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Jeffrey Frankel,1 David Staskin,2 Susann Varano,3 Michael J Kennelly,4 Rachael A Jankowich,5 Cornelia Haag-Molkenteller5 1Seattle Urology Research Center, Seattle, WA, USA; 2Tufts University School of Medicine, Boston, MA, USA; 3Clinical Research Consulting, Milford, CT, USA; 4Carolinas Medical Center, Charlotte, NC, USA; 5Urovant Sciences, Irvine, CA, USACorrespondence: Jeffrey Frankel, PO Box 1192, Mercer Island, WA 98040, USA, Tel +1 206 972 2775, Email jmfrankel@comcast.netAbstract: Pharmacologic treatment for overactive bladder (OAB), which is characterized by bothersome symptoms such as urgency and urge urinary incontinence (UUI), includes anticholinergics and β3-adrenergic receptor agonists. Anticholinergics are associated with adverse effects including dry mouth, constipation, cognitive impairment, and increased risk of dementia. Therefore, the drug class of β3-adrenergic receptor agonists may represent an effective, safe treatment option. Vibegron, a β3-adrenergic receptor agonist, was approved for use in Japan (2018) and the United States (2020). Over the past 3 years, 2 phase 3 trials (EMPOWUR, EMPOWUR extension) have been conducted with once-daily vibegron 75 mg for the treatment of OAB, and additional secondary and subgroup analyses have detailed the efficacy and safety of vibegron. In the international phase 3 EMPOWUR trial, treatment with vibegron was associated with significant improvements compared with placebo in efficacy outcomes of micturition frequency, UUI episodes, urgency episodes, and volume voided as early as week 2 that were sustained throughout the 12-week trial. The 40-week EMPOWUR extension study, following the 12-week treatment period, demonstrated sustained efficacy in patients receiving vibegron for 52 weeks. Treatment with vibegron was also associated with improvements in patient-reported measures of quality of life. Across studies, vibegron was generally safe and well tolerated. A separate, dedicated ambulatory blood pressure monitoring study showed that treatment with vibegron was not associated with clinically meaningful effects on blood pressure or heart rate. Across all studies, vibegron was efficacious, safe, and well tolerated and thus represents a valuable treatment option for patients with OAB. Here, nearly 1 year after US approval, we review the published data on efficacy and safety of vibegron 75 mg for the treatment of OAB.Keywords: adrenergic agonist, β-adrenergic receptor, urinary bladder overactive, urinary incontinence, vibegron

- Experimental models to represent the surgical methods of bladder transection in humans were performed on dogs and rabbits. The effects on vesical neurophysiology were studied by cystometry with bethanechoI supersensitivity testing; by in vitropharmacoIogicaI responsiveness; by determination of autonomic receptor densities using radio-ligand binding and by autonomic neurohistochemical staining. Analysis revealed that transection with or without neurovascular preservation resulted in an alpha-adrenergic denervation and cholinergic decentralization. A comparison with the surgical models is presented and proposed mechanisms of action are discussed in relation to the experimental results. [ABSTRACT FROM AUTHOR]

What is this summary about? People with overactive bladder need to use the bathroom many times a day to urinate (pee). This need may often be sudden and may cause some people with overactive bladder to have accidental bladder leakage. The EMPOWUR trial looked at how well a medicine called vibegron worked to help people with overactive bladder. The study also included another drug that was already available for treating overactive bladder called tolterodine and a pill with no medicine called a placebo . Both vibegron and tolterodine were compared with placebo . Participants had improvements in their overactive bladder symptoms after taking either vibegron or tolterodine compared to placebo . The medicine vibegron was approved in 2020 by the US Food and Drug Administration (also called the FDA) to treat overactive bladder. Researchers next wanted to see how well vibegron worked in people from the EMPOWUR trial split into 2 groups. One group was made of participants with overactive bladder who have accidental leakage. The second group was made of participants with overactive bladder who do not have accidental leakage. This is a plain language summary of the study of how well vibegron works for those 2 groups from the EMPOWUR study that was published in the International Journal of Clinical Practice . What were the results? Study participants who took vibegron needed to pee fewer times per day. The number of times they had little warning before the need to pee was also lower. The results were the same for study participants who did and did not have accidental leakage related to overactive bladder. What do the results mean? This study suggests that vibegron can improve symptoms in people with overactive bladder whether or not they have accidental bladder leakage., Competing Interests: D. S. is a consultant for Astellas, AzuraBio, Sumitomo Pharma America, Inc., and UroCure; is an investigator and meeting participant/lecturer for Astellas and Sumitomo Pharma America, Inc.; and holds other interests in AzuraBio and UroCure. J. F. is an advisor for Sumitomo Pharma America; a meeting participant/lecturer for Pfizer and Sumitomo Pharma America; and an investigator for Astellas, Exact Sciences, Johnson & Johnson, and Pfizer. S. G. G. was Executive Director at the National Association for Continence, Charleston, SC. J. O. G. is an employee of Sumitomo Pharma America, Inc., (© The Author(s), 2025.)

