Efficacy of vibegron, a novel selective β3-adrenoreceptor agonist, on urgency urinary incontinence with overactive bladder: Post-hoc analysis of phase III study

Yoshida M1, Takeda M2, Gotoh M3, Yokoyama O4, Kakizaki H5, Takahashi S6, Masumori N7, Nagai S8, Hashimoto K8, Minemura K8

Research Type

Clinical

Abstract Category

Overactive Bladder

Abstract 180
Overactive Bladder
Scientific Podium Short Oral Session 8
Wednesday 4th September 2019
14:37 - 14:45
Hall K
Overactive Bladder Urgency Urinary Incontinence Urgency/Frequency Incontinence
1.Department of Urology, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan, 2.Department of Urology, Graduate School of Medical Sciences, University of Yamanashi, Kofu, Yamanashi, Japan, 3.Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan, 4.Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan, 5.Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan, 6.Department of Urology, Nihon University School of Medicine, Tokyo, Japan, 7.Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan, 8.Kyorin Pharmaceutical Co., LTD, Tokyo, Japan
Presenter
M

Masaki Yoshida

Links

Abstract

Hypothesis / aims of study
Urinary incontinence is common in women, and prominently impairs patient quality of life (QOL). Urinary incontinence is categorized into 2 types: stress urinary incontinence and urgency urinary incontinence (UUI), the latter defined as urine leakage taking place simultaneously with or just after an urgency episode, which is an essential symptom for diagnosis of overactive bladder (OAB). A novel β3-adrenoreceptor agonist vibegron demonstrated efficacy and safety in Japanese OAB patients enrolled in the phase III trial (1), but evidence of its efficacy on UUI is scarce. Therefore, a post-hoc analysis of the phase III study was performed to evaluate the efficacy of vibegron on UUI in OAB patients.
Study design, materials and methods
Among the patients randomized and assigned to receive either vibegron 50 mg daily, 100 mg daily, placebo or imidafenacin 0.1 mg twice daily for 12 weeks in the phase III study, those who were assigned to receive vibegron or placebo and had UUI episode (>0 per day) were enrolled in this post-hoc analysis. Eligible patients were classified into mild-moderate UUI subgroup (>0 to <3 UUI episodes per day) or severe UUI subgroup (≥3 UUI episodes per day). Change from baseline in number of UUI episodes per day, number of urgency episodes per day, and voided volume per micturition was compared between the groups. In addition, percentage of patients who became UUI-free (zero UUI episodes per day) was calculated as diary-dry rate. Furthermore, percentage of patients with score 1 (feeling much better) or 2 (feeling better) assessed by Patient Global Impression (PGI) was calculated to identify response rate. For changes in individual micturition parameters from baseline to week 12, a constrained Longitudinal Data Analysis mode was used to calculate least squares means (LS means) and 95% confidence intervals, and between-group comparison was made. For the assessment of differences in the diary-dry rate and response rate, Chi-square test was used.
Results
Among the 989 patients included in the analysis, numbers of patients with mild-moderate UUI were 273, 281, and 277 in the vibegron 50 mg, 100 mg, and placebo groups, and numbers of those with severe UUI were 56, 46, and 56, respectively. Patients were aged 58.0-60.7 years, 91.1-100.0% were female, and 14.2-30.4% had a treatment history for OAB. In the sever UUI subgroup, the vibegron 100 mg group included more patients with higher age (60.7 years vs 58.7 and 58.1 years) and more females (100% vs 91.1 and 94.6% )  than in the vibegron 50mg and placebo groups; the vibegron 50 mg group included more patients with treatment history (30.4% vs 26.1 and 21.4% in the vibegron 100 mg and placebo groups). As for the baseline OAB symptoms, notable differences were not observed among the groups except for the voided volume per micturition (139.8, 146.0, and 152.9 in the vibegron 50mg, 100mg, and placebo groups) in the severe UUI. 
Changes in numbers of UUI episodes at week 12 in the vibegron 50 mg, 100 mg, and placebo groups were -1.04, -1.13, and -0.89 in the mild-moderate UUI subgroup and -2.95, -3.28, and -2.10 in the severe UUI subgroup. The changes were significant in the vibegron 50 mg and 100 mg groups versus placebo group (p<0.05, Table 1). The change in number of urgency episodes per day was significant in the vibegron 100 mg group versus placebo, both in the mild-moderate UUI subgroup (-2.25 vs -1.68, p<0.001) and the severe UUI subgroup (-4.04 vs -2.70, p=0.006) at week 12. In the vibegron 50 mg group, a significant change was observed in the mild-moderate UUI subgroup versus placebo (-2.11 vs -1.68, p=0.002). However, in the severe UUI subgroup, reduction in the number of urgency episodes per day was not significant versus placebo (-3.55 vs -2.70, p=0.064). Change in the voided volume per micturition was significantly greater in the vibegron 50 mg and 100 mg groups versus placebo group, both in the mild-moderate UUI subgroup (34.27, 31.28 vs 7.48 mL, p<0.001) and severe UUI subgroup (31.82, 30.74 vs12.26 mL, p<0.05) at week 12. 
In the mild-moderate UUI subgroup, diary-dry rates in the vibegron 50 mg, 100 mg, and placebo groups were 59.3%, 64.1%, and 50.5% (p<0.001, vibegron 50 / 100mg vs placebo), and 37.5%, 32.6%, and 17.9% in the severe UUI subgroup (p<0.05, vibegron 50/100mg vs placebo) at week 12. 
Response rates assessed by PGI in the vibegron 50 mg, 100 mg, and placebo groups were 61.2%, 63.3%, and 39.7% in the mild-moderate UUI subgroup and 55.4%, 52.2%, and 28.6% in the severe UUI subgroup. The response rates in the vibegron groups were significantly higher versus the placebo group (p<0.05, Table 2).
Interpretation of results
UUI has been reported to often trigger destructive consequences to the psychology and sexual / social life of the patients (2). In the present study, treatment with vibegron for 12 weeks significantly reduced UUI episodes and increased voided volume versus placebo, resulting in diary-dry rate of 59-64% in OAB patients with mild-severe UUI and 32-38% in those with severe UUI. In addition, 50-60% of the patients felt better or much better after 12-week vibegron treatment. These results suggest that vibegron may be useful in treatment of OAB patients with UUI regardless of severity, and in improving patient QOL.
Concluding message
Vibegron, a potent and selective β3-adrenoreceptor agonist, demonstrated efficacy by reducing UUI episodes and increasing voided volume per micturition, with response rate over 50% in patients with OAB. Vibegron was suggested to be a useful option for the treatment of OAB with UUI.
Figure 1 Table 1. Change in OAB parameters from baseline at week 12
Figure 2 Table 2. Response rate assessed by PGI
References
  1. Vibegron, a novel potent and selective ß3-adrenoreceptor agonist, for the treatment of patients with overactive bladder: a randomized, double-blind, placebo-controlled phase 3 study. Eur Urol 2018; 73;783-790.
  2. Impact of urinary incontinence on quality of life. Pelviperineology 2009; 28:51-53.
Disclosures
<span class="text-strong">Funding</span> Kyorin Pharmaceutical Co and Kissei Pharmaceutical Co <span class="text-strong">Clinical Trial</span> Yes <span class="text-strong">Registration Number</span> NCT01314872 <span class="text-strong">RCT</span> Yes <span class="text-strong">Subjects</span> Human <span class="text-strong">Ethics Committee</span> Ethics committee of Kyorin Pharmaceutical Co., and this study was approved by institutional review board at each study site <span class="text-strong">Helsinki</span> Yes <span class="text-strong">Informed Consent</span> Yes