Issues at Italian CDMO leads to US approval delay for Novartis’ inclisiran

The US FDA has issued a complete response letter for Leqvio (inclisiran) due to ‘unresolved facility inspection-related conditions’ at a third-party site run by Corden Pharma.

In October 2020, this publication reported the US approval of Novartis’ small interfering RNA (siRNA) therapy for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, Leqvio, was dependent on a regulatory inspection at a third-party manufacturer in Italy.

While Novartis spoke of regulatory delays of up to five months caused by COVID-19, it said it was confident of maintaining the US Food and Drug Administration (FDA) action date of December 23.

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But it was not COVID that turned out to be the problem, but rather the Italian drug product plant. According to a Novartis spokesperson, the FDA issued a Complete Response Letter (CRL) stating that it could not “approve the NDA by the Prescription Drug User Fee Act (PDUFA) action date of December 23, 2020, due to unresolved facility inspection-related conditions.”

We were told: “The conditions will be conveyed to the third-party European manufacturing facility within 10 business days. Satisfactory resolution of these conditions is required before the Novartis NDA may be approved.”

The facility in question is Corden Pharma Caponago, located just outside Milan, Italy, it was confirmed. The contract development and manufacturing organization (CDMO) is responsible for Leqvio’s drug product manufacturing, having been contracted by Leqvio’s developer The Medicines Company. (In 2013, Alnylam licensed inclisiran to The Medicines Company. Novartis acquired The Medicines Company for $9.7 billion in January 2020.)

Inclisiran is a subcutaneously administered siRNA that prevents the production of PCSK9 and has been developed as a potential treatment for hypercholesterolemia. The drug became the first and only approved siRNA low-density lipoprotein cholesterol (LDL-C) lowering treatment in Europe when the European Commission gave Novartis the thumbs up on December 11.

As for the US, Novartis was unable to detail its new approval timeline.

“We expect to have more clarity on timing in the coming weeks when we meet with both the third-party manufacturer and the FDA. Since the CRL is not related to safety or efficacy concerns, we are hopeful that the third-party facility inspection-related conditions can be resolved as quickly as possible. However, if FDA decides an inspection is required the timing will be dependent on FDA’s ability to restart foreign inspections.”