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An investigational carbetocin nasal spray for treating extreme hunger and other symptoms of Prader-Willi syndrome (PWS), a rare genetic disorder, received a near-unanimous thumbs-down from FDA advisors on Thursday.

In a 12-1 vote, the agency's Psychopharmacologic Drugs Advisory Committee agreed that the evidence from developer Levo Therapeutics's phase III trial was insufficient. Designed to demonstrate that the nasal spray could reduce hyperphagia (extreme, often debilitating hunger), anxiety, and distress behaviors in PWS patients, the trial was instead marred by inconsistent evidence of therapeutic benefit.

For some committee members, like Walter Dunn, MD, PhD, of UCLA Health in Los Angeles, the decision to vote "no" came down to how FDA framed the question at hand -- in short, whether there was "substantial evidence" of efficacy with the product.

"If the question posed were, 'is there modest evidence of effectiveness?' then I would have to reconsider my vote," Dunn said.

James Troendle, PhD, of the National Heart, Lung, and Blood Institute, also emphasized the importance of the question's wording before explaining his "no" vote. He called it an "interesting" choice not to have included anything about the drug's potential risk-benefit tradeoff.

Still, both panelists agreed that the phase III trial (LV-101-3-01) had unmistakable deficiencies.

"I don't even think they even met a low bar for evidence, let alone 'substantial' evidence -- it's far from that," Troendle remarked.

LV-101-3-01 compared the effects of two doses of carbetocin nasal spray -- 9.6 mg and 3.2 mg -- versus a placebo spray. The higher dose showed no significant benefits on either the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or the Children's Yale-Brown Obsessive-Compulsive Scale, which were the study's co-primary endpoints. Meanwhile, the lesser dose showed a significant benefit only on the HQ-CT scale, one of two secondary endpoints.

That this positive finding for the 3.2-mg dose was not also seen with the 9.6 mg dose was a point of contention for most of the panel members.

"The thing that stuck out to me most was that the 9.6-dose study did not replicate," said Satish Iyengar, PhD, of the University of Pittsburgh. "And given the fact that the 3.2-dose study didn't really hold up strongly to the sensitivity analysis ... I just have no confidence -- I have little confidence -- that it will replicate."

Leading up to the meeting, FDA staff noted in an of the drug's evidence that carbetocin was generally safe and well tolerated in both the phase III trial and its preceding phase II proof-of-concept trial (Study 114).

This positive safety profile moved patient representative Alice Shapley to cast the committee's only "yes" vote.

"I believe that substantial evidence was presented for the efficacy of carbetocin, with the liberal view of the terms 'substantial evidence,'" she said. "But in particular, I think in the light of the promising safety profiles of carbetocin, I'm convinced of the high ratio of benefit-to-risk for this treatment for the PWS community."

Testimonies from parents of children with PWS made up a majority of the meeting's emotional public comment period. Although there was a near-total consensus that there simply wasn't enough convincing evidence to support carbetocin's efficacy, almost all the panel members acknowledged how dire the medical issues are for those with PWS and their families.

This presented a bind for Jessica Jeffrey, MD, MPH, MBA, of UCLA's Semel Institute for Neuroscience and Human Behavior, who said after the vote that she would have loved to vote "yes" given the lack of any current therapies to treat hyperphagia; however, in the face of little supporting evidence, she agreed that the drug's efficacy could not be proven.

"The testimony of those affected by Prader-Willi syndrome are compelling, at times heartbreaking, and the unmet medical need is unquestionable," said Jess Fiedorowicz, MD, PhD, of the University of Ottawa in Canada. "It seems everyone on this committee recognizes that."

This, however, did not change his view that the study's results were less than substantial, and he added that even the reportedly significant secondary endpoint results may not be as solid as they were presented to be.

"The primary endpoints were definitively negative; secondary endpoints were encouraging but questionable, and not even statistically significant when appropriately analyzed," he concluded.

Despite its shortcomings, Fiedorowicz and others acknowledged that the efficacy signal from the lower dose should encourage further study of the drug.

While the FDA is not required to follow its advisory committees' recommendations, it typically does.

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