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: Sustained 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.

Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.

Design, setting, and participants: Prespecified 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.

Interventions: One 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 measures: Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.

Results: At 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 relevance: Treatment 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 registration: ClinicalTrials.gov identifier: NCT02597127.

Figures

Figure 1.. Time Courses of Percentage Change in PCSK9 and Low-Density Lipoprotein Cholesterol (LDL-C) With Single-Dose and 2-Dose Inclisiran

The data points are means, and the bars indicate 95% confidence intervals. Where appropriate, LDL-C measurements of patients who had returned to within 20% of their change from baseline LDL-C (and therefore no longer had available LDL-C values) were imputed with their individual baseline values.

Figure 2.. Time-Averaged PCSK9 and Low-Density Lipoprotein Cholesterol (LDL-C) Reductions to Day 360 After Single-Dose and 2-Dose Inclisiran

Where appropriate, LDL-C measurements of participants who had returned to within 20% of their change from baseline LDL-C (and therefore no longer had available LDL-C values) were imputed with their individual baseline values.

Figure 3.. Persistence of Response

Defined as days taken for individuals to return to within 20% of their change from baseline low-density lipoprotein cholesterol levels up to day 360.

Figure 4.. Month-to-Month Variation in Low-Density Lipoprotein Cholesterol (LDL-C) Levels Between Day 30 and Day 210

Boxes represent the median and interquartile range of LDL-C values measured throughout the study, and whiskers represent the minimum and maximum measured values.