s symptoms on his / her social habits. For example, an OAB subject may feel that his / her symptoms have affected his / her relationships with family / friends, have caused problems with his / her partner, have made him / her stay home more often than expected, and / or have led to a decrease in participation in social gatherings. For example, an improvement in the social interaction score indicates a decrease in the subject’s perception of the impact of OAB on his / her social habits.

[0114] As used herein, the term "symptom distress" refers to the OAB-q subscale, which includes eight items related to the frequency of symptoms such as urinary urgency, nocturia, and incontinence. As explained below in Example 6, the symptom distress scale items are rated from 1 (none at all) to 6 (very many), with higher symptom distress scores indicating greater symptom severity. Therefore, for example, a reduction in symptom distress or a decrease in a subject's symptom distress score during treatment refers to the subject's general perception of improvement in distress associated with OAB symptoms.

[0115] As used herein, the term "free base" refers to the basic compound itself, not in the form of a salt. For example, the free base of Vibergron is (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide.

[0116] As used in this article, the term "wet OAB" refers to overactive bladder defined by urinary frequency and urgency accompanied by urinary incontinence.

[0117] As used in this article, the term "dry OAB" refers to overactive bladder defined by urinary frequency and urgency without urinary incontinence.

[0118] The term "pharmaceutically acceptable salt" refers to those salts of compounds that are safe and effective for use in subjects and have the desired biological activity.

[0119] Pharmaceutically acceptable salts of basic compounds can be salts of organic acids or salts of inorganic acids. In some embodiments, organic and inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid, mandelic acid, succinic acid, and methanesulfonic acid. See generally the Journal of Pharmaceutical Science, 66, 2 (1977), which is incorporated herein by reference in its entirety.

[0120] As the term "C" is used in this article 最大 "" refers to the maximum plasma concentration of a drug after it has been administered.

[0121] As the term "T" is used in this article 最大 "" refers to the time it takes for the drug to reach its maximum plasma concentration after administration.

[0122] As used in this article, the term "AUC" refers to the area under the curve of the graph of plasma concentration versus time after drug administration.

[0123] The term "steady state" means that the amount of drug reaching the system is approximately the same as the amount leaving the system. Therefore, in a "steady state," the patient's body eliminates the drug at approximately the same rate as the rate at which it becomes available to the patient's system after being absorbed into the bloodstream.

[0124] As used herein, the terms “treated,” “treating,” or “treatment” or “therapeutic” mean to partially or completely reduce, alleviate, improve, or alleviate one or more symptoms or features of a disease, delay the onset of one or more symptoms or features of a disease, inhibit the progression of one or more symptoms or features of a disease, reduce the severity of one or more symptoms or features of a disease, reduce the incidence of one or more symptoms or features of a disease, or any combination thereof.

[0125] Generally, the term "treatment" refers to the action against an effect caused by a disease or pathological condition of concern to the subject, including (i) inhibiting the progression of the disease or pathological condition, in other words, slowing or stopping the development or progression of the disease or pathological condition, or one or more symptoms of such disorder or condition; (ii) alleviating the disease or pathological condition, in other words, causing the disease or pathological condition or its symptoms to subside; (iii) stabilizing the disease or pathological condition or one or more symptoms of such disorder or condition; (iv) reversing the disease or pathological condition or one or more symptoms of such disorder or condition to a normal state; (v) preventing the disease or pathological condition or one or more symptoms of such disorder or condition; and (vi) any combination thereof.

[0126] The term "treatment period" refers to the time during which a subject is given the drug. For example, a treatment period can range from approximately 2 weeks to approximately 2 years. In some implementations, the treatment period can be approximately 2 weeks, approximately 4 weeks, approximately 6 weeks, approximately 8 weeks, approximately 10 weeks, approximately 12 weeks, approximately 14 weeks, approximately 16 weeks, approximately 18 weeks, approximately 20 weeks, approximately 24 weeks, approximately 52 weeks, approximately 76 weeks, or approximately 104 weeks. The efficacy of the drug can be assessed by measuring certain parameters and calculating changes from baseline during the treatment period. Efficacy parameters include, but are not limited to, voiding, urge incontinence episodes, total incontinence episodes, and urgency episodes. Similarly, the safety of the drug can be assessed by measuring certain parameters and calculating changes from baseline during the treatment period. Safety parameters include, but are not limited to, systolic blood pressure, diastolic blood pressure, and heart rate.

[0127] The term "previously treated" refers to a subject with OAB who has previously received treatment for OAB or is currently receiving treatment for OAB other than vilbegaron. In some respects, the current or previous treatment is the administration of an anticholinergic drug. Examples of anticholinergic drugs include, but are not limited to, atropine, belladonna alkaloids, benztropine mesylate, clidinium, cyclopentolate, darifenacin, dicylomine, fesoterodine, flavoxate, glycopyrrolate, and homatropine hydrobromide. Hydrobromide, hyoscyamine, ipratropium, orphenadrine, oxybutynin, propantheline, scopolamine, methscopolamine, solifenacin, tiotropium, tolterodine, trihexyphenidyl, trospium, and their salts. In some embodiments, the subject has previously been treated with the anticholinergic drug tolterodine. In some aspects, the current or previous treatment is the administration of a β-3 agonist. Examples of β-3 agonists include, but are not limited to, mirabegron and soraberon. In some embodiments, the subject has previously been treated with the β-3 agonist mirabegron.

[0128] Another definition of urinary tract conditions can be found, for example, in Chapple et al. (2018) "Terminology report from the International Continence Society (ICS) Working Group on Underactive Bladder (UAB)" Neurology and Urodynamics 37:2928–2931.

[0129] Further discussions on HRQL and OAB-q can be found, for example, in Coyne et al. (2005) "The responsiveness of the Overactive Bladder Questionnaire (OAB-q)," Quality of Life Research 14: 849-855; and in Coyne et al. (2002) "Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: The OAB-q," Quality of Life Research 11: 563-574, each of which is incorporated in its entirety by reference.

[0130] Treatment This disclosure relates to a method for treating overactive bladder, the method comprising orally administering a dose of vebergellon to a subject with appropriate need, thereby maintaining the desired efficacy while minimizing undesirable side effects.

[0131] This disclosure provides a method for treating overactive bladder, comprising orally administering 75 mg of vebergellon daily to a subject with the corresponding need.

[0132] This disclosure provides a method for treating overactive bladder, comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the treatment achieves at least one of (1) to (5) a change from baseline during the treatment period: (1) The average number of urinations per 24 hours changed from approximately -1.3 times to approximately -2.3 times; (2) When the subject was a wet OAB patient, the average number of UUI episodes per 24 hours varied from about -1.5 to about -2.5; (3) The average number of urinary urgency episodes per 24 hours changed from approximately -2.2 times to approximately -3.2 times; (4) The average number of episodes of complete incontinence per 24 hours varied from approximately -1.7 to approximately -2.7; and (5) The average volume of urine per urination varied from about 18 mL to about 30 mL.

[0133] In some implementations, the treatment achieves at least two, at least three, at least four, or all five of the changes from baseline (1) to (5) during the treatment period.

[0134] In some implementations, the treatment achieved changes from baseline (1) and (2) during the treatment period, namely (1) a change in the average number of urinations per 24 hours from about -1.3 times to about -2.3 times; and (2) a change in the average number of UUI episodes per 24 hours from about -1.5 times to about -2.5 times when the subject was a wet OAB patient.

[0135] In some implementations, changes from baseline are adjusted for placebo. During placebo adjustment, changes during the treatment period can be at least one of the following: (1) The average number of urinations per 24 hours changed from about -0.1 times to about -1.0 times; (2) When the subject was a wet OAB patient, the average number of UUI episodes per 24 hours varied from about -0.1 times to about -1.1 times; (3) The average number of urinary urgency episodes per 24 hours changed from approximately -0.2 times to approximately -1.2 times; (4) The average number of episodes of complete incontinence per 24 hours varied from approximately -0.2 to approximately -1.2; and (5) The average volume of urine per urination varied from about 15 mL to about 26 mL.

[0136] In some implementations, when placebo adjustments were made during the treatment period, the treatment achieved changes (1) and (2), namely (1) a change in the average number of urinations per 24 hours from about -0.1 times to about -1.0 times; and (2) a change in the average number of UUI episodes per 24 hours from about -0.1 times to about -1.1 times when the subject was a wet OAB patient.

[0137] In some embodiments, this disclosure provides a method for maintaining daytime ambulatory blood pressure and treating overactive bladder in subjects with appropriate need, the method comprising orally administering a therapeutically effective amount of vilbegorone to the subject daily, wherein the therapeutically effective amount is about 75 mg. In some embodiments, this disclosure provides a method for treating overactive bladder in subjects with appropriate need and maintaining daytime ambulatory blood pressure, the method comprising orally administering a therapeutically effective amount of vilbegorone to the subject daily, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences a mean change in daytime ambulatory blood pressure from baseline of less than about 2.0 mmHg during the treatment period. For example, Tables 101 and 102 show mean increases in ambulatory systolic blood pressure from baseline of 0.89 mmHg and 0.19 mmHg, respectively, during a 4-week treatment period (full analysis set and per protocol set), while Table 103 shows a mean increase in ambulatory diastolic blood pressure from baseline of 0.5 mmHg during a 4-week treatment period (full analysis set). In some implementations, subjects experience the mean change in daytime ambulatory systolic blood pressure from baseline during the treatment period, wherein this mean change has an upper limit of a 90% confidence interval of less than about 3.5 mmHg compared to the mean change in subjects taking placebo. In some implementations, the upper limit of the 90% confidence interval is less than about 2.5 mmHg. In some implementations, the upper limit of the 90% confidence interval is about 2.0 mmHg. For example, Tables 101 and 102 show upper limits of the 90% confidence interval for mean daytime ambulatory systolic blood pressure of 2.49 and 2.00 (full analysis set and conforming protocol set, respectively), while Table 103 shows an upper limit of the 90% confidence interval for mean daytime ambulatory systolic blood pressure of 1.11 (full analysis set).

[0138] In some embodiments, subjects experience the mean change in diurnal ambulatory systolic blood pressure from baseline during the treatment period, wherein this mean change is less than about 1.0 mmHg compared to the mean change in subjects taking placebo, for example, about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0.4 mmHg, 0.5 mmHg, 0.6 mmHg, 0.7 mmHg, 0.8 mmHg, 0.9 mmHg, or a range between any two of the foregoing values. In some embodiments, subjects experience the mean change in diurnal ambulatory systolic blood pressure from baseline during the treatment period, wherein this mean change is less than about 0.5 mmHg compared to the mean change in subjects taking placebo, for example, about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0.4 mmHg, or a range between any two of the foregoing values. For example, as shown in Tables 101 and 102, during the 4-week treatment period, the mean change in daytime ambulatory systolic blood pressure from baseline was 0.81 mmHg and 0.41 mmHg higher than the mean change in placebo in subjects (full analysis set and conformity set, respectively).

[0139] In some implementations, subjects experience a mean change in daytime ambulatory systolic blood pressure from baseline of less than about 1.0 mmHg during the treatment period, for example, about 0.1 mmHg, 0.2 mmHg, 0.3 mmHg, 0.4 mmHg, 0.5 mmHg, 0.6 mmHg, 0.7 mmHg, 0.8 mmHg, 0.9 mmHg, or any two of the aforementioned values. In some implementations, subjects experience a mean change in daytime ambulatory systolic blood pressure from baseline of less than about 0.25 mmHg during the treatment period, for example, about 0.1 mmHg, 0.11 mmHg, 0.12 mmHg, 0.13 mmHg, 0.14 mmHg, 0.15 mmHg, 0.16 mmHg, 0.17 mmHg, 0.18 mmHg, 0.19 mmHg, 0.20 mmHg, 0.21 mmHg, 0.22 mmHg, 0.23 mmHg, 0.24 mmHg, or a range between any two of the aforementioned values. As shown in Table 102, for example, subjects experience a mean change in daytime ambulatory systolic blood pressure from baseline of about 0.19 mmHg during a 4-week treatment period.

[0140] In some implementations, subjects did not experience a greater mean change in daytime dynamic diastolic blood pressure from baseline during the treatment period than subjects taking placebo. For example, Table 103 shows that during a 4-week treatment period, the mean change in daytime dynamic diastolic blood pressure from baseline was only 0.04 mmHg lower than the mean change in placebo subjects.

[0141] In some implementations, subjects experience a mean change in diurnal dynamic diastolic blood pressure from baseline of less than about 0.75 mmHg during the treatment period, for example, about 0.1 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, 0.6 mmHg, 0.65 mmHg, 0.7 mmHg, or any two of the aforementioned values. As shown in Table 103, for example, subjects experience a mean change in diurnal dynamic diastolic blood pressure from baseline of about 0.5 mmHg during a 4-week treatment period.

[0142] In some embodiments, this disclosure provides a method for maintaining daytime ambulatory heart rate and treating overactive bladder in a subject with appropriate need, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbegorone, wherein the therapeutically effective amount is about 75 mg. In some embodiments, this disclosure provides a method for treating overactive bladder in a subject with appropriate need and maintaining daytime ambulatory heart rate, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbegorone, wherein the therapeutically effective amount is about 75 mg. In some implementations, subjects experience a mean change in daytime dynamic heart rate from baseline of less than about 1.25 bpm during the treatment period, for example, about 1.0 bpm, 1.01 bpm, 1.02 bpm, 1.03 bpm, 1.04 bpm, 1.05 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 aforementioned values. As shown in Table 103, for example, subjects experienced an average change of approximately 1.08 bpm in their daytime dynamic heart rate from baseline during the 4-week treatment period.

[0143] In some implementations, subjects experience the mean change in daytime dynamic heart rate from baseline during the treatment period, and this mean change is less than about 1.0 bpm compared to the mean change in subjects taking a placebo, 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 foregoing values. For example, Table 103 shows that during a 4-week treatment period, the mean change in daytime dynamic heart rate from baseline was 0.88 bpm higher than the mean change in subjects taking a placebo.

[0144] In some embodiments, this disclosure provides a method for maintaining 24-hour ambulatory blood pressure and treating overactive bladder in subjects with appropriate needs, the method comprising orally administering a therapeutically effective amount of vilbegorone to the subject daily. In some embodiments, this disclosure provides a method for treating overactive bladder in subjects with appropriate needs while maintaining 24-hour ambulatory blood pressure, the method comprising orally administering a therapeutically effective amount of vilbegorone to the subject daily. In some embodiments, the subject experiences a mean change in 24-hour ambulatory blood pressure from baseline of less than about 2.0 mmHg during the treatment period. For example, Table 103 shows a mean increase in 24-hour ambulatory systolic blood pressure of 0.61 mmHg from baseline and a mean increase in 24-hour ambulatory diastolic blood pressure of 0.51 mmHg from baseline during a 4-week treatment period.

[0145] In some implementations, subjects experience the mean change in 24-hour ambulatory systolic blood pressure from baseline during the treatment period, and wherein this mean change is less than about 0.75 mmHg compared to the mean change in subjects taking placebo, 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 foregoing values. For example, Table 103 shows that during a 4-week treatment period, the mean change in 24-hour ambulatory systolic blood pressure from baseline was 0.57 mmHg higher than the mean change in subjects taking placebo.

[0146] In some implementations, subjects experience a mean change in 24-hour ambulatory systolic blood pressure from baseline of less than about 0.75 mmHg during the treatment period, 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 aforementioned values. For example, Table 103 shows a mean increase in 24-hour ambulatory systolic blood pressure from baseline of 0.60 mmHg during a 4-week treatment period.

[0147] In some implementations, subjects did not experience a greater mean change in 24-hour ambulatory diastolic blood pressure from baseline during the treatment period than subjects taking placebo. For example, Table 103 shows that during a 4-week treatment period, the mean change in 24-hour ambulatory diastolic blood pressure from baseline was only 0.19 mmHg lower than the mean change in placebo subjects.

[0148] In some implementations, subjects experience a mean change of less than 0.75 mmHg from baseline in 24-hour ambulatory diastolic blood pressure during the treatment period, 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 any two of the aforementioned values. For example, Table 103 shows a mean increase of 0.51 mmHg in 24-hour ambulatory diastolic blood pressure from baseline over a 4-week treatment period.

[0149] In some embodiments, this disclosure provides a method for maintaining 24-hour ambulatory heart rate in a subject with appropriate need while simultaneously treating overactive bladder, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is about 75 mg. In some embodiments, this disclosure provides a method for treating overactive bladder in a subject with appropriate need while simultaneously maintaining 24-hour ambulatory heart rate, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is about 75 mg. In some embodiments, the subject experiences a mean change in 24-hour ambulatory heart rate from baseline of less than about 1.0 bpm during the treatment period, 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 foregoing values. As shown in Table 103, for example, the subject experiences a mean change in 24-hour ambulatory heart rate of about 0.80 bpm from baseline during a 4-week treatment period.

[0150] In some implementations, subjects experience a mean change in 24-hour ambulatory heart rate from baseline during the treatment period, wherein this mean change is less than about 1.0 bpm compared to the mean change in subjects taking a placebo, 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 aforementioned values. For example, Table 103 shows that during a 4-week treatment period, the mean change in 24-hour ambulatory heart rate from baseline was 0.96 bpm higher than the mean change in subjects taking a placebo.

[0151] In some embodiments, this disclosure provides a method for treating overactive bladder in a subject with appropriate need to maintain one or more of the following while simultaneously treating overactive bladder: 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 vilbegonone daily, wherein the therapeutically effective amount is about 75 mg. In some embodiments, this disclosure provides a method for treating overactive bladder while simultaneously 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 vilbegonone daily, wherein the therapeutically effective amount is about 75 mg.

[0152] In some implementation schemes, subjects in C 最大 The subject experiences an average change in systolic blood pressure 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, 0.45 bpm, or a range between any two of the aforementioned values. In some embodiments, the subject experiences an average change in systolic blood pressure of less than about 0.50 mmHg over 24 hours, 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 aforementioned values.

[0153] In some embodiments, the subject experiences a maximum mean change in blood pressure from baseline of less than about 2.0 mmHg within 0.5 to 6.5 hours after administration. In some embodiments, the subject experiences a maximum mean change in systolic blood pressure from baseline within 0.5 to 6.5 hours after administration, and wherein this maximum mean change is less than about 1.75 mmHg compared to the maximum mean change in a subject taking placebo, 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 foregoing values. In some implementations, the subject experiences a maximum average change in systolic blood pressure of less than about 2.0 mmHg from baseline within 0.5 to 6.5 hours after administration, such as 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 aforementioned values. In some implementations, the subject experiences the maximum mean change in diastolic blood pressure from baseline within 0.5 to 6.5 hours after administration, and wherein the maximum mean change is less than about 1.25 mmHg compared to the maximum mean change in a subject taking placebo, such as about 1.0 mmHg, 1.05 mmHg, 1.10 mmHg, 1.15 mmHg, 1.20 mmHg, or a range between any two of the foregoing values. In some implementations, the subject experiences a maximum mean change of less than 0.75 mmHg from baseline in diastolic blood pressure within 0.5 to 6.5 hours after administration, for example, approximately 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 aforementioned values.

[0154] In some implementations, the subject experiences a maximum mean change in heart rate from baseline of less than about 2.0 bpm within 0.5 to 6.5 hours after administration. In some implementations, the subject experiences a maximum mean change in heart rate from baseline within 0.5 to 6.5 hours after administration, wherein this maximum mean change is less than about 1.50 bpm compared to the maximum mean change in heart rate of subjects taking placebo, such as 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 foregoing values.

[0155] In some embodiments, this disclosure provides a method for treating overactive bladder, the method comprising orally administering, daily, a dose of vebergelon from about 75 mg to about 400 mg to a subject with appropriate need, wherein the subject experiences a smaller mean change in systolic blood pressure compared to a subject receiving a therapeutically effective dose of mirabéron. In some embodiments, the increase in the mean change in systolic blood pressure experienced by a subject receiving vebergelon is smaller than that experienced by a subject receiving a therapeutically effective dose of mirabéron, from about 1.5 mmHg to about 4.0 mmHg.

[0156] In some embodiments, this disclosure provides a method for treating overactive bladder, the method comprising orally administering, daily, a dose of vebergelon from about 75 mg to about 400 mg to a subject with appropriate need, wherein the subject experiences a smaller 24-hour mean change in systolic blood pressure compared to a subject receiving a therapeutically effective dose of mirabéron. In some embodiments, the increase in the 24-hour mean change in systolic blood pressure experienced by a subject receiving vebergelon is smaller than that experienced by a subject receiving a therapeutically effective dose of mirabéron, from about 1.0 mmHg to about 10.0 mmHg.

[0157] In some embodiments, this disclosure provides a method for treating overactive bladder, the method comprising orally administering, daily, a dose of vebegrin from about 75 mg to about 400 mg to a subject with appropriate need, wherein the subject experiences a smaller maximum mean increase in heart rate compared to a subject receiving a therapeutically effective dose of mirabéron. In some embodiments, the increase in the maximum mean increase in heart rate experienced by a subject receiving vebegrin is smaller than that experienced by a subject receiving a therapeutically effective dose of mirabéron, from about 2 bpm to about 14 bpm.

[0158] In some embodiments, the daily dose of vebegrin is from about 75 mg to about 200 mg. In some embodiments, the daily dose of vebegrin is less than about 400 mg or less than about 200 mg. In some embodiments, the daily dose of vebegrin is greater than about 75 mg.

[0159] In some embodiments, the therapeutically effective dose of mirabezon is from about 50 mg to about 200 mg. In some embodiments, the therapeutically effective dose of mirabezon is 50 mg, 100 mg, or 200 mg.

[0160] In some embodiments, this disclosure provides a method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with an appropriate need, wherein the subject has a weight greater than about 65 kg, and wherein the subject experiences a similar mean change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0161] In some embodiments, this disclosure provides a method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject is at or over approximately 67 years of age, and wherein the subject experiences a similar mean change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0162] In some embodiments, this disclosure provides a method for treating overactive bladder in a subject with bladder outlet obstruction (BOO), the method comprising orally administering 75 mg of vebergellon daily to the subject who has the appropriate need. 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 the subject for signs and / or symptoms of urinary retention.

[0163] In various embodiments related to ambulatory blood pressure and heart rate, the subjects are humans. In some embodiments, the human is male. In some embodiments, the human is female. In some embodiments, the human weighs more than about 65 kg. In some embodiments, the human weighs less than about 65 kg. In some embodiments, the human is at or above about 67 years of age. In some embodiments, the human is between about 67 and about 75 years of age. In some embodiments, the human is below about 67 years of age.

[0164] In various implementations involving ambulatory blood pressure and heart rate monitoring, the human is either predisposed to hypertension or at risk of developing hypertension. In other various implementations involving ambulatory blood pressure and heart rate monitoring, the human is predisposed to hypertension or at risk of developing hypertension. As used herein, the terms "predisposed to hypertension" or "hypertension" refer to a subject with hypertension or a subject taking antihypertensive medication. Hypertension generally means a systolic blood pressure (SBP) of approximately 139 mmHg or higher, a diastolic blood pressure (DBP) of approximately 89 mmHg or higher, or both.

[0165] In some implementations, the human patient has chronic kidney disease. In some implementations, the chronic kidney disease is stage 1, 2, 3a, or 3b. In some implementations, the human patient has a blood flow rate greater than approximately 30 mL / min / 1.73 m³ / min. 2 The estimated glomerular filtration rate (eGFR). In some implementations, the eGFR is selected from approximately 30 mL / min / 1.73 m 2 To approximately 44 mL / min / 1.73 m 2 Approximately 45 mL / min / 1.73 m 2 To approximately 59 mL / min / 1.73 m 2 Approximately 60 mL / min / 1.73 m 2 To approximately 89 mL / min / 1.73 m 2 or approximately 90 mL / min / 1.73 m 2 Or higher. In some implementations, eGFR is greater than approximately 72 mL / min / 1.73 m 2 eGFR less than approximately 72 mL / min / 1.73 m 2 .

[0166] This disclosure also provides a method for reducing the average number of urinations per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects who require it during the treatment period.

[0167] This disclosure also provides a method for treating overactive bladder and reducing the average number of urinations per 24 hours in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily during the treatment period.

[0168] This disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects in need during the treatment period.

[0169] This disclosure also provides a method for treating overactive bladder and reducing the average number of UUI episodes per 24 hours in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily during the treatment period.

[0170] This disclosure also provides a method for reducing the average number of urinary urgency episodes per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects who require it during the treatment period.

[0171] This disclosure also provides a method for treating overactive bladder and reducing the average number of urinary urgency episodes per 24 hours in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily during the treatment period.

[0172] This disclosure also provides a method for reducing the average number of episodes of complete incontinence per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects who require it during the treatment period.

[0173] This disclosure also provides a method for treating overactive bladder and reducing the average number of episodes of complete incontinence per 24 hours in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily during the treatment period.

[0174] This disclosure also provides a method for increasing the average volume of urine per urination in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon to subjects who require it daily during the treatment period.

[0175] This disclosure also provides a method for treating overactive bladder and increasing the average volume of urine per void in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily during the treatment period.

[0176] This disclosure provides a method for treating overactive bladder, comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the treatment achieves at least one of variations (1) to (5) during a 12-week treatment period: (1) A reduction in the average number of urinations per 24 hours that is greater than or equal to the reduction achieved with tolterodine extended-release (ER) 4 mg; (2) When the subject was a wet OAB patient, the reduction in the average number of UUI attacks per 24 hours was greater than or equal to the reduction achieved with tolterodine ER 4 mg; (3) The reduction in the average number of urinary urgency episodes per 24 hours is greater than or equal to the reduction achieved with tolterodine ER 4 mg; (4) A reduction in the average number of episodes of complete incontinence per 24 hours, greater than or equal to the reduction achieved with tolterodine ER 4 mg; and (5) The increase in average volume of each urination is greater than or equal to the increase achieved with tolterodine ER 4 mg.

