213006Orig1s000 OTHER REVIEW(S)

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

213006Orig1s000

OTHER REVIEW(S)

Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy

PATIENT LABELING REVIEW

Date: November 20, 2020

To: Nenita Crisostomo, RN Regulatory Project Manager Division of Urology, Obstetrics and Gynecology (DUOG)

Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP)

Sharon Williams, MSN, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP)

From: Lonice Carter, MS, RN, CNL Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Elvy Varghese, PharmD. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI)

Drug Name (established GEMTESA (vibegron) name): Dosage Form and Route: tablets, for oral use Application NDA 213006 Type/Number: Applicant: Urovant Sciences GmbH (Urovant)

Reference ID: 4705052 1 INTRODUCTION On December 26, 2019, Urovant Sciences GmbH (Urovant) submitted for the Agency’s review an original New Drug Application (NDA)/New Molecular Entity 213006 for GEMTESA (vibegron) tablets, for oral use. The purpose of this NDA is to propose an indication for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Urology, Obstetrics and Gynecology (DUOG) on February 4, 2020, for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) for GEMTESA (vibegron) tablets, for oral use.

2 MATERIAL REVIEWED • Draft GEMTESA (vibegron) PPI received on December 26, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on November 12, 2020. • Draft GEMTESA (vibegron) Prescribing Information (PI) received on December 26, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on November 12, 2020.

3 REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We reformatted the PPI document using the Arial font, size 10. In our collaborative review of the PPI we: • simplified wording and clarified concepts where possible • ensured that the PPI is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the PPI is free of promotional language or suggested revisions to ensure that it is free of promotional language • ensured that the PPI meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

Reference ID: 4705052 4 CONCLUSIONS The PPI is acceptable with our recommended changes.

5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the PPI is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the PPI. Please let us know if you have any questions.

4 Pages of Draft Labeling have been Wtihheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 4705052 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

LONICE J CARTER 11/20/2020 10:26:23 AM

ELVY M VARGHESE 11/20/2020 10:40:24 AM

SHARON W WILLIAMS 11/20/2020 10:41:45 AM

LASHAWN M GRIFFITHS 11/20/2020 11:07:00 AM

Reference ID: 4705052 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information****

Memorandum

Date: November 18, 2020

To: T D. Chang, Clinical Reviewer, M.D. Division of Urology, Obstetrics, and Gynecology (DUOG)

Nenita Crisostomo, RN Senior Regulatory Health Project Manager, DUOG

From: Elvy Varghese, PharmD. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

CC: Matthew Falter, PharmD Team Leader, OPDP

Subject: OPDP Labeling Comments for GEMTESA® (vibegron) tablets, for oral use

NDA: 213006

In response to DUOG’s consult request dated February 4, 2020, OPDP has reviewed the proposed product labeling (PI) and patient package insert (PPI) for the original NDA submission for GEMTESA® (vibegron) tablets, for oral use (Gemtesa).

Labeling: OPDP’s comments on the proposed labeling are based on the draft labeling received by electronic mail from DUOG (Nenita Crisostomo) on November 10, 2020 and are provided below.

A combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed, and comments on the proposed PPI will be sent under separate cover.

Thank you for your consult. If you have any questions, please contact Elvy Varghese at (240) 402-0080 or [email protected].

20 Pages of Draft Labeling have been Wtihheld in Full as 1 b4 (CCI/TS) immediately following this page Reference ID: 4703494 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

ELVY M VARGHESE 11/18/2020 09:46:58 AM

Reference ID: 4703494 Clinical Inspection Smnmary NDA213006

Clinical Inspection Summary Date October 8, 2020 From Ling Yang, M.D., Ph.D., FAAFP Min Lu, M.D., M.P.H., Team Leader Kassa Ayalew, M.D., M.P.H., Branch Chief Good Clinical Practice Assessment Branch (GCPAB) Division ofClinical Compliance Evaluation (DCCE) Office of Scientific Investigations (OSI) To Debuene Chang, M.D., Clinical Reviewer Mark Hirsch, M.D., Clinical Team Leader Nenita Crisostomo, Regulato1y Project Manager Division ofUrolo!ZV, Obstetrics and Gvnecolo12:v (DUOG) NDA # 213006 Applicant Urovant Sciences GmbH Dru2 Gemtesa (vibe12:ron) NME (Yes/No) Yes Review Priority Standard Proposed Indication(s) Treatment ofoveractive bladder with symptoms ofurge urinary incontinence, urgency, and urinary frequency Consultation Request Date Febrna1y 03, 2020 Summary Goal Date October 23, 2020 Action Goal Date December 23, 2020 PDUFA Date December 26, 2020

I. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS Clinical data from Studies RVT-901-3003 and RVT-901-3004 were subinitted to the Agency in support ofthis New Drng Application (NDA) for Gemtesa (vibegron) 75 mg oral tablets for the proposed indication. Three clinical investigators (Cis): Drs. Robe1i Heller (Site 10-123), Keila Hoover (Site 10-133) and John Pinches III (Site 10-156) were selected for clinical inspections.

The inspections verified the sponsor Urovant Sciences GmbH (Urovant) subinitted clinical data with source records at the CI sites. Based on the results ofthese CI inspections, Study RVT-901 3003 and RVT-901-3004 appear to have been conducted adequately, and the data generated by these sites and subinitted by the sponsor appear acceptable in suppo1i ofthe respective indication.

II. BACKGROUND Urovant subinitted NDA 213006 for Gemtesa (vibegron) 75 mg oral tablet on 12/26/2019. Vibegron, a highly selective beta-3 adrenergic receptor agonist, is administered once daily for the treatment ofoveractive bladder (OAB) with symptoms ofurge urina1y incontinence (UUI), urgency, and urina1y frequency. The sponsor subinitted data from two phase 3 clinical studies: RVT-901-3003, a 12-week efficacy and safety study; and RVT-901-3004, a 40-week long te1m safety study, to suppo1i the approval ofthe NDA.

Reference ID 4683195 Page 2 Clinical Inspection Summary NDA 213006

RVT-901-3003 Study RVT-901-3003 was a randomized, double-blind, placebo- and active [tolterodine extended release (ER)]-controlled multicenter study to evaluate the safety and efficacy of vibegron (RVT 901) in patients with symptoms of OAB. The primary study objective was to evaluate the efficacy of vibegron 75 mg compared to placebo in subjects with symptoms of OAB, specifically the frequency of micturitions and frequency of UUI episodes. The co-primary efficacy endpoints were change from baseline (CFB) at Week 12 in average number of 1) micturitions per 24 hours in all OAB subjects; and 2) UUI episodes per 24 hours in OAB Wet subjects.

The study consisted of a Screening Period (1-5 weeks), a single-blind placebo Run-in Period (all subjects took placebo once daily for 2 weeks), a randomized, double-blind Treatment Period (eligible subjects were randomized 5:5:4 to receive either vibegron 75 mg, placebo, or tolterodine ER 4 mg in a double-blind fashion once daily for 12 weeks. Visits were at baseline, Week 4, Week 8, Week 12) and a Safety Follow-up Period (4 weeks after the last dose). Subjects who completed the Week 12 Visit may be enrolled in the 40-week double-blind extension study RVT-901-3004.

The study screened a total of 3149 subjects, randomized 1515 subjects in 199 study centers in 6 countries: US (176), Canada (7), Poland (6), Hungary (5), Latvia (3) and Lithuania (2). The first subject was enrolled on March 26, 2018 and the last subject was completed on February 04, 2019.

RVT-901-3004 Study RVT-901-3004 was a phase 3, randomized, double-blind, active (tolterodine ER)-controlled multicenter extension study to evaluate the long-term safety of vibegron in patients with symptoms of OAB. The primary study objective was to evaluate the safety and tolerability of vibegron for up to 52 weeks in subjects with symptoms of OAB who previously completed treatment in Study RVT-901-3003. The primary safety endpoint was the incidence of any treatment-emergent adverse event (AE). Other safety endpoints were the extent of exposure and treatment compliance, clinical laboratory evaluations, vital signs, physical examinations, electrocardiograms (ECGs) and post- void residual (PVR) urine volume.

Subjects who were randomized to vibegron 75 mg or tolterodine ER 4 mg group in Study RVT 901-3003 continued the same treatment once daily in a blinded fashion for an additional 40 weeks. Subjects who were randomized to the placebo group in Study RVT-901-3003 were randomized 1:1 to receive blinded treatment of vibegron 75 mg or tolterodine ER 4 mg once daily for 40 weeks. Thus, through participation in both Studies RVT-901-3003 and RVT-901-3004, subjects originally randomized to vibegron or tolterodine ER received 52 weeks total treatment, and subjects originally randomized to placebo received 40 weeks total of vibegron or tolterodine treatment. This study consisted of a randomized double-blind Treatment Period (40 weeks), and a Safety Follow-up Period (4 weeks after the last dose of study treatment). Study visits were at Week 16, Week 24, Week 36, Week 44, and Week 52 (all relative to Day 1 of Study RVT-901-3003).

The study screened and randomized a total of 506 subjects, treated 505 subjects in 109 study centers in the US. The first subject was enrolled on June 14, 2018 and the last subject was completed on July 25, 2019.

