Astellas Pharma Europe, subsidiary of Tokyo-based Astellas Pharma, has reported results from three separate clinical trials that further support the efficacy and tolerability of mirabegron for overactive bladder (OAB).
Results from the three studies demonstrate: efficacy and tolerability of mirabegron in patients who have previously discontinued antimuscarinics—the current standard of care for OAB; safety and efficacy of mirabegron in OAB patients over a one-year period; and ocular safety of mirabegron with chronic use.
In a sub-group, post-hoc analysis of the phase III European-Australian trial, patients were randomized to mirabegron 50mg or 100mg, tolterodine ER 4mg (a licenced antimuscarinic therapy) or placebo. Mirabegron was found to be effective in reducing the mean number of incontinence episodes/24 hours and micturitions/24 hours in antimuscarinic-naive patients, as well as those who had discontinued prior antimuscarinic therapy, regardless of the reason for discontinuation. However, in patients who had discontinued prior antimuscarinic therapy due to lack of efficacy, only mirabegron demonstrated improvement in OAB symptoms—efficacy of tolterodine ER 4mg was similar to placebo.
The results of a large physician/patient survey support the findings that mirabegron could be an important development for patients who have failed on previous antimuscarinic therapy due to lack of treatment response. In this survey of 519 physicians (regarding 5,316 patients), pooled data across France, Germany, Spain and the U.K. found that the most common reason for switching antimuscarinics was lack of efficacy alone, accounting for 36% of 1,067 patients who switched therapy.
"We have waited 30 years for a completely new mechanism of drug action to treat OAB," said Dr. Vik Khullar, head of the department of urogynaecology at St Mary's Hospital in London and principal investigator of the European-Australian phase III trial. "These results demonstrate that mirabegron can benefit many patients, but in particular, will offer hope to those patients who have discontinued antimuscarinic therapy due to lack of efficacy, who currently have no other treatment options."
As a first-in-class drug, long-term safety and tolerability is important to establish. In a 12-month phase III safety and tolerability study, 2,444 patients were randomized to receive mirabegron 50mg, mirabegron 100mg or tolterodine ER 4mg. The study found both mirabegron and tolterodine improved key symptoms of OAB, with improvements in efficacy from the first measured time point (month one) and maintained throughout the one-year treatment period. Overall reported adverse events were similar across all groups; mirabegron 50mg (59.7%), mirabegron 100mg (61.3%) and tolterodine ER 4mg (62.6%). However, the incidence of dry mouth, the most common and bothersome side effect associated with antimuscarinics, was considerably higher with tolterodine ER 4mg than with mirabegron 50mg or mirabegron 100mg (8.6%, 2.8% and 2.3% respectively).
“Dry mouth is a very common and troublesome side effect for patients on treatment with antimuscarinics, which often leads to problems with eating, speaking and general quality of life," said Professor Christopher Chapple, consultant urological surgeon at Sheffield Teaching Hospitals and lead investigator of the study. "This study confirms that mirabegron, which represents a new class of oral agents, offers similar potential efficacy to an antimuscarinic, but without the same burden of dry mouth seen with antimuscarinics.”
Results of a phase Ib study of 305 healthy volunteers demonstrated mirabegron 100mg was non-inferior to placebo with regard to effect on intraocular pressure (IOP). This was based on a non-inferiority margin of 1.5mmHg. The adjusted mean change in IOP from baseline to day 56 was -0.3 mmHg for patients taking mirabegron and -0.2 mmHg for patients taking placebo (95% CI -0.4 to 0.3). Clinically, these results demonstrate mirabegron does not increase IOP after chronic administration in healthy volunteers over eight weeks and supports the ocular safety and tolerability of mirabegron.