Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials.

Background: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol.
Objectives: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran.
Methods: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed.
Results: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs.
Conclusions: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.
Competing Interests: Funding Support and Author Disclosures This study was sponsored by Novartis Pharma AG. Dr Wright has received advisory board fees from Boehringer Ingelheim; and has received past fees for consulting on lipid issues with The Medicines Company. Dr Koenig has received consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; has received consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi-Sankyo, New Amsterdam Pharma, and TenSixteen Bio; 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 Landmesser has received lecture fees and advisory fees from AstraZeneca, Boehringer Ingelheim, Sanofi, Berlin-Chemie, and Abbott; has received advisory fees from The Medicines Company; and has received grant support, lecture fees, and advisory fees from Amgen, Bayer, and Novartis. Dr Leiter has received grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; has received fees for serving on a steering committee and advisory board fees 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; and has received advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, Pfizer, and Sanofi. Dr Raal has received advisory board fees and lecture fees from Amgen, Sanofi, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. Dr Schwartz has received research support paid to his institution from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, 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. Drs Lesogor, Maheux, Stratz, Zang, and Ray were employed by Novartis at the time of analysis. Dr Ray has received support from the National Institute for Health and Care Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the National Institute for Health and Care Research Applied Research Collaboration Northwest London; 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 and 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.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)