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Rationale for Site Selection Three CIs: Drs. Robert Heller (Site 10-123), Keila Hoover (Site 10-133) and John Pinches III (Site 10-156) were requested for clinical inspection in support of the application. These sites were selected based on enrolling a high number of patients to the study treatment arms and/or with a high protocol violation rate.

III. RESULTS 1. Dr. Robert Heller, Site 10-123 12626 Riverside Dr., Suite 404 Valley Village, CA 91607-3456

This CI was inspected on July 7-10, 13 and 15, 2020 as a data audit for Study RVT 901-3003 and Study RVT 901-3004. This was the initial inspection for Dr. Heller.

For Study RVT 901-3003, the study site screened a total of 80 subjects, enrolled 50 subjects, with 48 subjects completed the study. The first subject was enrolled on 04/03/2018 and the last subject’s last follow-up visit was on 12/16/2018. All source records, including eligibility criteria were reviewed for 18 of the 50 enrolled subjects.

For Study RVT 901-3004, the study site screened and enrolled a total of 16 subjects, with 14 subjects completed the study. The first subject was enrolled on 07/19/2018 and the last subject’s last follow-up visit was on 06/29/2019. All source records, including eligibility criteria were reviewed for 7 of the 16 enrolled subjects.

Source records reviewed during the inspection included the study protocol and amendments, informed consent forms (ICFs), documentation of eligibility criteria and enrollment logs, medical records (including monitoring logs, laboratory tests, AEs, concomitant medication use), the investigational product (IP) accountability records, visit data, subject paper diaries, printouts of electronic case report forms (eCRFs) entries/audit trails and electronic database capture (EDC), protocol deviations and related regulatory documents [e.g., institutional review board (IRB) approvals and communications, staff training logs, financial disclosures and delegation of authority].

The inspection found adequate source documentation for inspected study subjects, with no significant deficiencies reported. The submitted data were verifiable with source records at the study site. The primary efficacy data source was verified. There was no evidence of underreporting of AEs. Study RVT-901-3004 had one serious AE (death of Subject (b) (6) due to arteriosclerotic cardiovascular disease), which was not study related and was appropriately reported.

At the end of the inspection, a Form 483 (Inspectional Observations) was not issued. Item discussed included the following:

1) Medical records were not obtained pre-enrollment for most subjects; and there was a delay between date of medical release form signed and date medical record request was sent.

2) The site does not require photo identification verification prior to enrolling subjects in the trial.

Reference ID: 4683195 Page 4 Clinical Inspection Summary NDA 213006

3) Discrepancy found in test article reconciliation – the clinical site reported more test kits returned (719) to sponsor than was received (695). There were 24 more kits returned than received.

Reviewer’s Comments: Official medical records released from subjects’ primary physicians are not required per the study protocol. However, during the screening stage, CI obtained and reviewed subjects’ medical history to determine eligibility. Verification of subjects’ identity is important to ensure data integrity by assuring patients were not enrolled across multiple clinical sites. The study protocol does not specify whether verification of subjects’ photo identifications are needed. Per the EIR, some of the subjects participated in previous clinical trials the site conducted and are known to the site. The CI agreed to verify subjects’ identity and will work on the reconciliation process to avoid double counting of test kits.

According to the study protocols, study subjects would use an eDiary to record micturitions and urine volume, while a paper diary would be used as a back-up. However, this study site didn’t use eDiaries per sponsor’s decision, only paper diaries were used. The sponsor was responsible for transcribing raw data collected in paper diaries into the eCRF. The inspection noted one discrepancy between raw data recorded in paper diaries at the site and data listing provided by the sponsor for Subject (b) (6) on a micturition. The sponsor reported the event as a micturition at 12:55 pm on (b) (6) However, on the subject’s diary “need to urinate immediately” box was checked but “urinate in toilet” and “accidently urine leakage” boxes were not checked for the specified time.

Reviewer’s Comments: Subject (b) (6) was assigned in the vibegron treatment group and had checked “urinate in toilet” boxe for other 8 times on (b) (6) except this one. This is unlikely to have a significant effect on the result of the primary efficacy endpoint.

In general, this clinical site appeared to be in compliance with Good Clinical Practice (GCP) except the observations noted above. These observations appear unlikely to have significant impacts on the overall efficacy and safety results.

2. Dr. Keila Hoover, Site 10-133 7371 SW 24th St. Miami, FL 33155-1402

This CI was inspected on August 4-7, 10 and 12, 2020 as a data audit for Study RVT 901-3003. This was the initial inspection for Dr. Hoover. The study site screened a total of 48 subjects, enrolled 40 subjects, with 39 subjects completed the study. The first subject was enrolled on 03/19/2018 and the last subject’s last follow-up visit was on 11/28/2018. All of the 40 enrolled subjects’ ICFs were reviewed. All source records of 25/48 screened subjects, including 22 of the 40 enrolled subjects, 3 screen failed subjects and 2 run-in failed subjects, were reviewed.

Study RVT 901-3004 was assigned but not inspected at this site by mistake. It was noted after the site inspection was closed. A discussion with ORA and DUOG decided that due to the pandemic situation and the Study had been inspected at the other two clinical sites with sufficient data, there is no need to return to the site to inspect Study RVT 901-3004.

Reference ID: 4683195 Page 5 Clinical Inspection Summary NDA 213006

Source records reviewed during the inspection included study protocol and amendments, ICFs, documentation of eligibility criteria and enrollment logs, medical records (including monitoring logs, visit reports, laboratory tests, AEs, concomitant medication use), IP accountability records, paper diaries, printouts of eCRFs entries/audit trails and EDC, protocol deviations, and related regulatory documents (e.g., IRB approvals and communications, staff training logs, financial disclosures and delegation of authority).

At the end of the inspection, a Form 483 was not issued. Discussed items included the following:

1) One subject (Subject (b) (6) ) who did not meet the inclusion criteria of ≥ 80% compliance with the run-in diary was enrolled and randomized. This subject continued in the study and was compliant with dairy after baseline.

2) Two subjects (Subjects (b) (6) ) did not have 7 consecutive diary entries prior to their study visit per protocol, although per sponsor’s clarification this is not a requirement.

3) One subject (Subject (b) (6) ) had a transcription error from the subject diary into the eligibility calculator: 8 urgency episodes were documented as 6.

4) Three subjects (Subjects (b) (6) ) had incorrect IP bottle numbers written in the source document.

5) Discrepancies identified including: 4 subjects (Subjects (b) (6) ) received IP bottles with no lot numbers; 1 subject (Subject (b) (6) ) had contradicting information of the time the diary was reviewed; 1 subject’s (Subject (b) (6) ) IP accountability was missing for 1 visit; 15 subjects took IP in the morning at the end of study visit instead of the day before (these were reported as protocol deviations, except for one subject-Subject (b) (6) ); and some illegible hand written dates or incorrect dates.

Reviewer’s Comments: All of the above identified issues were not reported in the submission, except the protocol deviations of dosing time for the 14 subjects. The CI acknowledged the overlook and implemented changes for improvement. These issues are insignificant isolated events that are unlikely to affect the safety or efficacy data of the study.

Reference ID: 4683195 Page 6 Clinical Inspection Summary NDA 213006

In general, this clinical site appeared to be in compliance with GCP except the items noted above. These findings appear unlikely to have significant impacts on the overall efficacy and safety results.

3. John Pinches, III, D.O., Site 10-156 8615 Knott Ave., Suite 9 Buena Park, CA 90620

This CI was inspected on July 7-10 and 13-15, 2020 as a data audit for Study RVT 901-3003 and Study RVT 901-3004. This was the initial inspection for Dr. Pinches.

For Study RVT 901-3003, the study site screened a total of 84 subjects (7 subjects re-screened), enrolled 70 subjects, with 65 subjects completed the study. The first subject was enrolled on 03/26/2018. All source records, including eligibility criteria were reviewed for 25 of the 70 enrolled subjects.

For Study RVT 901-3004, the study site screened and enrolled a total of 35 subjects, with 34 subjects completed the study. The first subject was enrolled on 07/10/2018 and the last subject’s last follow-up visit was on 07/02/2019. All source records, including eligibility criteria were reviewed for 12 of the 35 enrolled subjects.

Source records reviewed during the inspection included the study protocol and amendments, ICFs, documentation of eligibility criteria and enrollment logs, medical records (including monitoring logs, visit reports, laboratory tests, AEs, concomitant medication use), the IP accountability records, subject paper diaries, paper printouts of eCRFs entries/audit trails and EDC, protocol deviations and related regulatory documents (e.g., IRB approvals and communications, staff training logs, financial disclosures and delegation of authority).

The inspection found adequate source documentation for inspected study subjects, with no significant deficiencies reported. The submitted data were verifiable with source records at the study site. The primary efficacy data source was not entirely verified for Study RVT 901-3003 as subjects’ diaries were not entered by the site. There was no evidence of underreporting of AEs.

At the end of the inspection, a Form 483 was not issued. Discussion items included the following:

1) Two unreported AEs for Study RVT 901-3004: Subject (b) (6) elevated ALT (195 U/L) and Alk Phos (150 U/L) values at Visit 7 were not reported. The levels re-checked after 4 days returned to normal. Per protocol, repeating a lab analysis is an intervention of an abnormal laboratory parameters and meets the definition of AE. In addition, Subject (b) (6) abdominal pain on (b) (6) at Visit 8 was not reported.

2) Subject (b) (6) high potassium level (5.6 mmol/L) at Visit 7 was not checked for clinical significance.