[0177] In some embodiments, the change achieved by treatment in at least one of variations (1) to (5) is greater than the change achieved with tolterodine ER 4 mg. In some embodiments, the change achieved by treatment in at least one of variations (1) to (5) is equal to the change achieved with tolterodine ER 4 mg.

[0178] In some embodiments, the changes achieved in variations (2) and (4) are greater than those achieved with tolterodine ER 4 mg and greater than those achieved with vebergellon 50 mg or 100 mg. In some embodiments, the changes achieved in variation (1) are greater than those achieved with tolterodine ER 4 mg, but less than those achieved with vebergellon 50 mg or 100 mg. In some embodiments, the changes achieved in variation (5) are greater than those achieved with tolterodine ER 4 mg, but less than those achieved with vebergellon 50 mg or 100 mg.

[0179] In some implementations, the treatment achieved at least one of variations (1) to (5) during the 12-week treatment period: (1) The reduction in the average number of urinations per 24 hours was greater than that achieved with the same dose of mirabezon; (2) When the subject was a wet OAB patient, the reduction in the average number of UUI attacks per 24 hours was greater than that achieved with the same dose of mirabezon; (3) The reduction in the average number of urinary urgency episodes per 24 hours was greater than that achieved with the same dose of mirabezon; (4) The reduction in the average number of episodes of complete incontinence per 24 hours was greater than that achieved with an equivalent dose of mirabezon; and (5) The increase in average volume of urine per urination is greater than the increase achieved with the same dose of mirabezon.

[0180] In some implementations, the treatment achieved at least one of variations (1) to (5) during the 12-week treatment period: (1) A reduction in the average number of urinations per 24 hours that is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon; (2) When the subject was a wet OAB patient, the reduction in the average number of UUI attacks per 24 hours was greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon; (3) A reduction in the average number of urinary urgency episodes per 24 hours, which is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon; (4) A reduction in the average number of episodes of complete incontinence per 24 hours, greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon; and (5) The increase in average volume of urine per urination is greater than or equal to the increase achieved with 50 mg or 100 mg of vebergron.

[0181] In some implementations, the treatment achieved in variations (2) and (4) is greater than the variation achieved with 50 mg or 100 mg of vebergellon.

[0182] In some implementations, the treatment achieved at least one of variations (1) or (5) during the 12-week treatment period: (1) The reduction in the average number of urinations per 24 hours was less than that achieved with 50 mg or 100 mg of vebergellon; or (5) The increase in average volume of urine per urination was greater than the increase achieved with 50 mg or 100 mg of vebergellon.

[0183] This disclosure also provides a method for treating overactive bladder and reducing the average number of urinations per 24 hours in subjects with appropriate needs, the method comprising orally administering 75 mg of vebergellon to the subject daily for a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0184] This disclosure also provides a method for reducing the average number of urinations per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects in need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0185] In some embodiments, the subject is a human being 65 years of age or older. In some embodiments, the reduction or decrease in the average number of urinations in the subject over a 24-hour period is between approximately 1.0-fold and approximately 2.5-fold compared to a reduction or decrease achieved with a placebo, for example, approximately 1.0-fold, 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, or a range between any two of the foregoing values. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 1.5-fold and approximately 2.0-fold compared to a reduction or decrease achieved with a placebo. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 0.5 times and approximately 2.0 times that achieved with tolterodine extended-release (ER) 4 mg, for example, between approximately 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, or any two of the foregoing values. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 1.0 times and approximately 1.5 times that achieved with tolterodine extended-release (ER) 4 mg.

[0186] In some embodiments, this disclosure provides a method for reducing the average number of urinary urgency episodes per 24 hours from about -2.2 to about -3.5 times in a subject of appropriate need who is 65 years of age or older, the method comprising orally administering to the subject a therapeutically effective amount of vilbegon or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 75 mg per day. In some embodiments, this disclosure provides a method for treating overactive bladder while reducing the average number of urinary urgency episodes per 24 hours from about -2.2 to about -3.5 times in a subject of appropriate need who is 65 years of age or older, the method comprising orally administering to the subject a therapeutically effective amount of vilbegon or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 75 mg per day. In some embodiments, the subject achieves a change in the average number of urination episodes per 24 hours from about -1.3 to about -2.5 times; and / or, when the subject is a wet OAB patient, a change in the average number of urination episodes per 24 hours from about -1.5 to about -2.5 times. In some embodiments, the human is over 75 years of age.

[0187] In some implementations, the subject received an anticholinergic drug for up to 12 months prior to vilbegon administration. In some implementations, the reduction or decrease in the average number of urinations over a 24-hour period was approximately 1.0 to approximately 2.5 times that achieved with placebo, for example, approximately 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 times, or a range between any two of the foregoing values. In some implementations, the reduction or decrease in the average number of urinations over a 24-hour period was approximately 1.5 to approximately 2.0 times that achieved with placebo. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 0.5 times and approximately 2.0 times that achieved with tolterodine extended-release (ER) 4 mg, for example, between approximately 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, or any two of the foregoing values. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 1.0 times and approximately 1.5 times that achieved with tolterodine extended-release (ER) 4 mg.

[0188] In some implementations, the subject received a β-3 agonist other than vilbegan for up to 12 months prior to vilbegan administration. In some implementations, the average number of urinations over a 24-hour period was between approximately 1 and approximately 10 fewer than the average number of urinations in subjects receiving a placebo, for example, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times, or a range between any two of the foregoing values. In some implementations, the average number of urinations over a 24-hour period was between approximately 1 and approximately 4 fewer than the average number of urinations in subjects receiving a placebo. In some embodiments, the reduction or decrease in the average number of urinations over a 24-hour period is between approximately 1.0 and approximately 3.0 times greater than that achieved with tolterodine extended-release (ER) 4 mg, for example, approximately 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 times, or any two of the foregoing values. In some embodiments, the reduction or decrease 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.

[0189] This disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects in need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0190] In some embodiments, the subjects are humans aged 65 years or older. In some embodiments, the reduction or decrease in the average number of UUI episodes in the subjects over a 24-hour period is between approximately 0.5 times and approximately 2.0 times that achieved with placebo, for example, approximately 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, or a range between any two of the foregoing values. In some embodiments, the reduction or decrease in the average number of UUI episodes in the subjects over a 24-hour period is between approximately 1.25 times and approximately 1.75 times that achieved with placebo.

[0191] In some implementations, the subject received an anticholinergic drug for up to 12 months prior to vilbegorone administration. In some implementations, the reduction or decrease in the average number of UUI attacks over a 24-hour time period was approximately 1.0 to approximately 2.5 times that achieved with placebo, for example, approximately 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 times, or a range between any two of the foregoing values. In some implementations, the reduction or decrease in the average number of UUI attacks over a 24-hour time period was approximately 1.5 to approximately 2.0 times that achieved with placebo. In some embodiments, the reduction or decrease in the average number of UUI attacks over a 24-hour period is between approximately 0.5 times and approximately 2.0 times that achieved with tolterodine extended-release (ER) 4 mg, for example, between approximately 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, or any two of the foregoing values. In some embodiments, the reduction or decrease in the average number of UUI attacks over a 24-hour period is between approximately 1.25 times and approximately 1.75 times that achieved with tolterodine extended-release (ER) 4 mg.

[0192] In some implementations, the subject received a β-3 agonist other than vilbegan for up to 12 months prior to vilbegan administration. In some implementations, the reduction or decrease in the average number of UUI seizures over a 24-hour time period was approximately 2 to approximately 10 times that achieved with placebo, for example, approximately 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, or a range between any two of the foregoing values. In some implementations, the reduction or decrease in the average number of UUI seizures over a 24-hour time period was approximately 4 to approximately 6 times that achieved with placebo. In some implementations, the reduction or decrease in the average number of UUI attacks over a 24-hour period is between approximately 0.5 times and approximately 3.5 times that achieved with tolterodine extended-release (ER) 4 mg, for example, approximately 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, or a range between any two of the aforementioned values. In some implementations, the reduction or decrease in the average number of UUI attacks over a 24-hour period is between approximately 1.5 and approximately 3.0 times that achieved with tolterodine extended-release (ER) 4 mg.

[0193] This disclosure also provides a method for reducing the average number of urinary urgency episodes per 24 hours in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate need while reducing the average number of urinary urgency episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon to the subject with appropriate need daily for a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0194] This disclosure also provides a method for reducing the average number of total incontinence episodes per 24 hours in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate needs while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon orally to the subject with appropriate needs daily for a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER). This disclosure also provides a method for increasing the average volume of urine per void in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate needs while increasing the average volume of urine per void, the method comprising orally administering 75 mg of vebergellon orally to the subject with appropriate needs daily for a 12-week treatment period, wherein the increase is greater than or equal to the increase achieved with 4 mg of tolterodine extended-release (ER).

[0195] In some implementations, the reduction in the average number of urinations per 24 hours, the average number of UUI episodes per 24 hours, the average number of urinary urgency episodes per 24 hours, or the average number of total incontinence episodes per 24 hours is greater than the reduction achieved with tolterodine ER 4 mg. In some implementations, the reduction in the average number of urinations per 24 hours, the average number of UUI episodes per 24 hours, the average number of urinary urgency episodes per 24 hours, or the average number of total incontinence episodes per 24 hours is equal to the reduction achieved with tolterodine ER 4 mg.

[0196] In some embodiments, this disclosure provides a method for treating overactive bladder while reducing the average number of uncontrolled intrabladder (UUI) episodes in a subject (where the subject is female). In some embodiments, the reduction in UUI episodes in female subjects is greater than the reduction achieved in male subjects.

[0197] In some implementations, the increase in average volume per urination is greater than the increase achieved with tolterodine ER 4 mg. In some implementations, the increase in average volume per urination is equal to the increase achieved with tolterodine ER 4 mg.

[0198] This disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of urinations per 24 hours, the method comprising orally administering 75 mg of vebergellon to the subject with appropriate need daily for a 12-week treatment period, wherein the reduction is greater than that achieved with an equivalent dose of mirabezon.

[0199] This disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than that achieved with an equivalent dose of mirabezon.

[0200] This disclosure also provides a method for reducing the average number of urinary urgency episodes per 24 hours in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate need while reducing the average number of urinary urgency episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subjects with appropriate need during a 12-week treatment period, wherein the reduction is greater than that achieved with an equivalent dose of mirabezon.

[0201] This disclosure also provides a method for reducing the average number of total incontinence episodes per 24 hours in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate need while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vebergelone daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than that achieved with an equivalent dose of mirabezone.

[0202] This disclosure also provides a method for increasing the average volume of urine per void in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while increasing the average volume of urine per void, the method comprising orally administering 75 mg of vebergellon to the subject with appropriate need daily for a 12-week treatment period, wherein the increase is greater than that achieved with an equivalent dose of mirabezon.

[0203] This disclosure also provides a method for reducing the average number of urinations per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of urinations per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon.

[0204] This disclosure also provides a method for reducing the average number of UUI episodes per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of UUI episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon.

[0205] This disclosure also provides a method for reducing the average number of urinary urgency episodes per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of urinary urgency episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon.

[0206] This disclosure also provides a method for reducing the average number of total incontinence episodes per 24 hours in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while reducing the average number of total incontinence episodes per 24 hours, the method comprising orally administering 75 mg of vebergellon daily to the subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 50 mg or 100 mg of vebergellon.

[0207] This disclosure also provides a method for increasing the average volume of urine per void in a subject with overactive bladder, or a method for treating overactive bladder in a subject with appropriate need while increasing the average volume of urine per void, the method comprising orally administering 75 mg of vebergellon to the subject with appropriate need daily for a 12-week treatment period, wherein the increase is greater than or equal to the increase achieved with 50 mg or 100 mg of vebergellon.

[0208] In some implementations, the subject is treated with vilbeganone for a duration of treatment, or during a treatment period, wherein the treatment period is selected from the group consisting of approximately 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, and 52 weeks. In some implementations, the treatment period is a range between any of these number of weeks. In some implementations, the treatment period is selected from approximately 2 weeks, approximately 4 weeks, approximately 8 weeks, approximately 12 weeks, or approximately 52 weeks. In some implementations, the treatment period is approximately 12 weeks. In some implementations, the treatment period is approximately 52 weeks.

[0209] This disclosure provides a method for reducing coping behaviors in subjects with symptoms of overactive bladder, or a method for improving coping domain scores in subjects based on the OAB-q LF (OAB-q Long Scale). This disclosure also provides a method for treating overactive bladder in subjects with corresponding needs while simultaneously reducing coping behaviors or simultaneously improving coping domain scores in subjects based on the OAB-q LF (OAB-q Long Scale). The method includes oral administration of a therapeutically effective amount of vebergellon to a subject with corresponding needs daily during the treatment period, wherein the therapeutically effective amount is approximately 75 mg, and wherein the subject's coping behaviors are reduced compared to subjects receiving a placebo. The OAB-q LF coping domain score assesses certain aspects of OAB that are measurable tasks and important to the patient. In some embodiments, coping behaviors or tasks include, but are not limited to, planning a route to the restroom, carefully planning your commute, planning activities more carefully, reducing physical activity, locating the nearest restroom upon arrival at a new location, adjusting travel plans, avoiding activities far from the restroom, and discomfort when traveling with others. In some embodiments, the subject's coping behavior is reduced compared to before the subject started treatment with vebergellon (i.e., baseline), or compared to the coping behavior of a subject receiving placebo, tolterodine extended-release (ER) 4 mg, or another compound used to treat OAB. In some embodiments, the subject's coping domain score is improved compared to before the subject started treatment with vebergellon. In some embodiments, the subject's coping domain score is improved compared to a subject receiving placebo, tolterodine extended-release (ER) 4 mg, or another compound used to treat OAB. In some embodiments, this disclosure provides a method for improving the coping domain score of a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need during the treatment period. In some embodiments, the improvement in the coping domain score is greater than the improvement achieved with tolterodine extended-release (ER) 4 mg. In some embodiments, the improvement in the coping domain score is greater than the improvement achieved with placebo. In some embodiments, the improvement is measured from baseline. In some implementations, subjects receiving vebergelone showed an improvement of at least approximately 3.2 points in their coping domain scores compared to subjects receiving placebo. For example, as shown in Table 59, subjects treated with vebergelone during the 12-week treatment period experienced a 3.6-point improvement in their coping domain scores compared to subjects receiving placebo.

[0210] This disclosure also provides a method for improving sleep in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate need while simultaneously improving sleep, the method comprising orally administering 75 mg of vebegrin to the subject with appropriate need daily during the treatment period. In some embodiments, the improvement in sleep is greater than that achieved with 4 mg of tolterodine extended-release (ER). In some embodiments, the improvement in sleep is greater than that achieved with placebo. In some embodiments, the improvement is measured from baseline. In some embodiments, the sleep score of subjects receiving vebegrin improved by at least about 2.6 points compared to subjects receiving placebo. For example, as shown in Table 60, subjects treated with vebegrin experienced a 4.5-point improvement in sleep score over a 12-week treatment period compared to subjects receiving placebo.

[0211] This disclosure also provides a method for improving health-related quality of life (HRQL) in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate needs while simultaneously improving HRQL, the method comprising orally administering 75 mg of vebegrinone daily to the subject with appropriate needs during the treatment period. In some embodiments, the improvement in HRQL is greater than that achieved with 4 mg of tolterodine extended-release (ER). In some embodiments, the improvement in HRQL is greater than that achieved with placebo. In some embodiments, the HRQL includes one or more subscales selected from coping, anxiety, sleep, or social interaction. In some embodiments, the improvement in HRQL is measured from baseline. In some embodiments, subjects receiving vebegrinone showed an improvement in total HRQL score of at least about 3.8 points compared to subjects receiving placebo. For example, as shown in Table 60, subjects treated with vebegrinone during a 12-week treatment period experienced a 3.8-point improvement in total HRQL score compared to subjects receiving placebo.

[0212] This disclosure also provides a method for reducing symptom distress in subjects with overactive bladder, or a method for treating overactive bladder in subjects with appropriate need while simultaneously reducing symptom distress, the method comprising orally administering 75 mg of vebegrin to the subject with appropriate need daily during the treatment period. In some embodiments, the reduction in symptom distress is greater than that achieved with 4 mg of tolterodine extended-release (ER). 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 score of subjects receiving vebegrin is reduced by at least about -5.0 points compared to subjects receiving placebo. For example, as shown in Table 60, the symptom distress score of subjects treated with vebegrin during a 12-week treatment period was reduced by 6.9 points more than that of subjects receiving placebo.

[0213] In some implementations, the subjects had symptoms of urge incontinence, urinary urgency, and urinary frequency.

[0214] In some implementations, the subject has one or more symptoms of urgency urinary incontinence, urgency, frequency, and nocturia.

[0215] In some implementations, the subject is a mammal. In some implementations, the subject is a human or an animal. In some implementations, the subject is a human.

[0216] In some embodiments, the subject is over 18 years of age. In some embodiments, the subject is under approximately 18 years of age. In some embodiments, the subject is between approximately 6 and approximately 18 years of age, approximately 6 and approximately 12 years of age, or approximately 12 and approximately 18 years of age. In some embodiments, the subject is over approximately 20 years of age. In some embodiments, the subject is over approximately 25 years of age. In some embodiments, the subject is over approximately 30 years of age. In some embodiments, the subject is over approximately 35 years of age. In some embodiments, the subject is over 40 years of age. In some embodiments, the subject is over 45 years of age. In some embodiments, the subject is over 50 years of age. In some embodiments, the subject is over 55 years of age. In some embodiments, the subject is over 60 years of age. In some embodiments, the subject is at or over 65 years of age. In some embodiments, the subject is over 70 years of age. In some embodiments, the subject is over 75 years of age.

[0217] In some embodiments, the method includes crushing a drug unit dose composition containing vilbergerone prior to administration to a subject. In some embodiments, the crushed drug unit dose containing vilbergerone is administered orally to the subject.

[0218] In some implementations, the subject has kidney damage or is at risk of developing kidney damage. In some implementations, the subject has mild, moderate, or severe kidney damage.

[0219] In some implementations, the subject has received prior OAB therapy. In other implementations, the subject has not received prior OAB therapy.

[0220] In some embodiments, vebegelone is administered together with a second agent, which includes, for example, any agent described in this application. In some embodiments, vebegelone is administered concurrently with the second agent. In some embodiments, vebegelone and the second agent are administered sequentially. In some embodiments, vebegelone is administered before and / or after the second agent. The embodiments described below include such sequential administration.

[0221] In some implementations, the subject has been previously exposed to a β3-AR agonist, such as miraberione or sorabelon, either by receiving, taking, or otherwise.

[0222] In some implementations, the subject has been previously exposed to anticholinergic drugs, either by receiving, taking, or otherwise.

[0223] In some embodiments, this disclosure provides a method for treating overactive bladder in a treated subject with appropriate need, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is approximately 75 mg, and wherein after administering vilbeganol to the subject during the treatment period: a. The subjects experienced a decrease in the average number of urinations over a 24-hour period that was approximately 1.5 to 10 times greater than the decrease in the average number of urinations among subjects receiving a placebo; or b. The reduction in the average number of urge incontinence (UUI) episodes per 24 hours was approximately 1.7 to approximately 6 times that of the placebo-treated subjects.

[0224] In some implementations, the reduction in the average number of urinations in a subject over a 24-hour period is between approximately 1.5 and approximately 9 times, between approximately 1.5 and approximately 8 times, between approximately 1.5 and approximately 7 times, between approximately 1.5 and approximately 6 times, between approximately 1.5 and approximately 5 times, between approximately 1.5 and approximately 4 times, or between approximately 1.5 and approximately 3 times, compared to the reduction in the average number of urinations in a placebo-receiving subject over a 24-hour period. In some implementations, the reduction in the average number of urinations in a subject over a 24-hour period is between approximately 2 and approximately 4 times, compared to the reduction in the average number of urinations in a placebo-receiving subject. In some implementations, the reduction in the average number of urinations in a subject over a 24-hour period is between approximately 2 and approximately 3 times, compared to the reduction in the average number of urinations in a placebo-receiving subject.

[0225] In some implementations, the reduction in the average number of urge incontinence (UUI) episodes per 24 hours in the subject is approximately 1 to 2 times, approximately 1.1 to 1.9 times, approximately 1.3 to 1.8 times, approximately 1.4 to 1.8 times, or approximately 1.5 to 1.8 times compared to the reduction in the average number of urge incontinence (UUI) episodes per 24 hours in the subject, ...

[0226] In some implementations, the reduction in the average number of urge incontinence (UUI) episodes per 24 hours in subjects is approximately 5 to 6.5 times, approximately 5.1 to 6.4 times, approximately 5.2 to 6.3 times, approximately 5.3 to 6.4 times, approximately 5.4 to 6.1 times, or approximately 5.5 to 6.2 times compared to subjects treated with placebo. In some implementations, the reduction in the average number of urge incontinence (UUI) episodes per 24 hours in subjects is approximately 6 times compared to subjects treated with placebo.

[0227] In some implementations, the average number of urinations per 24 hours decreased by approximately -2.0 to approximately -4.0, approximately -1.9 to approximately -3.9, approximately -1.8 to approximately -3.8, approximately -1.7 to approximately -3.7, approximately -1.6 to approximately -3.6, approximately -1.5 to approximately -3.5, approximately -1.4 to approximately -3.4, approximately -1.3 to approximately -3.3, approximately -1.2 to approximately -3.2, approximately -1.1 to approximately -3.1, or approximately -1.0 to approximately -3.0. In some implementations, the average number of urinations per 24 hours decreased by approximately -1.3 to approximately -2.5.

[0228] In some implementations, the average number of urge incontinence (UUI) episodes per 24 hours decreased by approximately -2.0 to approximately -4.0, approximately -1.9 to approximately -3.9, approximately -1.8 to approximately -3.8, approximately -1.7 to approximately -3.7, approximately -1.6 to approximately -3.6, approximately -1.5 to approximately -3.5, approximately -1.4 to approximately -3.4, approximately -1.3 to approximately -3.3, approximately -1.2 to approximately -3.2, approximately -1.1 to approximately -3.1, or approximately -1.0 to approximately -3.0.

[0229] In some implementations, following administration of vilbegon to subjects during the treatment period, the average number of urinations over a 24-hour period decreased by approximately -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, and -2.8 times. The average number of urinations decreased from approximately -1.0 to -2.9 or -3.0 times per 24 hours, and the average number of UUI episodes decreased by approximately -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 times per 24 hours. In some implementations, the average number of urinations decreased from approximately -1.3 to approximately -2.5 times, and the average number of UUI episodes decreased from approximately -1.5 to approximately -2.5 times per 24 hours.

[0230] In some implementations, after administering vilbegon to subjects during the treatment period, the average number of urinations in subjects over a 24-hour period decreased by between approximately 1.5 and approximately 10 times compared to the average number of urinations in subjects receiving a placebo, and the average number of UUI episodes per 24 hours decreased by approximately -1.5 to approximately -2.5 times.

[0231] In some implementations, after administration of vilbegon to subjects during the treatment period, the average number of urinary urgency episodes per 24 hours decreased by approximately -1.5 to approximately -4.2, approximately -1.6 to approximately -4.1, approximately -1.7 to approximately -4.0, approximately -1.8 to approximately -3.9, approximately -1.9 to approximately -3.8, approximately -2.0 to approximately -3.7, approximately -2.1 to approximately -3.6, or approximately -2.2 to approximately -3.5.

[0232] In some implementations, following administration of vilbegon to subjects during the treatment period, the mean number of total incontinence episodes decreased by approximately -1.0 to approximately -3.0, approximately -1.1 to approximately -2.9, approximately -1.2 to approximately -2.8, approximately -1.3 to approximately -2.7, approximately -1.4 to approximately -2.6, approximately -1.5 to approximately -2.7, approximately -1.7 to approximately -2.7, approximately -1.6 to approximately -2.6, or approximately -1.5 to approximately -2.5. In some implementations, the mean number of total incontinence episodes decreased by approximately -1.7 to approximately -2.7.

[0233] In some embodiments, following administration of vilbegon to the subject during the treatment period, the average volume of each urination increases by approximately 10 mL to approximately 40 mL, approximately 11 mL to approximately 39 mL, approximately 12 mL to approximately 38 mL, approximately 13 mL to approximately 37 mL, approximately 14 mL to approximately 36 mL, approximately 15 mL to approximately 35 mL, approximately 16 mL to approximately 34 mL, approximately 17 mL to approximately 33 mL, approximately 18 mL to approximately 30 mL, approximately 19 mL to approximately 29 mL, approximately 20 mL to approximately 28 mL, or approximately 21 mL to approximately 27 mL. In some embodiments, the average volume of each urination increases by approximately 18 mL to approximately 30 mL.

[0234] In some implementations, the treated subject had previously been treated with an anticholinergic drug. In some implementations, the treated subject had been treated with an anticholinergic drug within 12 months prior to treatment with vilbeganone. In some implementations, the treated subject had been treated with an anticholinergic drug for more than 12 months prior to treatment with vilbeganone. In some implementations, the treated subject received anticholinergic drug concurrently with treatment with vilbeganone.

[0235] In some embodiments, the treated subject had previously been treated with a β-3 agonist other than vilbegrin. In some embodiments, the treated subject had been treated with a β-3 agonist other than vilbegrin within 12 months prior to vilbegrin treatment. In some embodiments, the treated subject had been treated with a β-3 agonist other than vilbegrin for more than 12 months prior to vilbegrin treatment. In some embodiments, the treated subject was treated with a β-3 agonist other than vilbegrin concurrently with vilbegrin treatment. In some embodiments, the β-3 agonist is mirabegron. In some embodiments, the β-3 agonist is sorapegron.

