lpsen Biopharmaceuticals Inc.: palovarotene

We also acknowledge receipt of your amendment dated October 19, 2022, which was not fully reviewed for this action.

You have not provided adequate support for the efficacy of palovarotene, thus the anticipated clinical benefit in the treatment of pediatric and adult patients with ibrodysplasia ossificans progressiva (FOP), specifically a benefit of palovarotene to prevent the formation of new heterotopic ossification (HO) (the proposed indication), has not been established.

1) Appropriateness of reliance on post-hoc analyses to support efficacy.

The potential for increased incidence of flare-ups with palovarotene treatment, particularly with higher doses, is a concern regarding both the efficacy and safety of the drug in patients with FOP.

Effectiveness for Human Drug and Biological Products, e.g., if you intend to rely on a single adequate and well controlled trial, you will need to provide confirmatory evidence of effectiveness.

As a path forward we recommend that the following additional data and data analyses as well as any other available data that may support the efficacy of palovarotene be submitted.

We note your submission received October 11, 2022, containing revised carton/container labeling in response to our comments sent on September 27, 2022.

We acknowledge and confirm accepibility of your December 20, 2022, submission containing your safety update proposal.

Section 505(0)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute.

We have determined that if NDA 215559 is approved, an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of increased palovarotene exposures in subjects with moderate-to-severe hepatic impairment.

Because the benefits of palovarotene for treatment of patients with FOP have not been established, we are unable to conduct a meaningful benefit risk assessment.