IPSEN BIOPHARMACEUTICALS INC – FDA CRL

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Ipsen Biopharmaceuticals Inc. regarding their New Drug Application (NDA 215559) for palovarotene capsules, submitted on April 29, 2022. The FDA determined that the application cannot be approved in its current form due to insufficient evidence establishing the efficacy of palovarotene in preventing new heterotopic ossification (HO) in pediatric and adult patients with fibrodysplasia ossificans progressiva (FOP).

Key issues include the reliance on post-hoc analyses for efficacy, the unsuitability of the external control group (Natural History Study) for evaluating chronic/flare-up dosing, and inconsistencies in efficacy data across different study phases. The FDA also raised concerns about observed negative new HO volume data, the lack of efficacy for flare-up-only dosing, and a potential increased incidence of flare-ups with palovarotene treatment, which impacts both efficacy and safety. Additionally, the company's plan for demonstrating substantial evidence of effectiveness, as required by regulatory guidance, was deemed unclear.

To address these deficiencies, the FDA recommends submitting additional comprehensive data and analyses, including detailed statistics on new HO sites, annualized HO metrics across various study periods, and comparative analyses of treated versus untreated subjects using improved methodologies like propensity score matching. Further required actions involve within-subject analyses, graphical representations of HO volume changes, and an exploration of factors contributing to disparate study results between different trials. These recommendations aim to provide robust evidence of palovarotene's clinical benefit.