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3) Study RVT 901-3003 data entry errors: Subject (b) (6) bladder volume was entered incorrectly (22 mL instead of 15 mL). Subjects (b) (6) dipstick urinalysis reports were not checked for leukocytes per requirement.

Reviewer’s Comments: All of the discussion items are noted isolated events and the CI acknowledged the overlook and implemented changes for improvement.

This study site didn’t use eDiaries per sponsor’s decision, only paper diaries were used. The sponsor was responsible for transcribing raw data collected in paper diaries into the eCRF. The inspection noted discrepancies between raw data on paper diaries and the data listings provided by the sponsor for incorrect micturition time. For example, subjects (b) (6) all had micturition time entering errors. In addition, two subjects (Subjects (b) (6) and Subject (b) (6) at Visit 8) each had an episode of delayed dose due to IP was not received on time. These were not reported as protocol deviations.

The investigator also listed “protocol deviations” as 33 subjects had urine analyses at Visit 5; and 19 subjects had ECGs at Visit 6.

Reviewer’s Comments: The protocol states that urine analysis can be done if clinically indicated to check for asymptomatic UTIs. The ECG tests were to evaluate cardiac function for those subjects who did not participate in the extension study. Conducting urine analysis and ECG are acceptable as safety precautions in clinical practice and thus, are not considered “protocol deviations”.

In general, this clinical site appeared to be in compliance with GCP except the discussion items noted above. These observations appear unlikely to have significant impacts on the overall efficacy and safety results.

{See appended electronic signature page}

Ling Yang, M.D., Ph.D. Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE:

{See appended electronic signature page}

Min Lu, M.D., M.P.H. Team Leader Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Reference ID: 4683195 Page 8 Clinical Inspection Summary NDA 213006

Kassa Ayalew, M.D., M.P.H Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CC: Central Doc. Rm.\NDA 213006 DUOG\Division Director\Hylton Joffe DUOG\CDTL\Mark Hirsch DUOG\Reviewer\Debuene Chang DUOG\Project Manager\Nenita Crisostomo OSI\DCCE\Division Director\Ni Khin OSI\DCCE\GCPAB\Branch Chief\Kassa Ayalew OSI\DCCE\GCPAB\Team Leader\Min Lu OSI\DCCE\GCPAB\Reviewer\Ling Yang OSI\DCCE\Program Analysts\Yolanda Patague

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LING YANG 10/08/2020 02:45:07 PM

MIN LU 10/08/2020 02:47:00 PM

KASSA AYALEW 10/09/2020 11:31:09 AM

Reference ID: 4683195 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS

Date: September 22, 2020

From: Interdisciplinary Review Team for Cardiac Safety Studies Division of Cardiology and Nephrology / CDER

Through: Norman Stockbridge MD, PhD Division Director Division of Cardiology and Nephrology / CDER

To: Nenita Crisostomo DUOG

Subject: ABPM Protocol Review NDA 213006 (SDN 002)

This memo responds to your consult to us dated 8/30/2020 regarding the sponsor’s ABPM protocol. The IRT reviewed the following materials:  Previous IRT reviews for NDA 213006 dated 05/07/2020 and 08/27/2020 in DARRTS;  Clinical study reports for the drug interaction studies 007 and 010; and  Proposed product labeling

Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document.

1 IRT Responses to Division’s Questions For Study P007 1) Is the Sponsor’s model to assess HR from the Holter monitor appropriate for use in these study results? Response: Yes, HR obtained using Holter recordings is an acceptable approach to evaluate a drug’s effect on HR.

2) Do you agree with the Sponsor’s study design plan that if the upper bounds for 2-sided 97% CI of the true mean change from baseline for both doses of vibegron, 100mg and

Reference ID: 4674107 150mg, + 4 mg tolterodine ER are both < 10 bpm, then the results support that “co administration of multiple doses of MK- 4618 and tolterodine ER does not increase HR to a clinically significant degree in healthy young males? Response: Yes, this seems to be a reasonable approach. The study aims to evaluate the pharmacodynamic interaction between vibegron and tolterodine. Excluding a 10 bpm upper confidence interval ensures that the mean change is reasonably likely to be <10 bpm—in this case, very unlikely to increase HR. The use of healthy males is also appropriate because they represent a more sensitive population to test for a pharmacodynamic interaction due to their higher intrinsic vagal tone at rest and a higher beta-receptor density compared to older individuals. 3) Do the study results show any clinically meaningful changes in HR or BP for vibegron co-administered with tolterodine? Response: There is no clinically meaningful increase in HR; the average change from baseline in 24-h average HR is <10 bpm. A lack of a HR effect was also observed in the ABPM study. 4) Any labeling recommendations based on the results from this study? Response: No. Similarly, tolterodine ER (Detrol LA) does not have increased HR listed as an adverse reaction in its product labeling in sections 5 and 6. Palpitations and tachycardia are listed in post-marketing experience. For Study P010 1) Are the antihypertensive representatives for the class of β-blockers and vasodilators appropriate and can the study results be extrapolated to each class? Response: Vibegron 75 mg QD does not increase or decrease BP as demonstrated in the ABPM study and there were no large decreases in BP when vibegron 100 mg QD was coadministered with metoprolol or amlodipine. We do not see the need to evaluate the BP effects with the concomitant use of other classes of antihypertensive drugs. 2) Do the study results show any clinically meaningful changes in SBP after single dose of 100 mg vibegron and at steady state for 7 days when co-administered with metoprolol or amlodipine? Response: No large changes were detected in the study. The study is designed only to detect large changes in BP (≥ 20 mmHg) which may cause a decrease in the dosing regimen of metoprolol or amlodipine.

3) Any labeling recommendations based on the results from this study? Response: No.

2 BACKGROUND

2.1 Product information Vibegron is a highly selective beta-3 adrenergic agonist which has been developed for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency,

Reference ID: 4674107 and urinary frequency. The recommended oral dose is one 75 mg tablet once daily with or without food.

2.2 Previous BP and HR findings Preclinical studies conducted with vibegron have shown cardiovascular effects. In anesthetized dogs, vibegron increased heart rate (up to +32%) and decreased mean blood pressure (up to 50%) following intravenous doses ranging from 0.3 to 7 mg/kg. In monkeys, heart rate increases were also observed at MK-4618 doses of ≥2.5 mg/kg; but tachyphylaxis to this effect was observed in repeated-dose oral safety pharmacology studies in monkeys. The effect of vibegron was evaluated in a dedicated ABPM study URO-901-1001, a randomized, placebo-controlled study in OAB patients receiving vibegron 75 mg qd or placebo for 28 days. There were no significant increases in placebo-adjusted mean change from baseline (ΔΔ) in daytime and 24-h average systolic BP, diastolic BP and HR.

3 Drug Interaction Studies Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of vibegron and the effect of vibegron on the pharmacokinetics of co- administered drugs (e.g. digoxin, metoprolol, oral contraceptives, rifampin, tolterodine ER, and warfarin)

3.1 Drug Interaction with Metoprolol or Amlodipine The study was designed to determine if MK-4618 could enhance antihypertensive effects of metoprolol and amlodipine. This was a 2-panel, randomized, partially-blinded, placebo-controlled 2-period crossover study to evaluate safety and tolerability of once-daily multiple oral doses of 100 mg MK-4618 when co-administered with a beta-blocker (Panel A) or with a vasodilator (Panel B). Panel A was to enroll 12 subjects who had been maintained on a stable dose of extended release metoprolol or another beta-blocker for at least 6 weeks prior to enrollment. Subjects in Panel A were administered extended release metoprolol in open-label fashion for the duration of the study. Subjects were co-administered once-daily oral doses of MK-4618 or matching placebo with metoprolol in Periods 1 and 2 for 7 consecutive days in crossover fashion. There was a 2 week washout between treatment periods.

Reference ID: 4674107 Panel B was to enroll 12 subjects who had been maintained on a stable dose of amlodipine for at least 6 weeks prior to enrollment. Subjects in Panel B were administered their usual dose of amlodipine in open-label fashion for the duration of the study. Subjects were co-administered once-daily oral doses of MK-4618 or matching placebo with amlodipine in Periods 1 and 2 for 7 consecutive days in crossover fashion. There was a 2 week washout between treatment periods. Reviewer’s comment: With 12 subjects per Panel, the study is not powered to detect small changes in BP with concomitant use of MK-4618 with metoprolol or amlodipine. The study can only evaluate large changes (≥20 mmHg) in BP that could lead to changes in dosing regimen of antihypertensive medications. Results:

Reference ID: 4674107 Reviewer’s comments: The figures above are from the CSR for Study P010. No large mean decreases (≥ 20 mmHg) were detected when MK-4618 was administered with metoprolol (Table 11-1) or amlodipine (Table 11-2).

