FDA CRL - ASCENDIS PHARMA

The FDA issued a Complete Response Letter (CRL) to Ascendis Pharma Bone Diseases A/S for its New Drug Application (NDA 216490) for palopegteriparatide injection, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act. The agency determined the application could not be approved in its current form due to significant product quality and device deficiencies.

Key issues identified include considerable variability in the delivered dose, a critical quality attribute, and insufficient data to demonstrate that revised assay and delivered volume specifications can effectively limit this variability. The FDA noted an anticipated high rate of batch failures with Ascendis Pharma's proposed specifications, suggesting inadequacies in the product's formulation and device design. Furthermore, stability data were deemed insufficient to support the product's shelf-life based on the revised delivered dose specification. The FDA expressed concerns that the high degree of potential dose variability could lead to dosing inaccuracies, dose overlapping, and potential safety risks like episodic hypocalcemia or hypercalcemia. Batch data from the Phase 3 trial did not reflect the expected variability of the commercial product, and the company's quantitative systems pharmacology modeling was not deemed sufficient to justify the anticipated variability.

To resolve these deficiencies, Ascendis Pharma is required to address all Chemistry, Manufacturing, and Controls (CMC) issues. This includes providing data to verify that the existing device consistently meets the proposed 1 ug dose delivered specification at release and throughout stability, aligning with a revised quality control strategy. A statistical control plan for lot release testing of device Essential Performance Requirements is also mandated.