No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: A meta-analysis of individual patient data

Authors

Philip D. Harvey, University of Miami Leonard M. Miller School of Medicine
Marwan N. Sabbagh, Barrow Neurological InstituteFollow
John E. Harrison, VU University Medical Center, Alzheimer Centre
Henry N. Ginsberg, Columbia University
M. John Chapman, Sorbonne Universite
Garen Manvelian, Regeneron Pharmaceuticals, Inc.
Angele Moryusef, Sanofi S.A.
Jonas Mandel, Sanofi S.A.
Michel Farnier, Point Medical

Document Type

Article

Abstract

Aims: Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtili-sin/kexin type 9 (PCSK9) inhibitor alirocumab. Methods and results: Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n= 1276),orezetimibe (n= 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n= 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age. Conclusions: Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.

Publication Date

2-1-2018

Publication Title

European Heart Journal

ISSN

0195668X

E-ISSN

15229645

Volume

39

Issue

5

First Page

374

Last Page

381

PubMed ID

29186504

Digital Object Identifier (DOI)

10.1093/eurheartj/ehx661

Recommended Citation

Harvey, Philip D.; Sabbagh, Marwan N.; Harrison, John E.; Ginsberg, Henry N.; Chapman, M. John; Manvelian, Garen; Moryusef, Angele; Mandel, Jonas; and Farnier, Michel, "No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: A meta-analysis of individual patient data" (2018). Neurology. 963.
https://scholar.barrowneuro.org/neurology/963