Novartis' Twice-Yearly siRNA Cholesterol-Lowering Drug Leqvio Receives CRL from U.S. FDA, Secures First Global Approval in EU

      Novartis(Novartis) recently announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for inclisiran, an innovative cholesterol-lowering drug indicated for the treatment of adult patients with hypercholesterolemia who have elevated LDL-C despite receiving the maximum tolerated dose of statin therapy.

The FDA stated that it was unable to approve the inclisiran New Drug Application (NDA) by the Prescription Drug User Fee Act (PDUFA) target date of December 23, 2020, due to unresolved issues related to facility inspections. These matters will be communicated to the European manufacturing facility, a third-party plant responsible for the production of inclisiran, within 10 working days. Satisfactory resolution of the pending facility inspection issues is required before NDA approval. Currently, the FDA has not conducted an on-site inspection. If it is determined that an inspection of the facility is necessary to approve the application,FDAThe schedule for resuming safe travel will be determined based on public health needs and other factors.

John Tsai, Global Head of Drug Development and Chief Medical Officer at Novartis, stated: “NovartisWe are highly confident in the quality of the submitted regulatory dossier for inclisiran, which includes a robust body of evidence related to efficacy and safety. We look forward toFDAMet with our third-party manufacturing partners to discuss the feedback received and next steps. We are committed to advancing this potential first-in-class, small interfering RNA (siRNA) cholesterol-lowering therapy to patients in the United States.”

On the 11th of this month, inclisiran was approved by the European Commission (EC) for marketing in Europe under the brand name Leqvio. It serves as an adjunct to diet control for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia in adults, specifically: (1) Leqvio in combination with statins or statins and other lipid-lowering therapies, for the treatment of patients who are unable to achieve LDL-C treatment goals despite receiving the maximum tolerated dose of statins; (2) Leqvio in combination with other lipid-lowering therapies, for the treatment of patients who are intolerant to statins or have contraindications to statin therapy.

Leqvio is administered via subcutaneous injection, with doses given at month 0 and month 3, followed by maintenance dosing every 6 months, requiring only two injections per year. Compared with currently available cholesterol-lowering therapies, Leqvio is expected to significantly improve long-term adherence.

It is worth mentioning that,Leqvio is the world’s first and only small interfering RNA (siRNA) therapy for lowering cholesterol (LDL-C).The active ingredient of this drug is inclisiran, a first-in-class siRNA with a novel mechanism of action. It potently and durably lowers LDL-C levels in patients with atherosclerotic cardiovascular disease (ASCVD), those with ASCVD risk equivalents, and those with heterozygous familial hypercholesterolemia (HeFH) through RNA interference (RNAi). These conditions are associated with heart attacks,Strokethe main driving factors, and may ultimately lead to patient death.

In Europe, cardiovascular disease (CVD) claims 3.9 million lives annually. Despite the widespread use of statins, 80% of high-risk patients fail to achieve the LDL-C targets recommended by clinical guidelines. Clinical data demonstrate that Leqvio effectively and sustainably lowers LDL-C in patients whose levels remain elevated despite receiving maximally tolerated lipid-lowering therapy, with a safety profile comparable to that of placebo. With its unique twice-yearly dosing regimen, Leqvio seamlessly integrates into patients’ routine medical visits, thereby improving adherence and enhancing patient outcomes.

This approval is based on the results of the ORION clinical research program, including Phase III trials involving more than 3,600 patients receiving statins at the maximum tolerated dose, which evaluated the safety, efficacy, and tolerability of inclisiran. The results demonstrated that in adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, and/or heterozygous familial hypercholesterolemia (HeFH), inclisiran administered as two subcutaneous injections per year following initial doses at months 0 and 3 produced sustained and effective reductions in low-density lipoprotein cholesterol (LDL-C): compared with placebo, LDL-C levels were effectively and consistently reduced by up to 52% (p < 0.0001).

Furthermore, treatment with inclisiran resulted in a sustained reduction in LDL-C levels over 17 months, with safety and tolerability profiles similar to those of placebo. Additional post hoc analyses demonstrated low variability among patients receiving inclisiran: 88% of patients achieved the guideline-recommended targets at any time point during the study (observed values).

Inclisiran is a first-in-class siRNA cholesterol-lowering drug developed by The Medicines Company (TMC).NovartisAcquired TMC for $9.4 billion in November 2019, thereby securing inclisiran. Currently, inclisiran is also under review by the U.S.FDAreview.

Inclisiran is the first cholesterol-lowering therapy in the siRNA class, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key mechanism by which the human body regulates LDL-C. The PCSK9 protein reduces the liver’s ability to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream, and LDL-C is widely recognized as a major risk factor for cardiovascular disease (CVD). Targeting PCSK9 offers a completely new therapeutic modality for combating LDL-C and is regarded as the most significant advance in lipid-lowering therapy since the advent of statins (such as Lipitor).

Inclisiran is a small interfering RNA (siRNA) that leverages the body’s natural RNA interference mechanism. By binding to messenger RNA (mRNA) encoding the PCSK9 protein, it reduces mRNA levels through RNA interference, thereby inhibiting hepatic production of PCSK9. This enhances the liver’s capacity to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream, resulting in reduced LDL-C levels.

To date, two monoclonal antibody drugs targeting PCSK9 protein inhibition have been approved for marketing: Amgen’s Repatha and Sanofi/Regeneron’s Praluent. Unlike monoclonal antibody-based PCSK9 inhibitors, inclisiran, as an RNAi therapeutic, exerts its effect by directly silencing the production of PCSK9 protein in the liver.

Despite lagging behind other PCSK9 inhibitors, the convenience of inclisiran’s maintenance regimen—requiring only two subcutaneous injections per year—provides it with significant market penetration opportunities in the cholesterol-lowering drug market. Credit Suisse previously predicted that inclisiran’s global annual sales would reach $1.13 billion in 2024. (Bioon.com)

Original Source: Novartis Receives Complete Response Letter from U.S.FDA for inclisiran