Investigational OAB agent demonstrates efficacy, tolerability

Results from three separate clinical trials further support the efficacy and tolerability of the investigational beta3-adrenoceptor agonist mirabegron for the treatment of OAB, researchers reported at the 2012 European Association of Urology annual congress in Paris.

Mirabegron is the first in a new class of OAB treatments to be submitted for regulatory approval.

In a sub-group, post-hoc analysis of a phase III European-Australian trial, patients were randomized to mirabegron, 50 mg or 100 mg; tolterodine ER (Detrol LA), 4 mg; 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, 4 mg was similar to placebo.

"We have waited 30 years for a completely new mechanism of drug action to treat OAB," said Vik Khullar, MD, of St. Mary’s Hospital, 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."

In a separate 12-month phase III safety and tolerability study 2,444, patients were randomized to receive mirabegron, 50 mg; mirabegron, 100 mg; or tolterodine ER, 4 mg. The study found that both mirabegron and tolterodine improved key symptoms of OAB, with improvements in efficacy from the first measured time point (month 1) and maintained throughout the 1-year treatment period. Overall reported adverse events were similar across all groups: mirabegron, 50 mg (59.7%); mirabegron, 100 mg (61.3%); and tolterodine ER, 4 mg (62.6%).

However, the incidence of dry mouth was considerably higher with tolterodine ER, 4 mg, than with mirabegron, 50 mg, or mirabegron, 100 mg (8.6%, 2.8%, and 2.3%, respectively).

"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," said lead investigator Christopher Chapple, MD, of Sheffield Teaching Hospitals, Sheffield, UK. "This provides an alternative potential option for patients who are unable to achieve the right balance of efficacy and tolerability with currently available antimuscarinic therapy for overactive bladder."

Results of a phase Ib study showed that mirabegron does not increase intraocular pressure (IOP) after chronic administration in healthy volunteers over 8 weeks. Antimuscarinics are not recommended for OAB patients with uncontrolled narrow-angle glaucoma because of their potential for mydriasis (prolonged pupil dilation). Mirabegron, 100 mg, was non-inferior to placebo with regard to effect on IOP. 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).

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