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Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia
Robert S Rosenson1, Lesley J Burgess2, Christoph F Ebenbichler3
1Metabolism and Lipids Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York.
Insights
Evinacumab significantly reduced LDL-C levels in patients with refractory hypercholesterolemia over 72 weeks. This lipid-lowering therapy was generally well tolerated, offering sustained cardiovascular risk reduction.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Refractory hypercholesterolemia poses increased atherosclerotic cardiovascular disease (ASCVD) risk.
- Maximally tolerated lipid-lowering therapies (LLTs) may not achieve guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds.
Purpose of the Study:
- To evaluate the longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia.
- Assess sustained LDL-C reduction and other lipid parameters with evinacumab treatment.
Main Methods:
- Randomized clinical trial with double-blind and open-label treatment periods.
- Patients received intravenous evinacumab (15 mg/kg every 4 weeks) during a 48-week open-label treatment period.
- Efficacy measured by changes in LDL-C and other lipids; safety assessed via treatment-emergent adverse events.
Main Results:
- Evinacumab (15 mg/kg) sustained LDL-C reduction by 45.5% at week 72.
- Significant reductions observed in apolipoprotein B, non-high-density lipoprotein cholesterol, total cholesterol, and triglycerides.
- Treatment-emergent adverse events occurred in 81.3% of patients; serious events were rare and unrelated to treatment.
Conclusions:
- Evinacumab provides sustained efficacy in lowering LDL-C in patients with refractory hypercholesterolemia.
- The drug was generally well tolerated, supporting its role in managing difficult-to-treat lipid disorders.
Importance:
Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD).
Objective:
To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia.
Design, Setting, And Participants:
This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs.
Interventions:
All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W.
Main Outcomes And Measures:
Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs).
Results:
A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment.
Conclusions And Relevance:
In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03175367.
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