Evinacumab Lipid Studies in Patients With Homozygous Familial Hypercholesterolemia - ELIPSE HoFH
Contribution To Literature:
The ELIPSE HoFH trial showed that evinacumab is superior to placebo in reducing LDL-C by approximately 50% among patients with HoFH on maximal tolerated lipid-lowering therapy.
Description:
The current trial sought to study the safety and efficacy of evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, compared with placebo in HoFH patients who were on maximal tolerated doses of a statin but had low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl.
Study Design
Patients were randomized in a 2:1 fashion to either intravenous evinacumab 15 mg/kg every 4 weeks (n = 43) or matching placebo (n = 22). The trial included a run-in period of up to 8 weeks for patients who did not have a diagnosis of homozygous familial hypercholesterolemia (HoFH) and opted to undergo genotyping for confirmation or whose background lipid-lowering therapy or apheresis schedules were not stable before screening.
- Total screened: 75
- Total number of enrollees: 65
- Duration of follow-up: 24 weeks
- Mean patient age: 41.7 years
- Percentage female: 54%
Inclusion criteria:
- Genetic or clinical diagnosis of HoFH
- Age ≥12 years
- Receiving stable lipid-lowering therapy at the maximum dose that did not cause unacceptable side effects
- LDL ≥70 mg/dl
Other salient features/characteristics:
- Genotype-confirmed HoFH: 67%
- Baseline LDL: 255 mg/dl, high-density lipoprotein (HDL) 44 mg/dl, triglycerides 97 mg/dl, apolipoprotein B (apoB) 171 mg/dl
Principal Findings:
The primary effectiveness endpoint, change in LDL-C from baseline for evinacumab vs. placebo, was -47.1% vs. +1.9% (p < 0.001).
- Absolute change in LDL: -134.7 vs. -2.6 mg/dl (p < 0.001)
- Effect was observed at week 2, maintained through 24 weeks
- Effect was similar among null-null and non-null variants
Secondary outcomes for evinacumab vs. placebo:
- Change in apoB from baseline: -41.4 vs. -4.5% (p < 0.001)
- ≥30% reduction in LDL-C: 84% vs. 18% (p < 0.001)
Safety outcomes for evinacumab vs. placebo:
- Flu-like illness: 11% vs. 0%
- Increase in alanine transaminase (ALT)/aspartate transaminase (AST): 5% vs. 10%
- Change in HDL from baseline: -29.6% vs. +0.8%
- No cardiovascular events
Interpretation:
The results of this trial indicate that evinacumab is superior to placebo in reducing LDL-C by nearly 50% among patients with HoFH (baseline LDL-C: 255 mg/dl) on maximal tolerated lipid-lowering therapy, including aphresis. LDL-C was reduced within 2 weeks, and sustained at 24 weeks.
This trial assessed the role of a novel lipid-lowering therapy, evinacumab, which acts as an inhibitor to ANGPTL3. All patients in this trial had HoFH, many of whom have virtually no LDL-C receptor expression. In these patients, statins and PCSK9 inhibitor agents are unlikely to provide meaningful benefit. This trial was small and underpowered for clinical outcomes. It is likely that LDL-C reduction would be associated with clinical benefit, but the effect of profound reduction in HDL-C (nearly 30%) on clinical outcomes will also need to be understood. These novel agents are also likely to be tested in different populations going forward; a comparison with existing therapies such as PCSK9 inhibitors and newer therapies such as inclisiran are also warranted.
References:
Raal FJ, Rosenson RS, Reeskamp LF, et al., on behalf of the ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med 2020;383:711-20.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Alanine Transaminase, Apolipoproteins B, Cholesterol, LDL, Cholesterol, HDL, Dyslipidemias, Genotype, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipids, Lipoproteins, HDL, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9, Triglycerides
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