3.2 Drug Interaction with Tolterodine Preclinical research studies have shown additive or synergistic effects of the combination of various antimuscarinic agents with MK-4618. Study 0070 was a double-blind, double dummy, randomized, placebo-controlled study to assess the safety, tolerability and multiple dose pharmacokinetics of MK-4618 doses of 100 mg (Panel I) and 150 mg (Panel II) in healthy male subjects when given alone and in combination with 4 mg tolterodine ER. To address the primary hypothesis, change from baseline in 24 hour weighted average HR (Holter data) from both groups was evaluated with a linear mixed effects model having treatment and period as fixed effects and subject as a random effect. A 2-sided 97% confidence interval (CI) for the true mean change from baseline following MK-4618 with tolterodine ER was calculated from the model. If the upper bound was less than 10, then the hypothesis that co- administration of multiple doses of MK-4618 and tolterodine ER does not increase HR on Day 7 over baseline in healthy young males was accepted for that dose of MK-4618. Results:

Reference ID: 4674107 Reviewer’s comment: The study showed (1) the mean incrase from baseline in 24-h average HR was less than 10 bpm for all treatment groups; and (2) the combined use of MK-4618 (100 mg or 150 mg QD) with tolerodine 4 mg QD compared to each treatment alone was also less than 10 bpm.

Thank you for requesting our input into the development of this product. We welcome more discussion with you now and in the future. Please feel free to contact us via email at [email protected]

Reference ID: 4674107 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

CHRISTINE E GARNETT 09/22/2020 02:02:32 PM

PRESTON M DUNNMON 09/23/2020 06:51:11 PM

NORMAN L STOCKBRIDGE 09/24/2020 05:04:33 AM

Reference ID: 4674107 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS

Date: August 27, 2020

From: Interdisciplinary Review Team for Cardiac Safety Studies Division of Cardiology and Nephrology / CDER

Through: Norman Stockbridge MD, PhD Division Director Division of Cardiology and Nephrology / CDER

To: Nenita Crisostomo, RPM DUOG

Subject: ABPM Protocol Review NDA 213006 (SDN 024)

This memo responds to your consult to us dated 7/27/2020 regarding the sponsor’s response to OCP’s Information Request. The IRT reviewed the following materials:  Sponsor’s response to OCP’s Information Request (eCTD 0022; link); and  Previous IRT review(s) for NDA 213006 dated 05/07/2020 in DARRTS.

1 IRT Responses Division Question: The Sponsor has responded to the ClinPharm team’s request for information on vital sign changes in the lower weight classes of <25% and <10% in studies 008, 1001, and 3003 to determine if there is a drug effect on vital signs for the lower weight groups. Does vibegron at 75mg daily dose have a drug effect on BP and HR for the lower weight groups?

Response: The submitted data do not support drug effects on BP and HR in the lower weight groups.

2 BACKGROUND

2.1 Office of Clinical Pharmacology’s Information Request OCP Request: To facilitate our review of this issue, provide additional vital signs comparisons by body weight (e.g. ≤ 10th & > 10th percentile, and ≤ 25th & > 25th percentile) in the US population (i.e., combined data from Study 008, Study 1001 and Study 3003). Instead of

Reference ID: 4662766 presenting blood pressure and heart rate changes as categorical values (such as >= 5 units, >=10 units, etc.), report mean changes from baseline in blood pressure and heart rate at Week 8 and at end-of-the treatment.

The sponsor concluded: The results of requested analysis show that the effects of once daily 75 mg vibegron on vital signs are similar to placebo and not clinically meaningful in patients with body weights in the ≤25th and ≤10th percentile groups.

Reviewer’s comment: We agree with the sponsor’s conclusions.

2.2 Previous ABPM Study findings No significant effects of vibegron on blood pressure (BP) was observed in this ABPM study as evidenced by an upper bound of 1.7 mmHg for the mean change from baseline in systolic BP. Using the Pooled Cohort Equations, this translates into excluding an excess of 0.2 CV events per 1000 patient years for OAB patients.

The effect of vibegron was evaluated in a dedicated ABPM study URO-901-1001, a randomized, placebo-controlled study in OAB patients receiving vibegron 75 mg qd or placebo for 28 days. There were no significant increases in placebo-adjusted mean change from baseline (ΔΔ) in daytime and 24-h average systolic BP, diastolic BP and HR.

Thank you for requesting our input into the development of this product. We welcome more discussion with you now and in the future. Please feel free to contact us via email at [email protected]

Reference ID: 4662766 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

LARS JOHANNESEN 08/27/2020 12:36:11 PM

CHRISTINE E GARNETT 08/27/2020 12:46:17 PM

NORMAN L STOCKBRIDGE 08/27/2020 01:13:44 PM

Reference ID: 4662766 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: July 9, 2020 Requesting Office or Division: Division of Urology, Obstetrics, and Gynecology (DUOG) Application Type and Number: NDA 213006 Product Name and Strength: Gemtesa (vibegron) tablet, 75 mg Applicant/Sponsor Name: Urovant Sciences GmbH (Urovant) OSE RCM #: 2019-2650-1 DMEPA Safety Evaluator: Denise Baugh, PharmD, BCPS DMEPA Team Leader: Briana Rider, PharmD, CPPS

1 PURPOSE OF MEMORANDUM The Applicant submitted revised container labels and carton labeling received on June 23, 2020 for Gemtesa. The Division of Urology, Obstetrics, and Gynecology (DUOG) requested that we review the revised container labels and carton labeling for Gemtesa (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 ASSESSMENT We previously recommended that the statement (b) (4) be removed from the principal display panel (PDP) of the container labels and carton labeling. We note the statement has been revised to read “One Tablet – Once Daily”; however, it has not been removed from the PDP. Upon further review, we note that the usual dosage is constant (i.e., one tablet once daily) and this statement does not hinder the prominence or readability of other critical information on the PDP. As such, we no longer object to inclusion of this statement on the PDP.

3 CONCLUSION

a Baugh D. Label and Labeling Review for Gemtesa (NDA 213006). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 JUN 01. RCM No.: 2019-2650. 1

Reference ID: 4638221 The Applicant implemented or considered all of our recommendations and we have no additional recommendations at this time.

2 Pages of Draft Labeling have been Wtihheld in Full as b4 (CCI/ TS) immediately following this page

Reference ID: 4638221 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

DENISE V BAUGH 07/09/2020 09:40:05 AM

BRIANA B RIDER 07/09/2020 09:46:19 AM

Reference ID: 4638221 Interdisciplinary Review Team for Cardiac Safety Studies QT Study Review Submission NDA 213006 Submission Number 001 Submission Date 12/27/2019 Date Consult Received 2/24/2020 Drug Name Gemtesa (Vibegron) Treatment of overactive bladder (OAB) with symptoms of Indication urge urinary incontinence, urgency, and urinary frequency Therapeutic dose 75 mg once daily (QD) with or without food Clinical Division DUOG Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document. This review responds to your consult dated 2/24/2020 regarding the sponsor’s QT evaluation. We reviewed the following materials:  Previous QT-IRT review under IND 106410 dated 08/29/2012 in DARRTS  Highlights of Clinical Pharmacology and Cardiac Safety (Submission 0006)  Study Report P012(Submission 0000)  Proposed Labeling (Submission 0000)

1 SUMMARY No significant QTc prolongation effect of Vibegron was detected in this QT assessment. The effect of vibegron was evaluated in a single dose, randomized, double-blind, placebo and active-controlled, 4-period, crossover, thorough QT (TQT) study (Study P012) in 52 healthy subjects. The highest dose of vibegron evaluated was 400 mg, which covers the worst case exposure scenario (i.e., 2-fold increase in the presence of strong CYP3A4 inhibitor). The data were analyzed using by-timepoint analysis as the primary analysis, which did not suggest that vibegron is associated with significant QTc prolonging effect in the QTc interval (refer to section 4.3) – see Table 1 for overall results. Moxifloxacin 400 mg treatment provided assay sensitivity as the lower bound of 90% CI of maximum mean increase in QTc values was greater than 5 msec (Table 1). The results from this analysis are further supported by the available nonclinical data (sections 3.1.2), concentration-response analysis (section 4.5) and categorical analysis (section 4.4). Table 1: The Point Estimates and the 90% CIs ECG parameter Treatment Time ∆∆QTcF 90% CI (msec) (msec) QTc Vibegron 200 mg 1 hour 5.0 (3.1, 6.9) QTc Vibegron 400 mg 1 hour 4.6 (2.7, 6.5)

Reference ID: 4627739 I Moxitloxacin 400 mg 12h our 11 i.1 I (9.2, 13.1)

The maximum mean increase in heart rate for the supratherapeutic dose of 400 mg was 12.4 bpm (90% CI: 10.7 - 14.1 bpm) at 3 hour postdose. The maximum increase in heaii rate for the 200 mg dose (which represents the steady state exposure at the therapeutic dose of vibegron) was less than 10 bpm. The increase in heait rate is not expected to impact the overall conclusion in this QT study.

1.1 RESPONSES TO QUE STIONS POSED BY SPONSOR Not applicable.

1.2 COMMENTS TO THE REVIEW DIVISION Question from the Division: Was the methodology of the estimated effects on SBP, DBP, and HR reasonable to extrapolate the observed effects of single doses of vibegron 200 mg and 400 mg on these pai·ameters to the proposed dosing regimen of vibegron 7 5 mg daily on these parameters? IRT's r esponse: Please refer to General Consult Review dated 05/0712020 in DARRTS.

