Novartis Receives Positive CHMP Opinion for Leqvio® (inclisiran), a First-in-Class siRNA Therapy Administered Twice Yearly for High Cholesterol

October 19, 2020 News /BioValleyBIOON/ --Novartis(Novartis) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending Leqvio (inclisiran) as an adjunct to diet control for the treatment of adult patients with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia.

The CHMP opinion represents the final step in the marketing authorization procedure prior to approval by the European Commission (EC). The CHMP opinion will now be submitted to the EC for review; the EC typically adopts the CHMP’s opinion and is expected to render its final decision by the end of the year. If approved,Leqvio will become the first and only small interfering RNA (siRNA) therapy for patients with hypercholesterolemia or mixed dyslipidemia.siRNA) therapy.

Inclisiran is a first-in-class siRNA therapy with a novel mechanism of action that effectively and sustainably lowers low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD), those with ASCVD risk equivalents, and those with heterozygous familial hypercholesterolemia (HeFH), thereby reducing the risk of heart attack,Strokeand the primary drivers of mortality.

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

The CHMP’s positive opinion 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 ASCVD, ASCVD risk equivalents, and/or HeFH, inclisiran administered as two subcutaneous injections per year following an initial two-dose regimen (at months 0 and 3) produced a durable and effective reduction in LDL-C: compared with placebo, LDL-C levels were effectively and sustainably 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, with the transaction successfully completed in January 2020. Currently, inclisiran is also under review by the U.S.FDAreview.

Inclisiran is the first cholesterol-lowering therapy in the small interfering RNA (siRNA) class, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key mechanism by which the human body regulates low-density lipoprotein cholesterol (LDL-C). The PCSK9 protein reduces the liver’s ability to clear 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 advance in 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 mechanism to bind to messenger RNA (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 low-density lipoprotein cholesterol (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.

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

Original Source: Novartis receives positive CHMP opinion for Leqvio®* (inclisiran), a potential first-in-class siRNA for the treatment of high cholesterol