Introduction: Vibegron is a selective β 3 -adrenergic receptor agonist that was approved by the US Food and Drug Administration in December 2020 for the treatment of overactive bladder in adults. This retrospective study assessed US pharmacy claims data to evaluate the real-world adherence and persistence of vibegron compared with mirabegron and with anticholinergics., Materials and Methods: This analysis used the Optum Research Database to identify adults with ≥1 pharmacy claim for vibegron, mirabegron, or an anticholinergic from April 1, 2021, to August 31, 2022. Patients had ≥ 90 days of continuous commercial or Medicare medical and pharmacy coverage preindex and ≥ 60 days of continuous pharmacy coverage postindex. Two independent propensity-score models matched patients treated with (1) vibegron versus mirabegron and (2) vibegron versus anticholinergics on key variables such as demographics and clinical characteristics, index copay, days' supply, and time of entry into analysis (index quarter). Adherence was measured by proportion of days covered (PDC) from index to the end of follow-up and was defined as PDC ≥ 80%. Persistence was defined as days to discontinuation of index medication (first 30-day gap) or end of follow-up., Results: The matched vibegron and mirabegron cohorts included 4921 and 9842 patients, respectively, and the matched vibegron and anticholinergic cohorts included 4676 and 9352 patients, respectively. Patients receiving vibegron had greater mean PDC versus patients receiving mirabegron (0.67 vs. 0.64, respectively; p < 0.001) or anticholinergics (0.67 vs. 0.58; p < 0.001). A greater percentage of patients receiving vibegron were adherent versus those receiving mirabegron (49.0% vs. 45.1%, respectively; p < 0.001) or anticholinergics (49.1% vs. 38.5%; p < 0.001). Persistence was longer with vibegron compared with both mirabegron (median [95% CI], 171 [159-182] vs. 128 [122-137] days, respectively; p < 0.001) and anticholinergics (172 [159-183] vs. 91 [91] days; p < 0.001)., Conclusion: In this retrospective analysis of pharmacy claims data, patients receiving vibegron exhibited significantly higher adherence and demonstrated longer persistence in comparison to matched patient cohorts receiving either mirabegron or anticholinergics., (© 2024 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Purpose: The efficacy and safety of vibegron, a β 3 -adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial., Materials and Methods: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs)., Results: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%)., Conclusions: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Introduction: Vibegron is a β 3 -adrenergic receptor agonist approved for overactive bladder (OAB). This analysis assessed real-world adherence and persistence with vibegron in patients with OAB, along with demographics and clinical characteristics associated with adherence and persistence., Methods: This retrospective study used the Optum Research Database to identify patients treated with vibegron from April 2021 to August 2022 (identification period). Patients had ≥ 60 days of continuous pharmacy coverage in a commercial or Medicare Advantage plan following the index fill (follow-up). Adherence was assessed as proportion of days covered (PDC) from index to end of follow-up and was defined as PDC ≥ 80%. Persistence was measured as days to discontinuation of therapy (30-day gap) or end of follow-up. Data for adherence and persistence are presented descriptively. Characteristics associated with adherence and persistence were analyzed using multivariable models among patients with medical and pharmacy benefits during the 90 days before index (baseline)., Results: Overall, 9992 patients had a vibegron claim during the identification period; 9712 had ≥ 2 months of follow-up. Mean (SD) age was 74.2 (10.7) years; 68.2% were female. Mean (SD) PDC was 0.64 (0.34). Median (95% confidence interval) persistence was 142 (132-153) days. Of the 5073 patients who were ≥ 18 years old with continuous baseline pharmacy and medical benefits ≥ 90 days before index, 2497 (49.2%) were adherent. Patients were more likely to be adherent and persistent if they received a greater days' supply for the index fill and had baseline medication count ≥ 6. Patients were more likely to discontinue if their index copay was > $45., Conclusion: Nearly half of the patients initiating vibegron were adherent. Factors associated with adherence and persistence were more likely to be related to prescribing practices than patient characteristics. These results suggest it may be best to follow up with patients approximately 4 to 5 months after initiating treatment with vibegron., (© 2024. The Author(s).)

