New Class of Drug Improves Symptoms of Overactive Bladder

Becky McCall

March 22, 2011

March 22, 2011 (Vienna, Austria) — Mirabegron (Astellas), the first in a new class of beta-3 adrenoceptor agonists to treat patients with overactive bladder syndrome (OAB), significantly reduces the incidence of urinary incontinence and micturition, according to results from 2 phase 3 studies presented here at the European Association of Urology 26th Annual Congress.

At once-daily doses of 50 and 100 mg, mirabegron was superior to placebo in the treatment of OAB, was well tolerated in the study populations, and demonstrated the promising therapeutic potential of this new class of drugs in the treatment of this syndrome.

The principal investigators of each of the studies — Victor Nitti, MD, from Langone Medical Center of New York University, New York City, for the North American study, and Vikram Khullar, MD, head of the Department of Urogynaecology at St. Mary's Hospital, London, United Kingdom, for the Europe/Australia study — presented the results.

"I feel very privileged to present these results for something for which we have waited almost 30 years, which is a drug for OAB with a new mechanism of action," said Dr. Khullar.

The 2 studies were multicenter, randomized, double-blind, parallel group, placebo-controlled trials. One study was carried out in 132 sites in the United States and Canada, and the other in 27 countries across Europe and in Australia. Patients had all experienced OAB for more than 3 months and had to have met an average frequency of micturition of more than 8 times in a 24-hour period plus 3 episodes of urgency during 3 days, with or without incontinence. Patients with stress-related incontinence were excluded, as were patients with an average daily urine volume greater than 3000 mL.

In the North American study, 1329 patients were randomly assigned to receive placebo or mirabegron 50 or 100 mg once daily; in the European/Australian study, the same randomization was used in 1987 patients, with the addition of a group that received once-daily slow-release oral tolterodine 4 mg. All compounds were given for 12 weeks. Patients kept a diary of micturition for 3 days before baseline assessment, at weeks 4, 8, and 12, and 30 days after trial end.

Both studies had 2 coprimary end points: the change from baseline to final visit (12 weeks) in the mean number of incontinence episodes per 24 hours, and the mean number of micturitions per 24 hours compared with placebo (< .05). Key secondary end points included change from baseline to final visit in mean volume of urine voided per 24 hours, change from baseline to week 4 in mean number of incontinence episodes per 24 hours, and change from baseline to week 4 in mean number of micturitions per 24 hours (< .05, compared with placebo).

Both coprimary end points showed statistically significant improvements, compared with placebo, between baseline and week 12 in both mirabegron groups. This was also true for mean volume voided during the same time.

In the North American study, the number of incontinence episodes per 24 hours dropped by 1.13, 1.47, and 1.63 in the placebo, 50 mg, and 100 mg groups, respectively. The number of micturitions per 24 hours dropped by 1.05, 1.66, and 1.75, respectively.

In the European/Australian study, incontinence episodes per 24 hours dropped by 1.17, 1.57, 1.46, and 1.27 in the placebo, 50 mg, 100 mg, and tolterodine groups, respectively, whereas the number of micturition events per 24 hours dropped by 1.34, 1.93, 1.77, and 1.59, respectively.

Referring to the use of coprimary end points, Dr. Nitti said that "Astellas chose to look at 2 of the most common symptoms of OAB, but when a trial has covariables, then there has to be a dip in both for the study to be successful, compared with placebo. With mirabegron, it succeeded on both counts — for incontinence episodes and for micturition — with both 50 and 100 mg."

With respect to secondary end points, statistically significant benefits in the number of incontinence episodes and micturitions were achieved for the shorter time point of 4 weeks. "Mirabegron worked well, and it worked early," Dr. Nitti continued.

Commenting on the secondary endpoints in the European/Australian study, Dr. Khullar added that patients receiving placebo found that the volume voided increased by 12 mL, whereas in the active groups, the volume doubled.

Of particular interest with mirabegron, as a first-in-class drug, are drug-related adverse events. "There were no significant cardiovascular events in the mirabegron group. Overall incidence of hypertension was similar across groups, and there was no effect on the [electrocardiogram] cycle QT interval. That's important because certain drugs can affect this and lead to cardiac risks," said Dr. Nitti about the North American study findings.

Treatment-emergent adverse effects were very similar to placebo in the mirabegron 50 and 100 mg groups, at 50.1%, 51.6%, and 46.9%, respectively, in the North American study, with hypertension being the most common adverse event. In the European/Australian study, treatment-emergent adverse events were 43.3%, 42.8%, 40.1%, and 46.7% for placebo, mirabegron 50 mg, mirabegron 100 mg, and tolterodine, respectively.

In the European/Australian study, "there wasn't an increase in the number of [adverse events] reported. In patients who discontinued because of an adverse event, the numbers were very small. Cardiac events were similar to the North American study, with 1 event in the tolterodine group. Hypertension was higher in the placebo and the tolterodine arms than in the mirabegron groups, which was very reassuring. For dry mouth, it is similar for placebo and both mirabegron groups at around 3%, but in tolterodine it is 10%," explained Dr. Khullar.

"The worry has always been that with the anticholinergic drugs, patients can go into urinary retention. Therefore, men have not received this medication because they might then need to be admitted and have catheterization. Because mirabegron stops the number of times urine is passed, rather than the bladder's ability to empty itself, it means that a similar problem doesn't happen. Now we suddenly have a drug without the concerns of the previous [anticholinergics], which is why this is a major step change," concluded Dr. Khullar.

Commenting on the studies, James Catto, MD, a urologist from the University of Sheffield, United Kingdom, said: "This is an exciting drug that brings a new class of medicines to a common clinical problem. The data from these phase 3 trials are promising, and we look forward to evaluating the role of this agent in our clinics. However, its initial use will be restricted to patients who fail or can't tolerate first-line treatment. These are a large minority, so we expect it could be used a lot. But, we will have to see its tolerability and effectiveness in our own patients."

The company responsible for the investigational compound, Astellas, Japan, intends to file for US Food and Drug Administration and European Medicines Agency approval this summer.

Dr. Khullar reports being a consultant to Astellas, Pfizer, and Allergan, but has not received any payment from Astellas to present these results. Dr. Nitti reports being a consultant to urology companies including Astellas, Allergan, Pfizer, Medtronic, and Uroplasty. Dr. Catto has disclosed no relevant financial relationships.

European Association of Urology (EAU) 26th Annual Congress: Posters 885 and 886. Presented March 21, 2011.

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