Phase II studies

Vibegron has been extensively evaluated in clinical studies [27]. A phase IIb trial supported the efficacy and safety of vibegron [28]. This randomised, double-blind study included an active control (tolterodine) and evaluated a range of vibegron doses in patients with OAB. The trial reported significant reductions in urinary frequency, urgency episodes and UUI episodes with vibegron 50 mg and 100 mg compared with placebo (p < 0.05), as well as improvements in HRQOL measures (Table 2). Efficacy was sustained throughout a 52-week extension study [29], underscoring the long-term benefits of vibegron. These trials provided critical insights into the optimal dosing and safety profile of vibegron 50 mg and 100 mg, paving the way for its phase III development.

Table 2 Efficacy outcomes with vibegron in significant clinical trials and subgroup analysesPhase III studies

Two multicentre, phase III trials conducted in Japan assessed the efficacy and safety of vibegron in patients with OAB [30, 31]. These trials demonstrated improvements in OAB symptoms, including urinary frequency, urgency episodes, UUI and nocturia (Table 2), with the differences significant versus placebo in the placebo-controlled trial (p < 0.05) [30]. Vibegron also increased voided volume per micturition compared with placebo, with notable efficacy evident from week 4 of treatment. Improvements in HRQOL were observed across several domains, and the treatment was well tolerated [30, 31].

EMPOWUR was a multicentre, international, randomised, double-blind, placebo- and active-controlled phase III study designed to assess the efficacy and safety of vibegron 75 mg once daily in adults with OAB [32]. Participants were randomised in a 5:5:4 ratio to receive vibegron, placebo or extended-release tolterodine 4 mg. The study enrolled 1,518 patients, 90.4% of whom completed the 12-week treatment period. The study population consisted primarily of women (85.2%) and had a mean age of 61 years, while 43% of participants were aged ≥ 65 years. At baseline, participants averaged 11.5 micturitions and 8.1 urgency episodes per day.

At week 12, vibegron demonstrated statistically significant reductions in daily micturitions and UUI episodes compared with placebo (Table 2); vibegron produced a numerically greater magnitude of effect than tolterodine [32]. For urinary frequency, the least-squares (LS) mean change from baseline (CFB) with vibegron was − 1.8 episodes per day, compared with − 1.3 episodes per day with placebo, yielding an LS mean difference of − 0.5 (95% confidence interval [CI] − 0.8 to − 0.2; p < 0.001). Tolterodine demonstrated an LS mean CFB of − 1.6 episodes per day, with an LS mean difference from placebo of − 0.3 (p = 0.10). For UUI, vibegron reduced episodes by − 2.0 per day, compared with − 1.4 per day for placebo, resulting in an LS mean difference of − 0.6 (95% CI − 0.9 to − 0.3; p < 0.0001). Significant reductions in both endpoints were observed with vibegron as early as week 2 and were sustained throughout the study. Efficacy was consistent across subgroups, including treatment-naïve patients and those with prior pharmacotherapy for OAB. It is important to note that EMPOWUR was not powered to detect differences between vibegron and tolterodine; therefore, any comparisons between the two are considered descriptive. The statistical analysis for efficacy compared active drug (vibegron or tolterodine) with placebo only.

Key secondary endpoints in EMPOWUR also demonstrated the superiority of vibegron over placebo [32]. At week 12, the LS mean CFB in urgency episodes was − 2.7 episodes per day with vibegron, compared with − 2.0 episodes per day for placebo, yielding an LS mean difference of − 0.7 (95% CI − 1.1 to − 0.2; p = 0.002). In addition, vibegron significantly increased voided volume per micturition, with an LS mean increase of 23.5 mL compared with 2.2 mL for placebo (LS mean difference 21.2 mL; 95% CI 14.3 to 28.1; p < 0.0001). In participants with OAB classified as wet (OAB wet), 52.4% of those treated with vibegron achieved a ≥ 75% reduction in UUI episodes at week 12, compared with 36.8% in the placebo group (p < 0.0001).

