TY - JOUR
T1 - Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis
AU - Wright, R. Scott
AU - Ray, Kausik K.
AU - Raal, Frederick J.
AU - Kallend, David G.
AU - Jaros, Mark
AU - Koenig, Wolfgang
AU - Leiter, Lawrence A.
AU - Landmesser, Ulf
AU - Schwartz, Gregory G.
AU - Friedman, Andrew
AU - Wijngaard, Peter L. J.
AU - Garcia Conde, Lorena
AU - ORION Phase III Investigators
AU - Kastelein, John J. P.
N1 - Funding Information: The analyses presented here were funded by Novartis Pharma AG. Statistical analysis was carried out by Summit Analytical, with funding from Novartis Pharma AG, Basel. Dr. Wright has received support from the Mayo Clinic and U.S. Department of Health and Human Services (HHS), Biomedical Advanced Research and Development Authority (BARDA) contract 75A50120C00096; has received fees for serving on steering committees from Boehringer Ingelheim and The Medicines Company; and has nonfinancial conflicts with AstraZeneca and Novartis. Dr. Ray has received support from the NIHR Imperial Biomedical Research Centre; has received lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; has received grant support, paid to his institution, lecture fees, and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; has received lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; has received fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; has received advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi-Sankyo; has received lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr. Reddy’s Laboratories; has received grant support and advisory board fees from Merck Sharp & Dohme; has received fees for serving on a clinical events adjudication committee from AbbVie; and has received fees for serving as principal investigator for a trial from Resverlogix. Dr. Raal has received advisory board fees and lecture fees from Amgen, Sanofi, Regeneron Pharmaceuticals, and The Medicines Company. Dr. Kallend was employed by and held stock options in The Medicines Company at the time of study; and was employed by DalCor Pharmaceuticals at the time of publication. Dr. Jaros has received fees for providing statistical analysis for trials from The Medicines Company and Novartis. Dr. Koenig has received consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; has received consulting fees from Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, and Daiichi-Sankyo; has received lecture fees from Berlin-Chemie, Bristol Myers Squibb, and Sanofi; and has received grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr. Beckmann Pharma. Dr. Leiter has received grant support paid to his institution, advisory board fees, and fees for CME from Amgen, Eli Lilly, and Regeneron Pharmaceuticals/Sanofi; has received fees for serving on a steering committee from Esperion; has received grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company, and Novartis; has received advisory board fees and fees for CME from Merck; and has received advisory board fees from HLS Therapeutics. Dr. Landmesser has received lecture fees and advisory fees from AstraZeneca, Amgen, Sanofi, Berlin Chemie, Novartis, and Abbott; has received advisory fees from The Medicines Company; and has received grant support, lecture fees, and advisory fees from Bayer. Dr. Schwartz has received research support, paid to his institution, from AstraZeneca, Resverlogix, Roche, and The Medicines Company; and has a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado. Dr. Friedman was employed by and held shares and stock options in The Medicines Company at the time of the study; and was employed by Novartis at the time of publication. Dr. Wijngaard was employed by and held shares and stock options in The Medicines Company at the time of the study; and was employed by and held shares and stock options in Novartis at the time of publication. Dr. Kastelein has received consulting fees from Akcea Therapeutics, AstraZeneca, CiVi Biopharma, Corvidia Therapeutics, CSL Behring, Daiichi-Sankyo, Draupnir Bio, Esperion, Gemphire Therapeutics, Madrigal Pharmaceuticals, Matinas BioPharma, NorthSea Therapeutics, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, REGENXBIO, Staten Biotechnology, and 89bio. Dr. Garcia Conde was employed by Novartis at the the time of publication. Publisher Copyright: © 2021 American College of Cardiology Foundation Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/9
Y1 - 2021/3/9
N2 - 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.
AB - 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.
KW - ASVCD
KW - RNA silencing
KW - inclisiran
KW - lipid-lowering therapy
KW - low-density lipoprotein cholesterol
UR - http://www.scopus.com/inward/record.url?scp=85101309304&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jacc.2020.12.058
DO - https://doi.org/10.1016/j.jacc.2020.12.058
M3 - Article
C2 - 33663735
VL - 77
SP - 1182
EP - 1193
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 9
ER -