Angiopoietin-like protein 3 inhibitor reduces LDL-c in homozygous FH

Introduction and methods

News - Mar. 31, 2020

Evinacumab Significantly Reduces LDL-C In Patients With Homozygous Familial Hypercholesterolemia

Presented at ACC.20 by Prof. Frederick Raal, PhD (Johannesburg, South Africa)

Homozygous Familial Hypercholesterolemia (HoFH) is a genetic disorder usually caused by loss of function mutations in the LDL receptor. Standard lipid-lowering therapies, such as statins and PCSK9 inhibitors, act mainly by the upregulation of LDL receptor function. Most HoFH patients are unresponsive or respond poorly to these therapies. Evinacumab is a fully human monoclonal antibody inhibitor of angiopoietin-like protein 3 (ANGPTL3) that reduces LDL-c independent of the LDL receptor.

This pivotal phase 3 trial evaluated the safety and efficacy of evinacumab in HoFH patients ≥12 years of age on stable maximally tolerated lipid-lowering therapies with LDL-c ≥70 mg/dL. Patients were randomized 2:1 to receive either evinacumab 15 mg/kg IV every 4 weeks (n=43) or placebo IV every 4 weeks (n=22). There was a double-blind treatment period of 24 weeks followed by an open-label treatment period of 24 weeks in which all patients received evinacumab.

The primary endpoint was the percentage change in calculated LDL-c from baseline to week 24 during the double-blind treatment period.

Main results

  • Treatment with evinacumab resulted in a rapid reduction in LCL-c that was already evident at week 2. Patients in the evinacumab group had a least square (LS) mean percentage change in LDL-c of -47.1% (SE: 4.6) at week 24. Patients in the placebo group had a percentage change in LDL-c of +1.9% (SE: 6.5). The difference between groups was -49.0% (SE:8.0, P<0.0001).
  • Patients receiving evinacumab had an average absolute reduction in LDL-c of 132 mg/dL.
  • The study further compared patients who had very minimal residual LDL receptor activity and who do not respond to PCSK9 inhibitor therapy (null/null), with patients with some residual LDL receptor function (not null/null). This study showed that the reduction in LDL-c with evinacumab was very similar in null/null patients compared to not null/null patients.
  • Safety results showed that treatment-emergent adverse events occurred in 81.0% of patients in the placebo group and in 65.9% of patients in the evinacumab group. Two serious adverse events occurred in the evinacumab group, but both were not considered related to evinacumab. No adverse events resulted in death or discontinuation of the studied drug.


This study showed that evinacumab significantly reduces LDL-c in patients with HoFH, regardless of LDL receptor function. Furthermore, evinacumab was generally well-tolerated. Evinacumab could therefore be an effective treatment option for HoFH patients who have high LDL-c levels despite being on multiple lipid-lowering therapies. The long-term safety of evinacumab will be further investigated in the open-label treatment period of the trial.


The results that evinacumab rapidly reduces LDL-c in patients who do not respond to PCSK9 inhibitors and that these reductions were maintained over the course of the therapy are impressive, according to discussant Eileen Handberg, PhD (Gainesville, FL, USA). Information about the effect of evinacumab in patients with different genotypes is very important in moving this field forward, as stated by Handberg. She further mentioned that long-term safety of the studied drug is extremely important, as these patients will need to use medications over the course of a lifetime. In future studies it would be interesting and important to investigate whether evinacumab could also work as a stand-alone therapy, instead of an additive to other lipid-lowering therapies.

- Our coverage of ACC.20 is based on the information provided during the congress –

Watch a video by prof. Raal

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