FDA Advisers Reject Desmopressin for Nocturia

Alicia Ault

January 13, 2015

A US Food and Drug Administration (FDA) advisory committee has voted against approval of desmopressin to reduce urine voiding in adults who awaken two or more times a night to urinate.

The agency's Endocrine and Metabolic Drugs Advisory Committee voted 10 to 5, with two abstentions, that the drug's benefit did not outweigh its risks. The committee's three urologists, however, along with the consumer representative and the panel's lone nephrologist, voted in favor of approval.

"It's a small clinical benefit," said Christian Pavlovich, MD, associate professor, urology, Johns Hopkins University School of Medicine, Baltimore, Maryland. In addition, he added, the drug's risk for hyponatremia was not a huge concern. "It's a small clinical risk," said Dr Pavlovich.

Unanswered Questions

Committee members who voted against approval said there were too many unanswered questions about both efficacy and safety, and that the numbers of patients studied were very small, given the potential for wide use of the drug.

Desmopressin, a synthetic analog of the neurohypophyseal nonapeptide hormone arginine vasopressin, was first approved in the United States in 1978 for central diabetes insipidus. It has received a variety of approvals during the ensuing decades, including for primary nocturnal enuresis in children. Parsippany, New Jersey–based Ferring Pharmaceuticals is seeking approval of a new formulation, an orally disintegrating tablet it is calling Nocdurna, for nocturia resulting from nocturnal polyuria.

That "melt" formulation has been approved by 80 countries, including most recently by Canada.

The FDA has twice previously rejected Nocdurna, however. Ferring initially sought approval to treat all adults with nocturia, regardless of the cause. The agency denied that application in part because of what it labeled weak efficacy and because of concerns about desmopressin's potential for causing hyponatremia. After the first rejection, Ferring conducted two new phase 3 studies, one in women and one in men, both lasting 3 months. But the FDA had many of the same concerns and rejected it again.

After more negotiations, the agency allowed Ferring to come back with new analyses of the phase 3 studies (CS-40 and CS-41) and to present them to the advisory committee.

In CS-40, 233 women who were randomly assigned to a 25-μg dose or placebo completed the trial. In CS-41, 327 men who completed the study received 50 μg, 75 μg, or placebo. To be eligible, patients had to have nocturia caused by nocturnal polyuria, which was defined as two or more voids a night, and nighttime urine production in excess of 33% of the 24-hour volume.

Patients with treatable causes of nocturia, such as uncontrolled diabetes mellitus, renal insufficiency, sleep apnea, and possible cardiac failure, were excluded. Those at higher risk for hyponatremia were also excluded. However, the FDA and panel members noted that the exclusions were not particularly rigorous, which meant there was a heterogeneous study population with various reasons for nighttime voiding.

At baseline, both women and men studied had an average of 2.9 voids per night, and the mean time to the first void was about 2.5 hours after going to sleep. The FDA's review of the data found that with the drug, the women had 0.24 fewer voids per night, and the men had 0.40 fewer voids per night. Overall, there was a mean reduction of about 1.7 voids per week in women and 2.8 voids per week in men.

Meaningful Results?

Ferring argued that the reduction in voids was meaningful both clinically and in terms of quality of life, but panelists were not convinced, saying the company had not provided direct evidence of a clinical benefit.

The endpoints were "not a measure of true clinical outcomes, such as objective measures of disturbed sleep, or real outcomes like fall or fracture," said Robert J. Smith, MD, committee chairman and professor of medicine at Brown University's Alpert Medical School in Providence, Rhode Island.

"As it is right now, we have to make several leaps of faith to go from fewer nocturnal voids to better sleep, to better-rested, better-functioning patients," said panelist Susan Heckbert, MD, PhD, professor of epidemiology at the University of Washington in Seattle. "We have to go even further to fewer falls and less mortality."

The FDA usually follows its panels' advice. The agency is expected to make a decision on Nocdurna's approval by the end of March.

In a statement after the meeting, Paul Korner, MD, MBA, Ferring's senior vice president, US development, said the company was disappointed in the panel's vote but that it remained "hopeful that the FDA will recognize the value of providing a new treatment option to adults with nocturia due to nocturnal polyuria."

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