[0236] In some implementations, subjects are concurrently exposed to, orally administered or otherwise exposed to, cytochrome P450 inhibitors, such as CYP3A inhibitors, and drugs that serve as substrates for the following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

[0237] In some implementations, subjects are concurrently exposed to, take or otherwise receive a CYP2D6 substrate.

[0238] CYP 2D6 substrates include, but are not limited to, imipramine, amitriptyline, fluoxetine, paroxetine, fluvoxamine, venlafaxine, duloxetine, mianserin, mirtazapine, opioids, codeine, morphine, tramadol, O-demethyltramadol, N,O-didemethyltramadol, oxycodone, hydrocodone, hydromorphone, tapentadol, haloperidol, risperidone, perphenazine, thioridazine, zuclopenthixol, and iloperidol. idone), aripiprazole, chlorpromazine, levomepromazine, remoxipride, minaprine, tamoxifen, hydroxytamoxifen, beta-blockers, metoprolol, timolol, alprenolol, carvedilol, bufuralol, nebivolol, propranolol olol), debrisoquine, flecainide, propafenone, encainide, mexiletine, lidocaine, sparteine, ondansetron, donepezil, phenformin, tropisetron, amphetamine, methoxyamphetamine, dextromethorphan. The following drugs are listed: xtromethamphetamine, atomoxetine, chlorphenamine, dexfenfluramine, dextromethorphan, dextrophenorphan, metoclopramide, perhexiline, phenacetin, promethazine, m-tyramine, warfarin, tolterodine, and p-tyramine.

[0239] In some implementations, subjects are concurrently exposed to, orally administered, or otherwise exposed to P-glycoprotein inhibitors.

[0240] CYP3A / P-glycoprotein inhibitors include, but are not limited to, amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, amphetamine, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, titranavir and ritonavir, verapamil, curcumin, cyclosporine A, eltrombopag, atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin (e.g., single dose), simeprevir, and p-aminohippuric acid. acid)(PAH)(b), probenecid, teriflunomide, cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim and vandetanib.

[0241] In some implementations, subjects are concurrently exposed to, orally ingested, or otherwise exposed to muscarinic receptor antagonists.

[0242] Muscarinic receptor antagonists include, but are not limited to, scopolamine, atropine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, bicyclic amine, flavonoids, oxybutynin, tiotropine, cyclopentolate, atropine methonitrate, benzhexol, tolterodine, solifenacin, dafenapyr, benztropine, mebeverine, procyclidine, and aclidinium bromide.

[0243] In some implementations, subjects are given approximately 75 mg of vebergellon daily, and are concurrently exposed to, orally or otherwise exposed to a muscarinic receptor antagonist.

[0244] In some implementations, subjects are given approximately 75 mg of vebergellon daily, and concurrently receive, take or otherwise be exposed to a CYP3A inhibitor.

[0245] In some implementations, subjects are administered approximately 75 mg of vebergellon daily, and concurrently receive, take or otherwise be exposed to a P-glycoprotein inhibitor.

[0246] In some implementations, the subjects were not concurrently receiving, taking, or otherwise exposed to a beta-blocker.

[0247] In some implementation schemes, the subjects were not concurrently receiving, taking, or otherwise exposed to amlodipine.

[0248] In some implementations, vebergellon is administered with meals, within 60 minutes after a meal, or within 2 hours after a meal.

[0249] In some implementations, vebegrin is administered on an empty stomach or before a meal. In some implementations, vebegrin is administered more than two hours before a meal. In some implementations, vebegrin is administered regardless of whether the subject has eaten.

[0250] In some implementations, vilbergerone is applied once daily, twice daily, or three times daily. In some implementations, vilbergerone is applied once daily.

[0251] In subjects taking vebergellon, there were no significant differences in changes in blood pressure (BP) and heart rate (HR) from baseline compared to subjects taking placebo. In some implementations, subjects experienced the mean maximum change in systolic blood pressure (SBP) from baseline during the treatment period (e.g., 8 or 12 weeks), and this mean maximum change was 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 compared to the mean maximum change in placebo subjects.

[0252] In some implementations, subjects are administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) is less than 2 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo. In some implementations, subjects are administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) is less than 1 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo.

[0253] In some implementations, subjects were over 65 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 2 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo. In some implementations, subjects were over 65 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 1 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo.

[0254] In some implementations, subjects were over 45 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 2 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo. In some implementations, subjects were over 45 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in SBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 1 mmHg compared to the mean maximum change in SBP experienced by subjects taking placebo.

[0255] In some implementations, subjects experience the mean maximum change in diastolic blood pressure (DBP) from baseline during the treatment period (e.g., 8 or 12 weeks), and this mean 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 compared to the mean maximum change in placebo subjects.

[0256] In some implementations, subjects are administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) is less than 2 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo. In some implementations, subjects are administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) is less than 1 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo.

[0257] In some implementations, subjects were over 65 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 2 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo. In some implementations, subjects were over 65 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 1 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo.

[0258] In some implementations, subjects were over 45 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 2 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo. In some implementations, subjects were over 45 years of age and were administered approximately 75 mg of vebergellon daily, and the mean maximum change in DBP from baseline experienced during the treatment period (e.g., 8 or 12 weeks) was less than 1 mmHg compared to the mean maximum change in DBP experienced by subjects taking placebo.

[0259] In some implementations, subjects were over 45 years of age, were administered approximately 75 mg of vebergellon once daily, and experienced a mean maximum change in DBP from baseline during the treatment period (e.g., 8 or 12 weeks) that was less than 1 mmHg compared to the mean maximum change in SBP ...

[0260] In some implementations, subjects were over 65 years of age, were administered approximately 75 mg of vebergellon once daily, and experienced a mean maximum change in DBP from baseline during the treatment period (e.g., 8 or 12 weeks) that was less than 1 mmHg compared to the mean maximum change in SBP ...

[0261] In some implementations, subjects experienced the maximum mean change in systolic blood pressure (SBP) from baseline 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 during the treatment period (e.g., 8 or 12 weeks).

[0262] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience a mean maximum change in SBP of less than 10 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks).

[0263] In some implementations, subjects were over 65 years of age and were given approximately 75 mg of vebergellon daily, and experienced a mean maximum change in SBP of less than 10 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks).

[0264] In some implementations, subjects were over 45 years of age and were given approximately 75 mg of vebergellon daily, and experienced a mean maximum change in SBP of less than 10 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks).

[0265] In some implementations, subjects experienced the maximum mean change from baseline in diastolic blood pressure (DBP) 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 during the treatment period (e.g., 8 or 12 weeks).

[0266] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience a mean maximum change of less than 7 mmHg in DBP from baseline during the treatment period (e.g., 8 or 12 weeks).

[0267] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience a change from baseline in the average number of urinations per 24 hours during the treatment period (e.g., 8 or 12 weeks), where this change is greater than that experienced by subjects taking placebo. The difference compared to placebo (i.e., the placebo-adjusted change) is from approximately -0.1 to approximately -1.5 times, for example, approximately -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 times, or a range between any two of the foregoing values. In some implementations, the placebo-adjusted change is from approximately -1.0 to approximately -0.1 times or from approximately -0.8 to approximately -0.2 times. In some implementations, the placebo-adjusted change is approximately -0.5 times.

[0268] In some embodiments, subjects are administered approximately 75 mg of vebergellon daily and experience a change from baseline in the average number of urinations per 24 hours, ranging from approximately -1.3 to approximately -2.5 times, during the treatment period (e.g., 8 or 12 weeks), for example, approximately -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, or -2.5 times, or a range between any two of the foregoing values. In some embodiments, the change from baseline in the average number of urinations per 24 hours is from approximately -1.3 to approximately -2.3 times, from approximately -1.5 to approximately -2.1 times, or from approximately -1.6 to approximately -2.0 times. In some embodiments, the change from baseline in the average number of urinations per 24 hours is approximately -1.8 times.

[0269] In some implementations, subjects had an average of ≥1 episode of urge urinary incontinence (UUI) per day prior to treatment and were administered approximately 75 mg of vebergellon daily. The change in the average number of UUI episodes experienced from baseline during the treatment period (e.g., 8 or 12 weeks) was greater than that experienced by subjects taking placebo. The difference compared to placebo (i.e., the placebo-adjusted change) was from approximately -0.1 episodes to approximately -1.5 episodes, for example, approximately -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 episodes, or a range between any two of the foregoing values. In some implementations, the placebo-adjusted change was from approximately -1.1 episodes to approximately -0.1 episodes or from approximately -0.9 episodes to approximately -0.3 episodes. In some implementations, the placebo adjustment is approximately -0.6 times.

[0270] In some embodiments, subjects are administered approximately 75 mg of vilbegon daily and experience a change in the mean number of UUI episodes from baseline ranging from approximately -1.3 to approximately -2.5 during the treatment period (e.g., 8 or 12 weeks), for example, approximately -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, or -2.5, or a range between any two of the foregoing values. In some embodiments, the change in the mean number of UUI episodes from baseline is from approximately -1.5 to approximately -2.5, from approximately -1.7 to approximately -2.3, or from approximately -1.8 to approximately -2.2. In some embodiments, the change in the mean number of UUI episodes from baseline is approximately -2.0.

[0271] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience a change from baseline in the average number of urinary urgency episodes per 24 hours during the treatment period (e.g., 8 or 12 weeks), where this change is greater than that experienced by subjects taking placebo. The difference compared to placebo (i.e., the placebo-adjusted change) is from approximately -0.4 to approximately -1.5 times, for example, approximately -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 times, or a range between any two of the foregoing values. In some implementations, the placebo-adjusted change is from approximately -1.2 to approximately -0.2 times or from approximately -0.9 to approximately -0.4 times. In some implementations, the placebo-adjusted change is approximately -0.7 times.

[0272] In some embodiments, subjects are administered about 75 mg of vebergellon daily and experience a change from baseline in the average number of urinary urgency episodes per 24 hours, ranging from about -2.2 to about -3.2, during the treatment period (e.g., 8 or 12 weeks), 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 a range between any two of the foregoing values. In some embodiments, the change from baseline in the average number of urinary urgency episodes per 24 hours is from about -2.2 to about -3.2, from about -2.4 to about -3.0, or preferably from about -2.5 to about -2.9. In some embodiments, the change from baseline in the average number of urinary urgency episodes per 24 hours is about -2.7.

[0273] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience a change from baseline in the average number of total incontinence episodes per 24 hours during the treatment period (e.g., 8 or 12 weeks), where this change is greater than that experienced by subjects taking placebo. The difference compared to placebo (i.e., the placebo-adjusted change) is from approximately -0.4 episodes to approximately -1.5 episodes, for example, approximately -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 episodes, or a range between any two of the foregoing values. In some implementations, the placebo-adjusted change is from approximately -1.2 episodes to approximately -0.2 episodes or from approximately -1.0 episodes to approximately -0.4 episodes. In some implementations, the placebo-adjusted change is approximately -0.7 episodes.

[0274] In some embodiments, subjects are administered approximately 75 mg of vebergellon daily and experience a change from baseline in the average number of total incontinence episodes per 24 hours, ranging from approximately -1.8 to approximately -2.8, during the treatment period (e.g., 8 or 12 weeks), for example, approximately -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7, or -2.8, or a range between any two of the foregoing values. In some embodiments, the change from baseline in the average number of total incontinence episodes per 24 hours is from approximately -1.8 to approximately -2.8, from approximately -2.0 to approximately -2.6, or from approximately -2.1 to approximately -2.5. In some embodiments, the change from baseline in the average number of total incontinence episodes per 24 hours is approximately -2.3.

[0275] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience variations in urine output (mL) with each urination, where such variations are greater than those experienced by subjects taking a placebo. The difference compared to placebo (i.e., the placebo-adjusted variation) is from approximately 20 mL to approximately 35 mL, for example, approximately 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 35 mL, or a range between any two of the foregoing values. In some implementations, the placebo-adjusted variation is from approximately 15.0 mL to approximately 26 mL, or from approximately 18.0 mL to approximately 23.0 mL. In some implementations, the placebo-adjusted variation is approximately 21.2 mL.

[0276] In some implementations, subjects are administered approximately 75 mg of vebergellon daily and experience variations in per-void volume (mL) from baseline during the treatment period (e.g., 8 or 12 weeks), ranging from approximately 18 mL to approximately 30 mL, from approximately 20 mL to approximately 28 mL, or from approximately 22 mL to approximately 26 mL. In some implementations, the variation in per-void volume (mL) from baseline is approximately 23 mL or approximately 24 mL.

[0277] In some implementations, the subject had an average of ≥1 episode of urge urinary incontinence (UUI) per day prior to treatment and was administered approximately 75 mg of vebergellon daily, and experienced a reduction of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% of the average number of daily UUI episodes during the treatment period (e.g., 8 or 12 weeks).

[0278] In some implementations, the subject had an average of ≥1 episode of urinary urgency per day prior to treatment and was administered approximately 75 mg of vebergelon daily, and experienced a reduction 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% of the average number of episodes of urinary urgency per day during the treatment period (e.g., 8 or 12 weeks).

[0279] In some implementations, subjects were over 65 years of age and were given approximately 75 mg of vebergellon daily, and experienced a mean maximum change of less than 7 mmHg in DBP from baseline during the treatment period (e.g., 8 or 12 weeks).

[0280] In some implementations, subjects were over 45 years of age and were given approximately 75 mg of vebergellon daily, and experienced a mean maximum change of less than 7 mmHg in DBP from baseline during the treatment period (e.g., 8 or 12 weeks).

[0281] In some implementations, subjects over 45 years of age were administered approximately 75 mg of vebergellon once daily and experienced a mean maximum change in DBP of less than 7 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks) and a mean maximum change in SBP of less than 10 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks).

[0282] In some implementations, subjects over 65 years of age were administered approximately 75 mg of vebergellon once daily and experienced a mean maximum change in DBP of less than 7 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks) and a mean maximum change in SBP of less than 10 mmHg from baseline during the treatment period (e.g., 8 or 12 weeks).

[0283] In some implementations, vilbegorone has an onset of action of approximately 4 weeks. In some implementations, vilbegorone has an onset of action of approximately 3 weeks. In some implementations, vilbegorone has an onset of action of approximately 2 weeks. As used herein, "onset of action" refers to the duration it takes for the drug's effect to become significant after administration.

[0284] As disclosed in this article, vebergellon is well tolerated in patients with OAB, with very few adverse events (greater than 2% and greater than placebo), including headache, nasopharyngitis, diarrhea, and nausea.

[0285] Viebergron has a similar incidence of other adverse events compared to placebo, such as hypertension, elevated blood pressure, tachycardia, hypotension, dizziness, urinary tract infection, urinary retention, dry mouth, constipation, and fatigue. In some embodiments, vibergron treatment does not cause any increased risk of hypertension compared to placebo. In some embodiments, vibergron treatment does not cause any increased risk of elevated blood pressure. In some embodiments, vibergron treatment does not cause any increased risk of tachycardia. In some embodiments, vibergron treatment does not cause any increased risk of hypotension. In some embodiments, vibergron treatment does not cause any increased risk of one or more of hypertension, elevated blood pressure, tachycardia, or hypotension.

[0286] For systolic blood pressure (SBP) and diastolic blood pressure (DBP), monitor changes from baseline. Measure categorical changes in SBP and DBP, such as changes ≥5 mmHg, ≥10 mmHg, ≥15 mmHg, or ≥20 mmHg.

[0287] Drug unit dose composition This disclosure provides a unit-dose pharmaceutical composition comprising a dose of the disclosed vibergron, wherein the unit-dose composition is suitable for oral administration. Those skilled in the art will recognize that oral dosage forms include, for example, forms such as liquid formulations, tablets, capsules, and gelcapsule tablets. In some embodiments, the unit-dose composition is a solid dosage form, such as tablets and capsules. In some embodiments, the unit-dose composition is a tablet.

[0288] Pharmaceutically acceptable excipients are those generally considered safe, such as lactose, microcrystalline cellulose, starch, calcium carbonate, magnesium stearate, stearic acid, talc, colloidal silica, mannitol, croscarmellose sodium, and hydroxypropyl cellulose. In some embodiments, the pharmaceutical unit-dosage compositions disclosed herein include diluents, disintegrants, binders, and lubricants. Generally, see Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing, Easton PA (2000), which is incorporated herein by reference in its entirety.

[0289] In some embodiments, the pharmaceutical unit-dose composition of this disclosure may be pulverized. In some embodiments, the pharmaceutical unit-dose composition of this disclosure is pulverized prior to oral administration.

[0290] Example Example 1 Vibegron tablet formulation The composition of Vibergellon tablets (50 mg, 75 mg and 100 mg) is shown in Table 1.

[0291] Table 1. Composition of Vibegelone Tablets

[0292] 1- Remove during processing Example 2 Clinical efficacy data A randomized, double-blind, placebo-controlled and active-drug-controlled, parallel-group two-part phase 2b study of vebergalone in men and women with oral anemia (stratified as wet and dry OAB) was completed. Part 1 was a dose-range study to evaluate the safety, tolerability, and potency of vebergalone, as well as a proof-of-concept study of concomitant dosing of vebergalone with tolterodine ER 4 mg. Approximately 980 participants in Part 1 were randomly assigned, on average, in a double-blind manner to one of seven treatment groups: vebergalone 3 mg, 15 mg, 50 mg, or 100 mg once daily for 8 weeks; tolterodine ER 4 mg once daily for 8 weeks; placebo once daily for 8 weeks; or vebergalone 50 mg in combination with tolterodine ER 4 mg for 4 weeks, followed by vebergalone 50 mg for 4 weeks. Part 2 was designed to further evaluate the safety and potency of concomitant dosing. In Part 2, 408 participants were randomly assigned in a double-blind 2:2:2:1 ratio to one of four treatment groups: vebergellon 100 mg, tolterodine ER 4 mg, vebergellon 100 mg combined with tolterodine ER 4 mg, or placebo, once daily for 4 weeks. Participants in both Part 1 and Part 2 had the option of a 1-year extension recruitment period. Participants were asked to maintain a voiding diary, recording each episode of intense urge, total incontinence, and urge incontinence. This paper summarizes the power data from Part 1 and Part 2.

[0293] At baseline, subjects must have an average of ≥8 urinations per log day in their voiding diary. Additionally, subjects in the wet OAB stratification must have an average of ≥1 urge incontinence episode per log day. Subjects in the dry OAB stratification must have an average of ≥3 urgency episodes per log day and an average of <1 urge incontinence episode per log day. For all subjects, the total number of urge incontinence episodes must exceed the total number of stress incontinence episodes.

[0294] The primary objective of this study was to evaluate the safety and tolerability of treatment with selected doses of vebergellon (alone or in combination with tolterodine) and to investigate the dose-related reduction in the mean number of urinations per day at week 8 compared to placebo.

[0295] In Part 1, at week 8, a statistically significant reduction in the mean number of daily urinations was observed in the vebegliflozin 100 mg and 50 mg treatment groups compared to the placebo group. For secondary endpoints, statistically significant reductions from baseline were also observed in the vebegliflozin 100 mg and 50 mg treatment groups compared to placebo. Secondary endpoints included urge incontinence and total incontinence (in subjects with wet OAB) and urinary urgency episodes in all subjects. For the secondary endpoint of volume per urination, statistically significant increases from baseline were also observed in the vebegliflozin 15 mg, 50 mg, and 100 mg treatment groups compared to placebo (Tables 2 and 3).

[0296] Table 2. Analysis of changes in urine output (ml) per void from baseline during week 8.

[0297]

[0298]

[0299] A double-blind, randomized, placebo-controlled, multicenter phase 3 study was completed to evaluate the safety and efficacy of vebergellon in men and women with oral urinary tract infection (OAB). After the placebo run-in period, 1,232 patients were randomized to receive a 12-week blinded study with either vebergellon 50 mg (N=370), vebergellon 100 mg (N=369), placebo (N=369), or imidafenacin 0.2 mg (comparator; N=117). Results demonstrated that once-daily vebergellon produced statistically significant reductions in the following efficacy parameters: voiding, UUI episodes, total incontinence episodes, and urinary urgency episodes (Table 4).

[0300] Table 4. Analysis of the change in average daily event count from baseline during week 12 - Constrained Longitudinal Data Analysis (cLDA) model

[0301] Example 3 Security data 3.1 Phase I safety data Safety data were collected from 16 Phase 1 studies, including 15 completed Phase 1 studies and 1 study that was terminated early (the study was terminated for reasons unrelated to efficacy or safety). In the Phase 1 programs, a total of 466 subjects received at least one dose of vebergellon; 238 subjects received a single dose ranging from 2 mg to 600 mg, and 238 subjects received multiple doses ranging from 25 mg to 400 mg, lasting up to 28 days. Vebergellon was generally well tolerated in the Phase 1 programs. No treatment-urgent serious adverse events (SAEs) or deaths were reported, and most adverse events (AEs) were transient and of mild to moderate intensity.

[0302] In the Phase 1 study, independent orthostatic hypotension (a decrease in systolic blood pressure >20 mmHg and / or a decrease in diastolic blood pressure >10 mmHg), with or without symptoms (e.g., lightheadedness, dizziness, presyncope), was observed. The incidence of orthostatic adverse events (AEs) after co-administration of vebegliflozin 100 mg or 150 mg and tolterodine ER 4 mg was similar to that after administration of vebegliflozin or tolterodine alone. In the Phase 1 multidose study, at doses up to 100 mg, AEs such as postural vertigo, dizziness, presyncope, or syncope did not show a clear dose-response relationship. However, postural vertigo was increased at doses of 100 mg and above, and the incidence of AEs “symptomatic orthostatic hypotension” tended to be higher at vebegliflozin doses >200 mg. No orthostatic adverse events occurred when vebergellon 100 mg was co-administered in subjects with essential hypertension who were on a stable treatment regimen of metoprolol (a representative beta-blocker) or amlodipine (a representative vasodilator).

[0303] A review of preliminary Phase 1 safety data indicated no clinically significant changes in laboratory safety parameters (chemical, hematological, and urinalysis) or ECG parameters (including PR, QRS, and QTc interval). A thorough QT study has been completed, and no clinically significant effects on QTc or blood pressure were found.

[0304] 3.2 Phase II Safety Data Safety data were collected from a completed single Phase 2B study in which 933 participants received at least one dose of vebegliflozin. During the primary study, participants received vebegliflozin doses ranging from 3 mg to 100 mg for up to 8 weeks (alone or in combination with tolterodine). Among participants who completed the parent study, 605 participants received vebegliflozin 50 mg (alone) or vebegliflozin 100 mg (alone or in combination with tolterodine 4 mg) for up to 52 weeks during the extension study. The placebo group was included in the primary study, and the group receiving tolterodine monotherapy was included in both the primary and extension studies. No deaths were reported during the studies. Vebegliflozin was generally well tolerated. No significant differences were observed in the incidence or severity of adverse events (AEs) or drug-related AEs compared to placebo in any treatment group.

[0305] Of the 1393 assigned participants in the primary study, 607 (43.6%) reported adverse events. The proportion of participants with one or more AEs in the vebegrinone 50 mg and vebegrinone 100 mg treatment groups was similar to that in the placebo group (see Table 14). Compared with placebo, the proportion of participants reporting one or more AEs was higher in the vebegrinone 15 mg and vebegrinone 50 mg + tolterodine 4 mg treatment groups. The most frequently reported AEs were dry mouth, headache, urinary tract infection (UTI), and nasopharyngitis. The incidence of dry mouth was higher in the tolterodine (alone or with vebegrinone) groups compared with the placebo group or the vebegrinone monotherapy group.

[0306] Of the 221 subjects, AEs were reported, with the lowest incidence reported in the vebergellon 100 mg treatment group. The proportion of subjects with drug-related AEs was similar in the vebergellon monotherapy groups compared to placebo, and only slightly higher in the concomitant therapy groups compared to placebo or either monotherapy. The proportion of subjects who discontinued treatment due to drug-related AEs was low and similar across all treatment groups.

[0307] A total of 9 SAEs were reported in 8 subjects, occurring in each treatment group (2 placebo; 1 vebergelone 3 mg; 1 vebergelone 50 mg; 3 tolterodine 4 mg; 1 vebergelone 50 mg + tolterodine 4 mg). The reported SAEs included atrial fibrillation, allergic reactions, stage IV lung adenocarcinoma, chronic obstructive pulmonary disease, hypertension, overdose, foot fracture, and in one subject, both gastroesophageal reflux disease and vertigo following a long-term hospitalization for a pan endoscopic procedure. Specific AEs were reported in no more than one subject. The investigators considered all SAEs to be unrelated to the study drug.

[0308] During the extended 52-week period, no significant differences were observed in the incidence of adverse events or serious adverse events among the treatment groups.

[0309] Of the 845 participants, 531 (62.8%) reported adverse events. The proportion of participants with one or more adverse events was similar across all treatment groups. The most frequently reported adverse events were UTI, nasopharyngitis, upper respiratory tract infection, and dry mouth. The incidence of dry mouth was higher in the tolterodine ER 4 mg treatment group compared to other treatment groups. The incidence of constipation was higher in the concomitant treatment group compared to the monotherapy group.

