Evinacumab in Patients With Refractory Hypercholesterolemia - Evinacumab for Refractory Hypercholesterolemia

Dec 10, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Regeneron Pharmaceuticals, Inc.
Date Presented:
11/15/2020
Date Published:
12/09/2020
Date Updated:
12/10/2020
Original Posted Date:
11/15/2020
References

Contribution To Literature:

The trial showed that evinacumab is superior to placebo in reducing LDL-C among patients with refractory hypercholesterolemia despite being on statins (with or without ezetimibe) and PCSK9 inhibitors (baseline LDL-C: ~150 mg/dl). Reductions were noted with both subcutaneous and intravenous regimens in a dose-dependent fashion.

Description:

The trial sought to study the safety and efficacy of evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, compared with placebo in patients who had refractory hypercholesterolemia despite maximal doses of statin ± ezetimibe and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor.

Study Design

This was a phase II trial. Patients were randomized in a 1:1:1:1 fashion to either subcutaneous (SC) evinacumab 450 mg every week (n = 40), evinacumab 300 mg every week (n = 43), evinacumab 300 mg every 2 weeks (n = 39), or matching placebo every week (n = 41). The trial included a run-in period of up to 8 weeks.

Similarly, patients were randomized in 1:1:1 fashion to intravenous (IV) evinacumab 15 mg/kg Q4W (n = 39), vs. evinacumab 5 mg/kg Q4W (n = 36), vs. placebo Q4W (n = 34). After 24 weeks, all three groups received open-label evinacumab 15 mg/kg for 24 weeks.

  • Total number of enrollees: 160 (SC), 106 (IV)
  • Duration of follow-up: 16 weeks
  • Mean patient age: 54 years
  • Percentage female: 62% (SC), 56% (IV)

Inclusion criteria:

  • Diagnosis of primary hypercholesterolemia (either heterozygous familial hypercholesterolemia [HeFH] or non-HeFH) with clinical atherosclerotic cardiovascular disease (ASCVD)
  • Age 18-80 years
  • Receiving stable lipid-lowering therapy with statin (± ezetimibe) at the maximum dose that did not cause unacceptable side effects for at least 4 weeks
  • PCSK9 inhibitor for at least 8 weeks
  • Low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or 100 mg/dl with or without clinical ASCVD, respectively

Exclusion criteria:

  • Known history of homozygous familial hypercholesterolemia (HoFH)
  • Other medication or nutracetical known to alter serum lipids
  • LDL apheresis within 2 months
  • Severe endocrine disease known to influence serum lipids/lipoproteins

Other salient features/characteristics:

  • White: 91% (SC), 94% (IV)
  • HeFH: 72% (SC), 81% (IV)
  • Baseline LDL: 150 mg/dl, high-density lipoprotein (HDL) 54 mg/dl, triglycerides (TG) 115 mg/dl, apolipoprotein B (apoB) 116 mg/dl (SC)
  • Baseline LDL: 145 mg/dl, HDL 55 mg/dl, TG 122 mg/dl, apoB 114 mg/dl (IV)
  • Any statin: 61.9%, high-dose statin: 44%, ezetimibe 30%, PCSK9 inhibitor 100% (SC)
  • Any statin: 83%, high-dose statin: 52%, ezetimibe 38%, PCSK9 inhibitor 96% (IV)

Principal Findings:

SC arms:

  • The primary effectiveness endpoint, least-squares mean percent change in LDL-C from baseline for evinacumab 450 QW vs. evinacumab 300 mg QW vs. evinacumab 300 mg Q2W vs. placebo: −47.2 vs. −44.0 vs. −29.7 vs. +8.8
  • Least-squares mean percent change in LDL-C vs. placebo for evinacumab 450 QW vs. evinacumab 300 mg QW vs. evinacumab 300 mg Q2W: −56% vs. 52.9% vs. −38.5% (p < 0.001 for all)

IV arms:

  • The primary effectiveness endpoint, least-squares mean percent change in LDL-C from baseline for evinacumab 15 mg/kg q4W vs. evinacumab 5 mg/kg Q4W vs. placebo: −49.9% vs. −23.5% vs. +0.6%
  • Least-squares mean percent change in LDL-C vs. placebo for evinacumab 15 mg/kg Q4W vs. evinacumab 5 mg/kg Q4W: −50.5% (p < 0.001) vs. −24.2% (p = 0.019)

Secondary outcomes:

SC arms:

  • Change in apoB from baseline to week 16 vs. placebo for evinacumab 450 QW vs. evinacumab 300 mg QW vs. evinacumab 300 mg Q2W: −45.5% vs. −42% vs. −26.6% (p < 0.001)
  • Change in triglycerides from baseline to week 16 vs. placebo for evinacumab 450 QW vs. evinacumab 300 mg QW vs. evinacumab 300 mg Q2W: −61.5% vs. −55.8% vs. −46.1% (p < 0.001)

IV arms:

  • Change in apoB from baseline to week 16 vs. placebo for evinacumab 15 mg/kg Q4W vs. evinacumab 5 mg/kg Q4W: −39.4% vs. −16.6%
  • Change in triglycerides from baseline to week 16 vs. placebo for evinacumab 15 mg/kg Q4W vs. evinacumab 5 mg/kg Q4W: −45.9% vs. −25.2%

Safety:

  • SC arms: Nausea: 10% vs. 2.4% vs. 10.3% vs. 7.7%
  • IV arms: Nasopharyngitis: 16.2% vs. 8.3% vs. 6.1%

Interpretation:

The results of this trial indicate that evinacumab is superior to placebo in reducing LDL-C among patients with refractory hypercholesterolemia despite being on statins, ezetimibe, and PCSK9 inhibitors (baseline LDL-C: ~150 mg/dl). Reductions were noted with both SC and IV regimens in a dose-dependent fashion. LDL-C was reduced within 2 weeks, and sustained at 16 weeks.

This trial assessed the role of a novel lipid-lowering therapy, evinacumab, which acts as an inhibitor to ANGPTL3. 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 reduction in HDL-C 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:

Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in Patients With Refractory Hypercholesterolemia. N Engl J Med 2020;383:2307-19.

Editorial: Martin SS. Factoring in ANGPTL3 When LDL Is Refractory. N Engl J Med 2020;383:2385-6.

Presented by Dr. Robert S. Rosenson at the American Heart Association Virtual Scientific Sessions, November 15, 2020.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: AHA20, AHA Annual Scientific Sessions, Antibodies, Monoclonal, Apolipoproteins B, Atherosclerosis, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Nasopharyngitis, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9, Triglycerides


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