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Study Summary

This randomized, double-blind, placebo-controlled, phase 2 trial evaluated the efficacy of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, on patients with refractory hypercholesterolemia (LDL-cholesterol ≥70 mg/dL with atherosclerosis or ≥100 mg/dL without atherosclerosis) who were currently taking maximal tolerated doses of lipid-lowering therapies. In total, 272 patients were randomly assigned to one of 7 groups: 2 placebo groups and 5 treatment arms with varying dosing, routes of administration (subcutaneous and intravenous), and timing. Change from baseline in the LDL-cholesterol level (the primary end point) was measured at week 16; the groups assigned to receive maximal dose evinacumab showed a least-squares mean difference (versus placebo) of approximately -50% (P <0.001; see accompanying Hurst’s Central Illustration). There was a 3 - 16% serious adverse event rate observed across all experimental groups.


Study Strengths: The design of the study provided excellent variability in the administration of the study drug, allowing dosing effect and administration strategy to be optimized when planning a phase 3 trial. The trial included patients with heterozygous familial hypercholesterolemia and those without, making the trial more applicable to both populations. The patient population was also well managed on maximal lipid lowering therapy, including over 95% of the patients in the trial on a PCSK9 inhibitor, and a large proportion of participants were female (~60%).

Study Limitations: A limitation of this phase 2 trial is the short follow-up (16 weeks); it is unclear whether the observed effect of evinacumab is sustained in the long term. In addition, no clinical outcomes were tested in this trial. A further limitation is that a very small proportion of the study population were black (2%) or Asian (2%); whether the effect can be observed in a more diverse population is not yet known.

Next Steps/Clinical Perspective: This study supports the potential use of evinacumab in patients with refractory hypercholesterolemia. Evinacumab significantly reduced the LDL-cholesterol level, by more than 50% at the maximum dose. In addition to the primary end point, the study also showed potential for this medication to significantly reduce apoB and triglyceride levels. However, the study showed a decrease in HLD-C levels of approximately 20-30 % and the clinical significance of the observed drop in HDL-cholesterol remains unknown.

Overall, this trial shows the potential benefit of a novel class of lipid lower agents when added to current maximal medical therapy. Yet, phase 3 trials are needed to show long-term efficacy and sustainability amongst a much larger study population. In addition, the drug needs to be trialed with the primary outcome of clinical event rates, as we do not yet know the clinical significance of the observed laboratory effect of decrease in LDL levels.

Trial Reference

Rosenson  RS, Burgess  LJ, Ebenbichler  CF,  et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med doi:10.1056/NEJMoa2031049

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