?The U.S. Food and Drug Administration (FDA) has not raised any concerns related to the efficacy or safety of inclisiran. The complete response letter is due to unresolved facility inspection-related conditions
?No onsite inspection was conducted of the single third-party facility in question. If a facility inspection is needed, FDA will define an approach once safe travel may resume based on public health need and other factors
?Novartis will work with FDA and the third-party manufacturing facility in Europe to complete the inclisiran review, to bring this potential first-in-class siRNA to patients in the U.S. as quickly as possible

Basel, December 18, 2020 — The U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for inclisiran, a potential treatment for hyperlipidemia in adults who have elevated low-density lipoprotein cholesterol (LDL-C) while being on a maximum tolerated dose of a statin therapy. 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. The conditions will be conveyed to the European manufacturing facility within 10 business days. The third-party facility is responsible for drug product manufacturing. Satisfactory resolution of the unresolved facility inspection-related conditions is required before the Novartis NDA may be approved. No onsite inspection was conducted. 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.

“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, 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 (EC) recently granted Novartis marketing authorization for Leqvio® (inclisiran) in Europe on December 11, 2020.

About inclisiran
Inclisiran (KJX839) is the first and only small interfering RNA (siRNA) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels via an RNA interference (RNAi) mechanism of action and could help improve outcomes for patients with atherosclerotic cardiovascular disease (ASCVD), a deadly form of cardiovascular disease1-3. With two doses a year and effective and sustained LDL-C reduction, inclisiran works as a complement to statins. Inclisiran works differently from other therapies by preventing the production of the target protein in the liver, increasing hepatic uptake of LDL-C and clearing it from the bloodstream3. Inclisiran is dosed initially, again at 3 months, and then once every 6 months. In three clinical trials, patients taking inclisiran maintained LDL-C reduction throughout each 6-month dosing interval1,2. Administered in-office as a subcutaneous injection, inclisiran is expected to integrate seamlessly into a patient’s healthcare routine1,2.

In the Phase III trials, inclisiran was well-tolerated1,2. The most common adverse events reported (?3% of patients treated with inclisiran and occurring more frequently than placebo) were injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity and dyspnea1,2. Among those, injection site reactions were the most frequent ones. Those were generally mild and none were severe or persistent1,2.

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

About Novartis in Cardiovascular-Renal-Metabolism
Bending the curve of life requires addressing some of society’s biggest public health concerns. Novartis has an established and expanding presence in diseases covering the heart, kidney and metabolic system. In addition to essential treatment Entresto® (sacubitril/valsartan), Novartis has a growing pipeline of potentially first-in-class molecules addressing cardiovascular, metabolic and renal diseases.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking etc. etc.

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References
1.Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507-1519. doi:10.1056/NEJMoa1912387.
2.Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. doi:10.1056/NEJMoa1913805.
3.Stoekenbroek RM, Kallend D, Wijngaard PL, et al. Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program. Future Cardiol. 2018;14(6):433–442.

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