Patients with an overactive bladder, or urge incontinence, experience sudden needs to urinate as a result of spasms or contractions of the bladder. The bladder normally stretches to hold more urine as it is produced, and while it can usually hold up to about half a litre, people normally start to feel a need to urinate once it contains about 200ml, thanks to nerve signals sent to the brain. With urge incontinence, these signals can be sent regardless of how much urine is in the bladder. Current drug treatments rely on antimuscarinic drugs such as tolterodine and darifenacin, but these do not always work, and commonly cause dry mouth symptoms that can lead to problems with talking and eating.
Astellas’ new drug, mirabegron, works differently – as a selective β-3-adrenoceptor agonist. Unlike the antimuscarinics, which bind to receptors in the bladder to inhibit involuntary contractions, mirabegron stimulates the β-3-receptors in the bladder’s detrusor muscle, which causes the muscle to relax during the urine storage phase. This improves storage ability, without having an impact on the patient’s ability to empty their bladder.
In a 12-month Phase III safety and tolerability study, 2,444 patients were given once-daily doses of 50 or 100mg mirabegron, or 4mg tolterodine ER.1 Both drugs improved symptoms, with effects maintained right through to the 12-month point, and most reported adverse events were similar for the two treatments, however nearly four times as many subjects given tolterodine reported dry mouth.
Antimuscarinic drugs are not recommended for patients with uncontrolled narrow angle glaucoma, because they have the potential to increase intraocular pressure. To test the safety of mirabegron in this patient subgroup, a Phase Ib study was carried out in 321 healthy volunteers with normal intraocular pressure.2
Subjects were given 100mg mirabegron or placebo daily for eight weeks. Of the 305 subjects who completed the study, the mean change in intraocular pressure from baseline through to day 56 was –0.3mmHg for the treated group, and –0.2mmHg for those given placebo, and none discontinued as a result of increased intraocular pressure.
The drug has recently been approved by the US FDA for the treatment of overactive bladder, with the trade name Myrbetriq, the first β-3 agonist to have this indication.
1. C.R. Chapple et al. 27th Annual Congress European Association of Urology (Paris, February 2012), Abst. AM12-1967:683
2. N. Martin et al. 27th Annu Congress European Association of Urology (Paris, February 2012), Abst. AM12-1967:686