Regeneron Announces Positive Phase 3 Results of ANGPTL3 Inhibitor Evinacumab, Reducing LDL Cholesterol by 49% in HoFH Patients

Regeneron Announces Positive Phase 3 Trial Results for Evinacumab in Patients with Homozygous Familial Hypercholesterolemia (HoFH) Published in The New England Journal of Medicine (NEJM)Regeneron Pharmaceuticals, Inc. announced today that The New England Journal of Medicine (NEJM) has published the positive results from a Phase 3 clinical trial of evinacumab in 65 patients with homozygous familial hypercholesterolemia (HoFH). Evinacumab is an investigational drug that binds to and inhibits the function of angiopoietin-like protein 3 (ANGPTL3). It demonstrates significant efficacy even in HoFH patients with little or no low-density lipoprotein (LDL) receptor activity. Currently, the Biologics License Application for evinacumab has been granted Priority Review by the U.S. Food and Drug Administration (FDA), with a decision expected by February 11 next year.

Patients with homozygous familial hypercholesterolemia (HoFH) exhibit severely elevated levels of “bad” cholesterol (low-density lipoprotein cholesterol, LDL-C), which increases their risk of premature atherosclerotic cardiovascular disease and cardiac events as early as adolescence. Treatment guidelines recommend early, intensive LDL-C lowering; however, many HoFH patients carry genetic mutations that cause dysfunction or absence of LDL receptors, resulting in a poor response to lipid-lowering therapies that rely on upregulating LDL receptor activity.

Trial data published in the NEJM demonstrated that the study met its primary endpoint. At week 24 of treatment, patients receiving evinacumab in addition to other lipid-lowering therapies (n=43) achieved a 49% reduction in LDL-C levels from baseline, compared with those receiving placebo plus other lipid-lowering therapies (n=22) (a 47% reduction with evinacumab versus a 2% increase with placebo; p<0.0001). In their NEJM paper, the researchers noted that genetic deficiency of ANGPTL3 is associated with additional lipid-lowering effects, including reductions in triglycerides, apolipoprotein B (ApoB), HDL and non-HDL cholesterol, and total cholesterol levels. Treatment with evinacumab mirrored these lipid-lowering effects.

▲ Patients treated with evinacumab showed a significant reduction in LDL-C levels (Image source: Reference [2])

Researchers also evaluated the efficacy of evinacumab in a post hoc analysis among patients with virtually absent (<2%) LDL receptor activity, who had a mean baseline LDL-C level of 258 mg/dL (n=10). In these patients, evinacumab reduced LDL-C by 72% from baseline compared with placebo (a 54% reduction with evinacumab versus a 19% increase with placebo; p=0.005).

“Although patients with homozygous familial hypercholesterolemia (HoFH) receive multiple lipid-lowering therapies, the vast majority never achieve target LDL-C levels, and their risk of premature heart disease remains elevated due to persistently high LDL-C levels,” said Professor Derick J. Raal, Head of the Department of Endocrinology and Metabolism at the University of the Witwatersrand in South Africa and principal investigator of the clinical trial. “If approved, evinacumab would represent a significant advance in the treatment of HoFH patients with substantial unmet needs.”

References:

[1] NEW ENGLAND JOURNAL OF MEDICINE PUBLISHES POSITIVE PHASE 3 EVINACUMAB RESULTS IN PATIENTS WITH SEVERE INHERITED FORM OF HIGH CHOLESTEROL. Retrieved August 20, 2020, from https://investor.regeneron.com/news-releases/news-release-details/new-england-journal-medicine-publishes-positive-phase-3

[2] Raal et al., (2020). Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med,

DOI: 10.1056/NEJMoa2004215

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