Novartis’ Twice-Yearly siRNA Therapy Leqvio (Inclisiran) Shows Consistent LDL-C Reduction Regardless of Age or Gender Ahead of Year-End Launch

Nov. 16, 2020 /BioValleyBIOON/ --Novartis(Novartis) recently announced data from three Phase IIIClinical Trials(ORION-9, ORION-10, ORION-11) Results of two pooled post hoc analyses. Leqvio (inclisiran) is a first-in-classsiRNATherapy is being developed for the treatment of adult patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH). These post hoc analyses evaluated the impact of age and sex on the efficacy and safety of inclisiran. The data showed that at month 17, inclisiran was well tolerated and effectively and sustainably reduced low-density lipoprotein cholesterol (LDL-C) when used in combination with other lipid-lowering therapies, regardless of patient age or sex. In these trials, inclisiran was administered once at months 1 and 3, and then every 6 months thereafter until month 17. These results were presented at the American Heart Association (AHA) 2020 ScientificConferencepublished above.

In a post hoc analysis of pooled results from the ORION Phase III trials involving more than 3,600 patients, treatment with inclisiran reduced LDL-C by approximately 51% in both women and men (50.6% and 50.6%, respectively) compared with placebo. Results from a second pooled analysis showed that patients across three age groups treated with inclisiran achieved similar LDL-C reductions of approximately 51% (<65 years: −51.3%; ≥65 to <75 years: −49.9%; ≥75 years: −51.0%)². Inclisiran was well tolerated in both analyses.

Leqvio（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.

Dr. Kausik Ray, Professor of Public Health at Imperial College London and Chief Investigator of the ORION-11 trial, stated: “The burden of high LDL-C and other ASCVD risk factors, as well as the potential for treatment-related side effects, may increase with age and vary by sex. These data are important because they demonstrate that, despite the challenges posed by age and sex in cholesterol-lowering therapy, inclisiran—a siRNA therapeutic administered twice yearly following an initial dosing regimen at months 1 and 3—has the potential to provide consistent efficacy and tolerability.”

NovartisDavid Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolism Drug Development, stated: “Regardless of age or sex, the inclisiran analyses continue to demonstrate consistent, effective, and sustained reductions in LDL-C throughout the dosing interval. As we reimagine the treatment landscape for ASCVD, these data further substantiate the potential of inclisiran as a first-in-class siRNA therapeutic that transforms LDL-C management with twice-yearly dosing following initial doses administered at months 1 and 3, while maintaining a favorable tolerability profile.”

Currently, inclisiran is under review by regulatory authorities in the United States and Europe. In mid-October this year, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion, recommending the approval of inclisiran as an adjunct to diet for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia. The European Commission (EC) is expected to make a final review decision in December 2020. Currently, inclisiran is also under review in the United StatesFDAreview.

If approved, Leqvio will become the first and only small interfering RNA (siRNA) therapy for patients with hypercholesterolemia or mixed dyslipidemia. Cardiovascular disease (CVD) claims millions of 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 inclisiran effectively and sustainably lowers LDL-C in patients whose LDL-C remains elevated despite receiving maximally tolerated lipid-lowering therapy, 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, thereby improving adherence and enhancing patient outcomes.

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.

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 an entirely new therapeutic modality to combat LDL-C and is regarded as the most significant advancement 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 process 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 the inhibition of PCSK9 protein 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, works by directly silencing the production of PCSK9 protein in the liver.

Despite lagging behind other PCSK9 inhibitors, inclisiran’s convenience of requiring only two subcutaneous injections per year during the maintenance phase provides it with strong 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: New Novartis analyses for investigational inclisiran demonstrate consistently effective and sustained LDL-C reduction at month 17 regardless of age and gender