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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

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).

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).

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.)

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.

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).

Background: The PREFER study was an assessment of medication tolerability, treatment preference and symptom improvement during treatment with mirabegron (M) and tolterodine (T) extended release (ER) in patients with overactive bladder (OAB). In this analysis of PREFER, patient-reported outcomes (PROs) were assessed during treatment., Methods: PREFER was a two-period, 8-week crossover, double-blind, phase IV study (NCT02138747) of treatment-naïve adults with OAB ≥3 months randomized to 1 of 4 treatment sequences (M/T; T/M; M/M; T/T), separated by a 2-week washout. Tolterodine ER was dosed at 4 mg for 8 weeks and mirabegron was dosed at 25 mg for 4 weeks then increased to 50 mg for the next 4 weeks. At each visit, PROs related to treatment satisfaction, quality of life and symptom bother were assessed using the OAB Satisfaction (OAB-S; 3 independent scales/5 single-item overall assessments), OAB-q (total health-related QoL [HRQoL] and subscales [Sleep, Social, Coping, Concern] and Symptom Bother scale) and Patient Perception of Bladder Condition (PPBC) questionnaires. Responder rates were reported for OAB-q subscales based on a minimal important difference (MID; ≥ 10-point improvement) and OAB-S Medication Tolerability score ≥ 90., Results: In total, 358 randomized patients received ≥1 dose of double-blind study medication and completed ≥1 post-baseline value (OAB-S scale, OAB-q, PPBC): M/T (n = 154), T/M (n = 144), M/M (n = 30) or T/T (n = 30). At end of treatment (EoT), mirabegron and tolterodine ER were associated with similar mean improvements in 7 of the 8 OAB-S scores investigated, OAB-q scales and PPBC. A higher percentage of patients achieved clinically relevant improvements (MID) in OAB-q scales and OAB-S Medication Tolerability score during treatment with mirabegron than tolterodine ER., Conclusions: On average, patients with OAB experienced improvements in treatment satisfaction, HRQoL and symptom bother that were of a similar magnitude during treatment with mirabegron or tolterodine ER. However, during mirabegron treatment, patients were more likely to achieve clinically relevant improvements in tolerability and HRQoL (as measured by the MID for the OAB-q or an OAB-S Medication Tolerability score ≥ 90) than during tolterodine ER treatment., Trial Registration: NCT02138747 ; registered May 13, 2014.

Background: Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine., Methods: Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models., Results: The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively., Conclusions: A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials., Trial Registration: The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).

Objective: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder., Subjects and Methods: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline., Results: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups., Conclusions: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.