Once-Daily Vibegron 75 mg Demonstrates Statistically Significant Benefits on Key Secondary Endpoints Including Quality of Life in Patients With OAB: Data From an International Phase 3 Trial (EMPOWUR)

Staskin D1, Varano S2, Frankel J3, Shortino D4, Jankowich R4, Mudd Jr P4

Research Type

Clinical

Abstract Category

Overactive Bladder

Abstract 181
Overactive Bladder
Scientific Podium Short Oral Session 8
Wednesday 4th September 2019
14:45 - 14:52
Hall K
Urgency Urinary Incontinence Urgency/Frequency Overactive Bladder
1.Tufts University School of Medicine, Boston, MA, 2.Clinical Research Consulting, Milford, CT, 3.Seattle Urology Research Center, Seattle, WA, 4.Urovant Sciences, Inc., Irvine, CA
Presenter
D

David Staskin

Links

Abstract

Hypothesis / aims of study
Vibegron is an investigational, novel, once-daily, oral β-3 adrenergic receptor agonist in development for treatment of overactive bladder (OAB) symptoms. The primary objective of the EMPOWUR study was to evaluate vibegron 75 mg vs placebo, with tolterodine as an active control, in adults with OAB. The study demonstrated statistically significant improvement vs placebo as early as week 2, which was maintained through week 12 (P<0.001) for the co-primary endpoints of change in frequency of daily micturitions and number of urge urinary incontinence (UUI) episodes. Presented here are the results for the key secondary efficacy endpoints of proportion of patients with a clinically meaningful ≥75% reduction [1] in average daily UUI episodes, average daily total incontinence episodes, average volume voided per micturition, and quality of life (QoL), as measured by the validated OAB Questionnaire long-form (OAB-q LF) [2]. Safety and tolerability were evaluated.
Study design, materials and methods
EMPOWUR was an international, randomized, double-blind, placebo- and active comparator-controlled, multicenter phase 3 trial in patients with/without UUI. Patients were aged ≥18 years with a history of OAB meeting OAB-wet or OAB-dry criteria. OAB-wet criteria were an average of ≥8 micturitions/day and ≥1 UUI episode/day. OAB-dry criteria were an average of ≥8 micturitions/day, ≥3 urgency episodes/day, and <1 UUI episode/day. Enrolled patients were randomized 5:5:4 to receive daily vibegron 75 mg, placebo, or tolterodine extended-release 4 mg. Patients completed a 7-day diary to record OAB symptoms prior to each study visit; items included micturitions, leakages, and urgency each day, and volume voided for one day each week. The mixed effects model for repeated measures (MMRM) analysis model using all OAB patients in the full analysis set includes treatment, visit, wet/dry OAB, sex, region, baseline, and visit by treatment interaction term. Key secondary endpoints use a hierarchical strategy using two-sided tests with α = 0.05. No adjustment for multiplicity was needed. QoL was assessed by the OAB-q LF for a 1-week recall period. The OAB-q LF includes a Health-Related Quality of Life (HRQL) scale (25 items) and a Symptom Bother scale (8 items). HRQL is the sum of 4 subscales: Coping, Concern/Worry, Sleep, and Social Interaction. The Coping subscale was a key secondary endpoint, with higher scores indicating better QoL. Change from baseline OAB-q LF score endpoints analysis uses an MMRM. Safety assessments were summarized using descriptive statistics and included incidence of adverse events, laboratory assessments, vital signs, and physical examination.
Results
EMPOWUR enrolled 1518 patients across 199 sites, including 547 patients (36.0%) treated with vibegron, 540 (35.6%) receiving placebo, and 431 (28.4%) receiving tolterodine. Treatment groups were well-balanced with mean patient ages of ~60 years; each group included ~85% women and ~77% with OAB wet. The adjusted proportion of patients achieving a clinically meaningful (≥75%) reduction in UUI episodes/day (UUI responders) was highest for vibegron (49.3%), compared with placebo (32.8%) (P<0.0001) and tolterodine (42.2%) at week 12 (Figure 1). Vibegron demonstrated rapid onset of effect, with statistically significantly more UUI responders by week 2 vs placebo (P<0.01). For average volume (mL) voided per micturition, the placebo-adjusted mean change from baseline was significantly improved (increased) at week 12 with vibegron by 21.2 mL (standard deviation [SD], 3.52; P<0.0001 vs placebo), which was numerically greater than with tolterodine, 13.3 mL (SD, 3.76; P<0.001 vs placebo) (Figure 2). The least-squares mean change from baseline for total daily incontinence was reduced by 2.3 episodes in the vibegron group at 12 weeks (Figure 2). Placebo-adjusted mean total daily incontinence episodes were significantly reduced at week 12 with vibegron, by -0.7 episodes (standard error [SE], 