Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol

Abstract

BACKGROUNDIn a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODSWe conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTSA total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONSIn our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. Original ArticleThe New England Journal of Medicine Downloaded from nejm.org at IMPERIAL COLLEGE LONDON on May 3, 2017. For personal use only. No other uses without permission.Copyright © 2017 Massachusetts Medical Society. All rights reserved.n engl j med 376;15 nejm.org April 13, 2017 1431Inclisir an in Patients with Elevated LDL Cholesterol L ow-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Statins have been shown to reduce LDL cholesterol levels and cardiovascular events in large outcome trials, findings that have made them the therapeutic cornerstone of clinical practice.1 Despite the proven efficacy of statins, there is considerable variability in individual responses to these drugs.2 Furthermore, some observational data suggest that as many as half of persons who begin statin therapy discontinue it within a year.3 Moreover, among patients receiving statin therapy who are at high...

Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): A New Promising Approach for the Management of Hypercholesterolemia

“…In the ORION-1 Phase 2 trial, at 180 days after administration, a single dose of inclisiran 500 mg decreased the blood PCSK9 levels by 59.3%, LDL-C levels by 41.9%, and total cholesterol levels by 26.6%. Inclisiran was well tolerated with similar numbers and proportions of adverse events reported in the inclisiran and placebo arms [22].…”

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