Intranasal Carbetocin Fails to Win Over FDA Advisory Committee

Despite pleas for approval during a public comment period, the FDA’s Psychopharmacologic Drugs Advisory Committee failed yesterday by a vote of 12-to-1 to recommend Levo Therapeutics’ intrasanal carbetocin — an oxytocin analogue delivered via a spray pump — for treatment of hyperphagia and related anxiety in children with a rare genetic disorder, Prader-Willi Syndrome.

Just one of the 13 panel members, Alice Shapely, of Los Angeles, voted in favor of the medication, saying that carbetocin’s excellent safety profile and signs of at least a modest benefit tipped the scales in the drug’s favor – especially for a highly problematic disorder with no available treatment.

“I’m convinced of a high benefit/risk ratio for carbetocin,” she said.

The drug-device product was tested in two doses: 9.6 mg and 3.2 mg. The pump itself passed with flying colors with no adverse events associated with the use of the device in either study. And the spray pump worked well, with no malfunctions, the company reported.

However, panel members said neither of the two clinical trials presented compelling efficacy evidence.

The phase 3 study, LV 101-3-01, randomized 130 patients to thrice-daily carbetocin 9.6 mg or 3.2 mg compared to placebo for eight weeks and continued in a 56-week follow-up study. However, the study was cut short due to COVID-19.

Among those who did complete it, there were no significant benefits on either of the primary endpoints: the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score and the Children’s Yale-Brown Obsessive-Compulsive Scale  (CY-BOCS) Severity Rating total score.

The smaller dose did show some promise on secondary endpoints relative to placebo. But the differences were very small, “and must be considered in the context of the lack of efficacy of the higher dose,” the FDA said. “The lack of efficacy of the 9.6-mg dose questions the biological plausibility of the nominally significant result observed for in carbetocin 3.2 mg.”

Panel members also expressed concern about the very complicated statistical analyses the company employed to reach those numbers.

“I would love to have voted yes,” said James J. McGough, of the University of California, Los Angeles. “This is a condition with dire consequences, and the safety profile is favorable. But there is significant evidence of bias in the study design. I’m worried about type 1 error, and the response just doesn’t meet the threshold of substantial efficacy.”

Thirteen advocates for the medication spoke during the public comment period, painting vivid pictures of how the medication changed the lives of their children. Instead of days and nights ruled by extreme food-seeking behaviors — eating from trash cans, garbage disposals, even stealing parents’ credit card numbers and arranging for food delivery away from the house – parents described completely changed children.  On the medication, they said, children are achieving milestones never imagined: graduating from high school, making friends, enjoying family vacations and envisioning a future free of relentless, insatiable – and life-threatening – hunger.

One clinician described the case of a young man with Prader-Willi who died from a gastric rupture related to a gorging incident. “We have to pin all of our hopes on the 3.2-mg dose of carbetocin,” she said. “It is standing between life and death for our kids.”

The panel did offer encouragement for Levo to continue investigation, however. Kim O. Witczak, the committee’s consumer representative, suggested families who benefitted from carbetocin should still be allowed to receive it.

“The idea of expanded access is an option for the families that do want it and I encourage the company to continue studying it,” Witczak said.

— Michele G. Sullivan