Vibegron was well tolerated in EMPOWUR, with an AE-related discontinuation rate of 1.7%, compared with 1.1% for placebo and 3.3% for tolterodine at week 16 (including the 12-week treatment period and the 4-week follow-up period) [32]. The incidence of hypertension, reported in 1.7% of vibegron-treated participants, was similar to placebo (Table 3). Other AEs, including headache, diarrhoea and nasopharyngitis, were mild and infrequent and occurred at incidences similar to those observed with placebo. Notably, dry mouth, a common AE of antimuscarinic therapies, occurred in 1.7% of vibegron-treated patients, 0.9% of the placebo group and 6.5% of the tolterodine group.

Table 3 Safety outcomes with vibegron in significant clinical trials and subgroup analyses

Subsequently, an analysis conducted by Frankel and colleagues aimed to determine the clinical meaningfulness of symptom reductions observed in the EMPOWUR trial [33]. Using an anchor-based methodology, the study linked changes in clinical endpoints, such as daily micturitions, urgency episodes and UUI episodes, with patient-reported outcomes, specifically the Patient Global Impression of Change (PGI-C). The analysis identified clinically meaningful thresholds, including a ≥ 15% reduction in micturitions, ≥ 50% reduction in urgency episodes and ≥ 75% and ≥ 90% reductions in UUI episodes, based on patient-perceived improvement.

Results demonstrated that significantly more patients treated with vibegron achieved meaningful symptom reductions compared with placebo [33]. For instance, 56.3% of vibegron-treated patients achieved a ≥ 15% reduction in micturitions compared with 44.6% of placebo recipients (p < 0.001), while 49.3% and 35.2% of vibegron-treated patients experienced ≥ 75% and ≥ 90% reductions in UUI episodes, respectively, compared with 32.8% and 23.5% with placebo (p < 0.0001 and p < 0.001, respectively).

Vibegron in OAB with and without incontinence

A subgroup analysis of the EMPOWUR trial assessed the efficacy of vibegron 75 mg in patients with OAB classified as either dry (OAB dry) or OAB wet (Table 2) [34]. Of the 1463 patients in the full analysis set, 336 (23%) were classified as having OAB dry and 1127 (77%) as having OAB wet; notably, a higher proportion of patients with OAB dry were men compared with the overall population (29.5% vs 14.8%), while patients with OAB wet were predominantly women (89.5% vs 70.5%).

At week 12, vibegron demonstrated significant reductions in daily urgency episodes compared with placebo in both subgroups [34]. Similarly, reductions in daily micturitions were significant with vibegron in both subgroups (OAB dry: LS mean difference − 0.8, 95% CI − 1.5 to − 0.1; OAB wet: − 0.5, 95% CI − 0.8 to − 0.1). Improvements were observed as early as week 2 for urgency episodes and week 4 for micturitions and were sustained throughout the 12-week study period. No significant differences were observed between tolterodine and placebo in either subgroup for these endpoints. Responder analyses further highlighted the efficacy of vibegron, including in patients with OAB dry, as 36.9% of those treated with vibegron achieved a ≥ 50% reduction in urgency episodes by week 12 compared with 23.1% with placebo (p < 0.05). The findings were consistent with those in the overall population and underscore vibegron’s ability to address the core symptoms of OAB, regardless of the presence or absence of UUI.

Vibegron in women

A prespecified subgroup analysis of the EMPOWUR trial examined the efficacy and safety of vibegron 75 mg in women, who constituted 84.9% (n = 1,286) of the trial population (Table 2) [35]. Women had a mean age of 59.5 years and most (80.9%) were classified as having OAB wet.

At week 12, vibegron demonstrated statistically significant improvements across key efficacy endpoints in women compared with placebo [35]. Reductions in daily micturitions were greater with vibegron (− 1.9) than with placebo (− 1.4; LS mean difference − 0.5, 95% CI − 0.8 to − 0.2). For UUI episodes, vibegron resulted in a mean reduction of − 2.1 compared with − 1.4 with placebo (LS mean difference − 0.7, 95% CI − 1.0 to − 0.4). These improvements were consistent with the overall trial population and highlight vibegron’s efficacy in addressing key OAB symptoms in women. Vibegron also improved HRQOL measures in women, including OAB-q subscale scores for coping, concern, sleep, symptom bother and overall HRQOL (all p < 0.01), as well as in PGI scores for severity, control, frequency, leakage and change (all p < 0.01).