Anticholinergic medications have long been a mainstay of overactive bladder (OAB) treatment. Oxybutynin, a first-generation anticholinergic, still accounts for more than half of all OAB medication prescriptions, despite associations with impaired memory and cognition, as well as mounting evidence that it may increase the risk of incident dementia. This review details the current literature regarding oxybutynin and cognition, including evidence from preclinical, clinical, and real-world studies that show that oxybutynin binds nonspecifically to muscarinic receptors in the brain and is associated with adverse cognitive outcomes. We also discuss society recommendations to reduce use of oxybutynin and other anticholinergics to treat OAB., Competing Interests: Declaration of Competing Interest Michael B. Chancellor, consultant for Cook MyoSite and AMAG Pharmaceuticals; other interests in Lipella Pharmaceuticals, Inc. Alvaro Lucioni, site principal investigator for Neuspara Inc. David Staskin, consultant for Astellas, AzuraBio, UroCure, and Sumitomo Pharma America; investigator and meeting participant/lecturer for Astellas and Sumitomo Pharma America; holds other interests in AzuraBio and UroCure., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

What is this summary about? This is a plain language summary of an article originally published in the Journal of Urology . Overactive bladder (also called OAB) has been treated with the same type of medicine for more than 40 years. Vibegron is in a newer class of medicine for treating overactive bladder called beta-3 adrenergic receptor agonists. The EMPOWUR study was a phase 3 clinical trial that looked at whether vibegron was safe and improved symptoms in people with overactive bladder. Vibegron was approved by the US Food and Drug Administration (also called the FDA) based in part on the results of this study. What were the results? Participants of the EMPOWUR study who took vibegron showed an improvement in their overactive bladder symptoms. These symptoms include the number of urinations (peeing), the urgent need to urinate, and accidental urination (bladder leaks). After 12 weeks, participants who took vibegron had significantly greater improvements than participants who took placebo. What do the results mean? This study suggests that vibegron could safely improve symptoms in people with overactive bladder. Clinical Trial Registration: NCT03492281 (ClinicalTrials.gov).

What is this summary about? This is a plain language summary of an article published in the journal Advances in Therapy . In 2020, the US Food and Drug Administration (also called the FDA) approved a medicine called vibegron to treat overactive bladder, also called OAB. The key results used to approve vibegron were from the EMPOWUR study. In the EMPOWUR study, participants who took vibegron had fewer urination episodes, urgency episodes, and bladder leaks each day than those who took a pill containing no medicine, called a placebo. At the end of the study, participants also rated how much their overactive bladder symptoms changed overall during EMPOWUR by responding to a survey. Many participants rated their overactive bladder symptoms as improved overall. This study asked if improvements in the number of urination episodes, urgency episodes, and bladder leaks caused by urgency were associated with feeling better overall. This study also looked at how many participants in the EMPOWUR study had improvements in the number of urination episodes, urgency episodes, and bladder leaks that were big enough to matter. A separate group of people with overactive bladder were asked about the magnitude of improvements that would be important to them. This group had not participated in the EMPOWUR study. What were the results? EMPOWUR participants who reported that taking medicine resulted in their overactive bladder symptoms getting better overall also generally reported fewer daily urinations, urgency episodes, and bladder leaks after treatment. Many had changes in their symptoms that were meaningful. Meaningful was defined for each symptom as: at least 15% fewer urinations, 50% fewer urgency episodes, and 75% fewer bladder leaks. Participants who received vibegron had meaningful reductions in the daily number of episodes of urination, urgency, and bladder leaks more often than those who received the placebo (pill with no active medicine). People with overactive bladder who did not participate in the study were interviewed and said that improvements to those symptoms, similar to those seen in the EMPOWUR study, would be important to them. What do the results mean? This study suggests that the results we measured in the EMPOWUR study may also reflect changes in overactive bladder symptoms that are big enough to be important to people with overactive bladder. Many participants who took vibegron in the EMPOWUR study felt that it helped to improve their individual overactive bladder symptoms. This may also help improve quality of life of participants. Clinical Trial Registration: NCT03492281 (ClinicalTrials.gov).

