TG reduction with ANGPTL3 antibody in patients with severe hypertriglyceridemia
A Phase 2 Trial of the Efficacy and Safety of Evinacumab in Patients with Severe Hypertriglyceridemia
Presented at ACC.21 by Robert Rosenson (New York, NY, USA)
Introduction and methods
Severe hypertriglyceridemia (sHTG) is defined as fasting triglycerides ≥500 mg/dL and it is a causal risk factor for acute pancreatitis (AP). Patients who had sHTG-related AP are at high risk of recurrent episodes requiring hospital admission. Evinacumab, a human monoclonal antibody directed to ANGPTL3, interferes in the inhibition of lipoprotein lipase and endothelial lipase by ANGPTL3. LOF mutations in ANGPTL3 have shown to significantly reduce triglyceride (TG) and other atherogenic lipoprotein levels.
In this phase 2 study the efficacy and safety of evinacumab was examined in patients with sHTG who had ≥1 prior hospitalization for AP.
Patients with sHTG were enrolled (medical history of fasting TGs ≥1000 mg/dL and during the trial fasting TGs ≥500 mg/dL). They were on a stable diet and lipid-lowering therapy.
51 Patients were categorized in 3 cohorts based on genotype according to presence of LOF mutations in LDL pathway genes: cohort consisted of 1 - 17 patients with familial chylomicronemia syndrome (FCS; bi-allelic LOF mutations in LPL or LPL-related genes), cohort 2 consisted of 15 patients with multifactorial chylomicronemia syndrome (MCS; heterozygous for LOF mutations in LPL or LPL-related genes, and cohort 3 consisted of 19 patients with MCS without LPL pathway mutations, most likely polygenetic hypertriglyceridemia.
Patients were randomized in a 2:1 ratio to evinacumab 15 mg/kg every 4 weeks or to placebo. The primary endpoint was the change in serum TGs from baseline to week 12.
- Patients with two traits of LOF variants in cohort 1 showed no response to evinacumab.
- Patients in cohort 2 with MCS showed a significant reduction in TG levels (~65%) as did patients in cohort 3 (~80%).
- TEAEs occurred in a similar rate in the evinacumab and placebo groups. Use of evinacumab 15 mg/kg was insufficient in some patients to maintain drug levels at the end of 4 weeks and TGs increased. These patients had repeat AP episodes.
In patients with sHTG but without FCS, treatment with evinacumab resulted in reduced fasting TG levels, but reductions were variable and dependent on genotype. In some patients drug levels of evinacumab were low at 4 weeks, and they had recurrent AP episodes.These findings support further assessment of effects of evinacumab in patients with sHTG. A higher dose of evinacumab will be studied; 20 mg/kg IV every 4 weeks in a phase 2b study.
The discussant Sahil Parikh, MD (New York, NY, USA) said that besides TG reduction, a reduction in HDL was observed in this patient cohort. The implications of this need further investigation in longer follow up and with HDL subfractionation. This will be important to understand with regard to CV outcomes.
- Our coverage of ACC.21 is based on the information provided during the congress –