Onset of action of the β3-adrenoceptor agonist, mirabegron, in Phase II and III clinical trials in patients with overactive bladder

Christopher R Chapple, Victor W Nitti, Vik Khullar, Jean Jacques Wyndaele, Sender Herschorn, Philip van Kerrebroeck, Mary Beth Blauwet, Emad Siddiqui, Christopher R Chapple, Victor W Nitti, Vik Khullar, Jean Jacques Wyndaele, Sender Herschorn, Philip van Kerrebroeck, Mary Beth Blauwet, Emad Siddiqui

Abstract

Purpose: Long-term persistence with pharmacotherapy for overactive bladder (OAB) requires a drug with an early onset of action and good efficacy and tolerability profile. Although antimuscarinics improve OAB symptoms within 1-2 weeks of initiating treatment, adherence after 3 months is relatively poor due to bothersome side effects (e.g., dry mouth and constipation). Mirabegron, a β3-adrenoceptor agonist, has demonstrated significant improvements in key symptoms of OAB and good tolerability after 12 weeks in Phase III studies.

Methods: This was a prespecified pooled analysis of three randomized, double-blind, placebo-controlled, 12-week studies, and a Phase II study, to evaluate efficacy and tolerability of mirabegron 25 and 50 mg versus placebo. The main efficacy endpoints were change from baseline to week 1 (Phase II only), week 4, and final visit in mean number of incontinence episodes/24 h, micturitions/24 h, and mean volume voided/micturition (MVV).

Results: A significant benefit for mirabegron 25 and 50 mg versus placebo was evident at the first assessment point, 4 weeks after initiation of therapy, in Phase III studies for incontinence, micturitions, and MVV. The earliest measured benefit was after 1 week, in the Phase II study. Quality-of-life parameters also significantly improved with mirabegron 25 and 50 mg as early as week 4. Significant benefits continued throughout the studies. Mirabegron was well tolerated.

Conclusions: The early onset of action and good overall efficacy and tolerability balance that mirabegron offers may lead to high rates of persistence with mirabegron in the long-term treatment of OAB.

Figures

Fig. 1
Fig. 1
Mean change from baseline at each visit in Study 178-CL-044: a the number of incontinence episodes/24 h (full analysis set-incontinence), b number of number of micturitions/24 h (full analysis set), and c volume voided/micturition (full analysis set). *Statistically significant treatment benefit relative to placebo without multiplicity adjustment (P < 0.05). BL baseline, FAS full analysis set, FAS-I full analysis set-incontinence
Fig. 2
Fig. 2
Mean change from baseline (±SE) at each visit in the pooled Phase III studies: a the number of incontinence episodes/24 h (full analysis set-incontinence), b number of number of micturitions/24 h (full analysis set), and c volume voided/micturition (full analysis set). #Statistically significant treatment benefit relative to placebo (P < 0.05) with multiplicity adjustment. *Statistically significant treatment benefit relative to placebo (P < 0.05) without multiplicity adjustment. SE standard error, FAS full analysis set

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Source: PubMed

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