Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Ekene A. Enemchukwu, MD, MPH, discusses the development of β3 agonists for the treatment of overactive bladder (OAB). Enemchukwu is an assistant professor of urology and, by courtesy, of obstetrics and gynecology and medical director of the Stanford Pelvic Health Center, Stanford University, Palo Alto, California
The discovery of the β3 receptor subtype occurred in the late 1980s. At that time, researchers discovered that β3 agonists had activity in adipose tissue, so the initial indication for this class of medications was actually going to be obesity and diabetes. It wasn't until the late 1990s, when evidence of β3 receptor subtype activity was linked to smooth muscle relaxation in the bladder, that the β3 agonist as a treatment for overactive bladder was conceived. In the late 1980s, the only medication available for the treatment of OAB was oxybutynin. That was approved by the FDA back in 1975. It wasn't until 1998 that the FDA approved our second antimuscarinic, tolterodine. So for over 20 years, the only medication we had available to treat overactive bladder was oxybutynin. So to hear of a new drug target for OAB was really exciting. It was in 2001 that this first compound—what we now know today as mirabegron [Myrbetriq]—was studied and showed some preclinical efficacy in several models of OAB and a favorable human safety profile. Then, in 2011, there were phase 3 clinical trials, and in 2012, mirabegron received its FDA approval in the US and also in Europe. Last year, we actually had the approval of the second drug in this class: vibegron [Gemtesa], which is also a selective β3 agonist.
β3 agonists really provided a new drug class of medications for patients with overactive bladder. Previously, there were no alternatives. β3 agonists relax the bladder smooth muscle via a novel mechanism, and that's by stimulating the β3 receptors. This novel mechanism has really revolutionized our ability to treat OAB with oral therapies because it avoids the bothersome side effects associated with antimuscarinic medications. These include dry mouth, constipation, dry eyes, blurry vision, and cognitive dysfunction. These are things that our patients complain about, and they really affect their quality of life. If the medication is negatively affecting their quality of life, they're not going to want to continue the medication. It's well established that β3 agonists are better tolerated than antimuscarinic medications. If medication is better tolerated, patients are probably more likely to take it and to continue. Secondly, I would say that β3 agonists also made combination oral pharmacotherapy possible for OAB; they really provided a second target in the bladder. So now we have the ability to take advantage of the synergistic effect of these 2 drug classes in the carefully selected patient.
β3 agonists have just provided a much-needed alternative. There are a fair number of patients that do not tolerate or have contraindications to antimuscarinic medications. In the past, we just didn't have much to offer those people in terms of oral therapy. I think the other point is that there's a growing body of evidence demonstrating an association between long-term antimuscarinic use and the development of cognitive impairment and dementia. This is really a concern and one that has led to clinical consensus statements from the American Urogynecologic Society, the American Urological Association, and the European Association of Urology as well. They've all issued recommendations to address this very real concern. And our patients are concerned too. β3 agonists really give us an alternative while we clarify this situation and collect more data. Finally, there are data to suggest that OAB therapy adherence is associated with improvements in urinary symptoms, quality of life, and decreased OAB-related health care costs. But we also all know that there are many factors that affect therapy adherence to oral medications, and these include cost, efficacy, and tolerability. We all agree that antimuscarinics and β3 agonists are efficacious. We have meta analyses that have shown that; however, antimuscarinic medications struggle a little bit more in the tolerability arena, whereas β3 agonists generally struggle a little bit more in the affordability arena. So we hope that as time goes on and more β3 agonists reach the market, that the affordability piece will be less of a barrier to patients.