Background: Overactive bladder (OAB) is characterized by urgency and frequency with (OAB wet) or without (OAB dry) urge urinary incontinence (UUI). In the phase 3 EMPOWUR trial, vibegron-a selective β 3 -adrenergic receptor agonist for the treatment of OAB-significantly improved daily number of urgency episodes and micturitions vs. placebo ( P  < 0.01). These post hoc analyses aimed to compare the efficacy of vibegron vs. placebo in OAB dry and wet populations., Methods: Patients were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, for 12 weeks. Baseline criteria for OAB dry included an average of ≥8 micturitions, ≥3 urgency episodes, and <1 UUI episode per diary day and for OAB wet included an average of ≥8 micturitions and ≥1 UUI episode per diary day. Change from baseline in mean daily number of urgency episodes and micturitions was assessed in both populations., Results: Of the 1463 patients included in the full analysis set, 336 (23%) had OAB dry (vibegron, N  = 123; placebo, N  = 115; and tolterodine, N  = 98), and 1127 (77%) had OAB wet (vibegron, N  = 403; placebo, N  = 405; and tolterodine, N  = 319). Vibegron was associated with significant reductions (95% CIs of the least squares mean differences [LSMD] does not include 0) from baseline at week 12 vs. placebo in mean daily urgency episodes for the dry (LSMD [95% CI], ‒1.0 [‒2.0, ‒0.1]) and wet (‒0.6 [‒1.0, ‒0.1]) populations. Vibegron was associated with significant reductions from baseline at week 12 vs. placebo in mean daily micturitions for the dry (LSMD [95% CI], ‒0.8 [‒1.5, ‒ 0.1]) and wet (‒0.5 [‒0.8, ‒0.1]) populations. There were no significant differences in either outcome between tolterodine and placebo for either the dry or wet populations in this study., Conclusions: In this subgroup analysis from the EMPOWUR trial, vibegron was associated with significant reductions compared with placebo in urgency episodes and micturitions in both the OAB dry and wet populations, suggesting that vibegron is similarly efficacious for these endpoints in patients with and without UUI. This trial is registered with NCT03492281., Competing Interests: DS is an advisor for Astellas, Urovant Sciences, and UroCure; a meeting participant, lecturer, and investigator for Astellas and Urovant Sciences; and holds other interests in UroCure. JF is an investigator for Urovant Sciences, an investigator and speaker for Astellas Pharma and Pfizer Inc., and a speaker for Tolmar Inc. SV is a consultant and speaker for Urovant Sciences, a principal investigator for Clinical Research Consulting, and holds academic positions at Sacred Heart University and the University of Bridgeport. MK has received grant and/or research study funding from Allergan, Amphora, Astellas, Axonics, Boston Scientific, Coloplast, Cook Myosite, Dignify Therapeutics, EBT Medical, FemPulse, Ipsen, Taris, and Uro1 and is a consultant for Allergan, Astellas, Boston Scientific, Coloplast, Laborie, and Urovant Sciences. DKN is a consultant for Urovant Sciences. MR is a consultant and speaker for Urovant Sciences; a consultant and speaker for Astellas Pharma; and a consultant for Ferring. DDS, RJ, and PNM were employees of Urovant Sciences at the time the work was conducted., (Copyright © 2022 David Staskin et al.)