Safety findings revealed a similar incidence of treatment-emergent adverse events (TEAEs) between vibegron (39.3%) and placebo (34.9%), with headache being the most frequently reported TEAE in the vibegron group (4.3% vs 2.6% with placebo; Table 3) [35]. The AE-related discontinuation rate was 1.5% for vibegron, 1.1% for placebo and 3.8% for tolterodine. These data reinforce vibegron’s favourable benefit-risk profile for women with OAB.

Vibegron in older patients

An analysis of the EMPOWUR trial evaluated the efficacy and safety of vibegron 75 mg in patients aged ≥ 65 years (n = 628) and ≥ 75 years (n = 179; Table 2) [36].

At week 12, patients treated with vibegron demonstrated significant improvements in OAB symptoms compared with placebo [36]. Among patients aged ≥ 65 years, LS mean reductions from baseline in daily micturitions and UUI episodes were − 1.9 (p < 0.0001) and − 2.0 (p < 0.001), respectively. Similarly, patients aged ≥ 75 years showed LS mean reductions of − 1.7 in micturitions (p < 0.05) and − 2.0 in UUI episodes (p < 0.0001). These changes were consistent with those observed in the overall population (Table 2).

Safety outcomes were favourable, with comparable AE rates for vibegron, placebo and tolterodine (Table 3) [36]. In patients aged ≥ 65 years, common AEs with vibegron included headache, dry mouth and upper respiratory tract infections, while hypertension occurred in 1.2%, which was lower than placebo (3.1%) and tolterodine (2.9%). Among those aged ≥ 75 years, urinary tract infection and diarrhoea were the most frequently reported AEs with vibegron, but cardiovascular-associated AEs were rare and similar to placebo. These findings underscore vibegron’s suitability for older patients, particularly given its minimal risk of anticholinergic-related side effects and drug-drug interactions.

Vibegron in long-term therapy

The long-term extension study of the EMPOWUR trial, conducted over 40 weeks with a subsequent 4-week safety follow-up, evaluated the safety, tolerability and efficacy of vibegron 75 mg compared with tolterodine 4 mg extended-release in adults with OAB [37]. Patients who completed the initial 12 week EMPOWUR study continued their original double-blind treatment or, if previously assigned to placebo, were directly randomised to either vibegron or tolterodine. This extension study enrolled 506 participants, with 505 receiving ≥ 1 dose of study medication and 430 completing the study. The primary endpoint was safety, while secondary endpoints included changes in the average daily number of micturitions, urgency episodes and UUI episodes [37].

The long-term safety profile of vibegron was consistent with the 12-week results [32]. The incidence of treatment-emergent AEs was similar between vibegron (62.6%) and tolterodine (54.3%; Table 3). Hypertension was the most common AE reported, occurring in 8.8% and 8.6% of patients, respectively. Dry mouth was more prevalent with tolterodine (5.2%) than vibegron (1.8%). Serious adverse events (SAEs) were rare, and discontinuations due to AEs were less common with vibegron (1.5%) than tolterodine (3.4%). No clinically meaningful changes in laboratory parameters, vital signs or other safety assessments were observed.

The study demonstrated that vibegron provided durable efficacy across all evaluated endpoints. Based on the analysis of the intention-to-treat population, LS mean reductions from baseline to week 52 in micturitions, UUI episodes urgency episodes and total incontinence episodes were greater for vibegron than tolterodine. Specifically, vibegron achieved reductions of − 2.4 micturitions and − 2.2 UUI episodes per day compared with − 2.0 and − 1.7, respectively, for tolterodine. Among patients with OAB wet, 61.0% of those receiving vibegron experienced a ≥ 75% reduction in UUI episodes by week 52, and 40.8% achieved complete resolution of UUI episodes. The efficacy observed in the initial 12-week trial was sustained throughout the 40-week extension, including among patients who switched from placebo to vibegron [37]. These findings reinforce vibegron’s potential as a well-tolerated and effective long-term treatment option for OAB [37].

