Evinacumab Cuts LDL Cholesterol in Homozygous FH

Hope for these hard-to-treat patients: more than half saw ≥ 50% decrease at 24 weeks, regardless of LDL receptor function.

Hope for these hard-to-treat patients: more than half saw ≥ 50% decrease at 24 weeks, regardless of LDL receptor function.

Evinacumab (Regeneron), a fully human monoclonal antibody inhibitor of angiopoietin-like protein 3 (ANGPTL3), substantially lowers LDL cholesterol in patients with homozygous familial hypercholesterolemia (FH), regardless of their LDL receptor function, and the novel drug does so with few side effects, a new study shows.

Homozygous FH is a rare genetic condition caused by LDL receptor loss-of-function mutations that prevent LDL cholesterol from being cleared from the circulation. Patients with this disease are hard to treat since they are generally less responsive to standard lipid-lowering therapies, including potent PCSK9 inhibitors, and often have to resort to LDL apheresis.

“Evinacumab may provide an effective treatment option for patients with homozygous FH who are unable to achieve target LDL cholesterol despite multiple conventional lipid-lowering therapies with or without apheresis,” said Frederick Raal, MBBCh, PhD (University of the Witwatersrand, Johannesburg, South Africa), who presented the findings Monday during the virtual American College of Cardiology 2020 Scientific Session. “Limitations of the study include the relatively short duration, particularly for conclusions regarding long-term safety of evinacumab. However, evinacumab safety is being further assessed in the open-label treatment period of the trial.”

Rapid and Lasting LDL-Cholesterol Decrease

For the study, Raal and colleagues enrolled 65 patients aged 12 years or older with homozygous FH and LDL cholesterol levels  greater than 70 mg/dL at screening. Following an 8-week run-in period for stabilization of background lipid-lowering therapy, 43 patients were randomized to receive evinacumab 15 mg/kg intravenously every 4 weeks and 22 to placebo. After a double-blind treatment period of 24 weeks, there was an open label period extension of 24 weeks where all patients received the study drug.

Mean patient age was 36.7 years in the placebo arm and 44.3 years in the study group, with just over half the population being female. The vast majority of patients had a history of coronary heart disease. More than two-thirds had some residual LDL receptor function—non-null/null genotype status—while about 30% had minimal or no LDL receptor function—null/null genotype status.

More than 90% were on statins, more than two-thirds were on ezetimibe, about 20% were taking lomitapibe, and just over one-third were on apheresis. Despite these treatments, mean patient LDL cholesterol and apoB levels at entry were about 250 mg/dL and about 170 mg/dL, respectively.

Evinacumab treatment resulted in a rapid and lasting decrease in LDL cholesterol compared with placebo from baseline to week 24 during the double-blind treatment period.

Outcomes in Homozygous FH Patients





P Value

% Change in LDL-C




< 0.0001

Absolute Change in LDL-C, mg/dL




< 0.0001

Patients With ≥ 30% Reduction in LDL-C




< 0.0001

Patients With ≥ 50% Reduction in LDL-C





Patients With LDL-C < 100 mg/dL





Evinacumab also significantly reduced apoB by 36.9%, non-HDL cholesterol by 51.7%, total cholesterol by 48.4%, and triglycerides by 50.4% (P < 0.0001 for all). However, the study drug did not have an effect on Lp(a).

When the researchers evaluated patients with null/null mutations specifically, the reduction in LDL cholesterol achieved was comparable to those with some residual LDL receptor activity.

“In terms of safety, there was very little difference between treatment emergent adverse events between those receiving placebo and evinacumab,” Raal said, noting that there were two serious adverse events—urosepsis and a suicide attempt—both in the evinacumab group, but neither was considered to be related to the study drug. Overall, 29% of patients receiving evinacumab and 17% receiving placebo reported any treatment-emergent adverse event, but none resulted in death or discontinuation during the study.

‘A Definite Advance’

Commenting after the presentation, Anne Carol Goldberg, MD (Washington University School of Medicine in St. Louis, MO), said “one of the major remarkable things about this study is the effect of evinacumab in the patients who are null/null, since most of the other medications we have aside from apheresis and lomitapibe involve upregulation of the LDL receptor. So this is a definite advance.”

