A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects
Mariko Harada-Shiba, Shazia Ali, Daniel A Gipe, Evelyn Gasparino, Vladimir Son, Yi Zhang, Robert Pordy, Alberico L Catapano, Mariko Harada-Shiba, Shazia Ali, Daniel A Gipe, Evelyn Gasparino, Vladimir Son, Yi Zhang, Robert Pordy, Alberico L Catapano
Abstract
Background and aims: Evinacumab, an angiopoietin-like protein 3 monoclonal antibody, reduced low-density lipoprotein cholesterol (LDL-C) significantly in a Phase 2 study of patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled Phase 1 study, we compared safety, tolerability, pharmacokinetics, and pharmacodynamics of evinacumab between healthy Japanese and Caucasian adults.
Methods: Subjects with LDL-C ≥2.6 and <4.1 mmol/L were enrolled to one of four dose cohorts: evinacumab subcutaneous (SC) 300 mg single dose, SC 300 mg once weekly for eight doses, intravenous (IV) 5 mg/kg, or IV 15 mg/kg once every 4 weeks for two doses. Each cohort comprised 24 subjects (12 Japanese; 12 Caucasian), randomized (3:1) to receive evinacumab or placebo within each ethnic group with a 24-week follow-up.
Results: The safety profile of evinacumab (IV and SC) in both ethnicities was comparable with placebo, with no serious or severe treatment-emergent adverse events. Pharmacokinetic profiles were comparable between Japanese and Caucasian subjects across IV and SC groups. Mean calculated LDL-C decreased from baseline with both IV doses, beginning on day 3 up to week 8. Triglyceride changes observed with evinacumab IV were rapid (seen by day 2) and sustained up to week 8. Evinacumab SC doses also reduced LDL-C and triglyceride levels, although lower doses induced smaller changes. Evinacumab (IV and SC) reduced other lipids, including apolipoprotein B, versus placebo.
Conclusions: In both ethnicities, evinacumab (IV and SC) was generally well tolerated, exhibiting comparable pharmacokinetic profiles. Dose-related reductions in LDL-C and triglycerides were observed with evinacumab in both ethnic groups.
Trial registration: ClinicalTrials.gov NCT03146416.
Keywords: Angiopoietin-like protein 3; Cardiovascular disease; Clinical trial; Evinacumab; Homozygous familial hypercholesterolemia; Lipids and lipoprotein metabolism.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Source: PubMed