A β3 Agonist, Mirabegron for the Treatment of Overactive Bladder - Supplement

As part of an added supplement, we at UroToday International Journal present the following added information regarding the article "Androgen Insensitivity Syndrome: Case Report With Review of the Literature." Reponses are provided by corresponding author Dr. Fotios Dimitriadis.

Q. What does your contribution add to the present knowledge? What's essential to understand about in terms of clinical practice?

A. Overactive bladder syndrome (OAB) has a negative impact on quality of life and social functioning. OAB affects 16.6% of the European population aged over 40 years, and it has a prevalence of 17% in the United States and 12% in Japan. Both men and women are equally affected by OAB, and the incidence rate increases with age. OAB syndrome has been caused by detrusor overactivity (DO), which is a urodynamic diagnosis based on the occurrence of involuntary detrusor contraction during cystometry. Currently, antimuscarinic drugs represent the first-line treatment for OAB. However, adverse effects such as dry mouth, pruritus, blurred vision, and constipation, among many others. The limitations of efficacy hinder their use.

Two muscarinic subtypes, M2 and M3, are present in the bladder. Although M2 is most abundant in detrusor cells (70 to 80 %), the M3 subtype is the major receptor mediating stimulation of detrusor contractions. In fact, beta-adrenoceptors in the bladder body of experimental animals and humans mediate relaxation to noradrenalin via β3-adrenoceptors, whereas in the same time noradrenaline stimulates contraction of the urethral and bladder neck smooth muscle via α1-adrenoceptors. Mirabegron, a novel selective b3-adorenoceptor agonist, is in development for the treatment of OAB. The current contribution underlines the potential pharmaceutical benefit of mirabegron in the treatment of OAB.

Q. Will this replace existing techniques or therapies now or in the near future? Will it impact the standard of care?

A. Phase II placebo-controlled clinical trials showed that mirabegron significantly improved the majority of variables when administered to patients with OAB. Mirabegron has been well tolerated with significant efficacy in reducing the number of incontinence episodes and mean micturition frequency. Commonly reported adverse effects were gastrointestinal adverse events and headache. This could impact the standard of care since the lower propensity of mirabegron to cause dry mouth and constipation may make it an attractive drug candidate for the treatment of OAB symptoms. Thus, the pharmaceutical armament of the treatment of OAB could be enhanced with a novel category of drugs, namely the b3-adorenoceptor agonists that could corroborate to the present standard pharmaceutical treatment of OAB or replace it when its efficacy is not the expected one.

Q. What are the three things that this technology does or enables that I should know to impact clinical practice? What's your take-home message for me as your colleague?

A. Mirabegron decreases the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats, and it decreases the frequency of non-micturition bladder contraction without the increase in residual urine in a rat bladder outlet obstruction model. This data indicate that mirabegron has good selectivity and agonist potency for β3-adrenoceptors and has different effects on bladder activity during filling from antimuscarinics.

Mirabegron enhances urine storage function at low-pressure bladder filling, without affecting the voiding contraction in the anesthetized rat bladder, suggesting that mirabegron significantly increases bladder capacity and does not directly inhibit voiding bladder contractions.

In phase II clinical trials (BLOSSOM and DRAGON studies), treatment with mirabegron was statistically and significantly superior to placebos with respect to the secondary efficacy variables mean volume per micturition, mean number of micturitions, mean number of incontinence episodes, nocturia episodes, urge incontinence episodes, and mean urgency episodes per 24 hours. Thus, these studies demonstrated that mirabegron significantly improved the majority of variables compared with placebos when administered to patients with OAB. Regarding the safety of mirabegron treatment, it causes less adverse events (mainly headache, urinary tract infection, blurred vision, and vascular disorders) compared to antimuscarinic drugs.

Mirabegron will be the first β3-adrenoceptor agonist to be released in patients with OAB. It has been demonstrated to be well tolerated and to have dose-dependent reduction of micturition frequency, episodes of urgency, and nocturia in OAB patients. The lower tendency of mirabegron to cause dry mouth and constipation may make it an appealing drug candidate for the treatment of OAB symptoms in elderly patients. The long-term safety data, including the risk of drug-related cardiac and vascular events caused by mirabegron in wider studies, is still awaited.