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- Title:
Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.
- Document type:
- Article; Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't
- Author(s):
- Wright, R Scott; Ray, Kausik K; Raal, Frederick J; Kallend, David G; Jaros, Mark; Koenig, Wolfgang; Leiter, Lawrence A; Landmesser, Ulf; Schwartz, Gregory G; Friedman, Andrew; Wijngaard, Peter L J; Garcia Conde, Lorena; Kastelein, John J P
- 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 < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. 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.
- Journal title abbreviation:
- J Am Coll Cardiol
- Year:
- 2021
- Journal volume:
- 77
- Journal issue:
- 9
- Pages contribution:
- 1182-1193
- Fulltext / DOI:
- doi:10.1016/j.jacc.2020.12.058
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/33663735
- Print-ISSN:
- 0735-1097
- TUM Institution:
- 273; Klinik für Herz- und Kreislauferkrankungen im Erwachsenenalter (Prof. Schunkert)
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