ANGPTL4 Inhibition in Adults with Elevated Triglyceride Levels

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and regulates triglyceride-rich lipoprotein metabolism. MAR001 is a monoclonal antibody against ANGPTL4 that is being evaluated for lowering triglyceride levels. METHODS: We conducted a two-part, phase 2b, double-blind, randomized, placebo-controlled trial. In part A, the focus of this report, we enrolled adults who had a nonfasting triglyceride level of at least 175 mg per deciliter and a remnant cholesterol level of at least 35 mg per deciliter at initial screening, followed by a fasting triglyceride level of at least 150 mg per deciliter and a remnant cholesterol level of at least 30 mg per deciliter on confirmatory screening. Participants were randomly assigned in a 1:1:1:1 ratio to receive MAR001 at a dose of 300, 450, or 900 mg or matching placebo subcutaneously every 4 weeks for 24 weeks. The primary end point was the percent change from baseline in the fasting triglyceride level at week 12, reported as the difference between each MAR001 dose group and the placebo group (placebo-adjusted change). RESULTS: A total of 236 participants were enrolled in the trial, with 177 assigned to receive MAR001 and 59 to receive placebo; a total of 235 participants received at least one dose of MAR001 or placebo and were included in the primary efficacy analyses. The mean age of the participants was 60.4 years, and 39% were women. The median triglyceride level at baseline was 249.5 mg per deciliter (interquartile range, 210.0 to 313.0). At week 12, in an intention-to-treat analysis, the placebo-adjusted least-squares mean percent changes in the fasting triglyceride level were -39.1 percentage points, -40.5 percentage points, and -45.3 percentage points for the 300-mg, 450-mg, and 900-mg doses, respectively (P<0.001 for all comparisons). Adverse events occurred in 123 of 177 participants (69%) in the pooled MAR001 group and in 45 of 58 participants (78%) in the placebo group. CONCLUSIONS: Inhibition of ANGPTL4 with MAR001 significantly reduced fasting triglyceride levels at 12 weeks. (Funded by Marea Therapeutics; TYDAL-TIMI 78 ClinicalTrials.gov number, NCT07028749.).