Evinacumab lowers triglyceride levels in severe hypertriglyceridaemia

Evinacumab resulted in a dramatic reduction in fasting triglyceride levels compared with placebo in a small phase 2 study, but treatment response varied by genotype [1]. Severe hypertriglyceridaemia (sHTG), defined as a fasting triglyceride level of ≥500 mg/dL, is a known risk factor for acute pancreatitis.

Angiopoietin-like protein 3 (ANGPTL3) helps to regulate plasma lipid levels via the inhibition of lipoprotein lipase (LPL) and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids [2]. A loss-of-function (LOF) variant of the ANGPTL3 gene results in lower levels of blood triglycerides. Evinacumab is a fully human monoclonal antibody inhibitor of ANGPTL3.

A phase 2, randomised, placebo-controlled trial (NCT03452228) explored the feasibility of evinacumab as a therapeutic option for sHTG. The trial assigned 51 patients to 1 of 3 different cohorts; cohort 1 (n=17) comprised patients with familial chylomicronaemia syndrome (FCS) and LOF mutations of the LPL pathways; cohort 2 (n=15) contained patients with multifactorial chylomicronaemia syndrome (MCS) in addition to LPL pathway LOF mutations; and cohort 3 (n=19) consisted of patients with MCS but no known LPL pathway mutations. Baseline characteristics were well-balanced between the cohorts.

The treatment protocol consisted of a 12-week double-blind treatment period followed by a 12-week single-blind treatment period. Participants were randomised at a 2:1 ratio in each cohort and received either intravenous (IV) placebo every 4 weeks or IV 15 mg/kg evinacumab every 4 weeks. Prof. Robert Rosenson (Icahn School of Medicine, NY, USA) presented the primary endpoint results from the double-blind treatment period in cohort 3.

The primary endpoint was change in serum triglyceride levels at week 12 among participants in cohort 3. At week 12, the least squares mean reduction in triglyceride was -27.1% (95% CI -71.2 to 84.6), and the corresponding median reduction in triglyceride was -68.8% (95% CI -84.1 to -38.8); an absolute median triglyceride reduction of 905 mg/dL.

Thus, in patients with sHTG due to MCS but with no known LOF mutations in LPL pathways, evinacumab significantly decreased the levels of fasting triglyceride. However, the response was variable across genotypes. Further investigation is warranted to better understand these differences. The investigators also called for further investigation into the effects of evinacumab in people with sHTG, in particular those who experienced acute pancreatitis. A phase 2b trial is already planned (NCT04863014) to assess evinacumab’s ability to prevent acute pancreatitis.

1. 
   
   1. Rosenson RS. A Phase 2 Trial of the Efficacy and Safety of Evinacumab in Patients with Severe Hypertriglyceridemia. Abstract 406-19, ACC 2021 Scientific Session, 15–17 May.
   2. Tikka A, Jauhiainen M. Endocrine 2016;52(2):187–193.

 

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Posted on 9 July, 202127 March, 2024