[0310] The proportion of subjects with drug-related adverse events (AEs) in the tolterodine ER 4 mg and concomitant dose groups was slightly higher compared to the vebergellon 50 mg and 100 mg treatment groups. The proportion of subjects discontinuing treatment with tolterodine ER 4 mg due to AEs or drug-related AEs was higher in the other treatment groups. During the extension period, a total of 46 SAEs were reported in 41 subjects. A higher overall incidence was reported in the tolterodine ER 4 mg and vebergellon 50 mg treatment groups compared to the vebergellon 100 mg treatment group. One drug-related SAE of paralytic ileus was reported in the tolterodine ER 4 mg treatment group; the subject discontinued treatment due to this AE.

[0311] Table 5 below summarizes common adverse events in patients with overactive bladder during the Vibegelone Phase 2 program.

[0312]

[0313] Serious adverse events observed during the first 12 weeks of treatment with vebergellon monotherapy included stage IV lung adenocarcinoma (n=1) and chronic obstructive pulmonary disease (n=1); overdose-related SAEs were reported in the vebergellon-tolterodine combination group. During the phase 2 extension study, SAEs reported by two or more subjects receiving monotherapy included cerebrovascular accident (n=2) and osteoarthritis (n=2). The only SAE reported in the vebergellon-tolterodine combination group was borrelia infection. SAEs potentially associated with changes in heart rate or blood pressure (at any time during treatment) included: loss of consciousness after 8 weeks of vebergellon treatment, which did not recur upon rechallenge (n=1), and atrial fibrillation (n=1) and dizziness (n=1) in the tolterodine monotherapy group. The frequency of injury was numerically higher in the tolterodine group than in the vebergellon group (2.1%, n=5 vs. 0.9%, n=4). Given the low incidence and lack of patterns of SAE, it is believed that vebegenine is not expected to cause serious events.

[0314] Based on non-clinical data and available data for similar compounds, potential risks that may be associated with vebergellon treatment include orthostatic hypotension and increased exposure (~2-fold) in patients taking concomitant strong P-gp inducers.

[0315] 3.3 Cardiovascular safety The cardiovascular safety of vebergalone has been evaluated in patients with oral angina pectoris (OAB) and healthy volunteers. In a 52-week extended randomized, placebo-controlled and active comparator (tolterodine)-controlled, two-part power and safety study, seven orthostatic adverse events (including postural vertigo, presyncope, and orthostatic hypotension) occurred in six (0.4%) subjects. These events occurred in one subject in each of the placebo group (0.5%), the vebergalone 15 mg group (0.3%), and the vebergalone 50 mg + tolterodine ER / vebergalone 50 mg treatment group (0.8%), and in three subjects (1.1%) in the vebergalone 100 mg group. These events occurred randomly throughout the study and were assessed by the investigator as mild in severity. None of the events led to discontinuation. The overall incidence of orthostatic symptoms was low.

[0316] Changes in BP and HR from baseline in each treatment group are shown in Table 6. For systolic blood pressure (SBP) and diastolic blood pressure (DBP), the mean changes at week 1 and the mean maximum changes over 8 weeks were comparable between placebo and vebergellon for 50 mg and 100 mg, with differences <1 mmHg. Categorical changes in SBP and DBP were also similar between placebo and vebergellon, where the percentage of vebergellon subjects with a DBP change from baseline >15 mmHg (1.3% for 100 mg vs. 0.5% for placebo) increased slightly at 100 mg. A dose-dependent pattern was detectable for HR, as the mean maximum change over 8 weeks was comparable to placebo (<2 bpm). Small differences in the percentage of subjects exceeding the categorical heart rate and blood pressure thresholds with vebergellon were similar to those in the tolterodine group.

[0317] Table 6. Changes in vital signs from baseline by dose for vilbegaron and tolterodine

[0318] In several Phase 1 studies, heart rate and blood pressure were assessed more intensively in healthy volunteers. A six-part, double-blind, randomized, placebo-controlled study was used to evaluate the safety, tolerability, and multi-dose pharmacokinetics of vebegliflozin in healthy subjects, including a specific analysis of heart rate. Depending on the cohort, doses ranged from 25 mg to 400 mg once daily for 7 to 28 days. Table 7 presents the least-squares mean and 90% confidence interval of the maximum change in the moving average heart rate (MA4 HR) from baseline over 4 hours after administration. The effect on heart rate was dose-dependent, and a 100 mg dose showed a difference of <1 bpm compared to placebo.

[0319] Table 7. Maximum MA4 HR on day 14 and differences between vibergron and placebo.

[0320] a. One participant from each of groups A and G discontinued their participation, and no data were available on day 14. b. Least squares average and corresponding 90% confidence interval c. Difference between least squares (active substance - placebo) and the corresponding 90% confidence interval calculated by the linear fixed effects model. Cardiovascular safety in healthy volunteers was also assessed in thorough QT studies following single doses of 200 mg and 400 mg, close to steady-state exposures to vebeguro at 100 mg and 200 mg, respectively. As shown in Table 8, the mean maximum effects on blood pressure and RR interval were reduced with lower doses. Log-log regression analysis was used to calculate the mean ± standard deviation C from the 75 mg dose using data from multiple vebeguro exposures (from three phase 1 studies). 最大 The AUC values ​​were 120 ± 74.7 ng / mL and 1140 ± 476 ng·h / mL, respectively. These estimates indicate that C 最大 The AUCs were approximately 1 / 3.3 and 1 / 2 of a single 200 mg dose, and 1 / 9.2 and 1 / 6 of a single 400 mg dose, respectively.

[0321] Table 8. Mean changes from baseline in single-dose pharmacokinetic parameters and RR interval versus placebo-corrected blood pressure.

[0322] Example 4 Dosage selection 4.1 Dosage Comparison Efficacy As seen in Table 9, the phase 2 study discussed in Example 2 demonstrated a dose-dependent effect on urination. Conversely, no dose-dependent effect on urge incontinence or total incontinence was observed. These data reveal a relatively shallow dose-response relationship between once-daily doses of 50 mg and 100 mg. Since the potency of vibegelone tends to stabilize from 50 mg to 100 mg, 75 mg achieves most of the potency attainable with 100 mg.

[0323] Table 9. Efficacy of Vibegliflozin 50 mg and 100 mg in Phase 2 studies.

[0324] Data reported as a difference, expressed as the LS average. a. Change in the average number of urinations from baseline during week 8 b. Change in the average number of seizures from baseline at week 8 c. The change in average discharge from baseline over a log day in week 8. Surprisingly, when measured at week 8, the reduction in UUI episodes and voiding was not proportional to the dose. Comparing data on the change from baseline at week 8 with 50 mg from the phase 2 trial (Table 3) with data on the change from baseline at week 8 with 75 mg from the phase 3 trial regarding UUI episodes (Table 15), unexpectedly, the 75 mg dose used in the phase 3 trial provided a lower reduction compared to the 50 mg dose used in phase 2. Similarly, the reduction in voiding with the 75 mg dose (Table 16) was lower than the reduction seen with 50 mg (Table 3).

[0325] 4.2 Mild side effects Vibergron showed greater exposure than dose-proportional increases. Surprisingly, increasing the dose from 50 mg to 100 mg resulted in C... 最大 Increase by about 3 times, C 最大 It is considered to be the pharmacokinetic parameter most closely related to cardiovascular effects. To correlate the pharmacokinetic parameters of a 75 mg dose, dose-C was established using data from a phase 1 study. 最大 Model and dose-AUC model. Based on simulations, it was found that a 75 mg dose of vebergellon avoided approximately 29% of the exposure observed at a 100 mg dose, subsequently reducing the upper limit of exposure achievable at a 100 mg dose. Anomaly C 最大 This reduction in value decreases the likelihood of clinically relevant cardiovascular effects.

[0326] In the phase 1 multiple-dose study, adverse events such as postural vertigo, vertigo, presyncope, and syncope did not show a clear dose-response relationship at doses up to 100 mg. However, postural vertigo was increased at doses ≥100 mg, and the incidence of the adverse event “symptomatic orthostatic hypotension” was higher at vebeglitron doses greater than 150 mg. Reducing the dose from 100 mg to 75 mg disproportionately reduced the risk of these dose-related adverse events, as a 25% reduction in dose resulted in C 最大 The bioavailability decreased by approximately 40% (120 ng / mL for 75 mg versus 206 ng / mL for 100 mg). Not wanting to be bound by theory, the greater-than-dose increase in bioavailability with increasing dose is likely due to efflux mediated by saturable P-glycoproteins (P-gp) in the intestine.

[0327] The lower exposure at a 75 mg dose compared to a 100 mg dose did not disproportionately reduce the risk of adverse events in specific populations. Subjects with moderate renal impairment had a mean 1.6-fold increase in AUC compared to subjects with normal renal function, while subjects receiving potent CYP3A / P-gp inhibitors had approximately a 2-fold higher exposure. Assuming a C... 最大 These specific groups achieved a 2-fold increase compared to those observed with vebergellon C at 100 mg. 最大 Larger Vibergron C 最大 The probability is 15% (see Figure 1 (For those showing approximately 50%-70% higher C levels than healthy young men). 最大 For older adults and women, it is important to minimize the exposure of subjects in extreme situations.

[0328] Example 5 Pharmacokinetic data for 75 mg and 100 mg doses A pharmacokinetic study evaluating the drug interaction between vilbergiaone and rifampin was completed. All subjects were healthy adults. A summary of preliminary results is presented in Table 10. Subjects received a single dose of vilbergiaone 75 mg on day 1, rifampin 600 mg QD on days 10–23, and a single dose of vilbergiaone 75 mg with a rifampin dose on day 17. Administration of vilbergiaone and rifampin was well tolerated in healthy male and female subjects. No serious TEAEs, SAEs, or deaths were reported during the study. Three of the 20 subjects (15%) experienced study drug-related AEs, two experienced headaches, and one experienced constipation, all of which were mild. No clinically significant changes or findings were observed in vital signs, ECG, or clinical laboratory assessments.

[0329] Table 10. Geometric Mean (%CV): Pharmacokinetic Parameters of Vibergron

[0330] A double-blind, double-pseudo-randomized, placebo-controlled study was completed to evaluate the drug interaction between vebergellon and tolterodine (a sensitive CYP2D6 substrate). All participants were healthy adults. Preliminary results are summarized in Table 11 and Figure 2In this study, subjects received either vebergelone 100 mg QD with tolterodine 4 mg QD or vebergelone 100 mg QD with tolterodine placebo on days 1–7. Subjects receiving tolterodine placebo were administered vebergelone 100 mg QD and tolterodine 4 mg QD on days 29–35. Subjects initially receiving tolterodine 4 mg QD were administered vebergelone 100 mg QD and tolterodine placebo on days 29–35. The study treatment was well tolerated, and there was no evidence of an increase in adverse events during the combination administration with vebergelone. As shown in Table 11, co-administration of vebergelone did not alter the geometric mean maximum plasma concentration (C0.05) of tolterodine. 最大 The elimination half-life of tolterodine alone and in the presence of vebergerol in steady state was similar. Furthermore, the change in plasma concentration of tolterodine alone over time was similar to that seen in the cases of tolterodine and vebergerol. Figure 2 These results demonstrate that vebergellon does not inhibit CYP2D6 and has a favorable drug-drug interaction profile when used in patients with OAB.

[0331] Table 11. Pharmacokinetic parameters of the vebergellon and tolterodine ER combination

[0332] Tolterodine ER 4 mg; Vibergelon 100 mg AUC = Area under the concentration-time curve from 0 hours to 24 hours; C 最大 = Maximum concentration; t 1 / 2 = Half-life; GM = Geometric mean; CV = Coefficient of variation; CI = Confidence interval; GMR = Geometric mean ratio A pharmacokinetic study evaluating the drug interaction between vilbegarol and metoprolol succinate (a moderately sensitive CYP2D6 substrate) was also completed. All participants were healthy adults. Preliminary results are summarized in Table 12 and Figure 3 In this study, subjects received a single dose of metoprolol succinate 100 mg with warfarin 10 mg on day 1, vebergelone 75 mg QD on days 8–16, vebergelone 75 mg QD with metoprolol succinate 100 mg and warfarin 10 mg on day 17, and vebergelone 75 mg QD on days 18–23. The treatment was well tolerated, and there was no evidence of an increased incidence of adverse events during the combination therapy with vebergelone. In the presence of vebergelone, the geometric mean C0 of metoprolol was [not specified]. 最大The AUC values ​​increased slightly. However, the elimination half-life of metoprolol alone and in combination with vebergelone was similar, suggesting that CYP2D6 is unlikely to be inhibited. The change in plasma concentration over time of metoprolol alone was similar to the profile seen in the case of metoprolol and vebergelone. Figure 3 ).

[0333] Table 12. Pharmacokinetic parameters of the combination of vilbegarol and metoprolol

[0334] Metoprolol 100 mg; Vibergelon 75 mg AUC = Area under the concentration-time curve from 0 to infinity; C 最大 = Maximum concentration; t 1 / 2 = Half-life; GM = Geometric Mean; CV = Coefficient of Variation; GLS = Geometric Least Squares; CI = Confidence Interval Example 6 Phase 3, randomized, double-blind, placebo-controlled and active ingredient (tolterodine) controlled clinical trial An international, phase 3, randomized, double-blind, placebo-controlled and active drug (tolterodine)-controlled, parallel-group, multicenter study was conducted in men and women with overactive bladder (OAB). Patient recruitment included individuals with wet OAB (those with uncontrolled urination (UUI) and involuntary incontinence accompanied by urinary urgency) and individuals with dry OAB (those without UUI). A total of 1,518 patients were randomized to one of the three groups across 215 study sites for a 12-week treatment period.

[0335] The study consisted of the following: a screening period (1 to 5 weeks), a single-blind adjustment period (2 weeks), a randomized double-blind treatment period (12 weeks), and a follow-up period (4 weeks).

[0336] This study evaluated the safety, tolerability, and potency of 75 mg vebegliflozin compared to placebo. Tolterodine ER 4 mg served as the active ingredient control. Patients were randomly assigned in a double-blind, 5:5:4 ratio to one of three treatment groups: vebegliflozin 75 mg, placebo, or tolterodine ER 4 mg. All patients received the medication once daily for 12 weeks during the treatment period. Patients were evaluated at weeks 4 and 8 between baseline and the week 12 visit.

[0337] 6.1. Qualification Standards To be eligible to participate in this study, patients must have met all of the following inclusion criteria and not meet any of the following exclusion criteria prior to recruitment.

[0338] 6.1.1 Inclusion Criteria 1. Willing and able to provide written informed consent.

[0339] 2. Male or female aged ≥18 years. Note: Up to 15% of patients may be male.

[0340] 3. A history of OAB (if diagnosed by a physician) lasting at least 3 months prior to the screening visit. Note: OAB is defined as urinary urgency, with or without urge incontinence (UUI), typically associated with urinary frequency and nocturia. Urodynamic evaluation is not required.

[0341] 4. Based on the patient voiding logs returned at both the break-in visit and the baseline visit, the wet or dry OAB criteria described below must be met (all complete log days must be used for eligibility). Logs returned at the break-in visit must contain at least 5 complete log days [not necessarily consecutive], and logs returned at the baseline visit must contain at least 4 complete log days. Mean values ​​should not be rounded to integers. a. Wet OAB Standard: i. The average number of ≥8.0 urinations per day per log entry; and ii. The average number of UUI episodes ≥1.0 per log day; and iii. If stress urinary incontinence is present, the total number of UUI episodes must be greater than the total number of stress urinary incontinence episodes from previous visit logs.

[0342] b. Dry OAB Standard: i. The average number of ≥8.0 urinations per day per log entry; and ii. The average number of ≥3.0 episodes of urinary urgency per day in each logbook; and iii. The average number of UUI episodes per log day <1.0; and iv. If stress urinary incontinence is present, the total number of UUI episodes must be greater than the total number of stress urinary incontinence episodes from previous visit logs.

[0343] 5. For women of reproductive potential: consent to abstinence from the screening visit to the completion of the follow-up visit or for the patient to use (or have her male partner use) an acceptable method of contraception (as defined in Section 5.2.1) with each sexual intercourse.

[0344] 6. For women of reproductive potential: agree not to donate oocytes (eggs) for at least one month after the last dose of the study treatment.

[0345] 7. ≥80% adherence to self-management of the study therapy has been demonstrated during the adjustment period.

[0346] 8. Can walk and, as determined by the researcher, is in good general physical and mental health.

[0347] 9. From the researcher's perspective, the ability and willingness to comply with the protocol requirements, including completing electronic questionnaires, patient voiding logs, and urine volume logs (which will require the ability to collect, measure, and record voiding volume by herself / him using graded urine collection and measurement containers [provided by the organizer if necessary]).

[0348] 6.1.2. Exclusion Criteria History of urinary system diseases 1. The patient has a history of 24-hour urine output greater than 3,000 mL within the past 6 months, or the measurement value on a urine output log day during the adjustment period is greater than 3,000 mL.

[0349] 2. Patients with lower urinary tract pathology that, in the investigator's opinion, may cause urinary urgency, frequency, or incontinence; lower urinary tract pathology includes, but is not limited to, urolithiasis, interstitial cystitis, prostate cancer, gastrointestinal (GI) cancer, tuberculosis, gallstones, urothelial tumors, prostatitis, and clinically relevant benign prostatic hyperplasia (BPH) or bladder outlet obstruction, as determined by the investigator. Note: Male patients with mild to moderate BPH who have no evidence of bladder obstruction as determined by the investigator may be included, provided they have been taking medication for BPH for at least one year prior to screening, and the dosage of herbal remedies, alpha antagonists, or other symptomatic treatments or medications has not changed in the three months prior to screening, and the dosage of 5α-reductase inhibitors has not changed in the six months prior to screening.

[0350] 3. Screen for patients with a history of surgery within the past 6 months to correct stress urinary incontinence, pelvic organ prolapse, or BPH.

[0351] 4. Current medical history or evidence of stage 2 or higher pelvic organ prolapse (prolapse beyond the hymenal ring).

[0352] 5. The patient is currently using a pessary to treat pelvic organ prolapse.

[0353] 6. A known medical history of an elevated post-void residual volume defined as greater than 150 mL.

[0354] 7. Have undergone bladder training or electrical stimulation within 28 days prior to screening, or plan to begin during the study.

[0355] 8. Active or recurrent (>3 episodes per year) urinary tract infection based on clinical symptoms or laboratory criteria (≥5 white blood cells [WBC] or a positive urine culture, defined as ≥10⁵ colony-forming units [CFU] / mL in one sample). Patients diagnosed with urinary tract infection (UTI) at screening visits can receive treatment and be re-screened once the infection has resolved.

[0356] 9. Requirements include indwelling catheterization or intermittent catheterization.

[0357] 10. Had received an intradetrusor injection of botulinum toxin within 9 months prior to screening.

[0358] Other medical history 11. Having uncontrolled hyperglycemia (defined as 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), or a condition that is considered uncontrolled by the investigator.

[0359] 12. Evidence of diabetes insipidus.

[0360] 13. Currently pregnant, breastfeeding, or planning to become pregnant during the planned duration of the study.

[0361] 14. A history of concurrent malignancy or any malignant tumor within 5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or cervical cancer in situ.

[0362] 15. Having uncontrolled hypertension (systolic blood pressure ≥180 mmHg and / or diastolic blood pressure ≥100 mmHg) or a resting heart rate >100 beats per minute (based on pulse).

[0363] 16. Patients with systolic blood pressure ≥160 mmHg but <180 mmHg are excluded unless the investigator and / or medical monitor deem it safe to continue the study and are able to complete the study according to the protocol; these patients must take stable antihypertensive medication for at least 90 days.

[0364] 17. All patients with signs and symptoms of uncontrolled hypertension, regardless of blood pressure measurement, were excluded from the study. These include, but are not limited to, neurological symptoms or findings, hematuria, proteinuria, retinopathy, unstable angina, and acute heart failure.

[0365] 18. Has narrow-angle glaucoma (primary open-angle glaucoma cannot be excluded).

[0366] 19. A history of cerebrovascular accident, transient ischemic attack, unstable angina, myocardial infarction, coronary intervention (e.g., coronary artery bypass grafting or percutaneous coronary intervention [e.g., angioplasty, stenting]) or neurovascular intervention (e.g., carotid artery stenting) within 6 months prior to the screening visit. Patients with these conditions should receive stable medical therapy for at least 3 months prior to the screening visit.

[0367] 20. Has a known history of liver disease.

[0368] 21. A history of injury, surgery, or neurodegenerative disease (e.g., multiple sclerosis, Parkinson's disease) that may affect the lower urinary tract or its nerve supply.

[0369] 6.2 Research Evaluation and Procedures The investigator or a qualified designated person reviewed previous medication use, including any clearance requirements specified in the protocol, and recorded the previous medications taken by the patient in the 28 days prior to starting the completion of the Screening eDiary.

[0370] All medications used to treat OAB were recorded within one year of the screening visit. Medication history was evaluated in male patients with a history of mild to moderate BPH to ensure a stable treatment regimen met eligibility criteria.

[0371] Concomitant medications were reviewed and documented at each study visit from screening to week 12, as well as at any unscheduled visits.

[0372] Male patients with mild to moderate bladder hypertension (BPH) who have no evidence of bladder obstruction as determined by the investigator may be included, provided they have been taking medication for BPH for at least one year prior to baseline and the dosage of herbal remedies, alpha antagonists, or other symptomatic treatments or medications has remained unchanged in the three months prior to baseline. For study eligibility, these BPH medications must have remained stable from screening to the baseline visit.

[0373] Patients with a history of hypertension must have been on a stable blood pressure regimen for 90 days prior to the baseline visit and must have been deemed safe to continue the study by the investigator and / or medical monitor and be able to complete the study according to the protocol.

[0374] 6.2.1 Patient's voiding log Participants used a patient voiding log (via electronic or paper log) to record the frequency of daily OAB symptoms by selecting the corresponding box for each symptom that occurred during a given daytime and nighttime period. OAB symptoms included all voiding, urgency, incontinence, and the main cause of incontinence.

[0375] "Journal day" is defined as the time between when the patient wakes up each morning and when the day begins (i.e., from when the patient wakes up yesterday to when the patient wakes up today; a period of approximately 24 hours).

[0376] A “complete log day” is defined as a log day in which the patient indicates they have recorded all urination and any leakage that occurred during that log day. Specifically, in the electronic log, the patient will answer “yes” to the corresponding item in the start-day questionnaire to indicate that their data from the previous log day is complete.

[0377] 6.2.2 Urine output log Urine volume data were collected separately from the patient using an electronic log of urine volume components or a paper urine volume chart. Urine volume charts are a tool used in clinical practice and clinical research to assess voiding function over a 24-hour period and are considered a useful tool in studies of patients with voiding symptoms. Urine volume can be collected on any day of the seven log days prior to the visit (1) and should be recorded for a continuous 24-hour period, starting from the time the patient first wakes up and continuing until the time the patient first wakes up the following day.

[0378] 6.2.3 Patient-reported results Patients completed a paper questionnaire at the start of each required study visit to assess perceived symptom relief, symptom distress, and health-related quality of life during the study visit. Recommended guidelines for using patient-reported outcome measures can be found in "Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims," ​​U.S. Department of Health and Human Services, Food and Drug Administration, December 2009, which is incorporated herein by reference in its entirety. These include the following questionnaires: 1. The overall impression items include the patient's overall severity impression (PGI - severity), the patient's overall control impression (PGI - control), the patient's overall frequency impression (PGI - frequency), the patient's overall leakage impression (PGI - leakage), and the patient's overall change impression (PGI - change).

[0379] 2. The Overactive Bladder Questionnaire (OAB-q Long Table [OAB-q LF], 1-week review) was a 33-item disease-specific questionnaire administered to patients, comprising a Health-Related QoL (HRQL) scale (25 items) and a Symptom Distress Scale (8 items). HRQL is a multi-domain concept representing a patient’s general perception of the physical, psychological, and social impacts of the disease and its treatment on their life. Claims of statistical and meaningful improvement in HRQL meant that: (1) all HRQL domains that were important for explaining how feelings or functions changed as a result of the target disease and its treatment in the clinical trial population were measured; (2) general improvement was demonstrated; and (3) no reduction was shown in any domain. In this study, the HRQL scales were divided into four subscales: Coping, Anxiety / Worry, Sleep, and Social Interaction. The Coping subscale (also known as the Coping domain score) was a secondary endpoint, with item scores ranging from 1 (never) to 6 (always), with higher scores indicating better QoL. The total HRQL score was calculated by summing the scores of the individual HRQL subscales. The Symptom Distress Scale items were scored from 1 (nothing at all) to 6 (very much), with higher symptom distress scores indicating greater symptom severity. The tool was developed and validated in both male and female patients with self-indulgent and incontinent OAB.

[0380] 3. The Work Productivity and Activity Impairment Questionnaire - Urinary Symptoms (WPAI-US) version 2.0 is a 6-item questionnaire that assesses health-related loss of work productivity due to urinary symptoms during a 1-week review period.

[0381] 4. The EQ-5D Health Questionnaire is a standardized tool used to measure health outcomes. It is applicable to a wide range of health conditions and treatments; it provides a simple descriptive overview and a single indicator value for health status.

[0382] 6.2.4 Remaining volume after discharge The risk of acute urinary retention or onset associated with increased post-void residual volume (PVR) is related to concerns about antimuscarinic therapy, which promotes smooth muscle relaxation by inhibiting acetylcholine-induced smooth muscle contraction. Acute urinary retention or incomplete bladder emptying may occur if the bladder cannot generate sufficient pressure during contraction to overcome outlet resistance in the urethra (due to poor detrusor contractility or severe obstruction, most commonly from BPH).

[0383] The amount of urine remaining in the bladder after expulsion (PVR) is an objective measurement that can serve as a proxy for impaired expulsion capacity.

[0384] PVR is performed via ultrasound during the visits indicated in the activity schedule.

