Novartis’ Investigational siRNA Cholesterol-Lowering Drug Inclisiran Demonstrates Highly Consistent LDL-C Reduction with Just Two Subcutaneous Injections Per Year

August 31, 2020 News /Bio ValleyBIOON/ --Novartis(Novartis) recently announced the evaluation of a first-in-class small interfering RNA (siRNA) Two Pivotal Phase III Trials of the Cholesterol-Lowering Drug Inclisiran for the Treatment of Hyperlipidemia in AdultsClinical Trial(ORION-10, ORION-11) Results of a post hoc analysis of pooled data. This analysis demonstrated that in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents, inclisiran administered as subcutaneous injections twice yearly following two initial doses (at Month 0 and Month 3) exhibited highly consistent efficacy across individual patients, with safety and tolerability profiles similar to those of placebo.

This analysis was presented at the 2020 European Society of Cardiology (ESC) Congress held recently. The analysis evaluated the efficacy and tolerability of inclisiran added to maximally tolerated statin therapy, based on two Phase III trials involving a total of more than 2,300 patients (1,164 of whom received inclisiran). The results showed thatLow inter-individual variability，99% of inclisiran-treated patients achieved a placebo-adjusted LDL-C reduction of ≥30%, with a mean reduction from baseline of 54.1% (observed values)。

At any time point during the study,88.4% of patients treated with inclisiran achieved at least a 50% reduction in LDL-C levels (observed values). After 17 months, 66.4% of patients in the inclisiran group maintained at least a 50% reduction in LDL-C levels, compared to only 2.5% in the placebo group (observed values).Overall, inclisiran was well tolerated, with a safety profile similar to that of placebo.

Dr. Kausik Ray, Principal Investigator of the ORION-11 study, Professor of Public Health at Imperial College London, and Consultant Cardiologist, stated: “This analysis confirms that inclisiran, as a small interfering RNA (siRNA), offers a highly consistent therapeutic profile. In both trials, nearly all patients achieved clinically meaningful reductions in LDL-C levels over 17 months, and the safety and tolerability of inclisiran were comparable to those of placebo. These efficacy and safety findings suggest that inclisiran will provide an effective treatment option for patients with ASCVD who fail to reach their LDL-C goals.”

NovartisDavid Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolism Drug Development, stated: “Under current standards of care, there remains an urgent need for innovative LDL-C-lowering therapies for patients who fail to achieve their LDL-C goals. This analysis reinforces our perspective on the therapeutic value of inclisiran and its potential as the first siRNA-based cholesterol-lowering therapy. With its unique twice-yearly dosing regimen, inclisiran, if approved, could seamlessly integrate into patients’ routine medical visits, helping us reimagine the treatment of ASCVD.”

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. Vas Narasimhan, CEO of Novartis, previously stated, “The acquisition of TMC and inclisiran enablesNovartis“...a unique opportunity to use a vaccine-like approach to open a new chapter in the treatment of the world’s leading causes of death and disability.”

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.

There is a genuine unmet medical need among patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) who have not achieved their LDL-C treatment goals and remain at significant risk of cardiovascular events despite receiving standard-of-care therapy. 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.

——ORION-10 and ORION-11 Studies:Conducted in patients with ASCVD (ORION-10 study) and in patients with ASCVD or ASCVD risk equivalents (ORION-11), who had elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapy. In these studies, patients were randomized to receive either inclisiran (300 mg dose, administered subcutaneously once at month 0 and month 3, and then 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 placebo-corrected reductions in LDL-C levels in the inclisiran treatment group were 52% and 50%, respectively;(2) FromAt months 3 and 18 of treatment, the inclisiran group demonstrated placebo-corrected reductions in LDL-C levels of 54% and 49%, respectively.(3) Adverse events occurring during treatment were generally 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 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 new therapeutic modality to combat 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 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, functions 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 mechanism. It binds to the mRNA encoding the PCSK9 protein, reducing mRNA levels through RNA interference and thereby preventing hepatic production of PCSK9. This enhances the liver’s capacity to clear 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 (ESC)-GalNAc conjugation technology, 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, 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 new analysis shows high consistency in lowering LDL-C in individual response with investigational inclisiran