Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

Published on Mar 9, 2021in Journal of the American College of Cardiology20.589
· DOI :10.1016/J.JACC.2020.12.058
R. Scott Wright55
Estimated H-index: 55
(Mayo Clinic),
Kausik K. Ray80
Estimated H-index: 80
(Imperial College London)
+ 11 AuthorsOrion Phase Iii Investigators1
Estimated H-index: 1
Sources
Abstract
Abstract Background Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. Objectives The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. Methods Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C–lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. Results A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was −50.7% (95% confidence interval: −52.9% to −48.4%; p  Conclusions These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.
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#1Kausik K. Ray (Imperial College London)H-Index: 80
#2R. Scott WrightH-Index: 55
Last. John J.P. Kastelein (UvA: University of Amsterdam)H-Index: 152
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Abstract Background Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-densit...
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Abstract Background Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascula...
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Abstract Background Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficac...
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