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) (51) International Patent Classification: A61K 31/519 (2006.01) A61P 13/10 (2006.01) Published: A61K 45/06 (2006.01) — With

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) (51) International Patent Classification: A61K 31/519 (2006.01) A61P 13/10 (2006.01) Published: A61K 45/06 (2006.01) — With ) ( 2 (51) International Patent Classification: Published: A61K 31/519 (2006.01) A61P 13/10 (2006.01) — with international search report (Art. 21(3)) A61K 45/06 (2006.01) — in black and white; the international application as fded (21) International Application Number: contained color or greyscale and is available for download PCT/IB2020/052484 from PATENTSCOPE (22) International Filing Date: 18 March 2020 (18.03.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/820,230 18 March 2019 (18.03.2019) US 62/830,302 05 April 2019 (05.04.2019) US 62/842,435 02 May 2019 (02.05.2019) US 62/885,767 12 August 2019 (12.08.2019) US 62/897,019 06 September 2019 (06.09.2019) US 62/904,429 23 September 2019 (23.09.2019) US (71) Applicant: UROVANT SCIENCES GMBH [CH/CH]; Viaduktstrasse 8, 405 1Basel (CH). (72) Inventor: MUDD, JR., Paul N.; c/o Urovant Sciences, Inc., 5281 California Avenue, Suite #100, Irvine, California 92617 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, ML, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — of inventorship (Rule 4.17 (iv)) (54) Title: USE OF VIBEGRON TO TREAT OVERACTIVE BLADDER (57) Abstract: The present disclosure is directed to a method of treating overactive bladder comprising orally administering to a subject in need thereof an amount of 75 mg of vibegron per day. USE OF VIBEGRON TO TREAT OVERACTIVE BLADDER BACKGROUND [0001] Overactive bladder (OAB) is a chronic and sometimes debilitating condition of the lower urinary tract. The function of the lower urinary tract is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes which involve a variety of afferent and efferent neural pathways, leading to modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of sympathetic and parasympathetic components of the autonomic nervous system as well as somatic motor pathways. These proximally regulate the contractile state of bladder (detrusor) and urethral smooth muscle, and urethral sphincter striated muscle. [0002] Overactive bladder, from a pathophysiologic perspective, has been linked with detrusor overactivity. OAB is characterized by the symptoms of urinary urgency, with or without urgency urinary incontinence, usually associated with frequency and nocturia. The prevalence of OAB in the United States and Europe has been estimated at 16 to 17% in both women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to neurological condition, bladder outlet obstruction, and other causes. [0003] Currently, the predominant class of drugs used to treat OAB is antimuscarinics. The clinical use of antimuscarinics is limited by modest efficacy and poor tolerability due to mechanism-based side effects including dry mouth, constipation and the potential for CNS adverse effects (e.g., cognitive impairment). High discontinuation rates have been observed for both tolterodine and oxybutynin, two commonly prescribed antimuscarinics, in both clinical trials and real-world settings. In addition, recent evidence from observational studies suggested that higher cumulative anticholinergic use is associated with an increased risk of dementia. See Gray SL, et a , JAMA Intern Med 2015; 175(3): 401-407. [0004] Beta-3 adrenergic receptor (P3-AR) activation is an effective way of relaxing the detrusor in normal and pathogenic states. Functional evidence in support of an important role for the P3-AR in urine storage emanates from studies in vivo. P3-AR agonists have demonstrated efficacy in alleviating symptoms of OAB. To date, only one P3-AR agonist, mirabegron (Astellas Pharma Global Development, Inc), has received marketing approval in the US and Japan for the treatment of OAB. Mirabegron activates the pi-AR in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Reductions in micturition frequency, urinary incontinence and urgency episodes, and increases in mean volume voided per micturition were observed with mirabegron [0005] Vibegron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2- yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[l,2-a]pyrimidine-6-carboxamide, is a potent and highly selective beta-3 adrenergic receptor (p3-AR) agonist demonstrating >9,000 fold selectivity for activation of -A over P2-AR and Pi-AR in cell based in vitro assays. See Edmondson etal., J . Med. Chem. 59:609-623 (2016). [0006] Vibegron is disclosed as a P3-A agonist in United States Patent Nos. 8,399,480 and 8,247,415, and WO20 18/224989. Synthetic methods for preparing vibegron are disclosed in United States Publication Nos. US 2017/0145014, US 2015/0087832, US 2016/0176884 and US 2014/0242645. All of the cited publications are herein incorporated by reference in their entireties. BRIEF DESCRIPTION OF THE DRAWINGS [0007] Figure 1 depicts an overlay of density plots of exposure with vibegron 100 mg and 75 mg, as estimated in special populations. [0008] Figure 2 depicts the mean (+SD) tolterodine plasma concentration vs. time profile alone and in the presence of vibegron. [0009] Figure 3 depicts the mean (+SD) metoprolol plasma concentration vs. time profile alone and in the presence of vibegron. [0010] Figure 4 depicts reduction in urge urinary incontinence (UUI) over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0011] Figure 5 depicts reduction in micturitions over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0012] Figure 6 depicts reduction in urgency episodes over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0013] Figure 7 depicts the change in urge incontinence responder rate over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0014] Figure 8 depicts percent of responders with 75% and 100% reductions in UUI episodes and 50% reduction in urgency episodes at week 12. [0015] Figure 9 depicts reductions in total incontinence episodes over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0016] Figure 10 depicts improvement in volume voided over time. Statistically significant onset of action was achieved at 2 weeks for the vibegron treatment. [0017] Figure 11 shows the time and events for the ABPM study. [0018] Figure 12 shows the 90% confidence interval for treatment difference in Day 28 change from baseline for ABPM systolic blood pressure. [0019] Figure 13 shows the 90% confidence interval for treatment difference in Day 28 change from baseline for ABPM diastolic blood pressure. [0020] Figure 14 shows the 90% confidence interval for treatment difference in Day 28 change from baseline for ABPM heart rate. [0021] Figure 15 shows the reduction in micturitions over 52 weeks. [0022] Figure 16 shows the reduction in Urinary Urge Incontinence (UUI) episodes over 52 weeks. [0023] Figure 17 shows the reduction in urgency episodes over 52 weeks. [0024] Figure 18 shows the reduction in total incontinence episodes over 52 weeks. [0025] Figure 19 shows the Kaplan Meier plot of time to 75% reduction in Urinary Urge Incontinence (UUI). [0026] Figure 20 shows the Kaplan Meier plot of time to 50% reduction in urgency. [0027] Figure 2 1 shows a plot of LS Mean of change from baseline urgency in the dry OAB population over time. SUMMARY [0028] The present disclosure provides a method of treating overactive bladder, the method comprising orally administering to a subject in need thereof an amount of 75 mg of vibegron per day. [0029] The present disclosure further provides a method of treating overactive bladder, the method comprising orally administering to a subject in need thereof an amount of 75 mg of vibegron per day, wherein the treatment achieves at least one of changes (1) to (5) from baseline over a treatment period: (1) a change in average number of micturitions per 24 hours of from about -1.3 to about -2.3; (2) a change in average number of UUI episodes per 24 hours of from about -1.5 to about -2.5 when the subject is an OAB Wet patient; (3) a change in average number of urgency episodes per 24 hours of from about -2.2 to about -3.2; (4) a change in average number of total incontinence episodes per 24 hours of from about -1.7 to about -2.7; and (5) a change in average volume voided per micturition of from about 18 mL to about 30 mL.
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