EAST HYATTSVILLE, Md. -- Prospects for an FDA approval of desmopressin (Nocdurna) as a treatment for adult nocturia remained dim as an advisory committee declined to endorse the indication.
The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10-5 against recommending approval of Nocdurna (desmopressin) to treat "nocturia due to nocturnal polyuria in all adult patients who awaken at least twice per night to void." Two members abstained from the vote.
While generic desmopressin is sometimes prescribed off-label for this condition, there are no FDA-licensed treatments for nocturia in the U.S. It's a highly prevalent problem, and approval could be a bonanza for Nocdurna's sponsor, Ferring Pharmaceuticals.
In Canada and elsewhere, Nocdurna is marketed for nocturia.
a urologist with appointments at Wake Forest University and the University of Virginia,, was one of the abstainers.
"As somebody who has nocturia, if I got up half a time less per night, it would not change my life at all," he said, referring to the co-primary endpoint in a clinical trial that demonstrated an adjusted mean reduction of 0.4 nighttime voids compared with placebo.
His opinion mirrored that of FDA reviewers in two previous cycles who rejected the drug. According to , director of the the agency's Metabolism and Endocrinology Products division, "[we] could not conclude from data submitted that the magnitude of the demonstrated placebo-adjusted effect size would have a meaningful impact on improving the symptoms or the daily function of patients affected by this condition."
of Yale School of Medicine, said he prescribes Nocdurna off-label and voted in favor of approving the drug.
"Just from the data that was presented, I'm convinced that the benefits outweigh the risks. The co-primary endpoints were met. Greater than 90% of the study subjects were [nocturnal polyuria patients] and I think there was safety demonstrated in clinical trials," Chai said.
History of Review
Desmopressin, the active ingredient of Nocdurna, promotes reabsorption of water to reduce urine volume, and is currently approved as a generic drug for diabetes insipidus, hemophilia A, type 1 von Willebrand disease, and nocturnal enuresis in children, noted submitted prior to the meeting.
The pivotal study in the first review cycle showed a statistically significant effect in the 100-mcg dosage group and not in subjects given 10, 25, and 50 mcg.
However, in issuing a Complete Response letter, the FDA asked Ferring to perform another clinical trial and lower the drug's dosage because of concerns of hyponatremia. Ferring then performed two very similar placebo-controlled trials, one for women, and another for men -- with an even lower dosage for female subjects. The co-primary endpoints were change from baseline in the average number of nocturnal voids over 3 months and a one-third reduction of nocturnal voids over 3 months.
The treatment effect size in both trials was described by the FDA as "modest," although statistically significant differences on both co-primary endpoints were found -- a mean reduction of 0.4 voids per night in men and 0.3 in women compared with placebo. FDA staff asked Ferring to provide "additional evidence of clinical benefit, such as improvement in health-related quality of life." The sponsor therefore submitted a report describing sleep improvements in nocturia patients taking Nocdurna.
Sleep quality
On Monday, Ferring, presented sleep quality analysis using the gender-specific pivotal trials that showed subjects taking Nocdurna had a longer "time to first waking." In women the first "void time" doubled from 2.4 hours at baseline to 5 hours with treatment. Men saw an increase from 2.4 hours to 4.3 hours. However, compared with placebo, the difference in both groups was less than an hour.
, of Weill Cornell Medical College and SUNY Downstate College of Medicine, who was paid by Ferring for his time and travel, argued that one of the key ways nocturia affects people is by impacting slow-wave sleep. He stressed that these interruptions, particularly in the first 3 to 4 hours of sleep -- when slow-wave sleep occurs -- could affect insulin sensitivity and glucose tolerance and possibly "be a harbinger of diabetes mellitus."
a professor of epidemiology at the University of Washington in Seattle, who voted against approval, noted that these clinical benefits remained speculative in the absence of direct evidence, which Ferring's studies did not provide.
"As it is right now, we have to make several leaps of faith to go from fewer nocturnal voids to better sleep, to happier, better-rested, better-functioning patients. And we have to go further to fewer falls and less mortality," she said.
Placebo effect
Another central point of discussion was the strong placebo effect, which several committee members hypothesized was in fact the result of lifestyle changes and behavior modifications.
Several committee members suggested studies with a "lifestyle lead-in" to control for the placebo effect. Others advocated looking at an "enriched population" with a higher baseline symptom burden and potentially greater decrements in voiding.
A Ferring statement issued after the vote indicated disappointment but added that "we remain hopeful that the FDA will recognize the value of providing a new treatment option to adults with nocturia due to nocturnal polyuria."
The FDA isn't required to follow the advice of its advisory committees, but it often does..