Journal Article

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial

Zhao, Jian, Ballantyne, Christie M., Baum, Seth J., Gewitz, Andrew, Banerjee, Poulabi, Rader, Daniel J., Whitcomb, David C., McGinniss, Jennifer, Rosenson, Robert S., Gaudet, Daniel, Pordy, Robert, Moriarty, Patrick M., Gonzaga-Jauregui, Claudia, Kershaw, Erin E., Ponda, Manish P., Bergeron, Jean, Rubba, Paolo

2023

Overview

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n  = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n  = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n  = 19). Fifty-one patients (males, n  = 27; females, n  = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 . The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/443/319/2723 / 692/699/75/2099 / Acute Disease / Angiopoietin / Biomedical and Life Sciences / Biomedicine / Cancer Research / Clinical trials / Female / Humans / Hyperlipoproteinemia Type I - drug therapy / Hyperlipoproteinemia Type I - genetics / Hypertriglyceridemia / Hypertriglyceridemia - drug therapy / Hypertriglyceridemia - genetics / Infectious Diseases / Lipase / Lipids / Lipoprotein lipase / Lipoprotein Lipase - genetics / Lipoproteins / Male / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Mutation / Mutation - genetics / Neurosciences / Pancreatitis / Pancreatitis - drug therapy / Pancreatitis - genetics / Placebos / Reduction / Risk factors / Single-Blind Method / Triglycerides