Study Summary

Inclisiran is a small interfering double-stranded RNA (siRNA) that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) production in the liver. The ORION-91 and ORION-102 studies were phase 3, double-blinded, randomized, controlled trials designed to compare inclisiran with placebo among patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD), respectively. In both trials, patients were randomly assigned 1:1 to inclisiran 300 mg or placebo. The study drug was given as a subcutaneous injection on days 1, 90, 270, and 450. The duration of follow-up was 18 months.

In ORION-9, all patients with HeFH received maximally tolerated statins and ezetimibe and had suboptimal LDL control (> 70 mg/dl) at baseline. Mean age was 56 years, 53% were female. Prior or planned use of a PCSK9 inhibitor was a major exclusion criterion. The primary outcome, percentage change in LDL-cholesterol level at day 510, was -41% in patients who received inclisiran (n = 242) and +8% in the placebo arm (n = 240) (P <0.0001). The absolute difference was 71 mg/dl of LDL cholesterol. No safety signals or major toxicities were observed. Mild adverse skin reactions occurred more frequently with inclisiran than placebo (13.7% vs 0.4%; P < 0.05).

In ORION-10, patients with ASCVD received either maximally tolerated statin therapy or were intolerant of statins. All patients had suboptimal LDL control (> 70mg/dl) at baseline. Prior or planned use of a PCSK9 inhibitor was a major exclusion criterion. The mean age of patients was 66 years, 30% were female, and 45% had diabetes. The primary outcome, percentage change in LDL-cholesterol level at day 510, was -56% in patients receiving inclisiran (n = 781) and +1% in the placebo arm (n = 780) (P <0.0001). Adverse skin events occurred in 2.6% of the inclisiran group and 0.9% of the placebo group.

Commentary

Study Strengths: Together, the ORION studies show that twice yearly injections of inclisiran, resulted in a significant reduction in LDL cholesterol among patients with HeFH and those with ASCVD. In both trials, the safety profile of inclisiran was similar to that of placebo, with the exception of mild site-related skin reactions. No serious adverse events occurred, including liver, muscle, or kidney toxicity.

Study Limitations: Neither of the trials included cardiovascular events as a prespecified primary endpoint.

Next Steps/Clinical Perspective: The magnitude of reduction in LDL cholesterol was similar to that observed with PCSK9 inhibitors. Longer clinical trials, powered for cardiovascular event-related outcomes, are now needed to determine whether inclisiran therapy, which can be administered only twice yearly, will translate into improved clinical benefit for patients.

Trial References

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Presented by Frederick  J. Raal at the American Heart Association Annual Scientific Sessions (AHA 2019); Philadelphia, PA, USA; November 18, 2019.
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Presented by R. Scott  Wright at the American Heart Association Annual Scientific Sessions (AHA 2019); Philadelphia, PA, USA; November 18, 2019.