A phase III open-label, non-controlled study conducted in Japan evaluated the 52-week efficacy and safety of vibegron 50 mg (n = 118) or 100 mg (n = 51) in patients with OAB [31]. Significant improvements from baseline in OAB symptoms, including urinary frequency, urgency episodes, UUI and nocturia were noted at week 4 and maintained at week 52 (Table 2). Improvements in HRQOL were observed and a dose increase to 100 mg improved OAB symptoms without increasing AEs in those patients who did not respond adequately to vibegron 50 mg. The incidence of AEs was 57.8% in 50 mg recipients and 49.0% in 100 mg recipients (Table 3). No novel, clinically significant AEs were seen with long-term treatment.

Vibegron in men with concomitant benign prostatic hyperplasia

COURAGE was a phase III, randomised, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of vibegron 75 mg once daily in men aged ≥ 45 years who had persistent symptoms of OAB despite receiving pharmacological treatment for benign prostatic hyperplasia (BPH; Table 2) [38]. The trial included men with OAB symptoms such as ≥ 8 micturitions and ≥ 3 urgency episodes per day over a period of ≥ 2 months, with BPH managed by α-blockers, with or without 5α-reductase inhibitors. Participants were randomised in a 1:1 ratio to receive either vibegron 75 mg or placebo over 24 weeks as an add-on to ongoing treatment with α-blockers, with or without 5α-reductase inhibitors [38]. The coprimary efficacy endpoints of the trial were the changes from baseline to week 12 in the mean daily number of micturitions and urgency episodes.

Results showed that vibegron significantly reduced daily micturition (LS mean difference − 0.74; p < 0.0001) and urgency episodes (− 0.95; p < 0.0001) compared with placebo. Significant improvements were also observed in nocturia (LS mean difference − 0.22; p = 0.002), UUI episodes (− 0.80; p = 0.003), International Prostate Symptom Score (IPSS) storage scores (− 0.9; p < 0.0001) and voided volume per micturition (15.07 mL; p < 0.0001). Efficacy was evident as early as week 2 and maintained throughout the study [38].

Safety data indicated that vibegron was well tolerated, with treatment-emergent AEs occurring in 45.0% and 39.0% of patients in the vibegron and placebo groups, respectively (Table 3). Common treatment-emergent AEs included hypertension, COVID-19, urinary tract infection and haematuria, with no clinically meaningful differences between groups. SAEs were infrequent, and no treatment-related SAEs were reported. Importantly, rates of urinary retention and increases in residual urine volume were comparable between the two groups, and vibegron did not result in significant changes in blood pressure, even among participants with preexisting hypertension [38].

The COURAGE trial concluded that vibegron 75 mg provides significant and clinically meaningful improvements in OAB symptoms among men with pharmacologically treated BPH, with a safety profile consistent with previous studies of vibegron in OAB populations [38].

Cardiovascular safety of vibegron

A dedicated 28-day, randomised, double-blind, placebo-controlled study evaluated the effects of vibegron 75 mg on ambulatory blood pressure (BP) and heart rate (HR) in patients with OAB [39]. The study randomised 214 adults aged 40–75 years, stratified by age, sex and hypertension status to receive vibegron or placebo. The primary endpoint was the change from baseline to day 28 in mean daytime systolic BP (SBP), with secondary endpoints including changes in diastolic BP (DBP), HR and mean 24 h BP and HR.