[0385] 6.3 Pharmacokinetic Sample Collection PK sampling was performed on a selected subgroup of patients (approximately 30% of the total study population) at selected locations to assess the impact of demographic covariates through population PK analysis.

[0386] 6.4 Safety Considerations Safety studies include adverse events, physical examinations, vital signs (and weight), and clinical laboratory tests.

[0387] An adverse event is any adverse medical condition that occurs in a patient or clinical study patient that is temporarily related to the use of the drug product, regardless of whether it is considered to be related to the drug product.

[0388] An adverse event can therefore be any adverse and unexpected sign (including abnormal laboratory findings), symptom, or illness (new or worsening) that is temporarily related to the use of the drug product or the procedure prescribed, whether or not it is considered to be related to the procedure prescribed by the drug product or the procedure.

[0389] Events that meet the definition of an adverse event include: 1. A worsening of the nature, severity, frequency, or duration of a pre-existing condition, excluding minor fluctuations; 2. Investigate new conditions detected or diagnosed after product application, even if the condition may have existed before the study began; 3. Injury or accident: If a medical condition has caused an injury or accident, the medical condition and the accident should be reported as two separate medical events (e.g., for a fall secondary to vertigo, "vertigo" and "fall" should be recorded separately). 4. Investigational abnormalities (e.g., laboratory parameters, vital signs, ECG) are only considered clinically significant by the investigator based on at least one of the following criteria: a. Induces clinical signs or symptoms; b. Active intervention is needed; c. The need to investigate the interruption or cessation of treatment.

[0390] 5. Signs, symptoms, or clinical sequelae of suspected interaction.

[0391] 6. Investigate signs, symptoms, or clinical sequelae of suspected overdose of the product or accompanying medication.

[0392] Researchers or field staff are responsible for detecting, recording, and reporting events that meet the definition of adverse events or serious adverse events.

[0393] Adverse events of clinical concern in this study included: 1. Potential major adverse cardiovascular and cerebrovascular events (MACCEs), which, according to the definition in the CAC charter, are adjudicated by an independent external expert clinical adjudication committee (CAC) into the following categories: Death or any event with fatal consequences Myocardial infarction / heart attack Cerebrovascular accident / stroke Hospitalized for unstable angina / chest pain Hospitalized due to heart failure Coronary artery revascularization / angioplasty / stent 2. High blood pressure: Adverse events related to hypertension were reported and classified as AECIs as follows: For patients who did not have hypertension at baseline (mean SBP <140 mmHg, DBP <90 mmHg), the mean of three systolic blood pressure (SBP) measurements at two consecutive visits must be ≥140 mmHg or the mean of three diastolic blood pressure (DBP) measurements must be ≥90 mmHg (or both); for patients who did not have hypertension at baseline, the mean of three systolic blood pressure measurements at two consecutive visits must be ≥140 mmHg or the mean of three diastolic blood pressure (DBP) measurements must be ≥90 mmHg (or both); or, For patients with hypertension at baseline, an increase of ≥20 mmHg in the mean of three SBP or ≥10 mmHg in DBP compared to baseline at two consecutive visits. The initiation of medication for treating hypertension in any patient, or the increase of the dosage of medication for treating hypertension in any patient.

[0394] 3. Adverse events consistent with orthostatic hypotension, as confirmed by orthostatic vital signs.

[0395] 4. Adverse events suggesting cystitis or urinary tract infection.

[0396] 5. Request temporary suspension or permanent cessation of laboratory AST or ALT values ​​for investigational drugs.

[0397] 6.5 Statistical Analysis The following lists the efficacy, safety, and exploratory endpoints used to evaluate differences in treatment and / or between treatments.

[0398] When describing the power variables of interest below, the description is limited to the primary time point of interest at week 12 of the study. However, many variables were measured at other time points and analyzed at other time points.

[0399] The common primary endpoint of effectiveness is: 1. Change from baseline in the mean number of 24-hour urinations at week 12 in all OAB patients; 2. CFB of the average number of UUI episodes per 24 hours in patients with wet OAB at week 12.

[0400] For the purposes of this study, the number of urinations was defined as the number of times a patient urinated in the toilet as indicated in their patient voiding log. Average daily urinations were calculated using daily entries from the patient voiding log, which was completed within 7 days prior to each study visit. The average daily urination count was calculated as the total number of urinations occurring on a complete log day divided by the number of complete log days in the patient voiding log. A complete log day required patient confirmation in their patient voiding log that all urinations and leakages had been recorded on that log day. The baseline was defined as the average number of urinations occurring during the last evaluable log period prior to the baseline visit.

[0401] The number of UUI episodes was defined as the number of times the patient had verified "urgency" as a cause of unintended urinary leakage. The mean daily UUI episodes at each study visit were calculated in the same manner as described above for voiding endpoints. Only patients with wet OAB were used to analyze the UUI endpoint.

[0402] The secondary effect endpoint is: 1. CFB of the average number of urinary urgency episodes (requiring immediate urination) within 24 hours in all OAB patients at week 12. 2. Percentage of all OAB patients with a 50% reduction in 24-hour urinary urgency (requiring immediate urination) compared to baseline at week 12. 3. Percentage of wet-type OAB patients with a 75% reduction in UUI episodes per 24 hours at week 12 compared to baseline. 4. CFB of the average number of daily urinations in all OAB patients at week 4 5. CFB of the average number of daily UUI episodes in wet OAB patients during week 4 6. CFB of all OAB patients at week 12 based on their coping scores from the Overactive Bladder Questionnaire Long Form (OAB-qLF, 1-week review). 7. The average number of urinations per 24 hours in all OAB patients up to week 2 CFB 8. The average number of UUI episodes per 24 hours in patients with wet OAB up to week 2 CFB 9. CFB of the mean number of total incontinence episodes in 24 hours during week 12 in patients with wet OAB 10. Average CFB excretion per urination in all OAB patients at week 12 Other secondary endpoints of effectiveness are: 1. CFB of all OAB patients at week 12 from the total HRQL score of OAB-qLF (1-week review). 2. CFB of all OAB patients at week 12 from OAB-q-LF (1-week retrospective) symptom distress scores 3. Percentage of wet-type OAB patients with zero UUI episodes at week 12 4. Percentage of all OAB patients with an average number of urinations <8 times per 24 hours at week 12. 5. Percentage of wet OAB patients with a 50% reduction in total 24-hour incontinence episodes per 12-week period compared to baseline. 6. CFB in all OAB patients at week 12 based on PGI-severity of overall bladder symptoms 7. CFB in all OAB patients at week 12 based on PGI-controlled overall control of bladder symptoms. The exploratory endpoint is: 1. Percentage of CFB in wet OAB patients on dry-type log days (zero UUI episodes) at weeks 12 and 4. 2. Percentage of CFB in wet OAB patients on dry diary days (zero total incontinence episodes) at week 12. 3. CFB of all OAB patients at week 12 and week 4 on the Work Productivity and Activity Disorders Questionnaire-Urinary Symptoms (WPAI-US) total score. 4. CFB of all OAB patients at week 12 with EQ-5D score 5. For all OAB patients with ≥1 NVU at baseline, CFB was calculated based on the mean number of NUVs per 24 hours at week 12. 6. CFB of all OAB patients at week 12 based on PGI-frequency of overall symptom frequency. 7. CFB of all wet OAB patients at week 12 based on PGI-leaking bladder symptoms, overall urgency-related leakage. 8. Overall changes in bladder symptoms based on PGI changes in all OAB patients at week 12 9. CFB of all OAB patients at week 12 from the OAB-qLF (1-week retrospective) anxiety score 10. CFB of all OAB patients at week 12 from sleep scores of OAB-qLF (1-week review). 11. CFB of all OAB patients at week 12 from social interaction scores of OAB-qLF (1-week review). 12. CFB of the average number of nighttime urinations in all patients at week 52 13. CFB of the mean number of nighttime urinations at week 52 in patients with nocturia at baseline. 6.6 Analyzing the Group In this study, the full analysis set (FAS) population was used as the primary population for power data analysis. Since incontinence-related endpoints will only apply to patients who met the definition of incontinence at study enrollment, a separate FAS definition and additional criteria are necessary to define the primary analysis population for incontinence endpoints.

[0403] The following FAS groups were defined in the study: 1. Full Analysis Set (FAS): All randomized OAB patients who received at least one dose of double-blind study treatment and had at least one evaluable change compared to baseline voiding measurements.

[0404] 2. Full Analysis Set of Incontinence (FAS-I): All randomized patients with wet OAB who received at least one dose of double-blind study treatment and had at least one evaluable change compared to baseline UUI measurements.

[0405] Patients in the protocol-compliant group (PP) and the protocol-compliant incontinence group (PP-I) will be excluded due to significant deviations from the protocol that could materially affect the primary efficacy endpoint. Supportive analyses of co-primary and secondary efficacy endpoints will be performed using the protocol-compliant group.

[0406] Patients will be included in their randomized treatment groups for efficacy data analysis using FAS and the protocol-compliant population.

[0407] In this study, the safety set (SAF) was used to analyze safety data. The SAF consisted of all patients who received at least one dose of the study treatment.

[0408] The PK population includes all subjects who have undergone a safe and centralized plasma PK sampling and have evaluable PK measurement results.

[0409] 6.7 Statistical Methods For the analysis of the common primary endpoints (change from baseline in the mean number of daily voidings at week 12 and the mean number of daily urge incontinence episodes at week 12, with placebo adjustments), a repeated measures mixed model (MMRM) with limited maximum likelihood estimation was used. This model corrects for dropout and accounts for the fact that measurements taken over time for the same patient tend to be correlated by using all available information about the patient within the same set of covariates to arrive at estimates of treatment effect in the non-dropout group. The analytical model for each power endpoint included items related to treatment, visits, 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 visits.

[0410] The primary inference was drawn from the treatment differences from baseline, derived from the MMRM model at week 12. As part of a secondary objective, the treatment differences at each post-baseline visit were also derived using the same MMRM model. The estimated treatment differences at each visit, along with 95% confidence intervals and relevant p-values, are shown in the summary of statistical analysis.

[0411] Unstructured covariance matrices are used to model the correlation between repeated measures. Kenward-Roger adjustment, along with restricted (or residual) maximum likelihood (REML), is used for statistical inference. If the unstructured covariance model fails to converge using the default Newton-Raphson algorithm, the Fisher scoring algorithm or other appropriate methods can be used to provide initial values ​​for the covariance parameters. In rare cases where none of the above methods yields convergence, structured covariance is used to model the correlation between repeated measures.

[0412] The same MMRM model described for the common primary endpoint was used to analyze the changes from the baseline effectiveness endpoint.

[0413] The Cochran-Mantel-Haenszel risk differential estimate was used to analyze the power endpoints of the proportion of patients with a mean reduction of at least 75% in the number of daily UUI episodes at week 12 and the proportion of patients with a mean reduction of 50% in the number of daily urinary urgency episodes at week 12. Missing week 12 data were analyzed using multiple imputation. The estimated difference in responder proportions and its 95% confidence interval were calculated using the Cochran-Mantel-Haenszel risk differential estimate stratified by OAB type (wet vs. dry) and sex (female vs. male), with weights proposed by Greenland and Robins.

[0414] The same statistical methods used to analyze the common primary and secondary efficacy endpoints were applied to the exploratory analysis. The exploratory responder analysis was performed using the same Cochran-Mantel-Haenszel model described above for the secondary endpoints.

[0415] Safety analyses were performed using the SAF and summarized by the treatment group as treated. The treatment emergency period was defined as the timeframe from the date of the first dose of treatment in a double-blind study to 28 days after the last dose of study treatment, or the start date of an alternative investigational dose, surgical intervention, or conversion to an extension study, whichever comes first. Safety was assessed through adverse event summaries, the frequency of treatment discontinuation due to adverse events, and clinical laboratory evaluations.

[0416] 6.8 Effects of subgroup analysis and baseline factors To determine whether treatment effects were consistent across subgroups, estimates of the intergroup treatment effect (with a nominal 95% confidence interval [CI]) for the primary endpoint were estimated and plotted in each category of the following categorical variables: 1. Region (the United States relative to the rest of the world) 2. Age categories (<40 years old, ≥40 years old to <55 years old, ≥55 years old to <65 years old, ≥65 years old to 75 years old, ≥75 years old) 3. Age categories (<65 years old, ≥65 years old) 4. Race (White relative to others) 5. Gender (female relative to male) 6. Previous OAB therapy (unexperienced versus experienced) 7. OAB Types (Wet OAB vs. Dry OAB) For each subgroup, the main MMRM model including the subgroups was fitted using the treatment interaction project, and the modeling results are presented. Consistency of treatment effects was descriptively assessed using summary statistics by category for the categorical variables listed above.

[0417] 6.9 Clinical Trial Data and Results The demographic data of the patients in this trial are shown in Table 13, and the subject disposition is shown in Table 14.

[0418] Table 13. Patient Demographic Data

[0419] Table 14. Subject configuration.

[0420] Vibergron achieved the co-primary endpoints demonstrating a statistically significant reduction in daily voiding and daily urge incontinence (UUI) compared to placebo (p<0.001 and p<0.0001, respectively). The co-primary power results are shown in Tables 15 and 16. Figure 4 and Figure 5 The results showed that vebegrin achieved statistically significant effects on the reduction of UUI and urination at two weeks, and the benefits persisted into week 12.

[0421] Table 15. Change in mean daily number of UUI seizures from baseline (least squared CFB mean at week 12)

[0422] Table 16. Change in mean daily urination frequency from baseline (week 12 CFB least squares mean)

[0423] The daily variation in urge incontinence (UUI) in several subgroups is shown in Tables 17-21.

[0424] Table 17. UUI: Overall and by subgroup (LS mean change from baseline at week 12 (placebo adjusted))

[0425] 1 Post-event analysis Surprisingly, women showed a greater reduction in UUI episodes than men.

[0426] Table 18. UUI: Overall and by subgroup (LS mean of CFB at week 12 (95% CI))

[0427] For subgroup analyses, covariates in the model included region, study visit, sex, baseline number of UUI episodes, treatment by sex, treatment by study visit, and treatment by sex and by study visit.

[0428] 1 Post-event analysis Table 19. UUI: Overall and by Subgroup (Descriptive Statistics: Week 12 CFB Mean (Q1, Q3))

[0429] Table 20. UUI: Whites vs. Non-Whites (Descriptive Statistics)

[0430] Table 21. UUI: Further subdivision of races (descriptive statistics)

[0431] Table 22. UUI: Females vs. Males (Descriptive Statistics)

[0432] The changes in daily urge incontinence (UUI) in subjects with / without BPH, subjects with / without prior (ACH) use, and subjects with / without prior β-3 (B3) agonist use are shown in Table 23. Subjects who had used ACH or B3 agonists in the past 12 months had a greater reduction in UUI after taking vibergron than subjects taking placebo.

[0433] Table 23. UUI: Overall and by subgroup (Descriptive statistics: Week 12 CFB mean (Q1, Q3))

[0434] As shown in Table 23, subjects with prior ACH use experienced a reduction of approximately 1.75 times the average number of UUI episodes over a 24-hour period compared to subjects treated with placebo, while subjects with prior B3 use experienced a reduction of between approximately 5 and 6 times the average number of UUI episodes over a 24-hour period compared to subjects treated with placebo.

[0435] Table 24 and Figure 19 The total time to the first 75% reduction in UUI seizures is shown. Table 25 shows the estimated time to the first 75% reduction in UUI seizures at weeks 2, 4, 8, and 12, and Table 26 shows the analysis of 75% UUI responders classified by baseline UUI severity up to week 12.

[0436] Table 24. Time to first occurrence of UUI seizures reduced by 75% (overall)

[0437] Note: NE = Unpredictable; the subject was examined at the last follow-up visit.

[0438] [1] The Cox model includes sex as a covariate. A hazard ratio estimate >1 indicates that more treated subjects achieved a 75% reduction compared to placebo.

[0439] [2] The stratified log-rank includes gender as a covariate.

[0440] Table 25. Time to first 75% reduction in UUI seizure frequency (estimates for weeks 2, 4, 8, and 12)

[0441] Table 26. Analysis of 75% of UUI respondents by baseline UUI severity (up to week 12)

[0442] [1] Proportional differences and corresponding CIs and P-values ​​were calculated using Cochran-Mantel-Haenszel risk difference estimates stratified by sex (female vs. male), with weights proposed by Greenland and Robins. - MIs were used to imput values ​​missing for any reason within the weeks analyzed. - The frequencies presented and the denominators used for percentages are based on patients in FAS-I, baseline UUI category, and randomization.

[0443] Table 27 shows the total time to first 100% reduction in UUI. Table 28 shows the estimated time to first 100% reduction in UUI attacks at weeks 2, 4, 8, and 12, and Table 29 shows the analysis of 100% UUI responders categorized by baseline UUI severity at week 12.

[0444] Table 27. Time to 100% reduction in the first occurrence of UUI seizures (overall)

[0445] Note: NE = Unpredictable; the subject was examined at the last follow-up visit.

[0446] [1] The Cox model includes sex as a covariate. A hazard ratio estimate >1 indicates that more treated subjects achieved a 100% reduction compared to placebo.

[0447] [2] The stratified log-rank includes gender as a covariate.

[0448] Table 28. Time to 100% reduction in the first occurrence of UUI seizures (estimates for weeks 2, 4, 8, and 12)

[0449] Table 29. Analysis of 100% UUI Responders by Baseline UUI Severity (up to Week 12)

[0450] [1] Proportional differences and corresponding CIs and P-values ​​were calculated using Cochran-Mantel-Haenszel risk difference estimates stratified by sex (female vs. male), with weights proposed by Greenland and Robins. - MIs were used to imput values ​​missing for any reason within the weeks analyzed. - The frequencies presented and the denominators used for percentages are based on patients in FAS-I, baseline UUI category, and randomization.

[0451] Table 30 and Figure 20The total time to the first 50% reduction in urinary urgency is shown. Table 31 shows the estimated time to the first 50% reduction in urinary urgency in weeks 2, 4, 8, and 12.

[0452] Table 30. Time to first 50% reduction in urinary urgency (overall)

[0453] Note: NE = Unpredictable; the subject was examined at the last follow-up visit.

[0454] [1] The Cox model includes sex as a covariate. A hazard ratio estimate >1 indicates that more treated subjects achieved a 50% reduction compared to placebo.

[0455] [2] The stratified log-rank includes gender as a covariate.

[0456] Table 31. Time to first 50% reduction in urinary urgency (estimated at weeks 2, 4, 8, and 12)

[0457] Note: NE = Unpredictable; the subject was examined at the last follow-up visit.

[0458] Variations in daily urination in several subgroups are shown in Tables 32–38. Subjects aged 65 years or older who were given vebeprofen showed a statistically significant reduction in urination compared to subjects in the same age group who were given tolterodine.

[0459] Table 32. Urination: Overall and by subgroup

[0460] 1 Age categories by treatment interaction were statistically significant. No other covariates were statistically significant as major effects or as subgroups by treatment interaction. Note: n represents the number of subjects in each treatment group at week 12.

[0461] 2 Post-event analysis Unexpectedly, > Subjects aged 65 years had a greater reduction in urination than subjects younger than 65 years.

[0462] Table 33. Voiding: Overall and by subgroup (mean LS of CFB at week 12 (95% CI))

[0463] 1 Post-event analysis Table 34. Urination: Overall and by subgroup (Descriptive statistics: mean CFB at week 12 (Q1, Q3))

[0464] Table 35. Urination: <65 years old relative to > 65 years old (descriptive statistics)

[0465] Table 36. Urination: Females vs. Males (Descriptive Statistics)

[0466] Table 37. Urination: Overall and by subgroup (Descriptive statistics: mean CFB at week 12 (Q1, Q3))

[0467] Table 38. Urination: Men with and without BPH (descriptive statistics)

[0468] Results for certain subgroups are shown in Table 39. A greater reduction in urination and UUI episodes was observed in the subgroup treated with vebergellon compared to the groups treated with tolterodine or placebo.

[0469] Table 39. Vibegrine efficacy in some subgroups during week 12

[0470] a During the previous 12 months b Calculate the total number of such events for a complete log day divided by the number of complete days. c Post-event analysis As shown in Table 39, subjects with prior ACH use experienced a reduction of approximately 0.7 times more in the average number of urinations over a 24-hour period compared to subjects treated with placebo, while subjects with prior B3 use experienced a reduction of approximately 2.9 times more in the average number of urinations over a 24-hour period compared to subjects treated with placebo.

[0471] Surprisingly, treated subjects (those previously treated with ACH or B3 agonists) showed improved reductions in voiding and / or UUI episodes compared to untreated subjects. This presents an unexpected benefit for patients who have sought other treatments, have not yet been successfully treated, and therefore have unmet needs.

[0472] Similarly, surprisingly, subjects ≥65 years of age treated with vebergellon showed improvements in reductions in voiding, urgency, and UUI episodes compared to those treated with placebo. This is significant because a higher number of patients experienced OAB symptoms in this demographic group.

[0473] Compared with placebo, vebergerone achieved statistical significance for all seven secondary endpoints: (1) reduction in daily urinary urgency episodes; (2) 75% and 100% reduction in UUI; (3) 50% reduction in daily urinary urgency; (4) reduction in daily total incontinence; (5) OAB-q response score; and (6) mean volume of urine per void. For example, data on the reduction in urinary urgency episodes are shown in Table 40 and Figure 6 and Figure 7 As shown in the image.

[0474] Table 40. Change in the average daily number of urinary urgency episodes from baseline (least squared CFB mean at week 12)

[0475] Data on the reduction in urinary urgency episodes in the dry group are shown in Tables 41 and 42. Figure 21 As shown in the image.

[0476] Table 41. Change in the average daily number of urinary urgency episodes from baseline in the dry group (least squared CFB mean at week 12)

[0477] The covariates included in the repeated measures mixed model are the number of study visits, the baseline number of urinary urgency episodes, and the treatment interactions through the study visits.

[0478] Hypothesis testing was performed on vebergerone-placebo.

[0479] The comparison between tolterodine ER and placebo is considered descriptive.

[0480] The reduction in urinary urgency in the dry group categorized by age group is shown in Table 42.

[0481] Table 42. Reduction in urinary urgency in the dry population by age group (change from baseline to week 12)

[0482] Note: The covariates included in the repeated measures mixed model are age category, study visits, baseline number of urinary urgency episodes, and interaction items.

[0483] Data on 50% of patients with dry OAB who responded to urinary urgency are shown in Table 43.

[0484] Table 43. Analysis of 50% of respondents with urinary urgency in the dry population

[0485] [1] Proportional differences and corresponding CIs and p-values ​​were calculated using Cochran-Mantel-Haenszel risk difference estimates stratified by sex (females vs. males), with weights proposed by Greenland and Robins. - MIs were used to imputate values ​​missing for any reason within the weeks analyzed. - The frequencies presented and the denominators used for percentages are based on patients and randomized treatments in the FAS.

[0486] Data on the reduction in urinary urgency episodes in 75% of UUI responders are shown in Table 44.

[0487] Table 44. Change in the average number of urinary urgency episodes per day from baseline in 75% of UUI responders

[0488] These analyses only included subjects who were considered 75% UUI responders at week 12 based on unadjusted interpolation values.

[0489] The covariates included in the repeated measures mixed model are the number of study visits, the baseline number of urinary urgency episodes, and the treatment interactions through the study visits.

[0490] The change in average displacement of 75% of UUI respondents from baseline to week 12 is shown in Table 45.

[0491] Table 45. Change in average voiding volume per urination from baseline in 75% of UUI responders (from baseline to week 12)

[0492] These analyses only included subjects who were considered 75% UUI responders at week 12 based on unadjusted interpolation values.

[0493] The covariates included in the repeated measures mixed model are study visits, region, baseline mean output, and treatments that interact with the study visits.

[0494] The changes in PGI-control among 75% of UUI respondents are shown in Table 46, while the changes in OAB-q coping among 75% of UUI respondents at week 12 are shown in Table 47. The changes in OAB-q symptom distress among 75% of UUI respondents at week 12 are shown in Table 48.

[0495] Table 46. PGI-Control Changes from Baseline for 75% of UUI Responders

[0496] These analyses only included subjects who were considered 75% UUI responders at week 12 based on unadjusted interpolation values.

[0497] The covariates included in the repeated measures mixed model are the study visit, baseline PGI-control score, and treatments that interact with the study visit.

[0498] Table 47. Changes in OAB-q responses among 75% of UUI respondents (from baseline to week 12)

[0499] These analyses only included subjects who were considered 75% UUI responders at week 12 based on unadjusted interpolation values.

[0500] The covariates included in the ANCOVA model are region and baseline score.

[0501] Table 48. Changes in OAB-q symptom distress in 75% of UUI responders (from baseline to week 12)

[0502] These analyses only included subjects who were considered 75% UUI responders at week 12 based on unadjusted interpolation values.

[0503] The covariates included in the ANCOVA model are region and baseline score.

[0504] Data on the reduction of urinary urgency episodes in certain subgroups are shown in Tables 49 and 50.

[0505] Table 49. Urinary urgency episodes: Overall and by subgroup (Descriptive statistics: mean CFB at week 12 (Q1, Q3))

[0506] Table 50. Daily episodes of urinary urgency: Reduction from baseline at week 12 (LS mean, (SE))

[0507] Data on complete incontinence are in Table 51 and Figure 9 As shown in Table 35, after 12 weeks of treatment, the mean change in total incontinence per day from baseline was reduced by 2.3 episodes. In the vebegrin 75 mg group, the placebo-adjusted mean number of total incontinence episodes per day was significantly reduced by -0.7 episodes at week 12 (SE, 0.16; P < 0.0001, relative to placebo), which was numerically greater than the reduction of -0.5 episodes in the tolterodine group (SE, 0.17; P = 0.0074 relative to placebo) (Table 35). A rapid and statistically significant improvement in total incontinence per day was observed in the vebegrin group at week 2 (-0.7 episodes, placebo-adjusted) and remained statistically significant at all time points, including week 12.