Introduction: Reductions in bothersome symptoms of overactive bladder (OAB) demonstrate improvement in clinical trials, but patient perception of meaningfulness of such improvement is lacking. In the 12-week phase 3 EMPOWUR trial, vibegron significantly reduced average daily number of micturitions, urgency episodes, and urge urinary incontinence (UUI) episodes vs placebo (P < 0.01 each). This analysis assessed meaningfulness of reductions in clinical endpoints observed in EMPOWUR using patient perception of improvement., Methods: An anchor-based approach using Patient Global Impression of Change (PGI-C) applied to phase 2 data allowed predefining phase 3 responder definitions. To confirm in phase 3, median change from baseline at week 12 in average daily number of micturitions, urgency episodes, and UUI episodes was generated for each PGI-C category and pooled across treatments. Based on predefined meaningful responder definitions, percentages of patients achieving ≥ 15% reduction in micturitions (post hoc), ≥ 50% reduction in urgency episodes (predefined), and ≥ 75% (predefined) and ≥ 90% (post hoc) reduction in UUI episodes were determined for patients receiving vibegron or placebo., Results: Across treatments, for micturitions, urgency episodes, and UUI episodes, median change from baseline to week 12 increased with greater subjective improvement based on PGI-C scores, and median reductions pooled across treatment groups were higher than the responder definitions that patients perceived as improved. Significantly more patients receiving vibegron vs placebo achieved ≥ 15% reduction in micturitions (56.3% vs 44.6%, respectively), ≥ 50% reduction in urgency episodes (39.5% vs 32.8%), ≥ 75% reduction in UUI episodes (49.3% vs 32.8%), and ≥ 90% reduction in UUI episodes (35.2% vs 23.5%) at week 12 (P < 0.05 each)., Conclusion: Significantly more patients treated with vibegron vs placebo in EMPOWUR achieved meaningful reductions in micturitions, urgency episodes, and UUI episodes that were associated with patient-perceived improvement. Results of these analyses support the meaningfulness of reductions in clinical endpoints observed in the 12-week EMPOWUR trial., Clinical Trials Registration: ClinicalTrials.gov identifier, NCT03492281., (© 2021. The Author(s).)

Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level overestimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings, we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow the calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).

Competing Interests: Conflict of interest statement: The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: D.S. is an advisor for Astellas, NewUro, Stimwave, UroCure, and Urovant Sciences; a meeting participant/lecturer and investigator for Astellas and Urovant Sciences; and holds other interests in UroCure.

Purpose: The long-term safety, tolerability and efficacy of vibegron in adults with overactive bladder were evaluated in the 40-week phase 3 EMPOWUR extension study., Materials and Methods: Patients who completed 12 weeks of once-daily vibegron 75 mg or tolterodine 4 mg extended release in EMPOWUR continued double-blind treatment; patients who completed 12 weeks of placebo were randomly assigned 1:1 to receive double-blind vibegron or tolterodine. The primary outcome was safety, measured by incidence of adverse events. Secondary outcomes included change from baseline at week 52 in average daily number of micturitions and urgency episodes (all patients), and urge and total urinary incontinence episodes (patients with overactive bladder wet) based on 7-day diary data., Results: Of 506 patients randomized 505 received ≥1 dose of medication, and 430 (85%) completed the study. A total of 12 patients (2.4%) discontinued owing to adverse events. The most common adverse events with vibegron/tolterodine (>5% in either group) were hypertension (8.8%/8.6%), urinary tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) and dry mouth (1.8%/5.2%). Improvements in efficacy end points were maintained for patients receiving vibegron for 52 weeks; least squares mean change from baseline to week 52 in micturitions was ‒2.4 for vibegron vs ‒2.0 for tolterodine; in urge urinary incontinence episodes ‒2.2 vs ‒1.7 (p <0.05); in urgency episodes ‒3.4 vs ‒3.2; and in total incontinence episodes ‒2.5 vs ‒1.9 (p <0.05). Among patients with overactive bladder wet 61.0% receiving vibegron experienced ≥75% reduction in urge urinary incontinence episodes after 52 weeks of treatment vs 54.4% with tolterodine, while 40.8% vs 34.2% experienced a 100% reduction., Conclusions: Vibegron demonstrated favorable long-term safety, tolerability and efficacy in patients with overactive bladder, consistent with results of the 12-week study.

