Abstract 16512: Alirocumab Treatment Was Not Associated With a Higher Risk of Neurocognitive Events in 3340 High and Very High Cardiovascular Risk Patients
Introduction: Subjective cognitive complaints have been reported by patients receiving lipid-lowering therapies (LLTs) such as statins. However, clinical trials of LLTs have offered no objective evidence to support this or an association with low LDL-C levels. We examined pooled data from 4 Phase 2 and 10 Phase 3 trials of alirocumab (ALI) 75 or 150 mg Q2W vs control (duration 8–104 wks; n=5234) to determine incidence of neurocognitive adverse events (AEs) with ALI.
Methods: In most studies, patients with hypercholesterolemia received maximally tolerated statin +/- other LLTs. All Phase 2 and 5 Phase 3 studies compared ALI vs placebo (PBO); 5 Phase 3 studies compared ALI vs ezetimibe (EZE). Neurocognitive AEs were self-reported by patients, confirmed by investigators and in the current analysis, categorized using a sponsor-proposed custom MedDRA query.
Results: 3340 patients received ALI (4029 patient-yrs exposure). Mean age was 58.5–62.1 yrs across groups. The incidence of neurocognitive AEs was 0.9% for ALI vs 0.7% for PBO (hazard ratio [HR] 1.24; 95% CI 0.57–2.68) and 1.2% for ALI vs 1.3% for EZE (HR 0.81; 95% CI 0.32–2.08) (Table). Rates of neurocognitive AEs were similar in ALI patients with two consecutive LDL-C levels <25 mg/dL (n = 5/839; 0.6%; 0.5/100 patient-yrs) vs ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-yrs). Zero and 1 (0.1%) ALI patients (PBO and EZE pools, respectively) had a neurocognitive AE leading to discontinuation, vs 2 (0.2%) PBO and 3 (0.4%) EZE patients. One PBO patient had a severe neurocognitive AE vs none with ALI or EZE. Across groups, neurocognitive AE rates were highest for age ≥75 yrs (3.9–6.9%) and lowest for <65 yrs (0.3–0.8%), with no significant difference between treatments.
Conclusions: In this study with 4029 patient-yrs exposure to ALI, rates of neurocognitive AEs were low overall (≤1.3%) with no significant differences between ALI vs control groups up to 104 wks. No association was found between neurocognitive AEs and LDL-C <25 mg/dL.
Author Disclosures: P.D. Harvey: Research Grant; Significant; Takeda pharma. Consultant/Advisory Board; Modest; Sunovion, Lindbeck, Roche, Acadia. Consultant/Advisory Board; Significant; Boeheringer Ingelheim, Sanofi, Takeda. M. Sabbagh: Research Grant; Significant; AstraZeneca, Avid Pharmaceuticals, Axovant, Genetech, Lilly Pharmaceuticals, Merck & Co, Pfizer, Piramal Imaging, Roche Diagnostics Corporation, vTv Therapeutics. Consultant/Advisory Board; Modest; Axovant, Biogen, FORUM Pharmaceuticals, Fujirebio Diagnostics, Humana, Lilly Pharmaceuticals, Sanofi. Consultant/Advisory Board; Significant; vTv Therapeutics. Other; Significant; Brain Health-Stock shareholder, Muses Labs-Stock shareholder, Versanum-Stock shareholder. J.E. Harrison: Employment; Significant; Metis Cognition Ltd. Research Grant; Modest; Memorabel. Speakers Bureau; Modest; Medscape, Lundbeck. Ownership Interest; Modest; MyCognition (patent), Neurotrack (share options). Consultant/Advisory Board; Modest; Abbvie, A2Q, Amgen, Anavex, AstraZeneca, Avonex, Avraham, Axon, Axovant, Biogen Idec, Boehringer Ingelheim, Catenion, CRF Health, DeNDRoN, Enzymotec, ePharmaSolutions, Eisai, Eli Lilly, Forum Pharma, GfHEu, Heptares, Janssen AI, Johnson & Johnson, Kaasa Health, Kyowa Hakko Kirin, MedAvante, Merck, Mind Agilis, Neurocog, Neurim, Neurotrack, Nutricia, Orion Pharma, Pharmanet/i3, Pfizer, Prana Biotec, PriceSpective, Probiodrug, Prophase, Prostrakan, Reviva, Roche, Servier, Shire, Takeda, TCG, TransTech Pharma, Velacor. Consultant/Advisory Board; Significant; Bracket, Lundbeck, MyCognition, Novartis, Sanofi, Takeda. Other; Modest; Royalties from Oxford University Press & Blackwell Publishers. H.N. Ginsberg: Research Grant; Significant; Merck, Sanofi, Regeneron, Amgen. Consultant/Advisory Board; Modest; Amarin, Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, ISIS, Janssen, Kowa, Merck, Novartis, Sanofi, Regeneron, Pfizer. J.M. Chapman: Research Grant; Significant; Kowa, Pfizer, CSL. Speakers Bureau; Significant; Amgen, Kowa, MSD, Regeneron, Sanofi. Honoraria; Significant; Amgen, MSD, Regeneron, Pfizer, Sanofi. G. Manvelian: Employment; Significant; Regeneron Pharmaceuticals Inc. A. Moryusef: Employment; Significant; Sanofi. J. Mandel: Other; Significant; Contractor for Sanofi mandated by IviData Stats. M.A. Farnier: Other Research Support; Significant; Sanofi, Regeneron, Amgen, Merck and Co. Speakers Bureau; Modest; Mylan. Speakers Bureau; Significant; Sanofi, Regeneron, Amgen, Merck and Co, Pfizer. Consultant/Advisory Board; Modest; Eli Lilly, AstraZeneca, Kowa, Akcea/Ionis. Consultant/Advisory Board; Significant; Sanofi, Regeneron, Pfizer, Amgen, Merck and Co.
- © 2016 by American Heart Association, Inc.