[0508] For mean displacement (mL), the placebo-adjusted mean change from baseline was significantly improved (increased) by 21.2 mL at week 12 in the vebergellon 75 mg group (SD, 3.52; P < 0.0001 relative to placebo), which was also numerically greater than that in the tolterodine group, 13.3 mL (SD, 3.76; P < 0.001 relative to placebo) (Table 36).

[0509] Table 51. Variation in the average number of complete incontinence days from baseline (least square CFB mean at weeks 2, 4, 8, and 12)

[0510] Table 52 shows the analysis of 75% of respondents with complete incontinence, while Tables 54-57 show the data for 50% of respondents.

[0511] Table 52. Analysis of 75% of respondents with complete incontinence

[0512] [1] Cochran-Mantel-Haenszel risk difference estimates (females vs. males) stratified by sex were used to calculate the proportion differences and corresponding CIs and p-values, with weights proposed by Greenland and Robins.

[0513] MI has been used to interpolate values ​​that are missing for any reason within the week number being analyzed.

[0514] The frequency of presentation and the denominator used for percentages are based on patients and randomized treatments in FAS-I.

[0515] Table 53. Change in the average number of urinary urgency episodes per day from baseline in 50% of respondents with complete incontinence

[0516] Note: - These analyses only include subjects who were considered to be 50% complete incontinence responders at week 12 based on unadjusted imputation values. - Covariates included in the repeated measures mixed model are study visits, baseline number of urinary urgency episodes, and treatment interaction through study visits.

[0517] Table 54. Changes in OAB-q coping scores from baseline in 50% of participants with complete incontinence (from baseline to week 12)

[0518] Note: These analyses only include subjects who were considered to be 50% complete incontinence responders at week 12 based on unadjusted imputation values.

[0519] The covariates included in the ANCOVA model are region and baseline score.

[0520] Table 55. Changes in OAB-q symptom distress scores from baseline in 50% of complete incontinence responders (changes from baseline to week 12)

[0521] Note: These analyses only include subjects who were considered to be 50% complete incontinence responders at week 12 based on unadjusted imputation values.

[0522] The covariates included in the ANCOVA model are region and baseline score.

[0523] Table 56. Change in mean volume per void from baseline in 50% of respondents with complete incontinence (from baseline to week 12)

[0524] Note: These analyses only include subjects who were considered to be 50% complete incontinence responders at week 12 based on unadjusted imputation values.

[0525] The covariates included in the repeated measures mixed model are study visits, region, baseline mean output, and treatments that interact with the study visits.

[0526] The variation in dry log days among 50% of the completely incontinent responders is shown in Table 57.

[0527] Table 57. Percentage change in dry log days among 50% of complete incontinence responders (from baseline to week 12)

[0528] Note: These analyses only include subjects who were considered to be 50% complete incontinence responders at week 12 based on unadjusted imputation values.

[0529] The covariates included in the repeated measures mixed model are study visits, the percentage of baseline dry log days, and treatments that interacted with the study visits.

[0530] Table 58 and Figure 10 The diagram shows the variation in average urine volume per urination.

[0531] Table 58. Changes in mean volume per urination (mL) from baseline (least squared CFB mean at weeks 2, 4, 8 and 12)

[0532] Patients treated with vebergalone also showed improvements in OAB-q coping scores (see Table 59). Compared with placebo, vebergalone demonstrated statistically significant improvements in the distress scale (p<0.0001), anxiety scale (p<0.0001), sleep scale (p<0.001), and coping scale (p=0.0038), as well as the total HRQL score (p<0.001), at week 12 (see Table 60). For the HRQL social interaction subscale, the difference in the mean LS between vebergalone and placebo was numerically improved, but did not reach statistical significance. P =0.1116). For all OAB-q scales measured, vebergelone was numerically superior to tolterodine. These patients reported improvements in QoL observed after treatment with vebergelone, which, compared to placebo, were similar to the significant improvements seen in the co-primary power endpoints of changes in the mean number of voiding and UUI episodes from baseline.

[0533] Table 59. Changes in OAB-q response scores from baseline (week 12 CFB least squares mean)

[0534] In the OAB-q coping score, a higher score corresponds to a higher quality of life.

[0535] The covariates included in the repeated measures mixed model are study visit, OAB type, gender, region, baseline OAB-q response score, and treatment interaction through the study visit.

[0536] Table 60. Changes in OAB-q scores from baseline (week 12 CFB least squares mean)

[0537] The covariates included in the repeated measures mixed model are study visit, OAB type, gender, region, baseline OAB-q response score, and treatment interaction through the study visit.

[0538] For symptom distress, higher scores correspond to more distressing symptoms. For other scores, higher values ​​correspond to higher quality of life, and lower scores indicate a lower amount of distress caused by symptoms.

[0539] Table 61 shows the OAB-q proportion of respondents at week 12. For the symptom distress score, a respondent was defined as having a change of ≥10 from baseline. For the symptom distress score, a respondent was defined as having a change of ≤10 from baseline. A higher proportion of patients indicates a favorable response.

[0540] As shown in the table, the odds ratio was statistically significant in the comparison of vebegliflozin and placebo scores on symptom distress and coping sub-items.

[0541] Table 61. OAB-q proportion of respondents in week 12 (full analysis set)

[0542] [1] 95% of the two-sided CI for the difference in responder proportions is based on the normal approximation.

[0543] [2] The odds ratio, corresponding 95% CI and P-value were derived from a process logistic regression model that included treatment, sex, OAB type and baseline value.

[0544] Note: Post-hoc analysis using the full analysis set; percentages are based on the number of subjects with non-missing baseline and week 12 values.

[0545] A comparison of the percentages of respondents who experienced a 75% and 100% reduction in UUI episodes and a 50% reduction in urinary urgency episodes. Figure 8 As shown in the figure, at week 12, compared with placebo (32.8%) and tolterodine (42.2%), the proportion of patients (49.3%) in the vebegliflozin 75 mg group who achieved a clinically meaningful (75% or more) reduction in daily UUI episodes (UUI responders) was the highest (49.3%). Vebegliflozin demonstrated rapid onset of action, with a statistically significant number of UUI responders at week 2 compared with placebo (p<0.01).

[0546] Vibergron is well tolerated with very few adverse events (>2% and greater than placebo). A summary of treatment-emergent adverse events is shown in Table 62. The most common adverse events (>2% and greater than placebo) were headache, nasopharyngitis, diarrhea, and nausea (see Table 63). Data on other adverse events are listed in Table 64. Adverse events in subjects aged ≥75 years are shown in Table 65.

[0547] Table 62. Summary of treatment of acute adverse events

[0548] Table 63. Comparison of the most common adverse events (≥2% in vebegliflozin and > placebo)

[0549] Table 64. Comparison of other adverse events (≥2% in vebergelone and > placebo plus all clinically significant AEs)

[0550] b Clinically relevant adverse events (AEs) Table 65. Summary of treatment-emergent adverse events in patients ≥75 years of age

[0551] No difference was observed between placebo and placebo in adverse events of hypertension, elevated blood pressure, and urinary tract infection. The dropout rate due to AEs was 1.1% for placebo, 1.5% for vebegliflozin, and 3.0% for tolterodine. Patients with at least one serious AE were placebo (1.1%), vebegliflozin (1.5%), and tolterodine (2.3%). Tachycardia was reported only in the tolterodine treatment group (0.2%).

[0552] Data on the vital signs of the subjects, including heart rate and blood pressure, are shown in Tables 66-74.

[0553] Table 66. Heart rate changes from baseline at week 12

[0554] Table 67. Subgroup heart rate changes from baseline at week 12

[0555] a Defined as an average systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg between two consecutive visits.

[0556] Table 68. Changes in heart rate classification from baseline at week 12

[0557] bpm = beats per minute Categorical changes were based on three consecutive post-baseline visits, and patients were counted in all applicable categories (e.g., if a patient had an increase of 12 units, the patient was counted in both the ≥ 5 unit column and the ≥ 10 unit column).

[0558] Table 69. Changes in systolic blood pressure from baseline at week 12

[0559] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0560] Table 70. Subgroup systolic blood pressure changes from baseline at week 12

[0561] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0562] a Defined as an average systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg between two consecutive visits.

[0563] Table 71. Changes in systolic blood pressure from baseline at week 12

[0564] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0565] Categorical changes were based on three consecutive post-baseline visits, and patients were counted in all applicable categories (e.g., if a patient had an increase of 12 units, the patient was counted in both the ≥ 5 unit column and the ≥ 10 unit column).

[0566] Table 72. Changes in diastolic blood pressure from baseline at week 12

[0567] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0568] Table 73. Subgroup diastolic blood pressure changes from baseline at week 12

[0569] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0570] aDefined as an average systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg between two consecutive visits.

[0571] Table 74. Classification of changes in diastolic blood pressure from baseline at week 12

[0572] Blood pressure assessments were performed in triplicate at each visit, and the average value was taken.

[0573] Categorical changes were based on three consecutive post-baseline visits, and patients were counted in all applicable categories (e.g., if a patient had an increase of 12 units, the patient was counted in both the ≥ 5 unit column and the ≥ 10 unit column).

[0574] Data on post-expiratory residual urine (PVR) for all subjects and subgroups are shown in Tables 75-77.

[0575] Table 75. Changes in post-void residual urine volume (PVR) from baseline to week 12.

[0576] Note that this protocol requires a baseline PVR of less than 150 mL. *At baseline, the number of patients in each treatment group (placebo, vibergron, and tolterodine) was 539, 544, and 430, respectively. Table 76. Changes in post-void residual urine volume (PVR) in women from baseline to week 12.

[0577] Note that this protocol requires a baseline PVR of less than 150 mL. *At baseline, the number of patients in each treatment group (placebo, vibergron, and tolterodine) was 459, 462, and 364, respectively. Table 77. Changes in post-void residual urine volume (PVR) in males from baseline to week 12.

[0578] Note that this protocol requires a baseline PVR of less than 150 mL. *At baseline, the number of patients (n) in each treatment group for placebo, vibergrenone, and tolterodine were 80, 82, and 66, respectively. Table 78. Changes in post-void residual urine volume (PVR) from baseline to week 12 in men with a history of BPH.

[0579] Note that this protocol requires a baseline PVR of less than 150 mL. Overall, vebergerone demonstrated strong efficacy in all OAB endpoints. (See Table 79) Table 79. Mean LS change from baseline at week 12 (placebo adjusted)

[0580] 1. Common primary endpoint; 2. Secondary endpoint; LS = Least Squares.

[0581] Compared with placebo, once-daily vebergalone 75 mg demonstrated significantly better potency across three secondary endpoints (and two co-primary endpoints), indicating further benefit of vebergalone for patients with uncontrolled urination (UUI). Vebergalone 75 mg demonstrated a statistically significant reduction in total incontinence episodes at week 2, and this significance remained throughout the 12-week treatment period. Vebergalone 75 mg demonstrated a clear increase in volume per void, a relatively objective measure of bladder capacity. Total incontinence episodes were reduced by half relative to baseline in the vebergalone group, and nearly half of the patients with UUI at baseline treated with vebergalone experienced at least a 75% reduction in UUI episodes after 12 weeks of vebergalone therapy. Vebergalone was well tolerated with very few adverse events (>2%), which were greater than those with placebo.

[0582] Furthermore, at week 12, once-daily vebergellon 75 mg showed statistically significant improvements compared to placebo in OAB-q coping scale, anxiety scale, sleep scale, symptom distress scale, and total HRQL score. These results demonstrate that 75 mg of vebergellon can objectively improve symptoms of OAB (urinary frequency, urgency, UUI) and increase QoL in patients with OAB.

[0583] Example 7 A double-blind, active-drug-controlled, multicenter, 40-week extension study based on a 12-week maternal study was conducted to evaluate the safety, tolerability, and potency of vebegliflozin 75 mg in men and women with overactive bladder (OAB). A phase 3, double-blind, active-drug-controlled, multicenter study was conducted in men and women with overactive bladder as an extension of the study described in Example 6 (“Mother Study”). Approximately 500 men and women with overactive bladder who had completed 12 weeks in the Mother Study were permitted to enroll at approximately 110 study sites in the United States.

[0584] All subjects randomized to vebergelone or tolterodine ER 4 mg in the parent study continued their same treatment. Subjects randomized to placebo in the parent study were randomized 1:1 to vebergelone or tolterodine, stratified by sex and baseline OAB type.

[0585] The primary endpoint was to evaluate the safety and tolerability of vebegrin in patients with symptoms of open obstructive urination (OAB) for up to 52 weeks. Secondary endpoints were to evaluate the mean number of voiding, urge incontinence (UUI) episodes, urgency episodes, and total incontinence episodes at week 52 as CFB. All CFB calculations used baseline values ​​from the maternal study.

[0586] Table 80 shows the population statistics for the overall group, while Table 81 shows the population statistics for the Vibergron group and the Tolterodine group.

[0587] Table 80. Population statistics of the overall group

[0588] Security set extension Table 81. Demographic data of the Vibergron and Tolterodin groups

[0589] Safety set expansion; baseline hypertension is based on baseline vital signs. Pre-existing hypertension is based on baseline vital signs and prior medical history. Table 82 shows the subject configuration for the overall group, while Table 83 shows the subject configuration for the vebegliflozin group and the tolterodine group.

[0590] Table 82. Subject configuration of the overall group

[0591] The randomization set was expanded; some reasons for discontinuation were not shown (e.g., patient withdrawal due to PI or sponsor, protocol bias, or lack of efficacy). Table 83. Subject configuration of the overall group

[0592] The randomization set was expanded; some reasons for discontinuation were not shown (e.g., patient withdrawal due to PI or sponsor, protocol bias, or lack of efficacy). Tables 84 through 87 show the adverse events that occurred during the study period. As shown in these tables, there was no significant difference between vebegliflozin and tolterodine in terms of hypertension.

[0593] Table 84. Summary of Treatment of Emergency Adverse Events

[0594] Security Analysis Set Extension SAE = Serious Adverse Event TEAE = Treatment for acute adverse events Table 85. Most common adverse events (in groups with >2% of vibergron cases)

[0595] Safety analysis set expansion; representing the number of patients Table 86. Selection of Adverse Events

[0596] Analyze set expansion; representing the number of patients Table 87. Adverse events leading to the discontinuation of investigational drugs

[0597] Safety analysis set expansion; representing the number of patients like Figures 15-18 As shown in Tables 88-95, baseline-adjusted changes were maintained over 52 weeks across all four efficacy endpoints (voidurization, UUI, urgency, and complete incontinence). Furthermore, vebeprofone demonstrated numerically better efficacy than tolterodine in all four categories.

[0598] Table 88. Urination in Week 52

[0599] Full analysis set extended SD = standard deviation Table 89. Decrease in urination during week 52

[0600] Full analysis set extension, CFB least squares mean at week 52. Covariates included in the repeated measures mixed model are study visits, treatment, treatment per study visit, baseline, OAB type, and sex.

[0601] Table 90. UUI onset in week 52

[0602] Full Analytical Set Extension SD = Standard Deviation Table 91. Reduction in UUI attacks in week 52

[0603] Full analysis set extension for incontinence, CFB least squares mean at week 52. Covariates included in the repeated measures mixed model are study visits, treatment, treatment interaction through study visits, baseline, and sex. Table 92. Urinary urgency episodes in week 52

[0604] Full Analytical Set Extension SD = Standard Deviation Table 93. Reduction in urinary urgency episodes at week 52

[0605] Full analysis set extension, CFB least squares mean at week 52. Covariates included in the repeated measures mixed model are study visits, treatment, treatment through study visit interactions, baseline, OAB type, and gender. Table 94: Onset of complete urinary incontinence in week 52

[0606] Full analysis set extension. SD = Standard Deviation Table 95. Reduction in episodes of complete urinary incontinence at week 52

[0607] Full analysis set extension for incontinence, CFB least squares mean at week 52. Covariates included in the repeated measures mixed model are study visits, treatment, treatment interaction through study visits, baseline, and sex. Table 96 shows the endpoints for urinary urgency and UUI responders at week 52.

[0608] Table 96. Urinary urgency and UUI responder endpoints at week 52

[0609] Full analytic set extension, incontinence full analytic set extension, multiple imputation of missing values As shown in Table 97, vebergerone demonstrated strong efficacy against all OAB endpoints at week 52.

[0610] Table 97. OAB endpoint in week 52

[0611] Table 98 shows the week 52 response sub-scores from the Quality of Life Long Scale (OABq-LF).

[0612] Table 98. Week 52 OAB-q LF Response Item Scoring

[0613] Full analysis set expansion; baseline values ​​from parent study. SD = Standard Deviation Example 8 A phase 1, double-blind, placebo-controlled study was conducted to evaluate the effects of vilbergerone on blood pressure and heart rate in subjects with overactive bladder (OAB). A phase 1, double-blind, placebo-controlled, multicenter study was conducted in men and women with overactive bladder. A total of 214 patients were randomized to approximately 10 study sites to enter one of two study groups (108 receiving placebo and 106 receiving 75 mg of vebergellon) for a 28-day treatment period.

[0614] This study evaluated the effects of vebegliflozin on blood pressure and heart rate. Objectives and endpoints are described below. The “daytime average” ABPM endpoint was calculated as the average of all valid ABPM readings taken while the subject was awake during the 24-hour monitoring period. The “24-hour average” ABPM endpoint was calculated as the average of all valid ABPM readings taken during the 24-hour monitoring period. The “maximum average” ABPM endpoint was calculated as the T… 最大 The maximum hourly average during the window period (0.5 to 6.5 hours after baseline cuff-fitting, and 0.5 to 6.5 hours after day 28).

[0615]

[0616] 8.1 Qualification Standards To be eligible to participate in this study, patients must have met all of the following inclusion criteria and not meet any of the following exclusion criteria prior to recruitment.

[0617] 8.1.1 Inclusion Criteria 1. Able to provide written informed consent, which includes compliance with the requirements and limitations listed in the consent form.

[0618] 2. Men or women aged 40 to 75 years (inclusive) at the time of screening (Visit 1). Note: Up to 30% of participants may be male.

[0619] 3. Subjects with a history of OAB. Note: OAB is defined as urinary urgency, with or without urge incontinence (UUI), usually associated with urinary frequency and nocturia.

[0620] 4. Based on bladder scan or ultrasound, post-void residual urine (PVR) should be at or below 100 mL during screening (Visit 1).

[0621] 5. Female participants are eligible to participate if they meet the following criteria: • Not of reproductive potential is defined as a premenopausal woman with a history of bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries), or hysterectomy; or a postmenopausal woman defined as having experienced spontaneous amenorrhea for 12 months. A recorded verbal medical history from the subject is acceptable.

[0622] • The female subject is of childbearing potential and agrees to use one of the contraceptive methods listed in Section 5.6.1 for an appropriate duration (as determined by the product label or the investigator) prior to initiation of medication to adequately minimize the risk of pregnancy at that time. Female subjects must consent to the use of contraception until the follow-up visit.

[0623] 6. For women of reproductive potential: agree not to donate oocytes (eggs) for at least one month after the last dose of the study treatment.

[0624] 7. Male weight at screening (visit 1) > 50 kg, and the weight of women > 45 kg, and a body mass index of 18.5 kg / m² 2 -35.0 kg / m 2 (including 18.5 kg / m) 2 and 35.0 kg / m 2 Within the range of ).

[0625] 8. The mid-arm circumference must be < 45 cm, to accommodate the largest size of ABPM sleeves.

[0626] 8.1.2 Exclusion Criteria 1. Subjects have a positive drug screening result at screening (Visit 1) unless the drug has been prescribed to the subject and is not a prohibited drug.

[0627] 2. At screening (Visit 1), ALT (alanine aminotransferase) or AST (aspartate aminotransferase) is >2.0 times the upper limit of normal (ULN), or bilirubin (total bilirubin) is >1.5 × ULN (or >2.0 × ULN if secondary to Gilbert syndrome or with a pattern consistent with Gilbert syndrome).

[0628] 3. At screening (Visit 1), <30 mL / min / 1.73 m 2 The glomerular filtration rate (eGFR).

[0629] 4. Screening (Visit 1) for a history of regular alcohol consumption within the past 6 months. Regular alcohol consumption is defined as: • Men consume an average of >14 drinks per week, or women >7 drinks per week. One drink equals (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of spirits with a standard alcohol content of 80%.

[0630] 5. Subjects have received the investigational product or device (including placebo) within the following time periods prior to the first dosing day of the current study: 30 days, 5 half-lives of the investigational product, or twice the duration of the biological effect (whichever is longer).

[0631] 6. Currently involved in or already involved in research on vebergerone.

[0632] 7. Use of any of the following prohibited medications (appropriate clearance periods are also provided for these medications): anticholinergic drugs; smooth muscle relaxants; β-2-adrenergic agonists for the treatment of stress urinary incontinence; β-2-adrenergic agonists; synthetic antidiuretic hormones; β-3-adrenergic agonists; botulinum toxin in the detrusor muscle; CNS stimulants; cannabis products; α-1-agonists (oral); NSAIDs; herbal supplements.

[0633] 8. The dosage of certain medications has been changed within 4 weeks prior to screening (Visit 1) (e.g., tricyclic antidepressants or combinations; serotonin and / or norepinephrine reuptake inhibitors; inhaled anticholinergics; antihypertensives not listed as contraindicated; alpha-1 antagonists; 5-alpha reductase inhibitors; phosphodiesterase type 5 inhibitors), or the administration of any of these medications is planned to be started or changed during the study.

[0634] 9. A history of sensitivity to any research treatment or excipient or component thereof, or a history of drug allergy or other allergic reactions, which the researchers consider contraindicated for their participation.

[0635] 10. If heparin is used during PK sampling (for those subjects who consent to PK sampling), subjects with a history of heparin sensitivity or heparin-induced thrombocytopenia should not be recruited.

[0636] 11. Pregnant women identified at screening or before administration of medication by a positive serum (screening visit 1) or urine (day 1) human chorionic gonadotropin test.

[0637] 12. Breastfeeding women who actively breastfeed.

[0638] 13. Subjects with uncontrolled hypertension (systolic blood pressure >160 mmHg and / or diastolic blood pressure >95 mmHg) or a resting heart rate (based on pulse) >100 beats per minute at screening (visit 1).

[0639] 14. Subjects with pre-existing conditions that interfere with normal gastrointestinal anatomy, function, or motility (including gastric bypass), liver function, and / or kidney function (which may interfere with the absorption, metabolism, and / or excretion of the study treatment).

[0640] 15. Subjects with active urinary tract infection on day -1 (visit 2).

[0641] 16. History of serious mental illness or neurological disease.

[0642] 17. History of asthma or chronic obstructive pulmonary disease requiring the use of inhaled β-2 agonists.

[0643] 18. History of uncontrolled diabetes (HbA1c>9%) at screening (Visit 1).

[0644] 19. A history of cerebrovascular accident, transient ischemic attack, unstable angina, myocardial infarction, coronary intervention (e.g., coronary artery bypass grafting or percutaneous coronary intervention [e.g., angioplasty, stenting]) or neurovascular intervention (e.g., carotid artery stenting) within 6 months prior to the screening visit. Subjects with these conditions should have been receiving stable medical therapy for at least 3 months prior to the screening visit.

[0645] 20. Subjects whose occupations or recreational activities involve lifting heavy objects and who are unwilling to forgo participating in these activities on the study day when ABPM measurements are collected.

[0646] 21. Subjects whose occupation (i.e., night shift worker) or recreational activities involve sleeping for at least 8 consecutive hours between 7 p.m. and 11 p.m.

[0647] 22. Exclusion criteria for ECG screening (single repeat is allowed for eligibility):

[0648] • Wolff Parkinson-White syndrome [unless curative ablation treatment] or atrial fibrillation Sinus arrest >3 seconds 23. Post-screening urine volume (PVR) >100 mL at screening (Visit 1).

[0649] 24. Subjects who did not pass the ABPM device test based on the pass / fail criteria in the research reference manual.

[0650] 25. A history of chronic pain or long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) for pain treatment, except for permitted low-dose aspirin therapy. Chronic pain is defined as daily pain that impairs daily life and requires specific daily pain management (e.g., daily pain medication, or routine acupuncture, electrical stimulation therapy, etc.).

[0651] 26. Any other condition, therapy, laboratory abnormality or other situation that the researcher believes may interfere with a subject's ability to comply with research procedures or render participation in the study not in the best interests of the subject.

[0652] 8.2 Research Evaluation and Procedures 8.2.1. Research products and other research treatments The term 'investigation treatment' is used throughout the protocol to describe a single dose of vebergellon or placebo.

[0653]

[0654] a. Only applicable to clinically witnessed doses. 8.2.2. Randomization / Treatment Assignment Subjects were randomized in a 1:1 ratio to receive one of two treatments: • Vibergelon 75 mg • Placebo matched with vebergellon 75 mg Randomization was stratified based on age (≤55 years or >55 years), sex (male or female), and pre-existing hypertension (yes or no).

[0655] Use the following restrictions to cap recruitment: • Up to 30% of the recruited participants can be male. • The maximum number of participants can be capped at 55% of those with a prior history of hypertension and / or high blood pressure at baseline. 8.2.3. Time and Event Table Figure 11 A table of timelines and events for the study is shown.

[0656] 8.4 Security Considerations Safety was assessed by evaluating clinical laboratory tests, physical examinations, vital sign measurements from visits at different time points during the study, and by recording adverse events (AEs).