Background: Quality of life (QOL) can be significantly impacted by symptoms of overactive bladder (OAB). Vibegron is a highly selective β 3 -adrenergic receptor agonist that showed efficacy in treatment of symptoms of OAB in the randomised, double-blind, placebo- and active-controlled phase 3 EMPOWUR trial. Here we report patient-reported QOL outcomes from the EMPOWUR trial., Methods: Patients were randomly assigned 5:5:4 to receive vibegron 75 mg, placebo or tolterodine 4 mg extended release, respectively, for 12 weeks. Patients completed the OAB questionnaire (OAB-q) at baseline and at week 12 and the patient global impression (PGI) scales for severity, control, frequency and leakage at baseline and at weeks 4, 8 and 12. Change from baseline at week 12 and responder rates (OAB-q: patients achieving a ≥10-point improvement; PGI: patients reporting best possible response) were assessed. Vibegron was compared with placebo, and no comparisons were made between vibegron and tolterodine., Results: Of the 1518 patients randomised, 1463 (placebo, n = 520; vibegron, n = 526; tolterodine, n = 417) had evaluable data for efficacy measures and were included in the analysis. Mean baseline OAB-q and PGI scores were comparable among treatment groups. At week 12, patients receiving vibegron had greater improvements from baseline in OAB-q subscores of coping, concern, sleep, health-related QOL total and symptom bother (P < .01 each) compared with patients receiving placebo; a greater proportion of patients receiving vibegron vs placebo were responders in the OAB-q coping (P < .05) and symptom bother scores (P < .0001). Compared with placebo, a greater proportion of patients who received vibegron achieved the best response on all PGI end-points at week 12 (P < .05 each) and were classified as responders (P < .05 each)., Conclusions: In the 12-week EMPOWUR trial, treatment with vibegron was associated with significantly greater and clinically meaningful improvement in OAB-q and PGI scores compared with placebo, consistent with improvements in OAB symptoms., Clinical Trial Registration: ClinicalTrials.gov identifier number NCT03492281., (© 2020 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Background: Overactive bladder (OAB) is common among older adults. The efficacy and safety of vibegron for the treatment of OAB were demonstrated in the international, phase III EMPOWUR trial. This subpopulation analysis from EMPOWUR assessed the efficacy and safety of vibegron in patients aged ≥ 65 and ≥ 75 years., Methods: In EMPOWUR, patients with OAB were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, once daily for 12 weeks. Coprimary efficacy endpoints were change from baseline at week 12 in average daily number of micturitions and urge urinary incontinence (UUI) episodes; a key secondary efficacy endpoint was change from baseline at week 12 in average daily number of urgency episodes. Safety was assessed through adverse events (AEs). Efficacy analyses compared vibegron with placebo; no efficacy comparisons were made between vibegron and tolterodine., Results: Of the 1463 patients with evaluable efficacy data, 628 patients were aged ≥ 65 years, and 179 were aged ≥ 75 years. After 12 weeks, patients treated with once-daily vibegron 75 mg in both age subgroups showed significant improvements from baseline versus placebo in all three symptoms of OAB: daily micturitions (≥ 65 years, P < 0.0001; ≥75 years, P < 0.05), UUI episodes (≥ 65 years, P < 0.001; ≥ 75 years, P < 0.0001), and urgency episodes (≥ 65 years, P < 0.01; ≥ 75 years, P < 0.01). Significant reductions from baseline versus placebo in daily micturitions, UUI episodes, and urgency episodes were observed beginning at week 2 for patients aged ≥ 65 years treated with vibegron. In patients aged ≥ 65 years, 50.0% of those receiving vibegron versus 29.8% receiving placebo experienced a ≥ 75% reduction in UUI episodes at week 12 (P < 0.0001). Rates of cardiovascular-associated AEs were low for patients receiving vibegron (<2% of patients in either age subgroup) and similar to rates in patients receiving placebo. In patients aged ≥ 65 years, hypertension was reported by 1.2%, 3.1%, and 2.9% of patients receiving vibegron, placebo, and tolterodine, respectively; in patients aged ≥ 75 years, hypertension was reported by 1.3%, 3.3%, and 2.1%, respectively., Conclusions: In this subpopulation analysis of patients with OAB aged ≥ 65 and ≥ 75 years from the EMPOWUR study, once-daily vibegron 75 mg showed rapid onset and robust efficacy versus placebo and was generally safe and well tolerated, consistent with results from the overall population., Trial Registration: ClinicalTrials.gov identifier NCT03492281; registered April 10, 2018.

