Encouraging Performance of Cardiovascular Drug Vindicates Novartis’ $9.7 Billion Buyout Deal

By Pavel Ryzhov, Ph.D.

Heart disease is the leading cause of death in the United States [1]. Among the types of heart disease, one of the most prevalent is atherosclerotic cardiovascular disease (ASCVD). It is caused by the gradual buildup of fats and cholesterol on the walls of blood vessels and the resulting deposition of clogging plaques. Low-density lipoprotein cholesterol (LDL-C) is the primary contributor to that process, and associated hyperlipidemia is, therefore, a critical underlying condition that can contribute to complications such as heart attack or a stroke [2].

The current treatment landscape already includes the administration of potent LDL-C reducing medicines such as statins. However, further lowering of LDL-C with novel types of treatments and searching for better patient adherence results is the focus of recent efforts by Novartis.

In a recent press-release [3], results were announced for two Phase III trials (ORION-10 and ORION-11), which evaluated patient responses to first-in-class LDL-C reduction medicine, inclisiran. Both were placebo-controlled, double-blind, and randomized trials that aimed to investigate the safety, efficacy, and tolerability of the treatment in patients with ASCVD, high LDL-C, and already receiving maximum doses of LDL-C lowering medicines like statin or ezetimibe. With 1561 and 1617 enrolled patients, and trials conducted at 145 sites in the US and 70 sites in seven countries in ORION-10 and ORION-11, respectively, they both met their primary endpoints.

Specifically, mean placebo-adjusted percentage change in LDL-C reduction was 52% (p<0.0001) and 50% (p<0.0001) at 17 months and demonstrated time-adjusted percentage change in LDL-C reduction was 54% (p<0.0001) and 49% (p<0.0001) from 3 to 18 months. The data from both studies were published online [4].

Results from the trials also showed low inter-individual variability, where almost 100% of treated patients showed over 30% reduction of LDL-C levels when adjusted to the placebo. Besides, the tolerability and safety profile of inclisiran was comparable to the placebo. According to David Soergel, Novartis’s Global Head of Cardiovascular, Renal and Metabolic Drug Development, the post-hoc analysis of the trials’ results “reinforced [their] view of inclisiran’s therapeutic value and its potential as the first cholesterol-lowering siRNA.”

Inclisiran is a double-stranded small interfering RNA (siRNA) that can be uptaken by hepatocytes, where it can increase LDL-C receptor expression on the cell surface and, thus, lower LDL-C levels in the blood. It does so by blocking the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. Binding of the enzyme to the receptor prevents it from the expression on the cell surface due to sequestering in the lysosome [5].

Thus, RNA interference with inclisiran would decrease the available pool of PCSK9 and increase LDL-C receptor numbers. Inclisiran is administered as a subcutaneous injection that is followed up after 3 months and every 6 months after that. Novartis previously added inclisiran to its R&D pipeline by acquiring The Medicines Company in 2019.

With the positive results from the trials, Novartis is expecting to receive the response from FDA and EMA, where inclisiran is currently under review for the treatment of primary hyperlipidemia in adults with high LDL-C on maximally tolerated doses of statins.

Editor: Rajaneesh K. Gopinath, Ph.D.

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References

1. https://www.novartis.com/news/media-releases/novartis-new-analysis-shows-high-consistency-lowering-ldl-c-individual-response-investigational-inclisiran

Author

Rajaneesh K. Gopinath