A novel approach to lowering LDL-cholesterol (LDL-C), with the ribonucleic acid (RNA) interference drug inclisiran, provides significant, dose-dependent and sustained reductions at 180 and 240 days in patients at high cardiovascular risk, according to the results of the ORION-1 study presented at the ACC and simultaneously published in the New England Journal of Medicine.

Investigators evaluated six different doses of inclisiran, which interferes with PCSK9 production, in 501 patients (average age 63 years, 35% women) in the phase 2 double-blind, placebo-controlled trial. About 69% of patients had atherosclerotic cardiovascular disease, 24% had diabetes, 5% had familial hypercholesterolemia and 13% were being treated for primary prevention. When they began the study, 73% of patients were taking a statin and 31% were on ezetimibe.

The primary endpoint of LDL-C reduction at 180 days was reduced by 27.9–41.9% with one subcutaneous injection and by 35.5–52.6% with two injections (p < 0.001). At 240 days, the reductions in PCSK9 and LDL-C remained significantly lower than baseline with all the studied doses of inclisiran. Two injections of the 300mg dose of inclisiran produced the greatest reduction in LDL-C, with 48% of patients receiving this dose achieving an LDL-C level <50mg/dL. The average baseline LDL-C level was 128.2mg/dL and baseline PCSK9 level was 424.3ng/mL.

The rate of serious adverse events was 11% with inclisiran and 8% with placebo. Injection site reaction occurred in 5% of the patients receiving inclisiran. Injections are given every three or six months. The results of this study will inform the dose and dosing regimen for the phase 3 cardiovascular outcomes study with this drug.