Results demonstrated no statistically significant or clinically meaningful differences between vibegron and placebo in changes from baseline for all measured cardiovascular parameters [39]. The LS mean difference for mean daytime SBP was 0.8 mmHg (95% CI − 0.9 to 2.5), and for mean daytime DBP, it was 0.0 mmHg (95% CI − 1.2 to 1.1). Mean daytime HR differed by 0.9 beats per minute (95% CI − 0.3 to 2.0) between groups. Similar findings were observed for 24-h ambulatory measurements, reinforcing that vibegron had no significant pressor effects. No statistically significant between-group difference in the incidence of AEs was noted between vibegron (46.2%) and placebo (25.0%), with hypertension reported in 4.7% and 3.7% of patients, respectively. Notably, no AEs of hypertension with vibegron were considered treatment-related, and one hypertension event was attributed to a prohibited concomitant medication. SAEs occurred in one patient per group (vibegron = postoperative pain; placebo = hypoglycaemia); neither was deemed related to treatment. No deaths or significant cardiovascular events were reported. The safety profile of vibegron was consistent with findings from previous trials. This study supports the cardiovascular safety of vibegron, showing no significant impact on BP or HR, even in subgroups with preexisting hypertension. These findings underscore vibegron’s suitability as a treatment option for OAB, particularly for patients with cardiovascular risk factors.

Vibegron vs mirabegron

The efficacy and safety of vibegron and mirabegron have been directly compared in at least two clinical trials [40, 41]. A randomised controlled study by Kinjo and colleagues in 199 treatment-naïve postmenopausal women with OAB found that both treatments (at 50 mg/day) provided significant improvements in OAB symptom scores (OABSS), voiding diary parameters and HRQOL measures over 12 weeks, with no significant differences between the two treatments [41]. Rates of TEAEs were comparable, with constipation being the most frequently reported event in both groups.

A multicentre, prospective, randomised, open crossover study by Wada and colleagues further examined these drugs in a cohort of 83 women with OAB, comparing their effects over two consecutive 8-week treatment periods [40]. Both treatments (at 50 mg/day) led to significant improvements in OABSS, nocturia and voided volume, but vibegron resulted in a significantly greater reduction in daytime urinary frequency compared with mirabegron (− 1.5 vs − 0.9 episodes/day; p = 0.016). In addition, a higher proportion of patients expressed a preference for vibegron over mirabegron (53% vs 27%), with the remaining 20% showing no preference. Safety outcomes were generally similar, though an increase in post-void residual volume exceeding 100 mL was observed in two vibegron-treated patients but not in those receiving mirabegron. This difference may not be clinically relevant as it was observed in only two out of 40 patients. The difference was not statistically significant (p = 0.16) and the two patients were elderly (73 and 77 years old) with a baseline PVR of 30 mL and 35 mL, respectively, suggesting possible preexisting voiding dysfunction.

In addition, the real-world adherence and persistence with vibegron compared with mirabegron and anticholinergic therapies for OAB have been evaluated in a retrospective claims analysis [42]. The analysis included data from 4921 patients receiving vibegron, matched with 9842 patients on mirabegron and 9352 on anticholinergics, based on propensity scores that accounted for demographic, clinical and prescription-related variables. The study evaluated adherence, defined as the proportion of days covered (PDC) over the follow-up period, and persistence, defined as the number of days to discontinuation or end of follow-up. Patients treated with vibegron demonstrated significantly higher adherence compared with both mirabegron (mean PDC: 0.67 vs 0.64, p < 0.001) and anticholinergics (0.67 vs 0.58, p < 0.001). In addition, a larger proportion of vibegron-treated patients achieved adherence (PDC ≥ 0.80) compared with mirabegron (49.0% vs 45.1%, p < 0.001) and anticholinergics (49.1% vs 38.5%, p < 0.001). Persistence was also significantly greater with vibegron (median duration of 171 days) compared with mirabegron (128 days; p < 0.001) and anticholinergics (91 days; p < 0.001). Interestingly, among patients discontinuing vibegron, approximately 54% initiated another OAB medication, with nearly half reinitiating vibegron. These findings suggest that vibegron may address common barriers to long-term adherence and persistence in OAB management, such as tolerability and perceived efficacy.

Despite these findings, further research is needed to clarify the long-term comparative benefits of vibegron and mirabegron, particularly regarding treatment adherence, persistence and tolerability in diverse patient populations. As noted in a letter to the editor by Dai and Deng, the absence of a placebo arm in these trials limits the ability to fully assess the relative efficacy of each drug, and future studies should incorporate placebo-controlled designs while also addressing patient comorbidities, including psychological factors that may influence treatment outcomes [43].