BETMIGA™ (mirabegron), a new oral treatment for overactive bladder, has the potential to provide relief for patients who have discontinued prior treatment due to insufficient efficacy or poor tolerability according to a post hoc analysis of the Phase III EU/Australian study.[1] The analysis investigated whether the benefits of mirabegron seen in a randomised, double-blind, placebo- and active-controlled Phase III study[2] were experienced by both treatment-naïve patients and those who had discontinued previous antimuscarinic treatment. The analysis found that both patient groups saw improvements from treatment with mirabegron compared to placebo, although as a post hoc analysis it was not powered to show statistical significance between treatment groups.[1] The analysis is published in the journal BMC Urology this month.[1]
Mirabegron represents the first new class of oral treatment for overactive bladder for over 30 years. Mirabegron is a potent and selective β3-adrenoceptor agonist which works in a completely different way to antimuscarinics, the only other class of oral treatment for overactive bladder symptoms available in Europe until recently.[3] Currently, around half of patients discontinue overactive bladder treatment after only three months.[4] The most common reasons for discontinuation are lack of efficacy or intolerable side effects.[5]
"This post hoc analysis provides evidence that mirabegron alleviates OAB symptoms not only in patients newly diagnosed with overactive bladder, but in patients who have previously tried antimuscarinic treatments, even those who had inadequate efficacy," commented Dr Vik Khullar, head of the Department of Urogynaecology at St. Mary's Hospital, London, United Kingdom, and lead author of the post hoc analysis. "Antimuscarinics are effective but a significant number of people discontinue treatment either due to lack of efficacy or intolerable side effects, so it is very important that we can provide alternative options for a condition that can have a significant impact on quality of life."
The original European-Australian Phase III study was a 12-week, multicentre, randomised, double-blind, parallel-group, placebo- and active-controlled Phase III trial, conducted at 189 sites in 27 countries throughout Europe and Australia.[2] In the study, mirabegron 50 mg and 100 mg* resulted in statistically significant reductions in the co-primary end points of mean number of incontinence episodes/24 h and mean number of micturitions/24 h compared with placebo.[2]
The post hoc analysis of this study showed that in patients who had discontinued antimuscarinic treatment, mirabegron resulted in improvements relative to placebo in the co-primary endpoint of mean frequency of incontinence episodes per 24 hours.[1] In patients who had received prior antimuscarinic therapy and in treatment-naïve patients, the magnitude of the effect of tolterodine was lower than that observed with either dose of mirabegron.[1] Adjusted mean changes from baseline to final visit (± standard error [SE]) for patients who had received prior antimuscarinic therapy were: -1.00 (± 0.15) for placebo; -1.10 (± 0.15) for tolterodine ER 4 mg; -1.48 (± 0.15) for mirabegron 50 mg; and -1.39 (± 0.15) for mirabegron 100 mg.[1] For antimuscarinic treatment-naïve patients the adjusted mean changes from baseline to final visit were: -1.39 (± 0.17) for placebo; -1.47 (± 0.16) for tolterodine ER 4 mg; -1.69 (± 0.17) for mirabegron 50 mg; and -1.54 (± 0.18) for mirabegron 100 mg.[1]
For the second co-primary endpoint of mean number of micturitions per 24 hours, mirabegron demonstrated numerical improvements relative to placebo in the frequency of micturitions in both treatment-naïve patients and those who had received prior antimuscarinic therapy.[1] Adjusted mean changes from baseline to final visit (± SE) in treatment-naïve patients were: -1.61 (± 0.16) for placebo; -1.90 (± 0.15) for tolterodine ER 4mg; -2.13 (± 0.16) for mirabegron 50 mg; and -1.98 (± 0.16) for mirabegron 100 mg.[1] Adjusted mean changes from baseline to final visit (± SE) in those who had received prior antimuscarinic therapy were: -1.06 (± 0.16) for placebo; -1.26 (± 0.16) for tolterodine ER 4mg; -1.74 (± 0.16) for mirabegron 50 mg; and -1.57 (± 0.16) for mirabegron 100 mg.[1]
In patients who had discontinued prior antimuscarinic therapy specifically due to insufficient efficacy, mirabegron showed numerical improvements in both primary endpoint outcomes whereas treatment with the antimuscarinic, tolterodine ER 4 mg, produced an effect size similar to placebo.[1]
Mirabegron is well tolerated with a low incidence of treatment-emergent events, including dry mouth, [2,6,7] one of the most common and bothersome side effects of antimuscarinics and often the reason for treatment discontinuation.[8] In the overall Phase III Europe-Australia study, the most frequently reported adverse events for mirabegron 50 mg were hypertension, headache, dry mouth and nasopharyngitis, although incidences were similar in the placebo group.[2] Dry mouth occurred with a similar incidence as with placebo (2.6% placebo; mirabegron 50 mg 2.8%) and a three-fold lower incidence than in patients receiving tolterodine ER 4 mg (10.1%).[2]
Astellas Pharma Europe Ltd. is an established leader in urology in Europe, committed to improving the lives of patients with urological conditions. Its current urology portfolio includes treatments for benign prostatic hyperplasia (BPH), overactive bladder and prostate cancer. With a strong emphasis on research and development, Astellas is dedicated to finding new treatments to meet unmet medical needs and has a number of treatments for urological conditions in development. As part of its ongoing commitment to the field, Astellas also provides and supports a wide range of educational opportunities for those working in the field of urology, designed to progress professional expertise and improve patient outcomes.
The paper is open access:
About overactive bladder
Overactive bladder is characterised by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia (awakening at night one or more times to empty the bladder) in the absence of infection or underlying pathology.[9] A survey of over 16,000 adult men and women in six European countries revealed that 17% of respondents had symptoms of overactive bladder and prevalence increased with age: 30% to 40% of those aged over 75 years were affected.[10] Overactive bladder can also have a major impact on quality of life; in the same survey, 65% of respondents indicated their daily lives were adversely affected.[10]
About mirabegron
Mirabegron is a once daily oral β3-adrenoceptor agonist discovered and developed by Astellas. It is the first compound approved in this new class of treatment for overactive bladder, using a novel mechanism of action, different to antimuscarinics, the current treatment standard. Antimuscarinics work by blocking muscarinic receptors in the bladder and inhibiting involuntary bladder contractions. Mirabegron works by stimulating the β3 receptors in the detrusor muscle of the bladder causing relaxation of the bladder muscle during the storage phase of the micturition cycle.[3] This improves the storage capacity of the bladder without impeding bladder voiding.[11]
Mirabegron is available in two doses: 25 mg and 50 mg. The recommended dose is 50 mg once daily with or without food.12 The 25 mg dose is reserved for special populations, such as those with mild / moderate renal and hepatic impairment using a strong CYP3A inhibitor.[12]
Astellas submitted a New Drug Application and Marketing Authorisation Application for mirabegron to the U.S. Food and Drug Administration and the European Medicines Agency in August 2011, received FDA approval on 28th June 2012, and European approval on 20th December 2012.[13] In Japan, Astellas was granted marketing approval under the trade name of BETANIS® tablet in July 2011. Additionally, there is a recently completed multiregional Phase III study in China, Korea, Taiwan, and India.