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

Abstract

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 .

Fig. 1. CONSORT diagram.

*A total of 17 patients were randomized to placebo; however, one patient who failed screening was erroneously randomized and was withdrawn from the study.

Fig. 2. Study design.

*One patient was randomized but not treated.

Fig. 3. Median percent change in fasting triglycerides.

a–c, Median (Q1 to Q3) percent change in fasting triglycerides from baseline to week 12 by cohort in the DBTP (exploratory end points). a, data for cohort 1; b, data for cohort 2; c, data for cohort 3.

Extended Data Fig. 1. Patient disposition by cohort.

^aIn total, 17 patients were randomized to placebo. However, one patient who failed screening was erroneously randomized and was withdrawn from the study. DBTP, double-blind treatment period; SBTP, single-blind treatment period.

Extended Data Fig. 2. Mean (SD) of total serum evinacumab concentrations by time and treatment group.

The DBTP includes all measurements until week 12 pre-dose; the SBTP includes all measurements from week 12 EOI. During the SBTP, all patients received IV evinacumab 15 mg/kg Q4W. D, day; DBTP, double-blind treatment period; EOI, end of infusion; IV, intravenous; PRE, pre-dose; Q4W, every 4 weeks; SBTP, single-blind treatment period; SD, standard deviation; W, week.

Extended Data Fig. 3. Individual log-scaled fold change from baseline in triglycerides versus log-scaled trough concentrations of total evinacumab.

Fold change is derived as (individual TG value at each timepoint)/(baseline TG value). Concentrations below the LLOQ were set to LLOQ/2. BLQ, below the limit of quantification; LLOQ, lower limit of quantification; N, number of patients; TG, triglyceride.