Novartis Reports Positive Pivotal Phase 3 Trial Results for Twice-Yearly Inclisiran in Atherosclerotic Cardiovascular Disease

Source | Jike Yaowen

Novartis Recently Announces Post-Hoc Analysis Results of Pooled Data from Two Pivotal Phase 3 Clinical Trials (ORION-10 and ORION-11) Evaluating Its First-in-Class Cholesterol-Lowering Drug Inclisiran for the Treatment of Hyperlipidemia in Adults. Both trials assessed the efficacy of Inclisiran in lowering low-density lipoprotein cholesterol (LDL-C) levels. The analysis demonstrated that, among patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents who were followed for more than 17 months, Inclisiran exhibited highly consistent LDL-C-lowering effects across individual patients following two initial doses (with the second dose administered three months after the first) and subsequent maintenance therapy via subcutaneous injection every six months. Furthermore, its safety and tolerability profile was comparable to that of placebo.

These analysis results were presented at the 2020 European Society of Cardiology (ESC) Congress. The two Phase 3 trials involved a total of more than 2,300 patients (1,164 of whom received Inclisiran), and this analysis evaluated the efficacy and tolerability of Inclisiran when added to maximally tolerated statin therapy. The results showed that inter-individual variability in the efficacy of Inclisiran was very low; after placebo adjustment, 99% of patients achieved an LDL-C reduction of ≥30%, with a mean reduction of 54.1% from baseline.

At any time point during the study, 88.4% of patients treated with inclisiran achieved at least a 50% reduction in LDL-C levels. On day 510, 66.4% of patients in the inclisiran group achieved at least a 50% reduction in LDL-C levels, compared with only 2.5% in the placebo group. Overall, inclisiran was well tolerated, with a safety profile similar to that of placebo.

The mechanism of action of inclisiran involves binding to the mRNA encoding the PCSK9 protein, thereby reducing mRNA levels through RNA interference and preventing hepatic production of the PCSK9 protein. The PCSK9 protein inhibits the recycling and reuse of LDL receptors. Therefore, 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.

Currently, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are reviewing the marketing authorization applications for Inclisiran. It is indicated for use in combination with diet therapy and statins at the maximum tolerated dose to treat primary hyperlipidemia in adults (including heterozygous familial hypercholesterolemia) by lowering LDL-C. In China, the clinical trial application for this long-acting siRNA lipid-lowering drug, Inclisiran, was accepted in June this year.

References:

[1] Major Update | Latest ESC Data: Inclisiran Potently Lowers LDL-C with High Consistency Across Individual Patients. Retrieved 2020-09-03, from https://mp.weixin.qq.com/s/kA64tKDAMCAz6Ffsp_K9Fg

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