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Randomized Controlled Trial
. 2022 Sep-Oct;16(5):676-684.
doi: 10.1016/j.jacl.2022.07.005. Epub 2022 Jul 21.

Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia

Daniel Gaudet  1 , Andrea Ruzza  2 , Ian Bridges  3 , Paul Maruff  4 , Adrian Schembri  5 , Andrew Hamer  6 , François Mach  7 , Jean Bergeron  8 , Isabelle Gaudet  9 , Julie St Pierre  10 , John J P Kastelein  11 , G Kees Hovingh  12 , Albert Wiegman  13 , Frederick J Raal  14 , Raul D Santos  15
Affiliations
Free article
Randomized Controlled Trial

Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia

Daniel Gaudet et al. J Clin Lipidol. 2022 Sep-Oct.
Free article

Abstract

Background: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients.

Objective: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH.

Methods: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test.

Results: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group.

Conclusion: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition.

Funding: This study was funded and designed by Amgen.

Keywords: Child; Cholesterol; Cognition; Cognitive dysfunction; Evolocumab; FH; Familial hypercholesterolemia; LDL; PCSK9.

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Conflict of interest statement

Declaration of Competing Interest Dr D Gaudet reports receiving consulting fees from HDL Therapeutics, Regeneron Pharmaceuticals, and Sanofi; and grant support from Esperion, Gemphire Therapeutics, HDL Therapeutics, Pfizer, Regeneron Pharmaceuticals, Sanofi, and The Medicines Company. Dr Ruzza reports employment with and holding stock in Amgen; and holding pending patent 63/032451 on PCSK9 inhibitors and methods of use thereof to treat cholesterol-related disorders. Mr Bridges reports employment with and holding stock in Amgen. Dr Maruff and Dr Schembri are employees of Cogstate Ltd., the company that provided the cognitive tests in this study. Dr Hamer reports employment with Cardiol Therapeutics Inc. and holding stock in Amgen. Dr Bergeron reports receiving lecture fees from Amgen and HLS Therapeutics Inc.; grant support from Akcea Therapeutics–Ionis Pharmaceuticals, Amgen, Kowa, Novartis, Regeneron Pharmaceuticals, Sanofi, and The Medicines Company; and serving on the advisory boards for Amgen and Novartis. Dr St Pierre–Takeda, Novo Nordisk, and Bausch Health. Dr Kastelein reports consulting fees from AstraZeneca, CiVi Biopharma, CSL Behring, Draupnir Bio, Esperion, Gemphire Therapeutics, Madrigal Pharmaceuticals, Matinas BioPharma, NorthSea Therapeutics, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, REGENXBIO, Staten Biotechnology, 89bio, OMEICOS Therapeutics, Serometrix. Dr Hovingh reports the following: employment with Novo Nordisk; consulting and speakers bureau fees from Aegerion Pharmaceuticals, Amgen, Regeneron Pharmaceuticals, and Sanofi; grant support from Aegerion Pharmaceuticals, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis Pharmaceuticals, Kowa, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, The Medicines Company; and serving on advisory boards for Aegerion Pharmaceuticals, Amgen, Regeneron Pharmaceuticals, Sanofi. Dr Wiegman reports research support for pharmaceutical trials of lipid-lowering agents from Amgen, Regeneron and Novartis. Dr Raal has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, and Novartis. Dr Santos reports receiving the following: consulting fees and lecture fees from Abbott, Amgen, AstraZeneca, Aché, EMS, Getz Pharma, Libbs, Merck, Merck Sharp & Dohme, PTC Therapeutics, Novo Nordisk, Novartis, Sanofi-Regeneron Pharmaceuticals; grant support from Amgen, Kowa, Esperion, Novartis, Sanofi-Regeneron Pharmaceuticals. The remaining authors have nothing to disclose.

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