Given that such a large percentage of study patients were able to achieve an LDL cholesterol level below 100 mg/dL, she asked how many were able to get to below 70 mg/dL.

“That would be a smaller percentage,” Raal replied. “About a third were receiving apheresis, so if they were still on apheresis, the addition of this therapy allowed many more to get to that target of below 70 mg/dL. Without apheresis, the percentage was less, but it's really the first time we are able to see patients with homozygous FH getting to these targets that we never thought would be possible in the past.”

Goldberg also questioned why evinacumab seemed to have “very little effect on Lp(a) as compared to what you can see sometimes with the PCSK9s, [where] also it’s not clear why they lower Lp(a).”

Raal said this likely speaks to evinacumab’s mechanism of action. “What we thought possibly why PCSK9 inhibitors work is that with marked upregulation of the LDL receptor there is probably some clearance of lipoprotein(a),” he said. “It doesn't explain, for example, how lomitapibe reduces Lp(a), so it was rather surprising that there was no change in Lp(a) seen in this study. But I think it really talks to a totally different mechanism of action [with] evinacumab probably clearing LDL cholesterol via a nonreceptor mechanism.”

With regard to side effects, Goldberg asked if evinacumab was associated with any of the flu-like symptoms, like malaise or slight fever, sometimes seen with PCSK9 inhibitors. “I'm wondering if you could speculate on whether you think this just represents a problem with foreign protein, a monoclonal antibody, or if you think there is some implication with regard to mechanisms [of] either the PCSK9 monoclonal antibody or evinacumab,” she said.

“Remarkably this drug was very well tolerated,” Raal replied, noting an advantage of evinacumab is that it given less often than the PCSK9 inhibitors. “If you can get away with giving an infusion once a month, as opposed to LDL apheresis, which is required every fortnight or often weekly, I think it's a huge advantage because the reduction seen, a 50% reduction, you don’t even achieve with fortnightly LDL apheresis.”

He added that while the data so far cannot give any clues as to outcomes, “with these sorts of reductions in LDL—and we believe LDL is the main cause in terms of the atherosclerosis—we’re hoping in the long term this will result in substantial benefit in terms of reduced cardiovascular events in the future. But unfortunately, that's going to need a longer-term follow-up in a bigger cohort of patients.”

A Singular Agent?

During a press conference, Eileen Handberg, PhD, ARNP-BC (University of Florida, Gainesville), called this study “truly sort of groundbreaking in terms of this population—the fact that they are able to go for a different mechanism in the patients who have not been able to be responsive to a PCSK9 inhibitor.” While the reductions in LDL were quite impressive, she continued, “the fact that they occurred so rapidly and remained over the course of therapy I think is extremely important.”

She agreed that gaining long-term data for evinacumab is important, especially because homozygous FH is not “a transient disease process but something that these patients are going to need over the course of their lifetime.”

Handberg’s concerns stem not from the trial specifically but from the intensive treatment load, and costs, in this patient population. “Here we again have another therapy that is going to be costly, and so how [are] these patients going to be able to have this type of therapy on top of the expensive medical therapy that they are already on for cholesterol-lowering?” she asked. “It would be interesting to know if some of the other drugs could be taken away with this treatment.”

Perhaps another trial is warranted to “figure out whether or not it truly needs to be additive or perhaps . . . this could be a singular agent in this population,” Handberg concluded. “The reductions are amazing, the tolerability seems to be well tolerated with no significant adverse events to speak of, and I look forward to seeing longer-term data with this compound.”


  • Raal F. Evinacumab in patients with homozygous familial hypercholesterolemia. Presented on: March 30, 2020. ACC 2020.

  • The study was funded by Regeneron Pharmaceuticals.
  • Raal reports receiving grants from Regeneron during the conduct of the study and personal fees from Amgen, Sanofi-Aventis, Regeneron, and The Medicines Company outside the submitted work.