Background: In older patients with overactive bladder (OAB), mirabegron, a β 3 -adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile., Objectives: Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet., Methods: We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug., Results: Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related., Conclusions: Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile., Trial Registration: This study is registered at ClinicalTrials.gov: NCT02216214.

Purpose: We assessed efficacy, safety and tolerability of vibegron, a novel, potent, highly selective β 3 -adrenoceptor agonist, administered 12 weeks at 75 mg once daily to patients with overactive bladder in an international phase III trial with placebo and active control., Materials and Methods: Adult patients with overactive bladder with 8.0 or more micturitions per day were randomized 5:5:4 to 75 mg vibegron, placebo or extended-release 4 mg extended-release tolterodine. Up to 25% of patients could have dry overactive bladder (less than 1.0 urge incontinence episode per day). Patients completed 7-day voiding diaries at baseline and weeks 2, 4, 8 and 12., Results: Of 1,518 randomized patients 90.4% completed the trial. At 12 weeks micturitions decreased by an adjusted mean of 1.8 episodes per day for vibegron vs 1.3 for placebo (p <0.001, co-primary end point) and 1.6 for tolterodine. Among incontinent patients urge incontinence episodes decreased by an adjusted mean 2.0 episodes per day for vibegron vs 1.4 for placebo (p <0.0001, co-primary end point) and 1.8 for tolterodine. Moreover, vibegron was statistically significantly superior to placebo for key secondary measures of number of urgency episodes, volume per micturition and proportion of incontinent patients with a 75% or greater reduction in urge incontinence episodes (all p <0.01). Among vibegron treated patients 1.7% discontinued treatment because of adverse events vs 1.1% for placebo and 3.3% for tolterodine. Incidence of hypertension was 1.7% for vibegron and for placebo., Conclusions: Once daily 75 mg vibegron provided statistically significant reductions in micturitions, urgency episodes and urge incontinence, and increased the volume per micturition. Treatment was well tolerated with a favorable safety profile.

Purpose: PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia., Materials and Methods: In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements., Results: Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful., Conclusions: The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

Background: Antimuscarinics are often used for treatment of overactive bladder (OAB), but exposure to medications such as antimuscarinics that have anticholinergic properties has been linked to adverse cognitive effects. A phase 4 placebo-controlled study (PILLAR; NCT02216214) described the efficacy and safety of mirabegron, a β 3 -adrenoreceptor agonist, for treatment of wet OAB in patients aged ≥65 years. This pre-planned analysis aimed to measure differences in cognitive function between mirabegron and placebo, using a rapid screening instrument for mild cognitive impairment: the Montreal Cognitive Assessment (MoCA)., Methods: Outpatients aged ≥65 years with wet OAB were randomized 1:1 to mirabegron or placebo, stratified by age (<75/≥75 years). There were no exclusion criteria regarding cognitive status. Patients randomized to mirabegron initially received 25 mg/day with an optional increase to 50 mg/day after week 4/8 based on patient/investigator discretion. The MoCA was administered at baseline and end of treatment (EoT, week 12). The study protocol was Independent Ethics Committee/Institutional Review Board-approved., Results: Of the 887 randomized patients who received ≥1 dose of study drug, 72.3% were female, 79.5% were white, and 28.1% were aged ≥75 years. All patients had ≥1 comorbidity and 94.3% were receiving ≥1 concomitant medication. One third of patients had a history of psychiatric disorders, the most common being depression (17.2%), insomnia (15.7%), and anxiety (11.4%). Baseline mean (standard error, SE) MoCA total scores were 26.9 (0.1) and 26.8 (0.1) in the mirabegron and placebo groups, respectively. Among patients with MoCA data available at baseline/EoT, 27.1% (115/425) and 25.8% (106/411) of mirabegron and placebo group patients, respectively, had impaired cognitive function at baseline (MoCA total score <26). There was no statistically significant change in adjusted mean (SE) MoCA total score from baseline to EoT in the mirabegron group (-0.2 [0.1]) or the placebo group (-0.1 [0.1])., Conclusions: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo., Trial Registration: NCT02216214 (prospectively registered August 13, 2014).