FDA Issues Complete Response Letter, Delaying U.S. Approval of Novartis' RNAi Cholesterol-Lowering Drug Inclisiran

On December 18, Novartis announced that it had received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its marketing application for inclisiran, a novel RNAi-based lipid-lowering therapy, indicating that the U.S. launch of this blockbuster drug will be delayed.

The FDA has not raised any questions regarding the efficacy and safety of inclisiran; the concerns lie in the manufacturing process. In its letter, the FDA stated that due to unresolved issues identified during the review of documents related to the production facility (facility inspection-related conditions), it could not approve the marketing application for inclisiran by the PDUFA date of December 23, 2020. The FDA will notify the European manufacturing facility of the relevant issues within 10 working days. The production of inclisiran is handled by a third-party manufacturer. The FDA indicated that approval of the drug’s marketing application would only be granted after the issues identified during the inspection have been satisfactorily resolved. Currently, the FDA has not conducted an on-site inspection of the facility. If an on-site inspection is deemed necessary, the FDA will schedule the unannounced inspection after taking into account the pandemic situation and other safety factors.

John Tsai, Head of Global Drug Development and Chief Medical Officer at Novartis, stated, “We are highly confident in the quality of inclisiran. We have submitted robust evidence of in vivo efficacy and safety in our marketing application dossier. We will meet with the FDA and our third-party manufacturing partners as soon as possible to discuss their feedback and next steps. We are committed to bringing this first-in-class innovative small-molecule RNAi lipid-lowering therapy to patients at the earliest opportunity.”

Inclisiran, developed by Alnylam Pharmaceuticals, is a first-in-class small interfering RNA (siRNA) drug for lowering LDL-C. The Medicines Company obtained the exclusive global rights for the development and commercialization of Inclisiran. Novartis acquired The Medicines Company in late 2019 for $9.7 billion, thereby bringing Inclisiran into its portfolio.

Inclisiran is administered via subcutaneous injection, with the first two doses given three months apart, followed by dosing every six months thereafter. On December 11, the European Union just approved the marketing application for inclisiran (Leqvio) for the treatment of hypercholesterolemia and mixed dyslipidemia in adults. The approval in the EU was based on positive results from the ORION studies. The results showed that inclisiran reduced LDL-C by up to 52% in patients who failed to reach their LDL-C targets despite treatment with the maximum tolerated dose of statins.