Clinical Trials Analysis Finds Evinacumab Could Reduce Triglyceride-Rich Lipoprotein

Robert Rosenson, MD
Credit: Cura Foundation

Use of evinacumab (Evkeeza) could reduce triglyceride-rich lipoprotein levels among patients with dyslipidemia, according to an analysis of 3 randomized clinical trials.

An analysis of a pair of phase 2 trials and the phase 3 ELIPSE trial, results suggest use of evinacumab was associated with reductions across all evinacumab-treated patient groups, with the highest doses of evinacumab associated with reductions of 50% or greater from baseline.

“In this post-hoc analysis of three separate clinical trials, treatment with evinacumab in patients with hypercholesterolemia or hypertriglyceridemia showed a reduction from baseline in [triglyceride-rich lipoprotein] levels. These data indicate that [triglyceride-rich lipoproteins] could be a future target for lipid-lowering therapies,” wrote investigators.

An angiopoietin-like 3 (ANGPTL3) inhibitor, evinacumab received initial approval from the FDA in 2021 as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to treat adult and pediatric patients aged 12 years and older with HoFH based on the ELIPSE trial. The first agent in its class to receive an indication from the FDA, evinacumab received a label expansion in March 2023 to include children aged 5 to 11 years of age.

Led by Robert Rosenson, MD, Director of Cardiometabolic Disorders at Icahn School of Medicine at Mount Sinai and an investigator in the pivotal ELIPSE trial, a team of investigators sought to evaluate how evinacumab might influence triglyceride-rich lipoprotein, which a growing evidence base suggests could have a causal relationship with atherosclerotic cardiovascular disease (ASCVD). The trials of interest in the current study were the phase 3 ELIPSE trial, a phase 2 trial of patients with severe hypertriglyceridemia and a phase 2 trial of patients with refractory hypercholesterolemia with or without ASCVD.

The primary outcome of interest for the study was change in triglyceride-rich lipoprotein levels from baseline to 12, 16, or 24 weeks for the phase 2 hypertriglyceridemia trial, the phase 2 refractory hypercholesterolemia trial, and the phase 3 ELIPSE trial, respectively. For the purpose of analysis, triglyceride-rich lipoprotein levels were calculated as total cholesterol minus HDL-C minus LDL-C. The trials secondary outcomes were changes other lipid parameters at the aforementioned time points.

Eligibility criteria overview:

• Phase 2 Hypertriglyceridemia: Fasting Triglycerides ≥ 500 mg/dL
• Phase 2 Refractory Hypercholesterolemia: LDL-C ≥ 70 mg/dL or ≥ 100 mg/dL for those with or without ASCVD
• Phase 3 ELIPSE: HoFH and LDL-C ≥ 70 mg/dL

Upon analysis, results indicated reductions in mean triglyceride-rich lipoprotein levels were observed in all evinacumab treatment arms, with reductions of 50% or greater from baseline observed at the greatest doses. Results also indicated levels of non-HDL-C and HDL-C were reduced from baseline among evinacumab-treated patients in all 3 trials.

In contrast, increases in mean triglyceride-rich lipoprotein levels were observed from baseline in most placebo treatment groups. Investigators pointed out an increase in LDL-C was observed among patients receiving evinacumab in the severe hypertriglyceridemia trial, which they note is “consistent with the broader role of evinacumab in [triglyceride-rich lipoprotein] metabolism, and may be due to the enhanced conversion of very-low density lipoprotein particles to low-density lipoprotein particles, and reduction in ApoCIII”.

Investigators called attention to multiple limitations in the study to consider. These included using a formula to calculate triglyceride-rich lipoprotein levels instead of direct measurement and the inclusion of patients with different clinical disorders from trials with varying eligibility criteria.

“These results are in addition to those previously showing that, for patients with HoFH, evinacumab can effectively reduce LDL-C, non-HDL-C, ApoB, and ApoCIII levels. Therefore, [triglyceride-rich lipoproteins] may be a target for future [lipid-lowering therapies],” investigators wrote.

References:

1. Rosenson RS, Rader DJ, Ali S, Banerjee P, McGinniss J, Pordy R. Evinacumab Reduces Triglyceride-Rich Lipoproteins in Patients with Hyperlipidemia: A Post-Hoc Analysis of Three Randomized Clinical Trials. Cardiovasc Drugs Ther. Published online March 6, 2024. doi:10.1007/s10557-024-07567-z
2. Center for Drug Evaluation and Research. FDA approves add-on therapy for patients with genetic form of severely high cholesterol. U.S. Food and Drug Administration. February 11, 2021. Accessed March 21, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0.
3. Regeneron Pharmaceuticals Inc. FDA approves first-in-class Evkeeza® (evinacumab-dgnb) for young children with ultra-rare form of high cholesterol. Regeneron Pharmaceuticals Inc. March 22, 2023. Accessed March 21, 2024. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-first-class-evkeezar-evinacumab-dgnb-young-children.