[0657] 8.5 Statistical Analysis The primary hypothesis is whether the change in mean daytime dynamic systolic blood pressure (CFB) from baseline to day 29 in the vebegliflozin group is less than 3.5 mmHg compared to the placebo group. The null and alternative statistical hypotheses are:

[0658] in μ v = Average daily CFB up to day 29 in the Vibergron group, and μ p= Mean daily CFB up to day 29 in the placebo group.

[0659] 8.6 Analyzing the Group Security Set (SAF) All participants who received at least one dose of the double-blind study treatment were enrolled in SAF. Participants were assigned to the treatment group corresponding to the study treatment they actually received. This population was used to summarize safety analyses collected during clinical visits and communications with field staff; a summary of baseline / demographic characteristics for SAF was also provided.

[0660] Full Analysis Set (FAS) All subjects who were randomized, received at least one dose of 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. Subjects were assigned to their randomized treatment group according to the intent-to-treat principle, regardless of the actual treatment received. This population was used for all analyses of ABPM measurements. If the FAS differed from the SAF, baseline / demographic characteristics were also provided for the FAS.

[0661] Pharmacokinetic population The PK population includes all subjects who have undergone plasma PK sampling and have evaluable concentration-time data for analysis.

[0662] 8.7 Final Analysis The final analysis was conducted after the study was completed and the final dataset was authorized.

[0663] The data were listed and summarized. Treatments were allocated based on the dosing schedule and were included in the data list. The list is categorized by subject, day, and time; summaries are provided by treatment, day, and time.

[0664] SAS system version 9.2 or later is used to analyze data and generate tables, graphs and lists.

[0665] 8.7.1 ABPM Analysis To analyze the ABPM endpoints (systolic and diastolic blood pressure and heart rate up to day 29 CFB), a generalized linear model (GLM) was used. FAS was used to analyze these endpoints; by definition, FAS has no missing data, therefore imputation of missing data was not required. The analytical model for each power endpoint included items such as treatment, age group (≤55 years vs. >55 years), sex (male vs. female), and pre-existing hypertension (yes vs. no), as well as baseline scores.

[0666] The main inference is derived from the treatment differences in CFB on day 29 from GLM. The estimated treatment differences are shown in the summary of statistical analysis along with two-sided 90% confidence intervals and relevant p-values. To test the main hypothesis in Section 8.5, the upper limit of the two-sided 90% confidence interval is compared with 3.5, and the null hypothesis is rejected if the upper limit is strictly less than 3.5.

[0667] The 24-hour mean dynamic baseline for systolic and diastolic blood pressure and heart rate is the arithmetic mean of all valid measurements taken between day -1 (when the cuff was worn) and day 1 (when the cuff was removed). The 24-hour mean for day 29 is the arithmetic mean of all valid measurements taken between day 28 (when the cuff was worn) and day 29 (when the cuff was removed).

[0668] Baseline time t 最大 The maximum SBP, DBP, and HR in the window are the maximum hourly averages of valid measurements taken from 0.5 hours to 6.5 hours after the cuff was worn on day -1. On day 28, t 最大 The maximum SBP, DBP, and HR in the window are the maximum hourly averages of the effective measurements from 0.5 hours to 6.5 hours after administration.

[0669] The mean daily dynamic baseline for systolic and diastolic blood pressure, as well as heart rate, is the arithmetic mean of all measurements taken during the time interval when the subject is awake. The same definition applies to measurements taken on day 29.

[0670] 8.8 Clinical Trial Data and Results The demographic data of the patients in this trial are shown in Table 99, and the subject configuration is shown in Table 100.

[0671] Table 99. Patient Demographic Data

[0672] SBP: Systolic blood pressure, DBP: Diastolic blood pressure, HR: Heart rate Table 100. Subject Configuration

[0673] Vibegliflozin achieved its primary endpoint: the mean change in daytime ambulatory systolic blood pressure from baseline during the treatment period was less than approximately 1 mmHg compared to the mean change in placebo-treated subjects, with an upper limit of the 90% confidence interval of less than 3.5 mmHg. Results are shown in Table 101 (full analysis set) and Table 102 (compliant protocol set).

[0674] Table 101. Mean diurnal variation of ABPM and SBP (mmHg) from baseline to day 28 - FAS

[0675] ABPM = Ambulatory blood pressure monitoring via Spacelabs 90207, SBP = Systolic blood pressure, LS mean = Least squares mean, CI = Confidence interval, FAS = Full analysis set Table 102. Mean diurnal ABPM SBP (mmHg) variation from baseline to day 28 - PPS

[0676] ABPM = Ambulatory blood pressure monitoring via Spacelabs 90207, SBP = Systolic blood pressure, LS mean = Least squares mean, CI = Confidence interval, PPS = Compliance protocol set Secondary endpoints describing changes in blood pressure and heart rate for the full analysis set and the conformity scheme set are shown in Tables 103 and 104. Figure 12 The 90% confidence intervals for treatment-related differences in ABPM systolic blood pressure from baseline on day 28 are shown. Figure 13 The treatment-related differences in ABPM diastolic blood pressure from baseline on day 28 are shown as 90% confidence intervals. Figure 14 The 90% confidence intervals are shown for the treatment-related differences in ABPM heart rate from baseline on day 28.

[0677] Table 103. Secondary endpoints of ABPM: changes from baseline to day 28

[0678] ABPM = Ambulatory Blood Pressure Monitoring, DBP = Diastolic Blood Pressure, HR = Heart Rate, SBP = Systolic Blood Pressure, LS Mean = Least Squares Mean, CI = Confidence Interval, FAS = Full Analysis Set Table 104. Maximum (0.5-hour to 6.5-hour) ABPM SBP (mmHg) variation from baseline to day 28 - PPS

[0679] ABPM = Ambulatory blood pressure monitoring via Spacelabs 90207, SBP = Systolic blood pressure, LS mean = Least squares mean, CI = Confidence interval, PPS = Compliance protocol set The categorized summary of changes from baseline on day 28, the study endpoint, is shown in Table 105.

[0680] Table 105. ABPM endpoint: Summary of changes from baseline on day 28

[0681] ABPM = Ambulatory Blood Pressure Monitoring, SBP = Systolic Blood Pressure, DBP = Diastolic Blood Pressure, HR = Heart Rate, FAS = Full Analysis Set Tables 106, 107, and 108 show the changes in clinical measurements of systolic blood pressure, diastolic blood pressure, and heart rate during the treatment period.

[0682] Table 106. Clinical vital signs: a summary of changes from baseline to day 28.

[0683] * n = Number of subjects with baseline and day 28 vital signs; SBP = Systolic blood pressure; DBP = Diastolic blood pressure; HR = Heart rate; CFB = Change from baseline; sd = Standard deviation; SAF = Safety set. Table 107. Summary of changes in clinical vital signs from baseline to end of treatment

[0684] * n = Number of subjects with baseline and treatment end assessments; SBP = Systolic blood pressure; DBP = Diastolic blood pressure; HR = Heart rate; CFB = Change from baseline; sd = Standard deviation; SAF = Safety set. Table 108. Clinical vital signs: a summary of changes from baseline after 3 consecutive visits over 28 days.

[0685] * n = Number of subjects with baseline and treatment end assessments; SBP = Systolic blood pressure; DBP = Diastolic blood pressure; HR = Heart rate; CFB = Change from baseline; sd = Standard deviation; SAF = Safety set. Changes in clinical vital signs in the subgroups are shown in Tables 109 to 114. For subjects weighing at least approximately 65.4 kg, systolic blood pressure increased between treatment and placebo. > 5 mmHg > 10 mmHg or > There was no difference in the number of subjects with a blood pressure of 15 mmHg. The same was true for subjects over 66 years of age.

[0686] Table 109 Clinical vital signs: Summary of changes in SBP from baseline to day 28 by subgroup

[0687] n = number of subjects with baseline and day 28 vital signs, SBP = systolic blood pressure, SAF = safety set, 25th percentile of eGFR = 72 mL / min / 1.73 m 2 The 25th percentile BW was 65.4 kg. Table 110. Clinical vital signs: Summary of changes in SBP from baseline to day 28 by subgroup

[0688] n = number of subjects with baseline and day 28 vital signs, SBP = systolic blood pressure, SAF = safety set, 75th percentile, age 66 years Table 111. Clinical vital signs: a summary of changes from baseline after 3 consecutive visits over 28 days.

[0689] n = Number of subjects with baseline and 3 post-baseline visits, SAF = Safety set, 25th percentile of eGFR = 72 mL / min / 1.73 m 2 The 25th percentile BW was 65.4 kg. Table 112. Clinical vital signs: a summary of changes from baseline after 3 consecutive visits over 28 days.

[0690] n = Number of participants with baseline and 3 post-baseline visits, SAF = Safety set, 75th percentile, age 66 years Table 113. Summary of changes in clinical vital signs (SBP) from baseline to the end of the treatment shift.

[0691] n = Number of subjects with baseline and any post-baseline visits, SAF = Safety set, SBP = Systolic blood pressure, eGFR, 25th percentile = 72 mL / min / 1.73 m 2 The 25th percentile BW was 65.4 kg. Table 114. Clinical vital signs (SBP): A summary of changes from baseline to the end of the treatment cycle.

[0692] n = Number of subjects with baseline and 3 post-baseline visits, SAF = Safety set, SBP = Systolic blood pressure, 75th percentile, age 66 years A summary of adverse events is shown in Tables 115, 116 and 117.

[0693] Table 115. Overall Treatment-Related Emergency Adverse Events

[0694] [1] Placebo: Increased blood pressure; Vibergron: 1.) Nausea, vomiting, dizziness; 2.) Back pain; 3.) Feeling hot and anxiety. Table 116. Most common adverse events: Vibergron >2% and > placebo

[0695] Table 117. Selected Adverse Events

[0696] Table 118 shows a comparison of QTc studies between Miraberon and Vibergron.

[0697] Table 118. Comparison of QTc studies – Miraberon and Vibergelon: BP and HR data in healthy subjects

[0698] The safety profile was consistent with the Phase 3 study described in Example 6, with one more adverse event (AE) in the vilbergerone group compared to the placebo group. Overall, this study confirms the safety profile of vilbergerone and has no clinically relevant effect on blood pressure.

[0699] The following are examples of some embodiments of the present invention: Implementation Scheme 1: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the treatment achieves at least one of (1) to (5) a change from baseline during the treatment period: (1) The average number of urinations per 24 hours changed from about -1.3 times to about -2.5 times; (2) When the subject was a wet OAB patient, the average number of UUI episodes per 24 hours varied from about -1.5 to about -2.5; (3) The average number of urinary urgency episodes per 24 hours varied from approximately -2.2 times to approximately -3.5 times; (4) The average number of episodes of complete incontinence per 24 hours varied from approximately -1.7 to approximately -2.7; and (5) The average volume of urine per urination varied from about 18 mL to about 30 mL.

[0700] Implementation Scheme 2: The method according to Implementation Scheme 1, wherein the treatment achieves at least two of the changes from baseline (1) to (5) during the treatment period.

[0701] Implementation Scheme 3: The method according to Implementation Scheme 2, wherein the treatment achieves changes from baseline (1) and (2) during the treatment period.

[0702] Implementation Scheme 4: The method according to any one of Implementation Schemes 1 to 3, wherein the average number of urinations per 24 hours varies from about -1.5 times to about -2.1 times, or preferably from about -1.6 times to about -2.0 times.

[0703] Implementation Scheme 5: The method according to any one of Implementation Schemes 1 to 4, wherein the average number of UUI attacks per 24 hours varies from about -1.7 times to about -2.3 times, or preferably from about -1.8 times to about -2.2 times.

[0704] Implementation Scheme 6: The method according to any one of Implementation Schemes 1 to 5, wherein the average number of urinary urgency episodes per 24 hours varies from about -2.4 times to about -3.0 times, or preferably from about -2.5 times to -2.9 times.

[0705] Implementation Scheme 7: The method according to any one of Implementation Schemes 1 to 6, wherein the average number of episodes of complete incontinence per 24 hours varies from about -1.9 times to about -2.5 times, or preferably from about -2.0 times to -2.4 times.

[0706] Implementation Scheme 8: The method according to any one of Implementation Schemes 1 to 7, wherein the average volume of each urination varies from about 20 mL to about 28 mL, or preferably from about 22 mL to about 26 mL.

[0707] Implementation Scheme 9: The method according to any one of Implementation Schemes 1 to 8, wherein the subject has symptoms selected from the group consisting of urge incontinence, urinary urgency, urinary frequency, or a combination thereof.

[0708] Implementation Plan 10: The method according to Implementation Plan 9, wherein the subject has symptoms of urge incontinence, urinary urgency, and urinary frequency.

[0709] Implementation Scheme 11: A method for reducing the average number of urinations per 24 hours in a subject suffering from overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to the subject in need during the treatment period.

[0710] Implementation Scheme 12: A method for reducing the average number of UUI episodes per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon to the subject as appropriate daily during the treatment period.

[0711] Implementation Scheme 13: A method for reducing the average number of urinary urgency episodes per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects who require it during the treatment period.

[0712] Implementation Plan 14: A method for reducing the average number of episodes of complete incontinence per 24 hours in subjects with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to subjects with appropriate need during the treatment period.

[0713] Implementation Scheme 15: A method for increasing the average volume of urine per void in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon to the subject as appropriate daily during the treatment period.

[0714] Implementation Scheme 16: The method according to any one of Implementation Schemes 1 to 15, wherein the subject is a human.

[0715] Implementation Scheme 17: The method according to Implementation Scheme 16, wherein the human being is female.

[0716] Implementation Scheme 18: The method according to Implementation Scheme 16, wherein the human being is male.

[0717] Implementation Scheme 19: The method according to any one of Implementation Schemes 16 to 18, wherein the human being is 65 years of age or older.

[0718] Implementation Scheme 20: The method according to any one of Implementation Schemes 16 to 18, wherein the human being is over 75 years of age.

[0719] Implementation Scheme 21: The method according to any one of Implementation Schemes 1 to 20, wherein the subject suffers from severe renal impairment.

[0720] Implementation Scheme 22: The method according to any one of Implementation Schemes 1 to 20, wherein the subject suffers from moderate renal impairment.

[0721] Implementation Scheme 23: The method according to any one of Implementation Schemes 1 to 22, wherein the subject is concurrently receiving a CYP3A / P-glycoprotein inhibitor.

[0722] Implementation Scheme 24: The method according to any one of Implementation Schemes 1 to 23, wherein the subject is concurrently receiving a CYP2D6 substrate.

[0723] Implementation Scheme 25: The method according to any one of Implementation Schemes 1 to 24, wherein the subject has received an anticholinergic drug for up to 12 months prior to administration of vilbegaron.

[0724] Implementation Scheme 26: The method according to any one of Implementation Schemes 1 to 25, wherein the subject has received a β-3 agonist other than vibegelone for up to 12 months prior to vibegelone administration.

[0725] Implementation Scheme 27: The method according to any one of Implementation Schemes 1 to 26, wherein vebegenone is applied once daily.

[0726] Implementation Scheme 28: The method according to any one of Implementation Schemes 1 to 27, wherein vibergron is applied as a free base.

[0727] Implementation Scheme 29: The method according to any one of Implementation Schemes 1 to 28, wherein vibergron is administered as a pharmaceutically acceptable salt.

[0728] Implementation Scheme 30: The method according to any one of Implementation Schemes 1 to 29, wherein the subject experiences the mean maximum change in systolic blood pressure from baseline during the treatment period, wherein the mean maximum change is less than 1 mmHg compared to the mean maximum change in a subject taking a placebo.

[0729] Implementation Scheme 31: The method according to any one of Implementation Schemes 1 to 29, wherein the subject experiences a mean maximum change of less than 8 mmHg in systolic blood pressure from baseline during the treatment period.

[0730] Implementation Scheme 32: The method according to any one of Implementation Schemes 1 to 29, wherein the subject experiences the mean maximum change in diastolic blood pressure from baseline during the treatment period, wherein the mean maximum change is less than 1 mmHg compared to the mean maximum change in a subject taking a placebo.

[0731] Implementation scheme 33: The method according to any one of implementation schemes 1 to 29, wherein the subject experiences a mean maximum change of less than 5 mmHg in diastolic blood pressure from baseline during the treatment period.

[0732] Implementation Scheme 34: The method according to any one of Implementation Schemes 1 to 33, wherein the treatment period is selected from the group consisting of 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, and 52 weeks.

[0733] Implementation Scheme 35: The method according to any one of Implementation Schemes 1 to 33, wherein vebegenol takes effect in about 4 weeks, about 3 weeks or about 2 weeks.

[0734] Implementation Scheme 36: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the treatment achieves at least one of variations (1) to (5) during a 12-week treatment period: (1) A reduction in the average number of urinations per 24 hours that is greater than or equal to the reduction achieved with tolterodine extended-release (ER) 4 mg; (2) When the subject was a wet OAB patient, the reduction in the average number of UUI attacks per 24 hours was greater than or equal to the reduction achieved with tolterodine ER 4 mg; (3) The reduction in the average number of urinary urgency episodes per 24 hours is greater than or equal to the reduction achieved with tolterodine ER 4 mg; (4) A reduction in the average number of episodes of complete incontinence per 24 hours, greater than or equal to the reduction achieved with tolterodine ER 4 mg; and (5) The increase in average volume of urine per urination is greater than or equal to the increase achieved with tolterodine ER 4 mg.

[0735] Implementation Scheme 37: The method according to Implementation Scheme 36, wherein the change achieved by the treatment is greater than the change achieved by using tolterodine ER 4 mg.

[0736] Implementation Scheme 38: The method according to Implementation Scheme 36, wherein the treatment achieves at least two of the changes from baseline (1) to (5) during the treatment period.

[0737] Implementation Scheme 39: The method according to Implementation Scheme 37, wherein the treatment achieves changes from baseline (2) and (4) during the treatment period.

[0738] Implementation Scheme 40: The method according to any one of Implementation Schemes 36 to 39, wherein the subject has symptoms selected from the group consisting of urge incontinence, urinary urgency, urinary frequency, or a combination thereof.

[0739] Implementation Scheme 41: The method according to Implementation Scheme 40, wherein the subject has symptoms of urge incontinence, urinary urgency and urinary frequency.

[0740] Implementation Scheme 42: A method for reducing the average number of urinations per 24 hours in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0741] Implementation Scheme 43: The method according to Implementation Scheme 42, wherein the subject is a human.

[0742] Implementation Scheme 44: The method according to Implementation Scheme 43, wherein the human is 65 years of age or older.

[0743] Implementation Scheme 45: The method described in Implementation Scheme 44, wherein the reduction in the average number of urinations over a 24-hour period is between approximately 1.5 times and approximately 2.0 times that achieved with placebo.

[0744] Implementation Scheme 46: The method according to Implementation Scheme 44, wherein the reduction in the average number of urinations over a 24-hour period is between approximately 1.0 to 1.5 times that achieved with tolterodine extended-release (ER) 4 mg.

[0745] Implementation Scheme 47: The method according to Implementation Scheme 43, wherein the subject has received an anticholinergic drug for up to 12 months prior to administration of vilbegaron.

[0746] Implementation Scheme 48: The method described in Implementation Scheme 47, wherein the reduction in the average number of urinations over a 24-hour period is between approximately 1.5 times and approximately 2.0 times that achieved with placebo.

[0747] Implementation Scheme 49: The method according to Implementation Scheme 47, wherein the reduction in the average number of urinations over a 24-hour period is between approximately 1.0-fold and approximately 1.5-fold compared to the reduction achieved with tolterodine extended-release (ER) 4 mg.

[0748] Implementation Scheme 50: The method according to Implementation Scheme 43, wherein the subject has received a β-3 agonist other than vilbegan for up to 12 months prior to vilbegan administration.

[0749] Implementation Scheme 51: The method described in Implementation Scheme 50, wherein the average number of urinations during the 24-hour period is between approximately 1 and approximately 4 fewer than the average number of urinations in subjects receiving a placebo.

[0750] Implementation Scheme 52: The method according to Implementation Scheme 50, wherein the reduction in the average number of urinations over a 24-hour period is between approximately 2.0 and approximately 2.5 times that achieved with tolterodine extended-release (ER) 4 mg.

[0751] Implementation Scheme 53: A method for reducing the average number of UUI episodes per 24 hours in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject in need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0752] Implementation Scheme 54: The method according to Implementation Scheme 53, wherein the subject is a human.

[0753] Implementation Scheme 55: The method according to Implementation Scheme 54, wherein the human is 65 years of age or older.

[0754] Implementation Scheme 56: The method described in Implementation Scheme 55, wherein the reduction in the average number of UUI attacks over a 24-hour period is between approximately 1.25 times and approximately 1.75 times that achieved with placebo.

[0755] Implementation Scheme 57: The method according to Implementation Scheme 55, wherein the subject has received an anticholinergic drug for up to 12 months prior to administration of vilbegaron.

[0756] Implementation Scheme 58: The method described in Implementation Scheme 57, wherein the reduction in the average number of UUI attacks over a 24-hour period is between approximately 1.50 times and approximately 2.0 times that achieved with placebo.

[0757] Implementation Scheme 59: The method according to Implementation Scheme 57, wherein the reduction in the average number of UUI attacks over a 24-hour period is between approximately 1.25 and approximately 1.75 times that achieved with tolterodine extended-release (ER) 4 mg.

[0758] Implementation Scheme 60: The method according to Implementation Scheme 55, wherein the subject has received a β-3 agonist other than vilbegan for up to 12 months prior to vilbegan administration.

[0759] Implementation Scheme 61: The method according to Implementation Scheme 60, wherein the reduction in the average number of UUI attacks over a 24-hour period is between approximately 4 and approximately 6 times that achieved with placebo.

[0760] Implementation Scheme 62: The method according to Implementation Scheme 60, wherein the reduction in the average number of UUI attacks over a 24-hour period is between approximately 1.5 to 3 times that achieved with tolterodine extended-release (ER) 4 mg.

[0761] Implementation Scheme 63: A method for reducing the average number of urinary urgency episodes per 24 hours in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0762] Implementation Scheme 64: A method for reducing the average number of episodes of complete incontinence per 24 hours in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject in need during a 12-week treatment period, wherein the reduction is greater than or equal to the reduction achieved with 4 mg of tolterodine extended-release (ER).

[0763] Implementation Scheme 65: A method for increasing the average volume of urine per void in a subject with overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject in need during a 12-week treatment period, wherein the increase is greater than or equal to the increase achieved with 4 mg of tolterodine extended-release (ER).

[0764] Implementation Scheme 66: The method according to any one of Implementation Schemes 63 to 65, wherein the subject is a human.

[0765] Implementation Scheme 67: The method according to Implementation Scheme 66, wherein the human being is female.

[0766] Implementation Scheme 68: The method according to Implementation Scheme 66, wherein the human being is male.

[0767] Implementation Scheme 69: The method according to any one of Implementation Schemes 63 to 68, wherein the human being is 65 years of age or older.

[0768] Implementation Scheme 70: The method according to any one of Implementation Schemes 63 to 68, wherein the human being is over 75 years of age.

[0769] Implementation Scheme 71: The method according to any one of Implementation Schemes 36 to 70, wherein the subject suffers from severe renal impairment.

[0770] Implementation Scheme 72: The method according to any one of Implementation Schemes 36 to 70, wherein the subject suffers from moderate renal impairment.

[0771] Implementation Scheme 73: The method according to any one of Implementation Schemes 36 to 72, wherein the subject is concurrently receiving a CYP3A / P-glycoprotein inhibitor.

[0772] Implementation Scheme 74: The method according to any one of Implementation Schemes 36 to 73, wherein the subject is concurrently receiving a CYP2D6 substrate.

[0773] Implementation Scheme 75: The method according to any one of Implementation Schemes 36 to 74, wherein vebegenone is applied once daily.

[0774] Implementation Scheme 76: The method according to any one of Implementation Schemes 36 to 75, wherein Vibergron is applied as a free base.

[0775] Implementation Scheme 77: The method according to any one of Implementation Schemes 36 to 76, wherein vibergron is administered as a pharmaceutically acceptable salt.

[0776] Implementation Scheme 78: The method according to any one of Implementation Schemes 36 to 77, wherein the subject experiences the mean maximum change in systolic blood pressure from baseline during the treatment period, wherein the mean maximum change is less than 1 mmHg compared to the mean maximum change in a subject taking a placebo.

[0777] Implementation Scheme 79: The method according to any one of Implementation Schemes 36 to 77, wherein the subject experiences a mean maximum change of less than 8 mmHg in systolic blood pressure from baseline during the treatment period.

[0778] Implementation Scheme 80: The method according to any one of Implementation Schemes 36 to 77, wherein the subject experiences the mean maximum change in diastolic blood pressure from baseline during the treatment period, wherein the mean maximum change is less than 1 mmHg compared to the mean maximum change in a subject taking a placebo.

[0779] Implementation Scheme 81: The method according to any one of Implementation Schemes 36 to 77, wherein the subject experiences a mean maximum change of less than 5 mmHg in diastolic blood pressure from baseline during the treatment period.

[0780] Implementation Scheme 82: The method according to any one of Implementation Schemes 1 to 81, wherein vebegenol takes effect in about 4 weeks, about 3 weeks or about 2 weeks.

[0781] Implementation Plan 83: A method for improving the response of a subject with overactive bladder compared to baseline, the method comprising orally administering 75 mg of vebergellon to a subject with appropriate need daily during the treatment period.

[0782] Implementation Scheme 84: The method according to Implementation Scheme 83, wherein the improvement is greater than that achieved with tolterodine extended-release (ER) 4 mg.

