Novartis Receives FDA Complete Response Letter on Inclisiran

Susan Jeffrey

December 21, 2020

The US Food and Drug Administration (FDA) issued a complete response letter regarding Novartis' new drug application (NDA) for inclisiran, a novel treatment for elevated low-density lipoprotein cholesterol (LDL-C) levels in patients with high LDL despite a maximum tolerated dose of statins, the company has announced.

"The FDA stated that the agency cannot approve the NDA by the Prescription Drug User Fee Act (PDUFA) action date of December 23, 2020, due to unresolved facility inspection-related conditions," notes a Novartis press statement, issued December 18. "The conditions will be conveyed to the European manufacturing facility within 10 business days."

No inspection of the third-party facility, which is responsible for product manufacturing, was conducted, the statement notes. "If it is determined that a facility inspection is needed to approve the application, the FDA will define an approach for scheduling once safe travel may resume based on public health need and other factors," the company said.

"Novartis is confident in the quality of the regulatory submission for inclisiran, which includes a robust body of evidence related to efficacy and safety. We look forward to meeting with the FDA and our third-party manufacturing partner to discuss the feedback received and next steps," said John Tsai, MD, head of global drug development and chief medical officer, Novartis. "We are committed to bringing this potential first-in-class small interfering RNA cholesterol-lowering treatment to patients as soon as possible."

The European Commission granted marketing authorization for inclisiran (Leqvio) in Europe on December 11, 2020, the statement notes.

Inclisiran is a novel small-interfering RNA agent that acts predominantly in the liver to reduce LDL cholesterol. Three phase 3 trials, ORION-9, ORION-10, and ORION -11, all showed an approximate halving of LDL cholesterol levels with treatment, which is given just twice a year by subcutaneous injection. The results were published online March 11 in The New England Journal of Medicine.

Treatment was well tolerated in the trials, the statement adds. The most common adverse events reported (≥3% of patients treated with inclisiran, occurring more frequently than with placebo) were injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea; injection site reactions were the most frequent. Effects were "generally mild and none were severe or persistent," the company notes.

Novartis obtained global rights to develop, manufacture, and commercialize inclisiran under a license and collaboration agreement with Alnylam Pharmaceuticals.

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