FDA Panel Backs Nasal Spray for Nocturnal Polyuria

WASHINGTON -- A nasal-spray formulation of desmopressin for nocturia received consistent, if sometimes tepid support from an FDA advisory committee.

At the conclusion of a day-long hearing, the Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) agreed in a 14-4 vote that results of the pivotal clinical trial showed that the benefits of the treatment outweighed potential risks. However, even the panelists who voted in the affirmative expressed reservations about a number of issues ranging from clinical trial design to episodes of hyponatremia linked to the drug to uncertainty about the most appropriate indication.

"I reluctantly voted yes," said Kevin McBryde, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases. "I think the incidence of hyponatremia was low ... I think the difference of about 120 mL of urine output between the placebo and the 1.5 microgram (desmopressin) group is enough that over the course of the night it saves them some nocturnal awakenings."

Over the years, various formulations of desmopressin have been evaluated as treatment for several types of bladder control problems, including pediatric enuresis (bedwetting). However, previous trials and formulations failed to pass muster with regulatory authorities.

The nasal-spray formulation delivers a lower dose that drug sponsor Serenity Pharmaceuticals hoped would improve the safety and efficacy of the drug, as compared with previous formulations. Support for the application for approval came from two randomized, placebo-controlled trials of intranasal desmopressin.

In one trial, patients were randomized to 0.75, 1.0, or 1.5 mcg of desmopressin or placebo. In the second trial, patients were randomized to 0.75 or 1.5 mcg of desmopressin or to placebo. Both trials had the same co-primary endpoints: change in the number of nocturia episodes and the percentage of patients who had at least a 50% reduction in the average number of nocturia episodes.

Both trials showed small but significant reductions in the mean number of nighttime trips to the toilet. Significant improvement was observed with the 1.5 mcg dose in both trials but with the 0.75 mg dose only in the second trial. Only the highest dose of desmopressin evaluated met both primary endpoints in both trials, the FDA staff noted in a report to BRUDAC.

The FDA staff also pointed out that the two trials had extensive exclusion criteria, resulting in a highly selected patient population. Neither trial had restrictions on fluid intake. Both factors raised questions about the generalizability of the results to the broader population of patients with nocturia, given that the application sought approval for use by adults of any age.

The staff report also pointed out that the trial evaluated the impact of desmopressin on "nocturia," which is a symptom, not a clinical diagnosis. That point provoked considerable discussion by the BRUDAC panel, which subsequently settled on the diagnosis of "nocturnal polyuria" as the appropriate indication prior to voting.

The FDA staff report concluded that "[intranasal desmopressin] 1.5 mcg demonstrated statistically significant reductions in nocturia with respect to both co-primary endpoints in both phase III trials and for the key secondary [the patient-reported outcome of Impact of Nighttime Urination] in the single phase III trial in which it was assessed. The clinical relevance of numerically small placebo-corrected changes is not clear."

"[Intranasal desmopressin] 0.75 mcg has not met the prespecified statistical criteria for efficacy in the treatment of nocturia."

The discussion that followed the review of data was wide ranging. The panel rejected the idea of approving the lower dose of desmopressin for the intent of titration to the higher dose. Several panelists pointed out that the Serenity report and presentation mentioned a reduction in falls secondary to nighttime trips to the toilet as a potential benefit. However, that was not a prespecified endpoint of the trial, and data indicated that falls were infrequent in both trials.

The safety discussion encompassed five deaths that occurred during the intranasal desmopressin clinical trial program. All the deaths involved older patients and appeared unrelated to the treatment, but the possibility of an association could not be ruled out with certainty. Serious adverse events in desmopressin-treated patients occurred at rates similar to those seen in the placebo-treated patients.

Much of the safety discussion focused on a few episodes of hyponatremia in the desmopressin arms. Some BRUDAC members wondered whether the effect might be more widespread and potentially more severe if the drug were used in a broad, unselected patient population.

Despite reservations, the BRUDAC members eventually agreed 17-1 that the data showed that 1.5 mcg dose of desmopressin had demonstrated efficacy, but not the 0.75 dose. They then agreed by a 14-4 margin that the drug's potential benefits outweighed potential risks.

The reservations -- and some confusion -- persisted during discussion after the vote.

Douglas C. Bauer, MD, of the University of California San Francisco, voted no but then acknowledged, "I thought I was voting on the broad indication of nocturia [as opposed to nocturnal polyuria], so I agree with what many of the 'yes' people have said."

Bauer added, "I think there are rare, serious side effects that will be magnified greatly if this is used in nonspecialist hands and applied to a very large number of patients, particularly those who are elderly and at highest risk."

Committee chair Vivian Lewis, MD, of the University of Rochester, voted yes but emphasized that the drug's indication should be limited to the diagnosis of nocturnal polyuria, rather than nocturia, which is a symptom. However, other members of the panel pointed out that clinical trial support for application evaluated the drug for treatment of nocturia.

The FDA is not bound by votes and recommendations of its advisory committees, but follows the recommendations in most instances.

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