Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR)

Open AccessJournal of UrologyAdult Urology1 May 2021Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study the International Phase 3 Trial (EMPOWUR)This article is commented on by following:Editorial Comment David Staskin, Jeffrey Frankel, Susann Varano, Denise Shortino, Rachael Jankowich, Paul N. Mudd StaskinDavid Staskin *Correspondence: St. Elizabeth Medical Center/Steward Health, 11 Nevins St.—DOB 303, Boston, Massachusetts 02135 telephone: 617-480-3411; FAX: 617-227-4023; E-mail Address: [email protected] Tufts University School Medicine, Financial interest and/or other relationship with Urovant Sciences. Astellas Pharma. New Uro B.V. More articles this author , FrankelJeffrey Frankel Seattle Urology Research Center, Seattle, Washington Pfizer Inc., Tolmar Ferring, Johnson Johnson. VaranoSusann Varano Clinical Consulting, Milford, Connecticut Sacred Heart Bridgeport. ShortinoDenise Shortino Sciences, Irvine, California JankowichRachael Jankowich MuddPaul View All Author Informationhttps://doi.org/10.1097/JU.0000000000001574AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: The long-term safety, tolerability efficacy vibegron in adults overactive bladder were evaluated 40-week phase EMPOWUR extension study. Materials Methods: Patients who completed 12 weeks once-daily or tolterodine 4 extended release continued double-blind treatment; patients placebo randomly assigned 1:1 receive tolterodine. primary outcome was measured incidence adverse events. Secondary outcomes included change baseline at week 52 average daily number micturitions urgency episodes (all patients), urge total urinary incontinence (patients wet) based 7-day diary data. Results: Of 506 randomized 505 received ?1 dose medication, 430 (85%) A (2.4%) discontinued owing most common events vibegron/tolterodine (>5% either group) hypertension (8.8%/8.6%), tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) dry mouth (1.8%/5.2%). Improvements end points maintained receiving weeks; least squares mean ?2.4 vs ?2.0 tolterodine; ?2.2 ?1.7 (p <0.05); ?3.4 ?3.2; ?2.5 ?1.9 <0.05). Among wet 61.0% experienced ?75% reduction after treatment 54.4% tolterodine, while 40.8% 34.2% 100% reduction. Conclusions: demonstrated favorable bladder, consistent results 12-week Abbreviations Acronyms AE event DBP diastolic blood pressure ER FAS-Ext full analysis set LS OAB SAE serious SBP systolic UUI defined as without incontinence,1 affects numerous worldwide.2–4 negatively quality life,5–8 decreases productivity,9,10 increases health care utilization economic burden.11,12 Anticholinergic agents have been mainstay OAB, but their use associated effects, particularly constipation,13 which contribute low rates adherence. large retrospective claims data anticholinergics showed that 92% switched initial anticholinergic treatment, 51.3% all within 24 months.14 Long-term also an increased risk dementia.15–19 American Urological Association guidelines diagnosis nonneurogenic recommend ?3-adrenergic receptor agonists pharmacological option combination behavioral therapy following therapy.13,20 novel, potent, highly selective agonist long half-life (25?38 hours).21,22 not inhibitor inducer major human cytochrome P450 enzymes such 3A4, 2D6 2C9.22–24 In previous studies, vibegron-treated statistically significant improvements symptoms compared placebo.21,25 (NCT03492281) 3, international, study (incontinence) OAB.26 1,518 5:5:4 mg, (active control), respectively. Treatment resulted rapid (within 2 weeks) coprimary <0.001, each) key secondary points. Early seen through 12. consistently numerically better measures well tolerated. This vibegron. Methods Design (NCT03583372) randomized, double-blind, active controlled, parallel-group once-daily, fixed-dose conducted 