2 RECOMMENDATIONS

2.1 ADDITIONAL STUDIES Not applicable.

2.2 PROPOSED LABEL Below are proposed edits to the label submitted to SND 001 (link) from the IRT. Our changes ai·e highlighted (addition, deletion) as a suggestion. We defer final labeling decisions to the Division. 12.2 Phan nacodynamics Cai·diac ElectroQhysiology

(b)(~l

(b)(4) - AccordinK to the spons01~ I

Reference ID 4627739 The reviewer does not agree (b) (4) the following reasons: (b) (4)

(b) (4) , we propose to use labeling language which report the fold difference based on study dose. This language is consistent with the “Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products – Content and Format” guidance. If the sponsor’s estimate of therapeutic Cmax was found acceptable after review of the overall clinical pharmacology package, we would agree (b) (4) (b) (4) and we recommend the following language: At an exposure 9X times the maximum concentration of the recommended daily dose (75 mg), vibegron does not prolong the QT interval to any clinically relevant extent.

3 SPONSOR’S SUBMISSION

3.1 OVERVIEW

3.1.1 Clinical The QT-IRT reviewed the QT assessment proposal previously (DARRTS 08/29/2012). The proposed study was a single-dose, randomized, double-blind, three-period crossover study in healthy subjects and it consists of placebo, 600 mg vibegron, and 400 mg moxifloxacin treatment. The proposed therapeutic dose was (b) (4) mg QD. The study protocol was found to be acceptable and the adequacy of dose/exposure remained a review issue depending on the characterization of the highest exposure scenario. Three changes related to the study protocol were made between IND 106410 in 2012 and the submission of NDA 213006 in December 2019. The therapeutic dose is lowered from (b) (4) mg QD to 75 mg QD, the highest tested dose is changed from (b) (4) mg to 400 mg, and the sponsor has included a 200 mg dose treatment that was not in the IND protocol. These changes are acceptable because the 400 mg dose provided at least 5.3-fold coverage for the maximum steady state concentration at the proposed therapeutic dose (75 mg QD) and covers the highest exposure scenario due to strong CYP3A4 inhibition (2-fold increase in Cmax).

Reference ID: 4627739 3.1.2 Nonclinical Safety Pharmacology Assessments Vibegron was a weak inhibitor of in vitro hERG tail current (Study TT09-4709), inhibiting only 21% of the current at the maximum testable concentration of 101 μM, 365-fold higher than the steady state Cmax in humans treated with 75 mg/day. In the definitive cardiovascular/respiratory safety pharmacology study (Study TT09 5605) in telemetered monkeys evaluating single oral doses of vibegron of 2.5, 15, and 135 mg/kg vibegron, transient dose-related increased HR, respiration rate, and body temperature, and decreased uncorrected QT interval were observed at all doses (≥ 2.5 mg/kg). Increases in the QTc interval were also observed at all doses; however, since the QTc changes were not dose related and the HR increases were large, they were believed to be due to inadequate correction of the QT interval and were not considered to be drug related. Decreased PR interval occurred at ≥ 15 mg/kg and increased diastolic blood pressure, respiration depth, and QRS interval were noted at 135 mg/kg. The NOAEL for this study was determined to be 2.5 mg/kg, associated with an exposure 0.22-fold of the steady state Cmax in humans treated with 75 mg/day.

3.2 SPONSOR’S RESULTS

3.2.1 By-Time Analysis Vibegron excluded the 10 msec threshold at the 400 mg supratherapeutic dose level for ΔΔQTcF. The sponsor observed dose-dependent RR decrease and concluded that was considered not clinically meaningful. Reviewer’s comment: The sponsor used a linear mixed-effects model to analyze QTcF. Sponsor’s ΔΔQTcF results are consistent with results from reviewer’s analysis. Similar change of HR for 400 mg dose level was also observed in reviewer’s analysis. Please see section 4.3 for more details.

3.2.1.1 Assay Sensitivity Assay sensitivity was established by the moxifloxacin arm based on one sided p-values (H0: mean difference < 5 msec) at 1, 2, 3, and 4 hours postdose comparing to sequentially adjusted alpha levels. Reviewer’s comment: Sponsor’s results are consistent with results from reviewer’s analysis. Please see section 4.3 for more details.

3.2.1.1.1 QT Bias Assessment Not applicable.

3.2.2 Categorical Analysis There were no significant outliers per the sponsor’s analysis for QTcF (i.e., > 500 msec or > 60 msec over baseline). Reviewer’s comment: Reviewer’s analysis results for QTcF are consistent with sponsor’s results. Reviewers analysis showed that two subject had observed HR values above 100 bpm. Please see section 3.2.2 for more details.

Reference ID: 4627739 3.2.3 Exposure-Response Analysis The sponsor did not conduct CQT analysis. Per protocol, CQT analysis is performed only if the outcome of the primary analysis is positive.

3.2.4 Safety Analysis There were no deaths or SAEs. One subject discontinued from the study due to a non- serious, mild AE of generalized rash 8 days after taking moxifloxacin in Period. There were no cardiac-related TEAEs. Reviewer’s comment: None of the events identified to be of clinical importance per the ICH E14 guidelines (i.e., seizure, significant ventricular arrhythmias or sudden cardiac death) occurred in this study.

4 REVIEWERS’ ASSESSMENT

4.1 EVALUATION OF THE QT/RR CORRECTION METHOD The sponsor used QTcF for the primary analysis. The slight increase in heart rate at the supratherapeutic dose of 400 mg (maximum effect [mean / 90%CI]: 12.4 bpm / (10.7 14.1) bpm) is not expected to impact the overall conclusion on QTc.

4.2 ECG ASSESSMENTS

4.2.1 Overall Overall ECG acquisition and interpretation in this study appears acceptable.

4.2.2 QT Bias Assessment Not applicable.

4.3 BY-TIME ANALYSIS The analysis population used for by time analysis included all subjects with a baseline and at least one post-dose ECG. There were 13 subjects enrolled in each of four sequences. There were four subjects (one in each sequences) missed one or two periods. The statistical reviewer used linear mixed effects model to analyze the drug effect by time for each biomarker (e.g., ΔQTcF, ΔHR) independently. The default model includes treatment, sequence, period, time (as a categorical variable), and treatment-by-time interaction as fixed effects and baseline as a covariate. The default model also includes subject as a random effect and an compound symmetric covariance matrix to explain the associated between repeated measures within period.

4.3.1 QTc Figure 1 displays the time profile of ΔΔQTcF for different treatment groups. The maximum ΔΔQTcF values by treatment are shown in Table 1.

Reference ID: 4627739 Figure 1: Mean and 90% CI of AAQTcF Timecourse unad·usted Cls . 15 14 13 12 11 10 9 u 8 '(ft 7 0 6 Ol '('.)" 5 - ~ ~ 4 u E 3 I '-' 2 a 1 ~ o +-~---::;~T+~+-~+-~~~~~~~~~~~...,,....~--1 -1 -2 .3 -4 .5 1 -6 1 .7

0 1 2 3 4 6 8 10 12 24 Time (hours) Actual Treatment

Vibegron 200 mg -- Vibegron 400 mg -- Moxifloxacin -- 400 mg Table 1: The Point Estimates and the 90% Cls Corresponding to the Largest Upper Bounds for AAC>TcF Actual Treatment N Time (hours) M QTCF (msec) 90.0% Cl (msec) Vibegron 200 mg 50 1.0 5.0 (3 1 to 6.9) Vibegron 400 mg 52 1.0 4.6 (2.7 to 6.5)

4.3.1.1 Assay Sensitivity The time-course of changes in .6..6.QTcF is shown in Figure 1. Table 2 shows the expected time-profile with a mean effect of greater than 5 msec at 2 hours post-dose after Bonfen oni adjustment for 4 time points. Table 2: The Point Estimates and the 90% Cl s Corresponding to the Largest Lower Bounds for AAQTcF N Time (hours) LiLiQTCF (msec) 90% Cl (msec) 97.5% Cl (msec) 51 2.0 11.1 (92, 131) (8.5to137)

4.3.2 HR Figure 2 displays the time profile of .6..6.HR for different treatment groups. The maximum .6..6.HR values by treatment are shown in Table 3.

Reference ID 4627739 Figure 2: Mean and 90% CI of AAHR Time Course

0 1 2 3 4 6 8 10 12 24 Time (hours) Actual Treatment - Vibegron 200 mg - Vibegron 400 mg - Moxiftoxacin 400 mg

Table 3: The Point Estimates and the 90% Cls Corresponding to the Largest Upper Bounds for AAHR Actual Treatment N Time (hours) M HR (beats/min) 90.0% Cl (beats/min) Vibegron 200 mg 50 8.0 6.3 (4.6 to 8.0) Vibegron 400 mg 52 3.0 12.4 (10.7to14.1)

Reviewer's comment: Large titi HR (> I 0 bpm) was observed at hours 2, 3, and 4for Vibegron 400 mg. However, the increases appear to be transient and on~y appear at superatheapeutic dose level. The HR increases was leveled offafter hour 4. Increases of HR are higher in period I than the other 3 periods for Vibegron 200 mg.

4.3.3 PR Figure 3 displays the time profile of titiPR for different treatment groups. The maximum titiPR values by treatment are shown in Table 4.

