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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213006Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRM) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) Application Type NDA Application Number 213006 PDUFA Goal Date December 26, 2020 OSE RCM # 2019-2648 Reviewer Name Theresa Ng, PharmD, BCPS Team Leader Laura Zendel, PharmD, BCPS Deputy Division Director Cynthia LaCivita, PharmD Review Completion Date December 9, 2020 Subject Evaluation of Need for a REMS Established Name Vibegron Trade Name Gemtesa Name of Applicant Urovant Sciences Therapeutic Class Beta-3 adrenergic agonist Formulation(s) 75 mg tablet Dosing Regimen One tablet orally once daily with or without food 1 Reference ID: 4714124 Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................................... 3 1 Introduction ..................................................................................................................................................................... 3 2 Background ...................................................................................................................................................................... 3 2.1 Product Information ........................................................................................................................................... 3 2.2 Regulatory History............................................................................................................................................... 4 3 Therapeutic Context and Treatment Options .................................................................................................... 4 3.1 Description of the Medical Condition .......................................................................................................... 4 3.2 Description of Current Treatment Options ............................................................................................... 4 4 Benefit Assessment ....................................................................................................................................................... 5 5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 6 5.1 Adverse Events (AEs) ......................................................................................................................................... 7 5.2 Deaths ....................................................................................................................................................................... 7 5.3 Hypertension.......................................................................................................................................................... 8 5.4 Urinary Retention ................................................................................................................................................ 8 6 Expected Postmarket Use ........................................................................................................................................... 9 7 Risk Management Activities Proposed by the Applicant ............................................................................... 9 8 Discussion of Need for a REMS ................................................................................................................................. 9 9 Conclusion & Recommendations ........................................................................................................................... 10 10 References .................................................................................................................................................................. 10 2 Reference ID: 4714124 EXECUTIVE SUMMARY This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Gemtasa (vibegron) is necessary to ensure the benefits outweigh its risks. Urovant Sciences (Urovant) submitted a New Drug Application (NDA) 213006 for vibegron with the proposed indication of treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. The risk associated with vibegron is urinary retention. The applicant did not submit a proposed REMS or risk management plan with this application. DRM along with the Division of Urological, Obstetrics and Gynecological Products (DUOG) agree that a REMS is not needed to ensure the benefits of vibegron outweigh its risks. The most common adverse events for vibegron were hypertension, urinary tract infections, and headache. These adverse events were comparable to the placebo group and or less than the adverse event rates observed with subjects in the tolterodine group. No difference was observed for hypertension events between vibegron and placebo groups, even in those subjects with or without pre-existing hypertension. This differed from Myrbetriq (mirabegron) which is in the same drug class as vibegron, approved in 2012 for OAB, and has a Warnings and Precaution for changes in BP effects. No clinically relevant changes from baseline in postvoid residual (PVR) volume for subjects treated with vibegron compared with placebo were found in the clinical development program for this application. However, due to increase postmarketing reports from Japan for vibegron, marketed as Boeva, the Applicant proposes to include urinary retention risk in the Warnings and Precaution section of the product labeling which is similar to Myrbetriq’s labeling. 1 Introduction This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) Gemtesa (vibegron) is necessary to ensure the benefits outweigh its risks. Urovant submitted a New Drug Application (NDA) 213006 for vibegron with the proposed indication of treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. This application is under review in the Division of Urology, Obstetrics, and Gynecology (DUOG). The applicant did not submit a proposed REMS or risk management plan with this application. 2 Background 2.1 PRODUCT INFORMATION Vibegron, a new molecular entitya, is a selective agonist of the human beta-3 adrenergic receptor (β3- AR) proposed for the use in the treatment of overactive bladder (OAB) with symptoms of urinary incontinence, urgency, and urinary frequency. The primary mechanism of action is through bladder relaxation during the filling phase and inhibition of the frequency of non-voiding activity, thus enhancing urine storage. a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity. 3 Reference ID: 4714124 Vibegron is supplied as an oral tablet and is intended to be used daily. The proposed dosing regimen is one 75 mg tablet daily with or without food. Vibegron will most likely be administered in an outpatient or long-term care setting. The duration of treatment for OAB is long-term.b Vibegron is not part of a drug class that has a boxed warning or REMS. Vibegron is currently approved and marketed in Japan as Boeva at 50 mg daily.c 2.2 REGULATORY HISTORY The following is a summary of the regulatory history for NDA 213006 relevant to this review: • 12/26/2019: NDA 213006 submission for treatment of treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency received • 06/15/2020: A Post Mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for vibegron. 3 Therapeutic Context and Treatment Options 3.1 DESCRIPTION OF THE MEDICAL CONDITION Overactive bladder (OAB) is a clinical syndrome characterized by urinary urgency with or without urinary incontinence, often accompanied by frequency and nocturia, in the absence of urinary tract infection or other obvious pathology.1 OAB is estimated to affect greater than 400 million people worldwide with rates ranging from 7-27% in men and 9-43% in women.2d Multiple studies demonstrated that living with OAB has negative effects on numerous quality of life domains including recreational life, depression, isolation, sexuality, and work productivity.1e 3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS First line treatments for OAB include modifying contributory medical and lifestyle factors and initiating pelvic floor exercises and bladder training. In the United States (US), two classes of medications are available for pharmacologic treatment: antimuscarinic agents and beta-adrenergic agonists. Anti- muscarinic agents including darifenacin, fesoterodine, oxybutynin, solifenacin, and tolteradine act by increasing bladder capacity and decreasing urgency through blockage of muscarinic receptor stimulation by acetylcholine during bladder storage. These agents may cause dry mouth, constipation, blurred vision, tachycardia, drowsiness, and decreased cognitive function. Mirabegron, a beta-adrenergic agonist, acts by bladder relaxation during the filling phase and inhibition of the frequency of non-voiding activity, thus enhancing urine storage.

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