Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins: pre-specified secondary end points in ORION 1

Background -The ORION-1 trial demonstrated that inclisiran, a small interfering RNA (siRNA) therapeutic that targets PCSK9 mRNA within hepatocytes, produces significant LDL-C reduction. The effects of inclisiran on other lipids are less well described. Methods -ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens vs placebo. Participants with elevated LDL-C despite receiving maximally tolerated statin therapy received a single- (200, 300 or 500mg) or two-dose starting regimen (100, 200 or 300mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non-HDL-C, apoB, VLDL-C, Lp(a), TG, HDL-C and ApoA1 at the primary efficacy timepoint (day 180) using mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, inter-individual variation in response, and lipid goal attainment. Results -The mean age of the 501 participants was 63 years; 65% were male; 69% had atherosclerotic cardiovascular disease; 73% used statins; mean LDL-C was 128mg/dL. A single dose of inclisiran reduced apoB, non-HDL-C, and VLDL-C over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non-HDL-C was lowered dose-dependently, by 25% from 148 ( ±43) mg/dL to 110 (±45) mg/dL in the 200mg single-dose group and by 46% from 161 (±58) mg/dL to 91 (±58) mg/dL in the two-dose 300mg group; for the same dosing regimens apoB was reduced by 23% from 101 (±23) to 78 (±29) mg/dL and by 41% from 106 (±31) to 65 (±33) mg/dL (p<0.001 for all groups vs placebo). In the 300mg two-dose group, all individuals experienced apoB- and non-HDL-C reductions. There was larger inter-individual variation in VLDL-C, triglycerides and Lp(a) reductions. In the 300mg two-dose group, the percentage of patients achieving guideline-recommended apoB goals for high- and very high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL cholesterol <100 mg/dL and <130 mg/dL. Conclusions -Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting synthesis of PCSK9 through siRNA may be a viable alternative to other approaches which target PCSK9. Clinical Trial Registration -URL: https://www.clinicaltrials.gov. Unique identifier: NCT02597127