NEJM Publishes Positive Results from Regeneron’s Trial of HoFH Therapy

Rare Daily Staff

The New England Journal of Medicine published positive results from a late-stage trial of Regeneron’s evinacumab in 65 patients with homozygous familial hypercholesterolemia, a rare genetic condition that causes elevated levels of so-called bad cholesterol.

Evinacumab is an experimental drug that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3). It is the first medicine of its kind to show efficacy in patients with homozygous familial hypercholesterolemia (HoFH), including patients with little to no low-density lipoprotein (LDL) receptor function.

Patients with HoFH have severely elevated levels of low-density lipoprotein cholesterol, or LDL-C, which increases their risk for cardiovascular disease as early as their teenage years. Treatment guidelines recommend early and intensive LDL-C lowering, but standard lipid-lowering therapies are generally ineffective or inadequate for people with HoFH. This includes statins and PCSK9 inhibitors.

As previously announced, the trial met its primary endpoint, showing that patients who added evinacumab to other lipid-lowering therapies reduced their LDL-C from baseline by 49 percent compared to lipid-lowering therapies alone at week 24.

At the same time point, evinacumab-treated patients also decreased LDL-C from baseline by 132 mg/dL compared to placebo.

The publication noted that the loss of ANGPTL3 has been associated with additional lipid-lowering effects, including lowered triglycerides, apolipoprotein B, HDL and non-HDL cholesterol, and total cholesterol. Evinacumab treatment mirrored these lipid-lowering effects.

“The vast majority of my patients with HoFH never reach their target LDL-C despite taking multiple lipid-lowering therapies, and they remain at increased risk of premature heart disease because of their persistently high LDL-C levels,” said Derick Raal, principal investigator and head of the division of Endocrinology and Metabolism at the University of the Witwatersrand, South Africa. “If approved, evinacumab will provide a major step forward for the treatment of patients with HoFH who have significant unmet needs.”

Researchers also assessed in a post hoc analysis the effect of evinacumab in patients with nearly non-existent LDL-receptor activity, whose mean baseline LDL-C levels were 258 mg/dL. Among these patients, evinacumab reduced LDL-C by 72 percent from baseline compared to placebo.

During the double-blind treatment period, 66 percent of evinacumab patients and 81 percent of placebo patients experienced at least one adverse event. Adverse events that occurred in at least 5 percent of patients, and more commonly with evinacumab, were influenza-like illness (11 percent evinacumab, no one on placebo) and rhinorrhea (7 percent evinacumab, no one on placebo). There were no deaths, major adverse cardiovascular events, or discontinuations due to adverse events.

“Today’s publication further demonstrates how evinacumab, through its novel mechanism of action, was able to reduce LDL-C levels in patients with all forms of HoFH, even those with nearly no LDL-receptor activity,” said George Yancopoulos, co-founder, president and chief scientific officer at Regeneron. “This validates our genetic-based approach, where Regeneron ANGPTL3 genetic research directly led to evinacumab, which we hope can become the standard of care in the treatment of HoFH.”

Regeneron’s application for approval to market evinacumab is under Priority Review with the U.S. Food and Drug Administration. The agency is expect to issue a decision by February 11, 2021. The agency previously granted Breakthrough Therapy designation to evinacumab for the treatment of hypercholesterolemia in patients with HoFH. Other regulatory submissions are ongoing.

Photo: George Yancopoulos, co-founder, president and chief scientific officer at Regeneron