Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Abstract

Importance\nSustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.\n\n\nObjective\nTo determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.\n\n\nDesign, Setting, and Participants\nPrespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.\n\n\nInterventions\nOne dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.\n\n\nMain Outcomes and Measures\nDuration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.\n\n\nResults\nAt baseline, among the 501 participants, 65% were men (n\u2009=\u2009326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n\u2009=\u200928 of 501), and 69% had established ASCVD (n\u2009=\u2009347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P\u2009<\u2009.001 between groups) and from 29.9% to 46.4% (P\u2009<\u2009.001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.\n\n\nConclusions and Relevance\nTreatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.\n\n\nTrial Registration\nClinicalTrials.gov identifier: NCT02597127.