[0783] Implementation Plan 85: A method for improving sleep in a subject with overactive bladder compared to baseline, the method comprising orally administering 75 mg of vebergellon to the subject as appropriate daily during the treatment period.

[0784] Implementation Scheme 86: The method according to Implementation Scheme 85, wherein the improvement in sleep is greater than the improvement achieved with tolterodine extended-release (ER) 4 mg.

[0785] Implementation Plan 87: A method for improving the health-related quality of life (HRQL) of subjects with overactive bladder compared to baseline, the method comprising orally administering 75 mg of vebergellon daily to subjects with appropriate needs during the treatment period.

[0786] Implementation Scheme 88: The method according to Implementation Scheme 87, wherein the improvement in HRQL is greater than the improvement achieved with tolterodine extended-release (ER) 4 mg.

[0787] Implementation Scheme 89: The method described in Implementation Scheme 87 or 88, wherein HRQL includes one or more subscales selected from coping, anxiety, sleep, or social interaction.

[0788] Implementation Scheme 90: A method for reducing symptom distress in subjects with overactive bladder compared to baseline, the method comprising orally administering 75 mg of vebergellon daily to subjects with appropriate needs during the treatment period.

[0789] Implementation Scheme 91: The method according to Implementation Scheme 90, wherein the reduction in symptom distress is greater than the reduction achieved with tolterodine extended-release (ER) 4 mg.

[0790] Implementation Scheme 92: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a mean change in daytime ambulatory blood pressure from baseline of less than about 2.0 mmHg during the treatment period.

[0791] Implementation Scheme 93: The method according to Implementation Scheme 92, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure from baseline during the treatment period, and wherein the mean change has an upper limit of a 90% confidence interval of less than about 3.5 mmHg compared to the mean change in subjects taking placebo.

[0792] Implementation Scheme 94: The method described in Implementation Scheme 93, wherein the upper limit of the 90% confidence interval is less than approximately 2.5 mmHg.

[0793] Implementation Scheme 95: The method described in Implementation Scheme 93, wherein the upper limit of the 90% confidence interval is approximately 2.0 mmHg.

[0794] Implementation Scheme 96: The method according to Implementation Scheme 92, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure from baseline during the treatment period, and wherein the mean change is less than about 1.0 mmHg compared to the mean change in a subject taking a placebo.

[0795] Implementation Scheme 97: The method according to Implementation Scheme 96, wherein the average change is less than about 0.5 mmHg compared to the average change in subjects taking placebo.

[0796] Implementation Scheme 98: The method according to Implementation Scheme 92, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure from baseline of less than about 1.0 mmHg during the treatment period.

[0797] Implementation Scheme 99: The method according to Implementation Scheme 98, wherein the average variation is less than about 0.25 mmHg.

[0798] Implementation Scheme 100: The method according to Implementation Scheme 92, wherein the subject did not experience a greater average change in daytime dynamic diastolic blood pressure from baseline during the treatment period than the subject taking placebo.

[0799] Implementation scheme 101: The method according to implementation scheme 100, wherein the subject experiences a mean change in daytime dynamic diastolic blood pressure from baseline of less than about 0.75 mmHg during the treatment period.

[0800] Implementation Scheme 102: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a mean change in daytime dynamic heart rate from baseline of less than about 1.25 bpm during the treatment period.

[0801] Implementation Scheme 103: The method according to Implementation Scheme 102, wherein the subject experiences a mean change in daytime dynamic heart rate from baseline during the treatment period, and wherein the mean change is less than about 1.0 bpm compared to the mean change in a subject taking a placebo.

[0802] Implementation Scheme 104: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a mean change in 24-hour ambulatory blood pressure from baseline of less than about 2.0 mmHg during the treatment period.

[0803] Implementation Scheme 105: The method according to Implementation Scheme 104, wherein the subject experiences a 24-hour ambulatory mean change in systolic blood pressure from baseline during the treatment period, and wherein the mean change is less than about 0.75 mmHg compared to the mean change in a subject taking a placebo.

[0804] Implementation Scheme 106: The method according to Implementation Scheme 104, wherein the subject experiences a mean change from baseline of less than about 0.75 mmHg in 24-hour ambulatory systolic blood pressure during the treatment period.

[0805] Implementation Scheme 107: The method according to Implementation Scheme 104, wherein the subject did not experience a greater mean change in 24-hour dynamic diastolic blood pressure from baseline during the treatment period than the subject taking placebo.

[0806] Implementation scheme 108: The method according to implementation scheme 104, wherein the subject experiences a mean change of less than 0.75 mmHg in 24-hour dynamic diastolic blood pressure from baseline during the treatment period.

[0807] Implementation Scheme 109: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a 24-hour dynamic heart rate variation from baseline of less than about 1.0 bpm during the treatment period.

[0808] Implementation Scheme 110: The method according to Implementation Scheme 109, wherein the average change is less than about 1.0 bpm compared to the average change of subjects taking placebo.

[0809] Implementation Scheme 111: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a C-type bladder pressure of less than about 0.50 mmHg. 最大 The average change in systolic blood pressure.

[0810] Implementation Scheme 112: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a mean change in systolic blood pressure of less than about 0.50 mmHg over 24 hours.

[0811] Implementation Scheme 113: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a maximum mean change in blood pressure of less than about 2.0 mmHg from baseline within 0.5 to 6.5 hours after administration.

[0812] Implementation Scheme 114: The method according to Implementation Scheme 113, wherein the subject experiences the maximum mean change in systolic blood pressure from baseline within 0.5 hours to 6.5 hours after administration, and wherein the maximum mean change is less than about 1.75 mmHg compared to the maximum mean change in a subject taking placebo.

[0813] Implementation Scheme 115: The method according to Implementation Scheme 113, wherein the subject experiences a maximum average change in systolic blood pressure of less than about 2.0 mmHg from baseline within 0.5 hours to 6.5 hours after administration.

[0814] Implementation Scheme 116: The method according to Implementation Scheme 113, wherein the subject experiences the maximum mean change in diastolic blood pressure from baseline within 0.5 hours to 6.5 hours after administration, and wherein the maximum mean change is less than about 1.25 mmHg compared to the maximum mean change in a subject taking placebo.

[0815] Implementation Scheme 117: The method according to Implementation Scheme 113, wherein the subject experiences a maximum average change in diastolic blood pressure of less than about 0.75 mmHg from baseline within 0.5 hours to 6.5 hours after administration.

[0816] Implementation Scheme 118: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject experiences a maximum average change in heart rate of less than about 2.0 bpm from baseline within 0.5 to 6.5 hours after administration.

[0817] Implementation Scheme 119: The method according to Implementation Scheme 118, wherein the maximum mean change is less than about 1.50 bpm compared to the maximum mean change in subjects taking placebo.

[0818] Implementation Scheme 120: A method for treating overactive bladder, the method comprising orally administering, daily, a dose of vebergellon from about 75 mg to about 400 mg to a subject with appropriate need, wherein the subject experiences a smaller maximum mean change in systolic blood pressure compared to a subject receiving a therapeutically effective dose of miraberione.

[0819] Implementation Scheme 121: The method according to Implementation Scheme 120, wherein the increase in the maximum mean change in systolic blood pressure experienced by the subject receiving vebegrin is smaller than that experienced by the subject receiving a therapeutically effective dose of miraberione, from about 1.5 mmHg to about 4.0 mmHg.

[0820] Implementation Scheme 122: A method for treating overactive bladder, the method comprising orally administering, daily, a dose of vebergellon from about 75 mg to about 400 mg to a subject with appropriate need, wherein the subject experiences a smaller mean 24-hour variation in systolic blood pressure compared to a subject receiving a therapeutically effective dose of miraberione.

[0821] Implementation Scheme 123: The method according to Implementation Scheme 122, wherein the increase in the 24-hour mean change in systolic blood pressure experienced by subjects receiving vebegrin is less than that experienced by subjects receiving a therapeutically effective dose of mirabéron, from about 1.0 mmHg to about 10.0 mmHg.

[0822] Implementation Scheme 124: A method for treating overactive bladder, the method comprising orally administering, daily, a dose of veberberine from about 75 mg to about 400 mg to a subject with appropriate need, wherein the maximum mean increase in heart rate experienced by the subject is smaller than that experienced by a subject receiving a therapeutically effective dose of miraberione.

[0823] Implementation Scheme 125: The method according to Implementation Scheme 124, wherein the maximum mean increase in heart rate experienced by the subject receiving vebegrin is less than that experienced by the subject receiving a therapeutically effective dose of miraberione, from about 2 bpm to about 14 bpm.

[0824] Implementation Scheme 126: The method according to any one of Implementation Schemes 120 to 125, wherein the therapeutically effective dose of mirabezone is from about 50 mg to about 200 mg.

[0825] Implementation Scheme 127: The method according to any one of Implementation Schemes 92 to 126, wherein the subject is a human.

[0826] Implementation Scheme 128: The method according to Implementation Scheme 127, wherein the human being is male.

[0827] Implementation Scheme 129: The method according to Implementation Scheme 127, wherein the human being is female.

[0828] Implementation Scheme 130: The method according to any one of Implementation Schemes 127 to 129, wherein the human has a weight greater than about 65 kg.

[0829] Implementation Scheme 131: The method according to any one of Implementation Schemes 127 to 129, wherein the human has a weight of less than about 65 kg.

[0830] Implementation Scheme 132: The method according to any one of Implementation Schemes 127 to 129, wherein the human being is at or over the age of about 67 years.

[0831] Implementation Scheme 133: The method according to Implementation Scheme 132, wherein the human being is from about 67 years old to about 75 years old.

[0832] Implementation Scheme 134: The method according to any one of Implementation Schemes 127 to 129, wherein the human being is under approximately 67 years of age.

[0833] Implementation Scheme 135: The method according to any one of Implementation Schemes 127 to 129, wherein the human being suffers from hypertension or is at risk of hypertension.

[0834] Implementation Scheme 136: The method according to any one of Implementation Schemes 127 to 129, wherein the human being suffers from chronic kidney disease.

[0835] Implementation Scheme 137: The method according to Implementation Scheme 136, wherein the chronic kidney disease is stage 1, stage 2, stage 3a or stage 3b.

[0836] Implementation Scheme 138: The method according to any one of Implementation Schemes 127 to 129, wherein the human body has a flow rate greater than about 30 mL / min / 1.73 m 2 The estimated glomerular filtration rate (eGFR).

[0837] Implementation Scheme 139: The method according to Implementation Scheme 138, wherein the eGFR is selected from approximately 30 mL / min / 1.73 m 2 To approximately 44 mL / min / 1.73 m 2 Approximately 45 mL / min / 1.73 m 2 To approximately 59 mL / min / 1.73 m 2 Approximately 60 mL / min / 1.73 m 2 To approximately 89 mL / min / 1.73 m 2 or approximately 90 mL / min / 1.73 m 2 Or higher.

[0838] Implementation Scheme 140: The method according to Implementation Scheme 138, wherein the eGFR is greater than approximately 72 mL / min / 1.73 m 2 .

[0839] Implementation Scheme 141: The method according to Implementation Scheme 138, wherein the eGFR is less than approximately 72 mL / min / 1.73 m 2 .

[0840] Implementation Scheme 142: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with an appropriate need, wherein the subject has a weight greater than about 65 kg, and wherein the subject experiences a similar mean change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0841] Implementation Scheme 143: A method for treating overactive bladder, the method comprising orally administering 75 mg of vebergellon daily to a subject with appropriate need, wherein the subject is at or over approximately 67 years of age, and wherein the subject experiences a similar mean change in systolic blood pressure from baseline during the treatment period compared to a subject taking a placebo.

[0842] Implementation Scheme 144: The method according to any one of Implementation Schemes 36 to 91, wherein at week 52, the decrease in the average number of urinations per 24 hours, the decrease in the average number of UUI episodes per 24 hours, the decrease in the average number of urinary urgency episodes per 24 hours, the decrease in the average number of total incontinence episodes per 24 hours, and / or the increase in the average volume of each urination is from about 100% to about 140% of those at week 12.

[0843] Implementation scheme 145: Vibergron for use in a method of treating overactive bladder in a treated subject, the method comprising orally administering about 75 mg of vibergron to the subject daily.

[0844] Implementation Scheme 146: Vibegrine for use according to Implementation Scheme 145, wherein after administration of vibegrine to the subject during the treatment period: a. The subjects experienced a decrease in the average number of urinations over a 24-hour period that was approximately 1.5 to 10 times greater than the decrease in the average number of urinations among subjects receiving a placebo; or b. The reduction in the average number of urge incontinence (UUI) episodes per 24 hours was approximately 1.7 to approximately 6 times that of the placebo-treated subjects.

[0845] Implementation Scheme 147: Vibergron for use according to Implementation Scheme 146, wherein the subject experiences a reduction in the average number of urinations over a 24-hour period of approximately 2 to approximately 4 times greater than the reduction in the average number of urinations of the subject receiving the placebo.

[0846] Implementation Scheme 148: Vibegaline for use according to Implementation Scheme 146 or 147, wherein after administration of vibegaline to the subject during the treatment period, the average number of times the subject urinates per 24 hours decreases from about 1.3 times to about 2.5 times, and the average number of times the subject experiences UUI episodes per 24 hours decreases from about -1.5 times to about -2.5 times.

[0847] Implementation Scheme 149: Vibergron for use according to any one of Implementation Schemes 146-148, wherein after administration of vibergron to the subject during the treatment period, the subject's average number of urinations during a 24-hour period is reduced by between approximately 1.5 and approximately 10 times compared to the average number of urinations in subjects receiving a placebo, and the average number of UUI episodes per 24 hours is reduced from approximately -1.5 times to approximately -2.5 times.

[0848] Implementation Scheme 150: Vibegron for use according to any one of Implementation Schemes 145-149, wherein the treated subject has previously been treated with an acetylcholinergic drug.

[0849] Implementation Scheme 151: Vibegaline for use according to Implementation Scheme 150, wherein the treated subject has been treated with acetylcholinergic drugs within 12 months prior to treatment with vibegaline.

[0850] Implementation Scheme 152: Vibegaline for use according to Implementation Scheme 150, wherein the treated subject has been treated with acetylcholinergic drugs for more than 12 months prior to treatment with vibegaline.

[0851] Implementation Scheme 153: Vibegron for use according to Implementation Scheme 150, wherein the treated subject is concurrently treated with an acetylcholinergic drug.

[0852] Implementation Scheme 154: Vibegaline for use according to any one of Implementation Schemes 145-149, wherein the treated subject has previously been treated with a β-3 agonist other than vibegaline.

[0853] Implementation Scheme 155: Vibegelone for use according to Implementation Scheme 154, wherein the β-3 agonist is Mirabelon.

[0854] Implementation Scheme 156: Vibegaline for use according to Implementation Scheme 154 or 155, wherein the treated subject has been treated with a β-3 agonist other than vibegaline within 12 months prior to treatment with vibegaline.

[0855] Implementation Scheme 157: Vibergron for use according to Implementation Scheme 154 or 155, wherein the treated subject has been treated with a β-3 agonist other than vibergron for more than 12 months prior to treatment with vibergron.

[0856] Implementation scheme 158: Vibegaline for use according to implementation scheme 154 or 155, wherein the treated subject is concurrently treated with a β-3 agonist other than vibegaline.

[0857] Implementation scheme 159: Vibegelone for use in a method of improving health-related quality of life (HRQL) in subjects with symptoms of overactive bladder, the method comprising orally administering approximately 75 mg of vibegelone to a subject daily during a treatment period, wherein the improvement is defined as HRQL compared to that of a subject receiving a placebo.

[0858] Implementation Scheme 160: Vibergron for use according to Implementation Scheme 159, wherein the HRQL includes one or more subscales selected from coping, anxiety, sleep or social interaction.

[0859] Implementation Scheme 161: Vibegelone for use according to Implementation Scheme 159 or 160, wherein the improvement in HRQL is greater than the improvement with tolterodine extended-release (ER) 4 mg.

[0860] Implementation scheme 162: Vibergron for use according to any one of implementation schemes 159-161, wherein the HRQL of the subject receiving vibergron is improved by at least about 3.8 points compared with the subject receiving placebo.

[0861] Implementation scheme 163: Vibegelone for use in a method of reducing coping behavior in subjects with symptoms of overactive bladder, the method comprising orally administering approximately 75 mg of vibegelone to a subject daily during a treatment period, wherein the subject's coping behavior is reduced compared to a subject receiving a placebo.

[0862] Implementation scheme 164: Vibegelone for use in a method for improving the coping domain score of a subject with symptoms of overactive bladder, the method comprising orally administering about 75 mg of vibegelone to a subject daily during the treatment period, wherein said improvement is compared to the coping domain score of a subject receiving a placebo.

[0863] Implementation Scheme 165: Vibegelone for use according to Implementation Scheme 164, wherein the improvement in response area score is greater than the improvement with tolterodine extended-release (ER) 4 mg.

[0864] Implementation scheme 166: Vibergron for use according to implementation scheme 164 or 165, wherein the coping domain score of the subject receiving vibergron is improved by at least about 3.2 points compared with the subject receiving placebo.

[0865] Implementation Scheme 167: Vibergron for use in a method of improving sleep in a subject with symptoms of overactive bladder, the method comprising orally administering approximately 75 mg of vibergron to the subject daily during a treatment period, wherein said improvement is compared to sleep in a subject receiving a placebo.

[0866] Implementation Scheme 168: Vibeglione used according to Implementation Scheme 167, wherein the improvement in sleep is greater than the improvement with tolterodine extended-release (ER) 4 mg.

[0867] Implementation scheme 169: Vibergron for use according to implementation scheme 167 or 168, wherein the sleep score of the subject receiving vibergron is improved by at least about 2.6 points compared with the subject receiving placebo.

[0868] Implementation Scheme 170: Vibegelone for use in a method of reducing symptom distress in a subject with symptoms of overactive bladder, the method comprising orally administering approximately 75 mg of vibegelone to the subject daily during a treatment period, wherein the reduction is compared to symptom distress in a subject receiving a placebo.

[0869] Implementation Scheme 171: Vibegaline for use according to Implementation Scheme 170, wherein the reduction in symptom distress is greater than the reduction with tolterodine extended-release (ER) 4 mg.

[0870] Implementation scheme 172: Vibergron for use according to any one of implementation schemes 170 or 171, wherein the symptom distress score of the subject receiving vibergron is reduced by at least about -5.0 points compared with the subject receiving placebo.

[0871] Implementation scheme 173: Vibergrenone for use in a method of maintaining daytime ambulatory blood pressure and treating overactive bladder in subjects with appropriate need, the method comprising orally administering about 75 mg of vibergrenone to the subject daily during the treatment period, wherein the subject experiences a mean change in daytime ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

[0872] Implementation Scheme 174: Vibegliflozin for use according to Implementation Scheme 173, wherein the subject experiences a mean change in diurnal dynamic systolic blood pressure during the treatment period, and wherein the mean change has an upper limit of a 90% confidence interval of less than about 3.5 mmHg compared to the mean change in a subject taking a placebo.

[0873] Implementation Scheme 175: Vibergron used according to Implementation Scheme 174, wherein the upper limit of the 90% confidence interval is less than about 2.5 mmHg.

[0874] Implementation Scheme 176: Vibergron for use as described in Implementation Scheme 175, wherein the upper limit of the 90% confidence interval is approximately 2.0 mmHg.

[0875] Implementation Scheme 177: Vibegliflozin for use according to any one of Implementation Schemes 173-176, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure during the treatment period, and wherein the mean change is less than about 1.0 mmHg compared to the mean change in a subject taking a placebo.

[0876] Implementation Scheme 178: Vibegliflozin for use according to Implementation Scheme 177, wherein the mean change is less than about 0.5 mmHg compared to the mean change in subjects taking placebo.

[0877] Implementation Scheme 179: Vibegliflozin for use according to any one of Implementation Schemes 173-178, wherein the subject experiences a mean change in daytime dynamic systolic blood pressure of less than about 1.0 mmHg during the treatment period.

[0878] Implementation Scheme 180: Vibergron for use according to Implementation Scheme 179, wherein the average variation is less than about 0.25 mmHg.

[0879] Implementation Scheme 181: Vibegelone for use according to any one of Implementation Schemes 173-180, wherein the subject did not experience a greater mean change in daytime dynamic diastolic blood pressure during the treatment period than the mean change in the subject taking placebo.

[0880] Implementation Scheme 182: Vibegaline for use according to any one of Implementation Schemes 173-181, wherein the subject experiences a mean change in diurnal dynamic diastolic blood pressure of less than about 0.75 mmHg during the treatment period.

[0881] Implementation scheme 183: Vibergron for use in a method of maintaining daytime dynamic heart rate in subjects with appropriate need while treating overactive bladder, the method comprising orally administering about 75 mg of vibergron to the subject daily, wherein the subject experiences a mean change in daytime dynamic heart rate of less than about 1.25 bpm during the treatment period.

[0882] Implementation Scheme 184: Vibegliflozin for use according to Implementation Scheme 183, wherein the subject experiences a mean change in daytime dynamic heart rate during the treatment period, and wherein the mean change is less than about 1.0 bpm compared to the mean change in a subject taking a placebo.

[0883] Implementation scheme 185: Vibergron for use in a method of maintaining 24-hour ambulatory blood pressure in subjects with appropriate need while treating overactive bladder, the method comprising administering about 75 mg of vibergron orally to the subject daily, wherein the subject experiences a mean change in 24-hour ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

[0884] Implementation Scheme 186: Vibegliflozin for use according to Implementation Scheme 185, wherein the subject experiences a 24-hour average change in systolic blood pressure during the treatment period, and wherein the average change is less than about 0.75 mmHg compared to the average change in a subject taking a placebo.

[0885] Implementation Scheme 187: Vibegliflozin for use according to Implementation Scheme 186, wherein the subject experiences a mean change in 24-hour dynamic systolic blood pressure of less than about 0.75 mmHg during the treatment period.

[0886] Implementation Scheme 188: Vibegelone for use according to any one of Implementation Schemes 185-187, wherein the subject did not experience a greater mean change in 24-hour dynamic diastolic blood pressure during the treatment period than the mean change in the subject taking placebo.

[0887] Implementation Scheme 189: Vibegliflozin for use according to any one of Implementation Schemes 185-188, wherein the subject experiences a mean change in 24-hour dynamic diastolic blood pressure of less than 0.75 mmHg during the treatment period.

[0888] Implementation scheme 190: Vibergelone for use in a method of maintaining 24-hour ambulatory heart rate in subjects with appropriate need while treating overactive bladder, the method comprising orally administering about 75 mg of vibergelone to the subject daily, wherein the subject experiences a mean change in 24-hour ambulatory heart rate of less than about 1.0 bpm during the treatment period.

[0889] Implementation Scheme 191: Vibegelone for use according to Implementation Scheme 190, wherein the mean change is less than about 1.0 bpm compared to the mean change in subjects taking placebo.

[0890] Implementation Scheme 192: Vibegaron for use according to any one of Implementation Schemes 173-191, wherein the subject suffers from hypertension.

[0891] Implementation Scheme 193: Vibegaline for use according to any one of Implementation Schemes 145-192, wherein Vibegaline is applied once daily.

[0892] Implementation Scheme 194: Vibergron for use according to any one of Implementation Schemes 145-193, wherein Vibergron is applied as a free base.

[0893] Implementation Scheme 195: Vibergren for use according to any one of Implementation Schemes 145-193, wherein vibergren is administered as a pharmaceutically acceptable salt thereof.

[0894] Implementation Scheme 196: Vibegaline for use according to any one of Implementation Sche...

Claims

1. A method for treating overactive bladder in a treated subject with corresponding need, the method comprising orally administering to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is about 75 mg, and wherein after administering vilbeganol to the subject during the treatment period: a. The subjects reported a reduction in the average number of urinations over a 24-hour period that was approximately 1.5 to 10 times greater than the reduction in the average number of urinations among the placebo-receiving subjects; or b. The reduction in the average number of urge incontinence (UUI) episodes per 24 hours in the subjects was approximately 1.7 to approximately 6 times the reduction in the average number of urge incontinence (UUI) episodes in subjects treated with placebo.

2. A method for reducing coping behaviors in subjects with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject with appropriate need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the coping behaviors of the subject are reduced compared to those of a subject receiving a placebo.

3. A method for improving the coping domain score of a subject with symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject with appropriate need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the improvement is defined as a comparison of the coping domain score of a subject receiving a placebo.

4. A method for reducing symptom distress in a subject suffering from symptoms of overactive bladder, the method comprising orally administering a therapeutically effective amount of vebergellon to a subject in need daily during a treatment period, wherein the therapeutically effective amount is about 75 mg, and wherein the reduction is compared to symptom distress in a subject receiving a placebo.

5. A method for maintaining daytime ambulatory blood pressure and treating overactive bladder in subjects with appropriate need, the method comprising administering orally to the subject daily a therapeutically effective amount of vilbeganol, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences a mean change in daytime ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

6. A method for maintaining daytime dynamic heart rate and treating overactive bladder in subjects with appropriate need, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences an average change in daytime dynamic heart rate of less than about 1.25 bpm during the treatment period.

7. A method for maintaining 24-hour ambulatory blood pressure in a subject with appropriate need while treating overactive bladder, the method comprising administering a therapeutically effective amount of vilbeganol orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences a mean change in 24-hour ambulatory blood pressure of less than about 2.0 mmHg during the treatment period.

8. A method for maintaining 24-hour ambulatory heart rate in a subject with appropriate need while treating overactive bladder, the method comprising administering a therapeutically effective amount of vebergellon orally to the subject daily, wherein the therapeutically effective amount is about 75 mg, and wherein the subject experiences an average 24-hour ambulatory heart rate variation of less than about 1.0 bpm during the treatment period.

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