Reference ID 4627739 Figure 3: Mean and 90% CI of AAPR Time Course 10 9 8 7 6 5 0 4 ;F. 3 0 'U' 2 T O> QJ +I VJ 1 Cl::'. E 0 a. '-'

0 1 2 3 4 6 8 10 12 24 Time (hours) Actual Treatment

- Vibegron 200 mg - Vibegron 400 mg - Moxiftoxacin 400 mg

Table 4: The Point Estimates and the 90% Cis Corresponding to the Largest Upper Bounds for AAPR

Actual Treatment N Time (hours) ~~PR ( msec) 90.0% Cl (msec) Vibegron 200 mg 50 100 -0.0 (-1.8to 1.7) Vibegron 400 mg 52 23.5 0.3 (-1.4 to 2.1)

4.3.4 QRS Figure 4 displays the time profile of D.D.QRS for different ti·eatment groups. The maximum D.D. QRS values by ti·eatment are shown in Table 5. Figure 4: Mean and 90% CI ofAAQRS Time Course 10 9 8

6 0 5 ;F. 0 4 O> 'U' QJ 3 +I VJ (/) E 2 aCl::'. '-'

0 1 2 3 4 6 8 10 12 24 Time (hours) Actual Treatment

- Vibegron 200 mg - Vibegron 400 mg - Moxiftoxacin 400 mg

Reference ID 4627739 Table 5: The Point Estimates and the 90% Cls Cor r esponding to the Largest Upper Bounds for AAQRS Actual Treatment N Time (hours) M QRS(msec) 90.0% Cl (msec) Vibegron 200 mg 50 1.0 0.7 (0.2 to 1.1) Vibegron 400 mg 52 2.0 1.2 (0.7 to 1.6)

4.4 CATEGORICAL ANALYSIS Categorical analysis were perfonned for different ECG measurements either using absolute values, change from baseline or a combination of both. The analysis was conducted using the safety population and includes both scheduled and unscheduled ECGs.

4.4.1 QTc None of the subjects experienced QTcF > 450 msec or ~QTcF > 30 msec.

4.4.2 HR Table 6 lists the categorical analysis results for maximum HR (<100 bpm and > 100 bpm). There were two subjects experienced HR > 100 bpm after receiving vibergron 400 mg (change from baseline 32.3% and 58.4%). The maximum of observed HR is 103.2 bpm. Table 6: Cate2orical Analysis for HR (maximum) Total (N) Value<= 100 beats/min Value > 100 beats/min

Actual Treatment #Subj. #Obs. # Subj. #Obs. # Subj. #Obs. 50 500 0 0 Vibegron 200 mg 50 500 (100.0%) (100.0%) (0%) (0%) 518 Vibegron 400 mg 50 2 2 52 520 (962%) (99.6%) (3.8%) (0.4%) 49 499 1 Placebo 1 50 500 (98.0%) (99.8%) (2.0%) (0.2%)

4.4.3 PR None of the subjects experienced PR greater than 220 msec.

4.4.4 QRS None of the subjects experienced QRS greater than 120 msec.

4.5 EXPOSURE-RESPONSE ANALYSIS Exposure-response analysis was conducted using all subjects with baseline and at a least one post-baseline ECG with time-matched PK. Two subjects did not receive the 200 mg dose of vibegron and 2 subjects did not receive the placebo.

4.5.1 QTc Prior to evaluating the relationship between drng-concentration and QTc using a linear model, the three key assumptions of the model needs to be evaluated using explorato1y analysis: 1) absence of significant changes in heait rate (more than a 10 bpm increase or

Reference ID 4627739 decrease in mean HR); 2) delay between plasma concentration and ΔΔQTc and 3) presence of non-linear relationship. Figure 2 shows the time-course of ΔΔHR, which suggests concentration-dependent increase in HR. Given the magnitude of HR increase (i.e. maximum effect slightly above 10 bpm, only at the supratherapeutic dose), it is reasonable to use QTcF as the primary endpoint. Figure 5 evaluates the time-course of drug-concentration and ΔΔQTc and do not appear to show significant hysteresis. Vibegron showed more than dose proportional PK as both AUC and Cmax increased by 2.8-fold compared to a 2-fold increase in dose. There is no delay between the plasma concentrations observed and ΔΔQTc. Figure 6 shows the relationship between drug concentration and ΔQTc and supports the use of a linear model. Figure 5: Time course of drug concentration (top) and QTc (bottom)

Reference ID: 4627739 Figure 6: Assessment of linearity of concentration-QTc relationship

20 . .. . '• 8 10 '""'.,u

_§,"' 0 LL .- -- ...... (.) I CJ

-20 ... . -30 .. 0 2000 4000 6000 Vibegron (nmol) Finally, the White Paper model was applied to the data and the goodness-of-fit plot is shown in Figure 7. The model does not suggest a positive exposure-response relationship within the studied exposure range. Predictions from the concentration-QTc model are provided in Table 7. Fi ure 7: Goodness-of-fit lot for QTc 15

'""'.,u 10 _§,"' l5 5 '$. 0 <1> +I LL 0 (.) 5 ~ ·5

-10

0 2000 4000 6000 Vibegron (nmoQ Table 7: Predictions from concentration-QTc model Actual Treatment Vibegron (nmol) M QTCF (msec) 90.0% Cl (msec) Vibegron 200 mg 824.4 -0.2 (-0.9 to 0.4) Vibegron 400 mg 2317.9 0.0 (-1.6 to 1.7)

4.5.1.1 Assay Sensitivity Not applicable.

4.6 SAFETY ASSESSMENTS See section 3.2.4. No additional safety analyses were conducted.

Reference ID 4627739 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

YU YI HSU 06/19/2020 11:11:41 AM

DALONG HUANG 06/19/2020 11:13:04 AM

RAMAN K BAWEJA 06/19/2020 11:21:29 AM

NAN ZHENG 06/19/2020 11:26:45 AM

MICHAEL Y LI 06/19/2020 11:28:18 AM

LARS JOHANNESEN 06/19/2020 02:48:56 PM

CHRISTINE E GARNETT 06/19/2020 02:50:44 PM

Reference ID: 4627739 LABEL, LABELING, AND PACKAGING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: June 1, 2020 Requesting Office or Division: Division of Urology, Obstetrics, and Gynecology (DUOG) Application Type and Number: NDA 213006 Product Name, Dosage Form, Gemtesa (vibegron) tablet, 75 mg and Strength: Product Type: Single Ingredient Product Rx or OTC: Prescription (Rx) Applicant/Sponsor Name: Urovant Sciences GmbH (Urovant) FDA Received Date: December 26, 2019 and March 11, 2020 OSE RCM #: 2019-2650 DMEPA Safety Evaluator: Denise V. Baugh, PharmD, BCPS DMEPA Team Leader: Briana Rider, PharmD, CPPS

Reference ID: 4617394 1 REASON FOR REVIEW As part of the approval process for Gemtesa (vibegron) tablets (NDA 213006), the Division of Urology, Obstetrics, and Gynecology (DUOG) requested that we review the proposed Gemtesa Prescribing Information (PI) and Patient Information labeling, trade and sample container labels and carton labeling for areas of vulnerability that may lead to medication errors.

2 MATERIALS REVIEWED We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed. Table 1. Materials Considered for this Review Material Reviewed Appendix Section (for Methods and Results) Product Information/Prescribing Information A Previous DMEPA Reviews B Human Factors Study C – N/A ISMP Newsletters* D – N/A FDA Adverse Event Reporting System (FAERS)* E – N/A Other F – N/A Labels and Labeling G N/A=not applicable for this review *We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED We reviewed the proposed Gemtesa labels and labeling for areas of vulnerability that could lead to medication errors. We identified the following areas of vulnerability with the proposed container labels (trade and professional sample) and carton labeling (professional sample):  The statement (b) (4) on the professional sample label and labeling can be improved for clarity.  The container label (trade and professional sample) and carton labeling (professional sample) does not contain a usual dosage statement in accordance with 21 CFR 201.55.  The proposed format for the expiration date (b) (4) is unclear; thus, we are unable to assess the appropriateness of the proposed format from a medication safety perspective.

Reference ID: 4617394  The dosage form ‘tablet’ is absent from the established name on the principal display panel of the container labels (trade and professional sample) and carton labeling (professional sample).  The statement (b) (4) which appears on the principal display panel (PDP) of the container labels (trade and professional sample) and carton labeling (professional sample) refers to the dosage form (b) (4) Additionally, inclusion of this statement on the PDP may decrease the prominence of other critical information that is recommended to appear on the PDP (e.g., proprietary name, established name).  The statement (b) (4) on the principal display panel of the container labels (trade and professional sample) and carton labeling (professional sample) lacks clarity. Specifically, the statement does not indicate (b) (4)

Additionally, we reviewed the proposed Prescribing Information (PI) and Patient Information labeling. We note the statement (b) (4) We are concerned that this statement may be misinterpreted (b) (4) We communicated our concerns to the Office of Pharmaceutical Quality (OPQ) and they clarified (b) (4)

We provide recommendations in Sections 4.1 and 4.2 below to address these concerns.

