The Medicines Company announced topline results from the pivotal phase 3 ORION-11 study that evaluated the efficacy and safety of inclisiran, an investigational twice-yearly cholesterol-lowering therapy.
Inclisiran is a chemically synthesized small interfering RNA (siRNA) that targets proprotein convertase subtilisin-kexin type 9 (PCSK9) messenger RNA. The subcutaneous (SC) injectable is being investigated for its ability to lower low-density lipoprotein cholesterol (LDL-C) through twice-a-year dosing.
In ORION-11, patients (N=1617) with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C despite maximum tolerated dose of statin therapy (with or without ezetimibe) were randomized to receive either inclisiran 300mg subcutaneously or placebo on Day 1, Day 90, and then every 6 months up to Day 540. The primary end points of the study were the percentage change in LDL-C from baseline to Day 510 and the time-adjusted percent change in LDL-C from baseline after Day 90 to Day 540.
Results showed inclisiran met both primary end points, achieving a placebo-adjusted LDL-C reduction of 54% (P <.0001) at Day 510 and a time-averaged placebo-adjusted LDL-C reduction of 50% (P <.0001) from Day 90 up to Day 540. Regarding safety, the proportion of adverse events was observed to be similar between the placebo and inclisiran treatment arms, however a difference was noted in the incidence of fatal and non-fatal myocardial infarctions (2.7% vs 1.2%, respectively) and fatal and non-fatal strokes (1.0% vs 0.2%, respectively). According to the Company, full detailed data will be submitted to a peer-reviewed journal.
“The results of the ORION-11 trial support the unprecedented potential of inclisiran to deliver assurance to clinicians and patients that LDL-C can be lowered in a sustained fashion over the long-term with an infrequent dosing regimen and an excellent safety profile,” said Kausik Ray, MD, principal investigator of ORION-11, professor of public health and Consultant Cardiologist at Imperial College London. “This is a groundbreaking new approach for preventing atherosclerotic cardiovascular disease with exciting implications at a population health level.”
The Company is currently conducting an open-label, long-term extension study (ORION-8) to investigate the efficacy and safety of inclisiran over the course of 3 years in patients who have completed the respective phase 3 ORION-9, ORION-10, and ORION-11 studies. The Company plans to submit a New Drug Application with the Food and Drug Administration in the fourth quarter of 2019.
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