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

Key PointsQuestionCan inclisiran reduce mean low-density lipoprotein cholesterol (LDL-C) exposure with an infrequent dosing regimen, thereby offering sustained LDL-C lowering with infrequent dosing? FindingsIn this prespecified analysis of a randomized clinical trial, 1 dose of inclisiran lowered time-averaged LDL-C levels over 1 year by 29.5% to 38.7%, and 2 doses at day 1 and day 90 lowered time-averaged LDL-C over 1 year by 29.9% to 46.4% in a dose-dependent manner. A 50% LDL-C reduction was maintained for at least 6 months after 2 doses of 300 mg on day 1 and day 90. MeaningThrough potent and durable lowering of LDL-C with a twice-a-year dosing regimen, inclisiran could offer a sustained lipid-lowering therapeutic option in the future. ImportanceSustained 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. ObjectiveTo determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen. Design, Setting, and ParticipantsPrespecified 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. InterventionsOne 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. Main Outcomes and MeasuresDuration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year. ResultsAt baseline, among the 501 participants, 65% were men (n=326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n=28 of 501), and 69% had established ASCVD (n=347 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<.001 between groups) and from 29.9% to 46.4% (P<.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. Conclusions and RelevanceTreatment 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. Trial RegistrationClinicalTrials.gov identifier: NCT02597127 This prespecified analysis of a randomized clinical trial analyzes whether inclisiran, a small interfering RNA, reduces mean low-density lipoprotein cholesterol exposure with an infrequent dosing regimen.