4 CONCLUSION & RECOMMENDATIONS We find the proposed Gemtesa labels and labeling vulnerable to medication errors. See Sections 4.1 and 4.2 below for our recommendations. 4.1 RECOMMENDATIONS FOR DIVISION OF UROLOGY, OBSTETRICS, AND GYNECOLOGY (DUOG) A. Prescribing Information 1. How Supplied/Storage and Handling Section a. We note the statement (b) (4) We are concerned that this statement may be misinterpreted (b) (4) We communicated our concerns to the Office of Pharmaceutical Quality, and they clarified (b) (4)

B. Patient Information 1. ‘How should I store GEMTESA?’ Section

Reference ID: 4617394 a. We note the statement (b) (4) appears under the heading titled ‘How should I store GEMTESA?’ in the Patient Information. We are concerned that this statement may be misinterpreted (b) (4) We communicated our concerns to the Office of Pharmaceutical Quality, and they clarified (b) (4)

Therefore, we recommend removal of this statement from the Patient Information labeling under the heading titled ‘How should I store GEMTESA?’. 4.2 RECOMMENDATIONS FOR UROVANT SCIENCES GMBH (UROVANT) We recommend the following be implemented prior to approval of this Application: A. Professional Sample: Container Labels and Carton Labeling 1. The professional sample container label and carton labeling states “ (b) (4) We recommend you consider revising the statement (b) (4) to read ‘Sample: not for sale’, for clarity. B. General: Container Labels and Carton Labeling – Trade and Professional Sample 1. The container labels and carton labeling do not contain a usual dosage statement in accordance with 21 CFR 201.55. Ensure the usual dosage statement is present in accordance with 21 CFR 201.55. For example, consider revising the statement (b) (4) to read ‘Recommended Dosage: See prescribing information’, or address this concern by other means. 2. As currently presented, the format for the expiration date is (b) (4) However, it is unclear whether the month (b) (4) will be displayed using numerical (for example, 06) or alphabetical (for example, JU) characters. Therefore, we were not able to assess the appropriateness of the proposed expiration date format from a medication safety perspective. Please clarify whether you propose to use only numerical characters for the expiration date, or whether you propose to use alphabetical characters for the month. Additionally, to minimize confusion and reduce the risk for deteriorated drug medication errors, FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day, if space permits. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month.a

a Guidance for Industry: Product Identifiers Under the Drug Supply Chain Security Act Questions and Answers. 2018. Available from: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs gen/documents/document/ucm621044.pdf

Reference ID: 4617394 3. The dosage form is not present as part of the established name on the principal display panel (PDP). Per 21 CFR 201.10(g)(1), the established name shall accompany the proprietary name on the label and labeling. The established name should include the finished dosage form. Revise the established name to include the dosage form, tablet, on the PDP. If space does not permit the dosage form to appear on the same line as the active ingredient, we recommend placing the finished dosage form on the next line below the active ingredient. See Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (lines 326 – 343).b 4. The statement (b) (4) appears on the principal display panel (PDP). We advise against using the term (b) (4) . Additionally, we recommend removing the statement (b) (4) from the PDP to maximize the prominence of the following information on the PDP: proprietary name, established name, product strength, and warnings (if any) or cautionary statements (if any). 5. The statement (b) (4) on the principal display panel lacks clarity. Specifically, the statement does not indicate (b) (4) We recommend you revise this statement from (b) (4) (b) (4) to read ‘Tablet may be swallowed whole or crushed’ to specify that the tablet may be ‘swallowed’ whole.

b Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors. 2013. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance documents/safety-considerations-container-labels-and-carton-labeling-design-minimize-medication-errors

Reference ID: 4617394 APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION Table 2 presents relevant product information for Gemtesa received on December 26, 2019 and March 11, 2020 from Urovant Sciences GmbH (Urovant) Table 2. Relevant Product Information for GEMTESA Initial Approval Date N/A Active Ingredient vibegron Indication Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency Route of Administration oral Dosage Form tablet Strength 75 mg Dose and Frequency One tablet once daily; swallow tablet whole with water; may be crushed and mixed with (b) (4) How Supplied 30 count bottle with a child resistant cap 90 count bottle with a child resistant cap (b) (4) Storage Store at

Reference ID: 4617394 APPENDIX B. PREVIOUS DMEPA REVIEWS On May 19, 2020, we searched for previous DMEPA reviews relevant to this current review using the terms, ‘Gemtesa’, ‘vibegron’ and ‘NDA 213006’. Our search identified no previous reviews.

Reference ID: 4617394 APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed Using the principles of human factors and Failure Mode and Effects Analysis,c along with postmarket medication error data, we reviewed the following Gemtesa labels and labeling submitted by Urovant Sciences GmbH (Urovant)

 Container label received on December 26, 2019  Carton labeling received on December 26, 2019  Professional Sample Container Label received on December 26, 2019  Professional Sample Carton Labeling received on December 26, 2019  Prescribing Information (Image not shown) received on March 11, 2020, available from \\cdsesub1\evsprod\nda213006\0007\m1\us\114-labeling\draft\labeling\20200311 gemtesa-pi-clean.docx

G.2 Label and Labeling Images Container label – 30 count (b) (4)

c Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

8 2 Pages of Draft Labeling have been Wtihheld in Full as b4 (CCI/ TS) immediately following this page Reference ID: 4617394 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

DENISE V BAUGH 06/01/2020 01:19:59 PM

BRIANA B RIDER 06/01/2020 07:43:06 PM

Reference ID: 4617394 Interdisciplinary Review Team for Cardiac Safety Studies ABPM Study Review Submission NDA 213006 Submission Number 001 Submission Date 12/27/2019 Date Consult Received 2/14/2020 Drug Name Vibegron Treatment of overactive bladder (OAB) with symptoms of urge urinary Indication incontinence, urgency, and urinary frequency Therapeutic dose 75 mg qd Clinical Division DBRUP Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document. This review responds to your consult dated 2/14/2020 regarding the sponsor’s ABPM study. We reviewed the following materials:  Protocol review by Dr. Grant (IND 106410, DARRTS 10/05/2018);  Study report for URO-901-1001 (eCTD 0000); and  Study report for URO-901-3003 (eCTD 0000).

1 SUMMARY No significant effects of vibegron on blood pressure (BP) was observed in this ABPM study as evidenced by an upper bound of 1.7 mmHg for the mean change from baseline in systolic BP. Using the Pooled Cohort Equations, this translates into excluding an excess of 0.2 CV events per 1000 patient years for OAB patients. The effect of vibegron was evaluated in a dedicated ABPM study URO-901-1001, a randomized, placebo-controlled study in OAB patients receiving vibegron 75 mg qd or placebo for 28 days. There were no significant increases in placebo-adjusted mean change from baseline (ΔΔ) in daytime and 24-h average systolic BP, diastolic BP and HR (section 4.2). The results for the 24-h average parameters are shown in Table 1. Table 1: The Point Estimates and the 95% CIs (FDA Analysis) ABPM Treatment Metric ∆∆ 95% CI parameter Systolic BP Vibegron 75 mg qd 24-h average 0.5 (-1.3 to 2.4) Diastolic BP Vibegron 75 mg qd 24-h average -0.3 (-1.5 to 1) Heart Rate Vibegron 75 mg qd 24-h average 1 (-0.3 to 2.2)

Reference ID: 4604874 For further details on the FDA analysis please see section 4.

1.1 RESPONSES TO QUESTIONS POSED BY SPONSOR Not applicable.

1.2 COMMENTS TO THE REVIEW DIVISION Not applicable.

2 RECOMMENDATIONS

2.1 ADDITIONAL STUDIES Not applicable.

2.2 PROPOSED LABEL Below are proposed edits to the label submitted to eCTD 0007 (link) from the CS-IRT. Our changes are highlighted (addition, deletion). Each section is followed by a rationale for the changes made. Please note, that this is a suggestion only and that we defer final labeling decisions to the Division. 12.2 Pharmacodynamics Blood pressure In a 4-week randomized, placebo-controlled, ambulatory blood pressure study in OAB patients (n=197n=200), daily treatment with GEMTESA 75 mg was not associated with (b) (4) clinically significant changes in blood pressure. (b) (4) (b) (4)

We propose to use the n from the FAS population and to describe the study as being negative.

3 SPONSOR’S SUBMISSION

3.1 OVERVIEW

3.1.1 Clinical Study URO-901-1001 is a dedicated ABPM study in 197 patients (FAS population) with overactive bladder randomized to placebo (n=101) or vibegron 75 mg qd (n = 96) for 28 days. The study included two ABPM visits (baseline and day 28) with 3 measurements per hour during daytime (8a to 10p) and 2 measurements per hour during night time (10p to 8a). At each ABPM visit there was an option to repeat the ABPM recording to meet the ABPM validity criteria (< 6 consecutive readings during daytime, < 8 missing readings during daytime and < 20 readings missing overall). DCN reviewed the ABPM study protocol for study URO-901-1001 previously (IND 106410, DARRTS 10/05/2018) and noted that: 1) it was unclear if maximum PD effect would have been reached at day 29 and 2) the study should be powered for a two-sided α

Reference ID: 4604874 rather than one-sided as proposed by the sponsor. The final study report included a change to 2-sided test as recommended. The choice of 28-days of dosing for this study is based on steady-state drug levels being reached within 7 days of dosing. This justification seems reasonable as no BP changes were observed following longer dosing duration in a phase 3 study (URO-901-3003) with 12 weeks of dosing (Δ Systolic BP: 0.2 mmHg (95% CI: -0.9 to 1.2 mmHg), Table 59).

3.2 SPONSOR’S RESULTS The sponsor used the full analysis (FAS) set for the primary analysis, which included all subjects that received at least one dose of double-blind treatment and had a valid baseline and 28-day ABPM measurement.

