FDA Issues CRL for Inclisiran, Cites Facility Inspection Issue


The US FDA has declined to approve inclisiran ahead of its PDUFA date of December 23, instead issuing a CRL citing unresolved facility inspection issues.

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Despite showing promise in phase 3 clinical trials, the US Food and Drug Administration has issued a complete response letter (CRL) to Novartis for their lipid-lowering synthetic siRNA agent inclisiran.

A statement from Novartis noted the FDA did not cite concerns related to the efficacy or safety of inclisiran, rather the FDA expressed concerns related to unresolved facility inspection-related conditions.

“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, Head Global Drug Development and Chief Medical Officer at Novartis, in the aforementioned statement. “We are committed to bringing this potential first-in-class small interfering RNA cholesterol-lowering treatment to patients as soon as possible.”

In recent years, clinicians and researchers have seen major strides in lipid management. From icosapent ethyl to bempedoic acid, many had expected the next landmark approval for lipidologists to come from inclisiran—based on the impact on hyperlipidemia demonstrated in the ORION trials and Novartis’s acquisition of The Medicine Company following AHA 2019.

Announced on December 18, the issuance of the CRL from the FDA comes 5 days before the Prescription Drug User Fee Act (PDUFA) action date for inclisiran of December 23 and 7 days after the European Commission (EC) granted marketing authorization to inclisiran (Levqio) in Europe on December 11. According to Novartis, the conditions referenced in the letter will be conveyed to the European manufacturing facility responsible for producing the drug within 10 business days of the statement.

Novartis went on to note no onsite inspections of the manufacturing facility had been conducted and resolution of the unresolved inspection is required before inclisiran could receive approval from the FDA. Novartis pointed out if an onsite inspection were required, the FDA would define the approach they deem acceptable once safe travel resumes.

With the potential for lipid-lowering benefit with injections coming just twice per year, inclisiran has the potential to transform treatment algorithms for adults struggling to manage their hyperlipidemia.

For more on inclisiran, check out our podcast with Kausik Ray, PhD, from ESC 2020 as we discuss the ORION trials and other clinical data.

Prof. Kausik Ray on ORION data from ESC Congress 2020.

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