Novartis Receives First-Ever Global Approval for Leqvio® (inclisiran), a Twice-Yearly siRNA Therapy to Lower LDL Cholesterol

December 14, 2020 News /Bio ValleyBIOON/ --NovartisNovartis recently announced that the European Commission (EC) has approved Leqvio (inclisiran) as an adjunct to diet for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, specifically: (1) Leqvio in combination with statins or statins and other lipid-lowering therapies, for patients who are unable to achieve LDL-C treatment goals on the maximum tolerated dose of statins; (2) Leqvio in combination with other lipid-lowering therapies, for patients who are intolerant to statins or have contraindications to statins.

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.

Notably, with this approval, Leqvio has become the first and only small interfering RNA (siRNA) therapy globally.siRNA) LDL-C lowering therapy. The active ingredient of this drug is inclisiran, a first-in-class siRNA with a novel mechanism of action. Through RNA interference (RNAi), it potently and durably reduces LDL-C levels in patients with atherosclerotic cardiovascular disease (ASCVD), those with ASCVD risk equivalents, and those with heterozygous familial hypercholesterolemia (HeFH). These conditions are associated with heart attacks,Strokethe primary drivers, 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, LDL-C levels remained reduced for 17 months with inclisiran treatment, and its safety and tolerability were similar to those of placebo. Additional post hoc analyses showed 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 novel therapeutic approach to combating LDL-C and is regarded as the most significant advancement in the field of lipid-lowering therapy since the introduction of statins (such as Lipitor).

Inclisiran is a small interfering RNA (siRNA) that leverages the body’s natural RNA interference process to bind to mRNA encoding the PCSK9 protein. By reducing mRNA levels through RNA interference, it inhibits hepatic production of the PCSK9 protein, thereby enhancing the liver’s ability to clear LDL-C from the bloodstream and achieving a reduction in LDL-C levels.

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

Although lagging behind other PCSK9 inhibitors, inclisiran’s convenience of only two subcutaneous injections per year during the maintenance phase 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 EUapproval for Leqvio®* (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year**