ANGPTL3 Inhibitor Goes the Extra Mile in Homozygous FH

A novel monoclonal antibody against ANGPTL3 achieved large LDL cholesterol reductions in homozygous familial hypercholesterolemia (HoFH), according to the small ELIPSE HoFH trial.

Evinacumab injections cut LDL cholesterol by 47.1% from baseline to week 24, compared with a 1.9% increase with placebo over this period (P<0.001), reported a team of researchers led by Frederick Raal, MD, PhD, of the University of the Witwatersrand in Johannesburg, South Africa.

The 49.0% relative between-group difference in LDL corresponded to an absolute difference of -132.1 mg/dL (P<0.001). LDL cholesterol reduction was observed as early as 2 weeks into evinacumab therapy. Patients in the evinacumab group also had significantly greater reductions in apolipoprotein B, non-HDL cholesterol, and total cholesterol than those in the placebo group.

“These reductions were achieved regardless of the use of extensive background lipid-lowering therapies with or without apheresis,” the investigators emphasized.

Topline results of ELIPSE HoFH had been released last year and the full report is now published in the Aug. 20 issue of New England Journal of Medicine.

“It is well established that LDL cholesterol levels predict cardiovascular risk and that cardiovascular benefit from lipid-lowering therapies is proportional to the absolute reduction in the LDL cholesterol level,” Raal’s group said.

Evinacumab was accepted for priority review by the FDA just last week. A decision on approval is expected by Feb. 11, 2021, for an indication in the ultra-rare genetic disorder that results in low or absent LDL receptor activity.

ELIPSE HoFH was conducted at 30 sites in 11 countries. The double-blind trial had participants randomized 2:1 to evinacumab (IV infusion every 4 weeks at a dose of 15 mg/kg body weight) or placebo.

The 65 patients with HoFH included were on stable lipid-lowering therapy. Mean age was 41.7 years, and women made up 54% of the group.

Average LDL cholesterol was 255.1 mg/dL at baseline, despite most patients being on statins (94%), a PCSK9 inhibitor (77%), and ezetimibe (Zetia, 75%). One-third were undergoing apheresis.

Significant reductions in LDL cholesterol were shown by both HoFH patients with null-null variants (-43.4% vs +16.2% with placebo) and those with non-null variants (-49.1% vs -3.8%).

“This finding is important because patients with null-null variants have a higher cardiovascular risk and are less responsive to therapies that depend on LDL-receptor activity than those with non-null variants,” according to Raal and colleagues.

The investigators observed similar adverse event rates between groups (66% with evinacumab vs 81% with placebo).

“No patients discontinued either evinacumab or placebo because of an adverse event; there were no deaths. Antidrug antibodies did not develop during the treatment period in any of the patients,” they noted, adding that neither group suffered any cardiovascular events over follow-up.

There was more flu-like illness in the evinacumab arm. And two serious adverse events occurred: one a case of urosepsis and the other a suicide attempt.

Assessed as a safety outcome, HDL cholesterol was reduced by 29.6% after 24 weeks of evinacumab treatment, compared with an increase of 0.8% on placebo — in line with prior studies on the ANGPTL3 inhibitor.

“Whether this decrease in HDL-C offsets some of the clinical benefit of LDL-C reduction is uncertain. In prior studies, individuals with loss-of-function variants of ANGPTL3 have lower levels of LDL-C, HDL-C, and triglycerides compared with controls, and lower odds of developing atherosclerotic cardiovascular disease (despite the lower HDL-C levels),” according to Dhruv Kazi, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

Long-term cardiovascular outcomes trials will be needed, commented Jennifer Robinson, MD, MPH, of University of Iowa in Iowa City.

As helpful as that would be, it is “unlikely given the rarity of this clinical condition (and its devastating clinical consequences),” Kazi told MedPage Today.

PCSK9 inhibitors and statins have been noted to increase HDL to a modest degree, in the 10% range.

“Our trial was not designed to assess the effect of treatment on a reduction in clinical events, but the absolute reduction in LDL cholesterol levels was substantial,” Raal’s group added.

The trial was limited by the relatively short treatment period and small sample.

An ongoing open extension study is expected to provide additional information regarding the safety of evinacumab, Kazi noted.

For now, he said, it appears on track to become an “important third- or fourth-line therapy” for HoFH after statins, ezetimibe, and PCSK9 inhibitors.