3.2.1 Primary endpoint The primary endpoint analyzed by the sponsor was change from baseline compared to placebo for daytime systolic BP. The daytime period was determined via diary. The sponsor’s analysis model included age group, sex and pre-existing hypertension as covariates along with the baseline ABPM value. The results of this analysis did not suggest significant changes in systolic BP. Reviewer’s comment: The results of the reviewer’s analysis using the conventional analysis model within the team (only adjusting for baseline BP) was consistent with the results of the sponsor’s analysis, see section 4.2 for details.

3.2.2 Secondary endpoints No changes in secondary endpoints, including diastolic BP and heart rate as well as other time intervals (24-h, clock-based day/nighttime or maximum 0.5 to 6.5 h post-dose) were observed using the predefined analysis model. The sponsor also analyzed the proportion of subjects with increased blood pressures meeting pre-defined categorical thresholds (systolic BP: ≥ 15 mmHg, diastolic BP: ≥ 10 mmHg, and heart rate: ≥ 10 bpm). This analysis did identify few subjects meeting these cutoffs (≤4 for mean daytime and mean 24-h), with similar proportions between the treatment groups. Reviewer’s comment: These results are consistent with the reviewer’s analysis of other BP endpoints (section 4.2), hourly average analysis (section 4.3.1) and outlier analysis (section 4.3.2).

3.2.3 Cardiovascular risk in targeted patient population Not applicable.

4 REVIEWERS’ ASSESSMENT The analysis population used in the reviewer’s assessment was the full analysis population.

Reference ID: 4604874 4.1 DEMOGRAPHICS The population demographics is presented in Table 2 for the FAS population by treatment arm. Except for treatment for hypertension, all variables were derived directly from the datasets provided and match the sponsor’s demographics table. The treatment for hypertension variable was derived by determining which subjects were taking a beta blocker or RAS inhibitor. Table 2: ABPM study demographics (FAS) Placebo Vibegron 75mg (n=101) (n=96) Sex Female 74 (73.3%) 73 (76.0%) Male 27 (26.7%) 23 (24.0%) Age (years) mean (sd) 59.2 (8.2) 59.4 (8.6) (min, max) (42.0, 75.0) (40.0, 74.0) Race Black 13 (12.9%) 15 (15.6%) Other 2 (2.0%) 2 (2.1%) White 86 (85.1%) 79 (82.3%) Weight (kg) mean (sd) 78.9 (13.9) 76.6 (13.6) (min, max) (47.1, 109.6) (54.2, 112.7) Body Mass mean (sd) 28.9 (3.9) 27.9 (3.8) 2 Index (kg/m ) (min, max) (18.9, 34.7) (19.9, 34.7) Systolic BP mean (sd) 121.5 (13.4) 119.8 (15.5) (mmHg) (min, max) (89.0, 160.0) (91.0, 174.0) Diastolic BP mean (sd) 76.3 (8.2) 75.0 (8.7) (mmHg) (min, max) (57.0, 98.0) (56.0, 95.0) Pre-existing N 70 (69.3%) 58 (60.4%) hypertension Y 31 (30.7%) 38 (39.6%) Diabetes N 94 (93.1%) 79 (82.3%) Y 7 (6.9%) 17 (17.7%) Treatment for N 81 (80.2%) 72 (75.0%) HBP* Y 20 (19.8%) 24 (25.0%) * Beta blocker or RAS inhibitor

4.2 PRIMARY ENDPOINT The primary endpoint for this study was change from baseline in daytime systolic BP, daytime was defined using patient diary. The reviewer compared the change from baseline in systolic BP for 24-h, daytime, and nighttime using both clock time using sponsor’s definition (daytime: 8a to 10p and night time: 10p to 8a) for both the conventional model (FDA: treatment and baseline) and sponsor’s model (see section 3.2.1). The results (Figure 1) were consistent across BP metrics, time-windows and models showing a general lack of significant changes in BP and HR. Analysis of the

Reference ID: 4604874 change from baseline by treatment group consistently showed a lack of change from baseline for the placebo group confirming lack of a placebo effect (Figure 2). Figure 1: Change from baseline and placebo (primary endpoint)

Figure 2: Change from baseline by treatment group

4.3 SECONDARY ENDPOINT

4.3.1 Hourly averages or visit average Analysis of hourly changes was conducted using a linear mixed-effects model with average baseline, treatment, time and treatment*time interaction as fixed effects a random intercept by subject. Time in this analysis was clock time. The results of this analysis are shown in Figure 3. The confidence limits from this analysis should be interpreted with caution as the study was not powered for hourly averages. Nevertheless, the analysis does not suggest any significant difference between drug and placebo, consistent with the primary endpoint for systolic and diastolic BP.

Reference ID: 4604874 Figure 3: Placebo and baseline-adjusted changes in hourly averages

4.3.2 Outlier analysis The cumulative distribution was used to visualize differences in the distribution of change from baseline in 24-h average for systolic BP, diastolic BP and heart rate (Figure 4). Consistent with the primary endpoint, this analysis does not show any systematic differences between the treatment arms. Figure 4: Cumulative distribution for change in 24-h averages

4.4 CARDIOVASCULAR RISK ASSESSMENT To put the increase in BP excluded by the ABPM study in perspective we used the baseline demographics for OAB patients in study URO-303-3003 to predict the increase in atherosclerotic cardiovascular disease (ASCVD) events as a function of drug-induced increase in systolic BP using the Pooled Cohort Equations. The Pooled Cohort Equations predicts 10-year risk for ASCVD events.1 The predicted ASCVD risk can be categorized into low risk (<7.5%), intermediate risk (≥7.5% to <20%) and high risk (≥20%).2

1 Goff DC Jr et al., 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(suppl 2):S49-S73 2 Arnett DK, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019.

Reference ID: 4604874 The population demographics is presented in Table 2 for the FAS population by treatment arm. Except for treatment for hypertension all variables were derived directly from the datasets provided and match the sponsor’s demographics table. The treatment for hypertension variable was derived by determining which subjects were taking a beta blocker or RAS inhibitor. While, the population used for CV risk prediction and the ABPM study population were similar with regards to sex, age and baseline systolic BP differences for treatment for BP and diabetes were observed between the two studies. These differences are not expected to impact the ability to use the findings of the ABPM study in OAB patients to predict expected increase in ASCVD events based on the demographics of OAB patients in study URO-303-3003. Table 3: Demographics for population used for CV risk prediction Tolterodine ER + Vibegron + Placebo Placebo Placebo (n=526) (n=520) (n=417) Sex Female 449 (85.4%) 445 (85.6%) 352 (84.4%) Male 77 (14.6%) 75 (14.4%) 65 (15.6%) Age (years) mean (sd) 60.8 (13.3) 59.9 (13.3) 59.8 (13.2) (min, max) (18.0, 93.0) (19.0, 89.0) (19.0, 91.0) Race Black 74 (14.1%) 79 (15.2%) 69 (16.5%) Other 30 (5.7%) 35 (6.7%) 31 (7.4%) White 422 (80.2%) 406 (78.1%) 317 (76.0%) Total mean (sd) 192.6 (37.9) 193.2 (43.7) 192.9 (38.9) cholesterol (min, max) (mg/dL) (91.3, 343.4) (86.6, 600.9) (102.1, 321.7) Systolic BP mean (sd) 124.3 (11.9) 123.2 (12.4) 124.0 (12.0) (mmHg) (min, max) (94.0, 171.0) (89.0, 164.0) (87.0, 157.0) Diabetes N 427 (81.2%) 444 (85.4%) 346 (83.0%) Y 99 (18.8%) 76 (14.6%) 71 (17.0%) Treatment for N 318 (60.5%) 339 (65.2%) 253 (60.7%) HBP* Y 208 (39.5%) 181 (34.8%) 164 (39.3%) * Beta blocker or RAS inhibitor The reviewer was unable to locate information about smoking status and HDL cholesterol, two variables that are necessary to calculate the predicted risk. The variables were imputed by multiple-imputation using NHANES data from 2002 – 2017 grouped by sex and age. Majority of OAB patients in this study are predicted to be at low / intermediate risk for ASCVD events at baseline (low/borderline: 56%; intermediate: 27% and high: 17%). Using the baseline ASCVD risk the increase in ASCVD events related to drug-induced changes in BP can be predicted by repeating the steps above for different increases over each individual subject’s baseline BP. The result of this analysis is visualized in Figure 5

Reference ID: 4604874 for increases over each individual subject’s baseline systolic BP of 0 to 5 mmHg in increments of 1 mmHg. This analysis suggests ≤0.2 ASCVD events per 1000 patient years using the upper-bound of the change from baseline in the 24-h average systolic BP for vibegron 75 mg qd (Figure 2). Figure 5: Predicted increase in ASCVD events for OAB patients

4.5 MISSING DATA The missing data percentage across subject per time-point is shown in Figure 6 showing a generally low missing data percentage (<7.5%) without any apparent patterns in missing data indicating good data quality. Figure 6: Missing data analysis

Reference ID: 4604874 5 APPENDIX

5.1 PROTOCOL REVIEW DCN has previously reviewed study protocol for this ABPM study (IND 106410, DARRTS 10/05/2018).

Reference ID: 4604874 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

LARS JOHANNESEN 05/07/2020 12:33:07 PM

FORTUNATO F SENATORE 05/07/2020 12:57:43 PM

CHRISTINE E GARNETT 05/07/2020 01:01:43 PM

NORMAN L STOCKBRIDGE 05/07/2020 01:02:51 PM

Reference ID: 4604874