109 sites United States. It period 4-week safety followup period. had same double-blinded additional 40 (52 treatment). randomization carried out central Web-based interactive response system stratified type (wet dry) gender. trained paper diaries screening visit. recorded micturitions, urgency, reason (urge, stress other) voiding diary.26 extension, 7 days before 16, 24, 44 visits. Participants Eligibility criteria described previously.26 inclusion criterion having Eligible participants required ?80% compliance self-administration ?4 Key exclusion inability complete any reason; history current evidence clinically condition could confound results, interfere ability comply procedures make participation patient’s best (eg gastrointestinal, renal, hepatic, cardiovascular, lymphatic psychiatric disorder during EMPOWUR); uncontrolled hyperglycemia (fasting glucose >150 mg/dl nonfasting >200 mg/dl); (SBP ?180 mmHg ?100 mmHg); resting heart rate >100 beats per minute; signs regardless measurement. Outcomes treatment-emergent extent exposure, compliance, clinical laboratory evaluations, vital signs, physical examinations, electrocardiograms post-void residual urine volume via ultrasound. AEs collected time first until visit completed. coded preferred term organ class Dictionary Regulatory Activities version 20.1, severity investigator. Duration exposure last day. determined tablets/capsules dispensed returned unused patient. patients, patients. Exploratory percentage ?50% episodes, episodes. Statistical Analyses Planned enrollment approximately 500 EMPOWUR; no formal sample size calculation performed. comprised evaluable micturition measurement assessments summarized descriptively group. No inferential statistical testing data, imputation performed missing Changes analyzed using mixed model repeated restricted maximum likelihood estimation. For terms visit, stratification factors found be (OAB [FAS-Ext only], gender), value interaction treatment. visits 2, 4, 8, 12, 52. post hoc interaction, baseline, (FAS-Ext only) Adjusted means standard errors 95% CIs each group estimated. study, baseline; (ie 12). comparisons prespecified. Multiple methods used estimate values exploratory responder responders difference between groups observed values. nonparametric sensitivity confirm test. Reported p cover both analyses. Ethical Conduct Conference Harmonisation Technical Requirements Registration Pharmaceuticals Human Use Good Practice. Each investigator obtained approval institutional review board, research ethics board independent committee initiation. provided written informed consent EMPOWUR, undergoing procedures. Results June 2018 July 2019. (vibegron 274, 232) medication (fig. 1). completion 85% overall, similar groups. discontinuation withdrawal (17 6.2% vibegron, 15 232, 6.5% tolterodine). AEs, smaller proportion those discontinuing (4 1.5%) (8 3.4%). Figure 1. Patient disposition (randomized set). Asterisk indicates 1 patient did Demographic characteristics balanced (table Overall age 61 years, 235 (46.5%) being ?65 years old. Most (395 505, 78.2%) female, (395, OAB. Table demographics (safety extension) Characteristic Tolterodine Wks No. pts 92 181 273 91 141 232 Mean±SD yrs 58.8±13.69 62.1±12.39 61.0±12.91 62.1±12.14 60.6±12.98 61.2±12.65 (%): Yrs 36 (39.1) 93 (51.4) 129 (47.3) 43 63 (44.7) 106 (45.7) ?75 8 (8.7) 23 (12.7) 31 (11.4) 13 (14.3) 16 (11.3) 29 (12.5) women (%) 73 (79.3) 140 (77.3) 213 (78.0) 70 (76.9) 112 (79.4) 182 (78.4) Wet 71 (77.2) 146 (80.7) 217 (79.5) 108 (76.6) 178 (76.7) Dry 21 (22.8) 35 (19.3) 56 (20.5) (23.1) 33 (23.4) 54 (23.3) preexisting (%)* 39 (42.4) 97 (53.6) 136 (49.8) (34.1) 72 (51.1) 103 (44.4) Preexisting vitals medical Tolerability are shown table 2. meaningful differences median duration noted exposed (280 overall 364 generally tolerated over SAEs. Similar incidences commonly reported groups, except mouth, more frequently (5.2%) than (1.8%). Hypertension (8.8% 8.6% tolterodine), followed (6.6% 7.3% Observed SAEs assessed related moderate collagenous colitis (with vibegron), syncope (tolterodine) severe cardiac failure (tolterodine). One death (arteriosclerotic cardiovascular disease, considered drug sponsor). parameters, meaningful. 