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Ahead of an advisory committee on the matter, FDA staff expressed concerns over conflicting efficacy data on a carbetocin nasal spray for treating various symptoms brought on by Prader-Willi syndrome.

On Thursday, the FDA's will decide whether drug developer Levo Therapeutics has provided enough evidence to support the claim that the carbetocin spray taken three times daily is an effective method for treating hyperphagia, anxiety, and distress associated with Prader-Willi syndrome, for which no pharmacologic treatment currently exists.

Prader-Willi syndrome is a rare genetic disorder caused by paternal deletions in chromosome 15q11-13 and affects roughly one in every 10,000-30,000 individuals. The disease has a chronic course and is associated with a shorter life expectancy.

Support for the proposed indication rests largely on a phase III trial (LV-101-3-01) that compared the effects of two doses of the carbetocin nasal spray (9.6 mg, primary endpoints; 3.2 mg, secondary endpoints) with a placebo spray.

As described in ahead of the meeting, the trial's co-primary endpoints -- changes after 8 weeks from baseline in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Severity Rating score for the 9.6 mg dose versus placebo -- did not yield any statistically significant results, with least squares mean differences of -1.2 points (95% CI -3.7 to 1.3, P=0.3493) on the HQ-CT and -0.608 (95% CI -2.89 to 1.67, P=0.6001) for the CY-BOCS endpoint.

The same measures were used for the 3.2 mg carbetocin dose compared with placebo. Here, changes from baseline to 8 weeks with carbetocin were "nominally" significant for HQ-CT scores, but no different for the CY-BOCS endpoint:

• HQ-CT: -3.14 points (95% CI -5.69 to -0.59, P=0.0162)
• CY-BOCS: -0.76 (95% CI -3.07 to 1.54, P=0.7270)

"Reliance on a single large multicenter trial to establish effectiveness should generally be limited to situations in which the trial has demonstrated a clinically meaningful and statistically very persuasive effect on mortality, severe or irreversible morbidity, or prevention of a disease with potentially serious outcome, and confirmation of the result in a second trial would be impracticable or unethical," FDA staff noted in the briefing documents.

"The approach of using one adequate and well-controlled clinical investigation plus confirmatory evidence does not appear applicable to this application, as no confirmatory evidence has been identified," they added.

The phase III trial's full data set consisted of 130 participants ages 7-18 years with genetically confirmed Prader-Willi syndrome. The 9.6 mg group included 44 participants; the 3.2 mg and placebo groups each had 43. Over an 8-week control period, patients received the drug three times a day with meals, followed by 56 weeks of follow-up during which patients could either continue on their assigned dose or switch to another.

There were 17 serious adverse events in a total of 16 participants over the course of the trial. Nine adverse events ultimately led to eight patients discontinuing the drug during the long-term follow-up period and extension, and were primarily related to psychiatric issues like emotional distress, aggression, and other behavior disorders. Overall, though, FDA staff deemed the drug safe and well tolerated in the phase III trial, and in an earlier phase II trial (Study 114).

In 2015, the FDA declined the company's request for a breakthrough therapy designation based on results from Study 114. While the drug showed statistically significant improvements compared with placebo on the Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness (HPWSQ-R), the agency deemed the differences between the groups too small.

In November 2020, FDA determined that the results of the two trials were insufficient to support moving forward with a new drug application (NDA), but Levo went ahead and filed the NDA in April of this year. After consultation with senior leadership, FDA decided the application could be filed, with questions about the study designs and the statistical and clinical meaningfulness of the findings to be addressed in a comprehensive review of the data.

The FDA is not required to follow the advice of its advisory committees, but it often does.

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