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Effect of 1 or 2 Doses of Inclisiran on LDL-C
Study Questions:
Does inclisiran, a small interfering RNA administered subcutaneously, reduce mean low-density lipoprotein cholesterol (LDL-C) exposure with an infrequent dosing regimen?
Methods:
This is a prespecified analysis of ORION-1, a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Eligible participants had either a history of atherosclerotic cardiovascular disease (ASCVD) with LDL-C >70 mg/dl or ASCVD risk equivalents (e.g., type 2 diabetes or familial hypercholesterolemia) with LDL-C >100 mg/dl despite maximally tolerated statin therapy. Participants were followed monthly for LDL-C level by ultracentrifugation (β quant) 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. Patients were administered one dose (200, 300, or 500 mg on day 1) or two doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. The primary outcome was 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), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28), and 69% had established ASCVD (n = 347). Baseline LDL-C was 128 mg/dl. 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% to 65% for those receiving a single dose, and between 56% and 83% of those receiving two doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 30% to 39% (p < 0.001 between groups) and from 30% to 46% (p < 0.001 between groups) for those who received two doses. The two-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:
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.
Perspective:
In contrast to the commercially available PCSK9 antibodies, which block the PCSK9 enzyme that has been produced, inclisiran blocks the expression of the gene that leads to intracellular formation of PCSK9. The ability to reduce dosing from 26 per year to 2 per year is attractive. Although safety was reportedly good, only 250 patients on active drug were followed for 1 year in this study. And considering the mechanism is not the same as the PCSK9 antibody, data would seem inadequate to claim it is safe; in particular, adverse liver function, impact on statin safety, and off-target effects if the drug stays in the liver for long periods of time. A 5-year outcome study in 15,000 patients with ASCVD is ongoing to establish safety and impact on CV events.
Keywords: Atherosclerosis, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Metabolic Syndrome, Proprotein Convertases, Primary Prevention, RNA, Small Interfering, Subtilisins, Ultracentrifugation
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