New Drug for Overactive Bladder Recommended for FDA Approval
April 5, 2012 — The US Food and Drug Administration’s (FDA’s) Advisory Committee for Reproductive Health Drugs has voted 7 to 4 in favor of approving mirabegron (Astellas Pharma), a new class of oral drug for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. There was 1 abstention.
"Overall, the committee has a sense that there is marginal efficacy, but…the majority feel that the benefits outweigh the risks," concluded committee chair Julia Johnson, MD, professor and chair of obstetrics and gynecology at the University of Massachusetts Medical School in Worcester. "This is seen as a new agent which potentially can be used for individuals who have not had success with other available agents."
If approved, mirabegron, a selective human beta 3-adrenoceptor agonist, "would represent a novel third mechanism of action in the treatment of OAB," said FDA spokesperson Mark Hirsch, MD, medical team leader, Division of Reproductive and Urologic Products, Center for Drug Evaluation and Research.
The current mainstays of medical treatment for OAB are anticholinergic medications, the majority of which are antimuscarinic. In addition, in August 2011, a supplemental new drug application for Botox (Allergan) was approved as an intravesical treatment of neurogenic OAB, Dr. Hirsch said.
Although current treatments reduce urine voiding by inhibiting the contraction of the detrusor muscles, mirabegron facilitates urine storage by activating beta 3-adrenoceptors in the bladder, thereby flattening and lengthening the bladder base, according to the company.
In making their voting decisions, members of the FDA advisory committee focused on both the efficacy and safety of mirabegron, based on evidence from 41 studies conducted over the course of approximately 10 years and including 10,552 participants.
The primary and secondary efficacy objectives were achieved in the 3 phase 3 studies, each of 12 weeks’ duration, as well as a single 1-year active-controlled study and several phase 1 studies, noted Dr. Hirsch.
On average, mirabegron 50 mg reduced urinary frequency from baseline by 0.55 micturitions per 24 hours and reduced incontinence episodes from baseline by 0.40 per 24 hours compared with placebo. In addition, there was an increase of 11.9 mL from baseline in mean volume voided per micturition.
"In other words, mirabegron patients experienced on average 4 [fewer] micturitions per week, and in incontinence patients, 3 [fewer] incontinence episodes per week, compared to placebo," Dr. Hirsch said.
The committee voted 8 to 4 that the data provided "substantial evidence" for the benefit of the drug, although many committee members struggled over the word "substantial."
"The term ‘substantial’ was important in our decisions…. Indeed, this was a statistically significant finding, but whether or not it was clinically significant is not yet clear," said Dr. Johnson. "However, the sponsors did meet the requirements of the FDA, and because this is a unique medication, it may offer us other opportunities for treatment of this significant disorder, and therefore the group as a majority feels that it is worthy of potential approval."
However, there were several safety issues including cardiovascular (CV) risks, cancer, and hepatotoxicity, which the FDA asked the advisory committee to consider before voting.
Specifically, patients treated with mirabegron had increases in blood pressure of approximately 3 mm Hg compared with placebo in phase 1 studies, and approximately 0.5 to 0.75 mm Hg in phase 3 studies.
In addition, phase 1 studies associated the drug with a heart rate increase of approximately 3 to 4 beats per minute compared with placebo, whereas phase 3 studies showed an increase of approximately 1 beat per minute.
A model proposed by the FDA predicting the clinical implications of these CV effects suggested that, based on phase 3 data, this could translate to an additional 187 CV events per million patients per year over baseline risk, and in high-risk patients an additional 556 events per million patients per year. Similarly, using phase 1 data, this additional number of events could be 839 and 1336, respectively, said the FDA’s Rajanikanth Madabushi, PhD. However, this calculation was criticized by company spokespeople, and its value was debated.
Additional safety issues were raised over evidence of an increased risk for neoplasms, a "modest" increase in mild urinary tract infections coupled with postmarketing reports of increased urinary retention from Japan (where mirabegron was approved in July 2011), and rare hepatotoxicity and hypersensitivity issues.
However, the committee voted 9 to 3 that adequate safety had been demonstrated for mirabegron.
"The impression overall of the majority of the committee was that the side effects have been examined well, that the company did look at the CV issue and neoplasm issue as requested. However…evaluation regarding CV health and risk of neoplasm and other issues need to be ongoing," said Dr. Johnson.
The company’s recommendation is for an oral dose of 50 mg once daily with or without food, or 25 mg once daily in populations with severe renal impairment or moderate hepatic impairment.
However, several committee members suggested the lower dose should be considered for all patients, in light of what some called "marginal" evidence of benefits, coupled with safety concerns.
"It is imperative for us to find the minimally effective dose. I believe, to be quite honest, that we’re voting on a dose of convenience," said committee member Daniel Gillen, MD, from the University of California, Irvine, who voted against the approval.
"I think the need is great," said Richard Bockman, MD, PhD, from the Hospital for Special Surgery in New York City, who voted for the drug’s approval. "This is a new agent in a new class…. Agents in principal that already exist are widely used, safe, and perceived to have efficacy by great numbers of patients. This agent, I think, can achieve the same status, perhaps better. I agree that there needs to be continued monitoring."
There was 1 public presentation against and none in support of the drug’s approval.
"We don’t believe that a drug which reduces the frequency of urination and incontinence episodes by less than once per day compared to placebo addresses the problems in a way that will be meaningful in women’s lives," said Kate Ryan, from the National Women’s Health Network. "The health improvement offered by this drug is not worth the potential problems it may cause," she added, noting that the drug will likely be prescribed to patients with less severe symptoms than those of patients in clinical trials. "Women want a real solution. Unfortunately, this drug doesn’t meet that standard."
In addition to its application to the FDA, the company has also submitted applications for marketing mirabegron to the European Medicines Agency (August 2011), as well as in Brazil (December 2011), Canada (February 2012), and Switzerland (March 2012).