Novartis Announces Successful Phase III Trials of Inclisiran, a First-in-Class siRNA Therapy for LDL-C Reduction with Twice-Yearly Subcutaneous Dosing
Mar 23, 2020 10:23
CST Updated
10:13
Novartis
Drug Development and Manufacturing
March 23, 2020/Bio ValleyBIOON/--Novartis(Novartis) recently announced the evaluation of a first-in-class small interfering RNA (siRNA) Three pivotal Phase III trials of the cholesterol-lowering drug inclisiran for the treatment of hyperlipidemia in adultsClinical TrialThe results have been published in the New England Journal of Medicine (NEJM). All three trials met their primary endpoints, demonstrating that inclisiran, administered as two initial doses followed by subcutaneous injections twice yearly, provides sustained and effective reduction of LDL-C compared with placebo. Across the three trials, the safety profile of inclisiran was similar to that of placebo, and it was well tolerated.
Currently, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are reviewing the marketing authorization application for inclisiran, indicated for adult patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who have elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapy. If approved,Inclisiran will become the first and only cholesterol-lowering drug in the siRNA class.
Inclisiran is a first-in-class siRNA cholesterol-lowering drug developed by The Medicines Company (TMC). In November 2019, Novartis announced the acquisition of TMC for $9.4 billion, a transaction that was successfully completed in January 2020. Novartis CEO Vas Narasimhan previously stated, “The acquisition of TMC and inclisiran enablesNovartis“...a unique opportunity to open a new chapter in the treatment of the leading global causes of death and disability, using a vaccine-like approach.”
There is a genuine unmet medical need among patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) who have not achieved their low-density lipoprotein cholesterol (LDL-C) treatment goals despite receiving standard-of-care therapy and remain at significant risk for cardiovascular events. Inclisiran, administered via a unique subcutaneous regimen twice yearly, seamlessly integrates with routine healthcare provider (HCP) visits, thereby improving adherence and clinical outcomes in patients with ASCVD or FH.
——The ORION-10 and ORION-11 Studies:The studies were conducted in patients with ASCVD (ORION-10 trial) and in patients with ASCVD or ASCVD risk equivalents (ORION-11 trial), all of whom had elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapy. In these trials, patients were randomized to receive either inclisiran (300 mg administered subcutaneously at baseline, at 3 months, and every 6 months thereafter) or placebo, in addition to their existing maximally tolerated lipid-lowering therapy, for a treatment duration of 18 months.
The results showed that in the ORION-10 and ORION-11 studies: (1) at month 17 of treatment, the inclisiran group had placebo-adjustedLDL-C levels reduced by 52% and 50%, respectively; (2) From the 3rd month to the 18th month of treatment, the inclisiran treatment group, after placebo adjustment,LDL-C levels were reduced by 54% and 49%, respectively.(3) The adverse events that occurred during the treatment were generally similar between the inclisiran group and the placebo group.
— ORION-9 Study:Conducted in patients with heterozygous familial hypercholesterolemia (HeFH) who have elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapy. HeFH is a rareHeredityGenetic disorders can cause high levels of LDL-C and lead to early onset of ASCVD. In this study, patients were randomly assigned to receive either inclisiran (300 mg dose, administered subcutaneously at month 0 and month 3, then every 6 months thereafter) or placebo for 18 months while continuing their existing maximally tolerated lipid-lowering therapy.
The results showed: (1) At month 17 of treatment, the inclisiran group, after placebo adjustment,LDL-C levels reduced by 50%; (2) From the 3rd to the 18th month of treatment, the inclisiran group, after placebo adjustment,LDL-C levels reduced by 45%; (3) LDL-C levels were significantly reduced across all FH genotypes. (4) The overall incidence of adverse events during treatment was similar between the inclisiran group and the placebo group.
Inclisiran is the first cholesterol-lowering therapy in the small interfering RNA (siRNA or sir-nah) 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 advance in lipid-lowering therapy since the introduction of statins (such as Lipitor).
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, works by directly silencing the production of PCSK9 protein in the liver. Inclisiran is a small interfering RNA (siRNA) that leverages the body’s natural RNA interference process. It binds to the messenger RNA (mRNA) encoding the PCSK9 protein, thereby reducing mRNA levels through RNA interference and preventing hepatic PCSK9 protein synthesis. This mechanism enhances the liver’s ability to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream, resulting in reduced LDL-C levels.
Currently, inclisiran is in Phase III clinical development to evaluate its ability to lower LDL-C with twice-yearly dosing. Inclisiran was developed by Alnylam Pharmaceuticals using its proprietary Enhanced Stabilization Chemistry-GalNAc conjugate technology (ESC-GalNAc), which enables GalNAc chemical modification of RNA fragments to enhance stability and facilitate liver-targeted drug delivery. The Medicines Company (TMC) entered into a license and collaboration agreement with Alnylam, securing global rights for the development, manufacturing, and commercialization of inclisiran.
Despite lagging behind other PCSK9 inhibitors, inclisiran’s convenience of only twice-yearly subcutaneous administration 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)