With a 12 to 1 vote against by the FDA Advisory Panel, the odds are against Levo’s carbetocin in Willi Prader syndrome receiving marketing approval from the FDA, especially as the FDA follows the advice of its Advisory Panel approximately 80% of the time.
I thought I’d have a look at Levo’s Phase 3 trial details to try to get a feel for whether the Advisory Panel’s thumbs down might have been expected.
The Phase 3 primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for a carbetocin 9.6 mg arm vs placebo.
The first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for a carbetocin 3.2 mg arm vs placebo.
The 9.6mg dose failed to achieve statistical significance on either of the primary outcome measures or any of the secondary outcome measures.
However, the 3.2mg dose achieved statistical significance on one of the primary outcome measures and some of the secondary outcome measures.
Both doses demonstrated “numeric trends toward improvement” in the second primary outcome but did not reach statistical significance versus placebo.
Given the failure to meet the primary endpoint, and failure of both doses on the second primary outcome measure, it’s probably not surprising that the Advisory Panel recommended against approval on the grounds of insufficient evidence of efficacy.
What this particular case does highlight, imo, is that measuring success on clinical trial outcomes, especially in rare diseases, can be a grey area. Though its higher dose clearly failed, Levo met one of the primary outcome measures (it only had to meet one) and multiple secondary outcome measures using a lower dose (not the dose specified in the primary endpoint) and decided to chance its data with the FDA. In addition, the company had the support of multiple PWS parents who attended the Advisory Panel meeting, begging for approval because they had seen results such as children finally being able to sleep through the night.
The fat lady hasn’t sung just yet. Final judgement will be cast by the FDA before the end of this year.
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