Novartis' RNAi Therapy Inclisiran Granted Clinical Trial Approval in China Following $9.7B Acquisition

Reposted from | Medical Perspective

The Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has recently announced that inclisiran injection, a Class 1 new drug submitted by Novartis, has received implicit approval for clinical trials, with the indication being “primary hypercholesterolemia.” Inclisiran is an investigational RNA interference (RNAi) innovative therapy designed to lower cholesterol levels. In late 2019, Novartis acquired The Medicines Company for $9.7 billion, thereby bringing its flagship therapy, inclisiran, into its portfolio. This marks the first time the drug has been approved for clinical trials in China. Notably, inclisiran has the potential to become the first RNAi therapy for a common disease, as RNAi therapies have previously been predominantly used to treat rare diseases.

Source: CDE Official Website

Inclisiran is an RNA interference (RNAi) therapy targeting PCSK9, developed using Alnylam Pharmaceuticals’ GalNAc delivery system. It binds directly to the mRNA encoding the PCSK9 protein, reducing mRNA levels through RNA interference, thereby preventing hepatic production of the PCSK9 protein. The PCSK9 protein inhibits the recycling and reuse of low-density lipoprotein (LDL) receptors. Consequently, lowering PCSK9 protein levels allows more LDL receptors to return to the surface of hepatocytes, where they can bind to more LDL particles and clear them from the bloodstream.

Moreover, the unique feature of inclisiran is that patients only need to receive two subcutaneous injections per year to control cholesterol levels, providing a convenient treatment option for patients.

▲Mechanism of Action of Inclisiran (Image source: Reference [3])

Currently, the marketing application for inclisiran is under review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), for use in "adult patients with ASCVD or HeFH who have persistently elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapy." If approved, inclisiran will become the first siRNA-based cholesterol-lowering drug.

According to a press release previously issued by Novartis, inclisiran met the primary endpoints in three pivotal Phase 3 clinical trials for the treatment of hyperlipidemia in adults, with the trial results published in the New England Journal of Medicine (NEJM). The study results demonstrated that, compared with placebo, subcutaneous administration of inclisiran twice yearly following two initial doses achieved sustained and significant reductions in LDL-C. Meanwhile, inclisiran exhibited good tolerability and a safety profile comparable to that of placebo.

Notably, in the pivotal Phase 3 clinical trial (ORION-11) evaluating inclisiran for lowering low-density lipoprotein cholesterol (LDL-C), the drug met all primary and secondary endpoints and demonstrated a favorable safety and tolerability profile. The success of this clinical trial highlights the potential of RNA interference (RNAi) therapy in treating prevalent diseases with large patient populations, given that RNAi therapies have previously been predominantly utilized for rare diseases affecting smaller patient groups.

Furthermore, Novartis and The Medicines Company are conducting a Phase 3 clinical trial named ORION-4, aimed at validating the efficacy of inclisiran in reducing the risk of major adverse cardiovascular events (MACE) and cardiovascular mortality, with clinical trial results expected in 2024.

Low-density lipoprotein cholesterol (LDL-C), also known as "bad" cholesterol, is a major risk factor for cardiovascular disease. Despite the widespread use of statins to lower LDL-C levels, heart disease remains one of the leading causes of death worldwide. Many patients fail to achieve adequate control of their LDL-C levels even with optimal statin dosing, creating an urgent need for innovative therapies to help further reduce LDL-C levels.

References:

[1] The New England Journal of Medicine Publishes Results from Three Key Trials on the Cholesterol-Lowering Drug Inclisiran. Retrieved Mar 25, 2019, from https://mp.weixin.qq.com/s/iHirpdekh_yieVLBDhUWXg

[2] Novartis enters into agreement to acquire The Medicines Company. RetrievedNovember 25, 2019, from https://www.novartis.com/sites/www.novartis.com/files/novartis-agreement-acquire-medicines-company-investor-presentation.pdf

[3] Kosmas et al,(2018). Inclisiran: A New Promising Agent in the Management ofHypercholesterolemia. Diseases, https://doi.org/10.3390/diseases6030063

[4] The Medicines CompanyAnnounces Positive Topline Results from First Pivotal Phase 3 Trial ofInclisiran. Retrieved August 26, 2019, fromhttps://www.businesswire.com/news/home/20190826005164/en

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