0.16; P<0.0001 vs placebo), which was numerically greater than the reduction with tolterodine, -0.5 episodes (SE, 0.17; P=0.0074 vs placebo) (Figure 2). Rapid and statistically significant improvement in total daily incontinence was observed at week 2 (-0.7, placebo-adjusted) with vibegron and maintained statistical significance through week 12. Vibegron demonstrated statistically significant improvements on the Symptom Bother (P<0.0001), Concern (P<0.0001), Sleep (P<0.001), and Coping (P=0.0038) scales and total HRQL score (P<0.001) vs placebo at week 12 (Figure 2). The least-squares mean difference between vibegron and placebo was numerically improved for the HRQL Social Interaction subscale but did not reach statistical significance (P=0.1116). Vibegron results were numerically better than tolterodine results for all OAB-q LF scales measured (Figure 2). The most common adverse events (> placebo and >2%) were headache (vibegron, 4.0%; placebo, 2.4%; tolterodine, 2.6%), nasopharyngitis (vibegron, 2.8%; placebo, 1.7%; tolterodine, 2.6%), diarrhea (vibegron, 2.2%; placebo, 1.1%; tolterodine, 2.1%), and nausea (vibegron, 2.2%; placebo, 1.1%; tolterodine, 1.2%). Notably, hypertension was 1.7% for vibegron and placebo, and 2.6% for tolterodine.
Interpretation of results
In EMPOWUR, once-daily vibegron 75 mg demonstrated statistically significantly better efficacy vs placebo on the co-primary and all key secondary endpoints, indicating benefit of vibegron for OAB patients with urinary incontinence. Vibegron demonstrated statistically significant reductions in total incontinence by week 2, which was maintained throughout the 12-week treatment period. Approximately half of vibegron-treated patients with UUI had ≥75% reductions in UUI episodes after 12 weeks of therapy. Vibegron also demonstrated a clear increase in volume voided per micturition, an objective measure for increasing bladder capacity. In addition, vibegron demonstrated greater QoL improvements on the OAB-q LF in the Symptom Bother, Coping (key secondary endpoint), Sleep, and Concern subscale scores, and total HRQL score vs placebo at week 12, and numerically better results than tolterodine on every scale. Vibegron tolerability was favorable, with very few adverse events >2% and greater than placebo.
Concluding message
Once-daily vibegron 75 mg demonstrated statistically significant benefits vs placebo on the co-primary and all key secondary endpoints, including QoL, in OAB patients. Vibegron significantly increased the number of patients achieving a clinically meaningful (≥75%) reduction in daily UUI episodes, significantly increased volume of urine voided per micturition, and decreased daily incontinence episodes, with rapid onset of action by 2 weeks. Statistically significant improvements in the OAB-q LF were demonstrated for the Coping, Concern, Sleep, and Symptom Bother scales, and the total HRQL score vs placebo at week 12. The EMPOWUR results demonstrate that 75 mg vibegron improved the symptoms of OAB (frequency, urgency, UUI) and increased the QoL of patients suffering from OAB. Vibegron may represent an important new therapy to address a large unmet need for patients with OAB.
Figure 1 Figure. 75% Responders for Urge Urinary Incontinence at Week 12a
Figure 2 Table. Key Secondary Endpoints, Including Quality of Life, at Week 12
References
  1. Subak LL, Brown JS, Kraus SR, Brubaker L, Lin F, Richter HE, Bradley CS, Grady D; Diagnostic Aspects of Incontinence Study Group. The “costs” of urinary incontinence for women. Obstet Gynecol. 2006;107(4):908-916.
  2. Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, Kurth H, Abrams P. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002;11(6):563-574.
Disclosures
<span class="text-strong">Funding</span> D Staskin is an investigator for Urovant Sciences Inc. and is a consultant to Astellas Pharma, Ferring Pharmaceuticals, and New Uro B.V.; J Frankel is an investigator for Urovant, an investigator and speaker for Astellas Pharma and Pfizer Inc., and a speaker for Tolmar Inc.; S Varano is an investigator for Urovant, and is a consultant to Avadel Pharmaceutical and Maplewood Senior Living; D Shortino, R Jankowich, and PN Mudd Jr are employees of Urovant Sciences, Inc. and may be shareholders. <span class="text-strong">Clinical Trial</span> Yes <span class="text-strong">Registration Number</span> NIH ClinicalTrials.gov, NCT03492281 <span class="text-strong">RCT</span> Yes <span class="text-strong">Subjects</span> Human <span class="text-strong">Ethics Committee</span> The study was approved by the review board/committee at each of the sites in this multicenter phase 3 trial. <span class="text-strong">Helsinki</span> Yes <span class="text-strong">Informed Consent</span> Yes