FDA Panel: Approve Mirabegron for Overactive Bladder

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.