171 (62.6) 126 (54.3) due (1.5) (3.4) 9 (3.3) 10 (4.3) resulting (0.4)* 0 (0) treatment-related investigator† (0.4) (0.9) >2% Hypertension‡ (8.8) 20 (8.6) Urinary 18 (6.6) 17 (7.3) Headache (5.5) (3.9) Diarrhea (4.8) (1.7) Nasopharyngitis (5.2) Constipation (3.7) 6 (2.6) Nausea (3.0) Upper respiratory Bronchitis (2.9) (1.3) Anemia Hyperglycemia Residual vol Back pain (2.2) Musculoskeletal 5 (1.8) Arteriosclerotic judged investigators sponsor. Vibegron: colitis; tolterodine: failure. Defined ?140 ?90 (or both) consecutive hypertension; increase ?20 ?10 initiation Durable Reductions sustained throughout (figs. 3). analysis, treated significantly greater Further reductions numbers A) B) improvement separate UUI, time, 52-week only (FAS-Ext). Calculated divided days. Baseline baseline. 3. incontinence). <0.05. 4. (A) (FAS-Ext) (B) baseline* (FAS-Ext)† Mean Change (95% CI) 90 83 Micturitions ?1.0 (?1.6 ?0.5) ?0.8 (?1.4 ?0.2) episodes‡ ?0.6 (?0.8 ?0.3) ?0.4 (?0.7 ?0.1) Urgency ?0.7 (?1.3 ?0.9 (?1.5 Total (?0.9 (?1.0 Post analysis. Full incontinence: 69 group, 64 point analyses 71.1% 61.9% tolterodine-treated 52, diary; fig. 5). 49.4% 51.0% 5. Percentage achieving (urgency FAS-Ext: 176 patients; 143 patients). Discussion study.26 evident measured. switching measures. leading discontinuation. occurred durable control across points, including addition, 75% diary). Nonclinical suggests resistant desensitization, may contributed study.27,28 Furthermore, achieved further parameters effect), likely changes continuing limitation potential selection bias elected enter extension. Such mitigated factors: 1) controlled opposed open-label study; 2) extension; 3) vast majority completers (506/587, 86.2%) participate eligible enroll pharmacotherapy conjunction treatments.13,20 However, high therapy,14 many report poor treatment.14,29 few (1.5%) AEs. benefits 2-week onset lack inhibition CYP2D6, drug-metabolizing enzyme.21,22 available single, fixed does require adjustment titration Conclusions once Nearly two-thirds 40% became dry. Given anticholinergics, represents appealing Acknowledgments Editorial support Curry Rockefeller Group, LLC (Tarrytown, York), funded Sciences (Irvine, California). References : An Urogynecological (IUGA)/International Continence Society (ICS) joint terminology female pelvic floor dysfunction. 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Increased dementia beta-3 agonist: population-based cohort 2020; 126: 183. 17. Bladder antimuscarinics cognitive decline elderly Alzheimers Dement (N Y) 2017; 3: 139. 18. Cumulative strong incident prospective 2015; 175: 401. 19. cognition, brain metabolism, atrophy cognitively normal older adults. Neurol 73: 721. 20. Guideline amendment 202: 558. 21. (RVT-901/MK-4618/KRP-114V) administered monotherapy concomitantly multicenter, IIb, trial. 75: 274. 22. Discovery vibegron: potent beta3 adrenergic Chem 59: 609. 23. Mirabegron: off target effects uses beyond Br Pharmacol 2018; 4072. 24. novel ?3-adrenoreceptor nocturia post-hoc placebo-controlled 26: 369. 25. Vibegron, agonist, 783. 26. III, evaluate EMPOWUR. 204: 316. 27. Randomized active-controlled assess 12-month mirabegron, ?3-adrenoceptor 63: 296. 28. Functional activation ?2- signalling. 1995; 114: 1045. 29. Patient-reported reasons medication. 105: 1276. under Registration: NCT03583372 (www.clinicaltrials.gov). 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