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Cited by 140Lipid metabolism and disordersPancreatitis Pathology and TreatmentLipoproteins and Cardiovascular Health

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial

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Rosenson, Robert S., Gaudet, Daniel, Ballantyne, Christie M., Baum, Seth J., Bergeron, Jean, Kershaw, Erin E., Moriarty, Patrick M., Rubba, Paolo +9 more·2023·Nature Medicine
DOI 10.1038/s41591-023-02222-wPMC PMC10033404
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Abstract

Abstract Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .

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  • ANGPTL3 inhibition is associated with reductions in HDL-C levels.

    “Notably, ANGPTL3 inhibition is also associated with reductions in HDL-C levels, an effect whose clinical significance is uncertain; whether this translates into any impact on cardiovascular outcomes remains to be determined [54].”

    From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [54]

    Table 2 (Results; page unavailable) shows mean HDL-C reductions from baseline in all three evinacumab-treated cohorts. However, the Results state that HDL-C was not substantially affected, and the differences from placebo were not statistically significant. The unqualified association with HDL-C reduction overstates this trial’s finding. (LLM, conf=0.83)

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  • Evinacumab reduces triglyceride levels by 50 to 70% in early-phase trials involving patients with severe or refractory hypertriglyceridemia.

    “Evinacumab also reduces triglyceride levels, with observed reductions ranging from 50 to 70% in early-phase trials involving patients with severe or refractory HTG [54–56].”

    From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [54]

    The Results (Efficacy of triglyceride lowering; page unavailable) report median reductions of 64.8% in cohort 2 and 68.8% in a post hoc analysis of cohort 3, supporting the claimed range for some patients with severe hypertriglyceridemia. But responses differed across cohorts: the week-12 median reduction was 27.7% in cohort 1 and 81.7% in cohort 3, and the prespecified primary endpoint was not met. Thus 50–70% does not describe the trial's full range of observed reductions. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In a phase 2 trial (NCT03452228), intravenous evinacumab 15 mg/kg every 4 weeks resulted in highly variable, but sometimes marked TG reductions, up to 70-80%, in patients with multifactorial chylomicronemia without LPL loss-of-function variants, whereas modest effect was observed in those with complete LPL deficiency.

    “In a phase 2 trial (NCT03452228) [108], intravenous evinacumab 15 mg/kg every 4 weeks resulted in highly variable, but sometimes marked TG reductions, up to 70–80%, in patients with multifactorial chylomicronemia without LPL loss-of-function variants, whereas modest effect was observed in those with complete LPL deficiency.”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [108]

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    Experimental — accuracy not yet measured

  • ANGPTL3 inhibition may reduce the burden of triglyceride-rich lipoproteins and their atherogenic remnants by enhancing LPL-mediated lipolysis and remnant clearance.

    “By enhancing LPL-mediated lipolysis and remnant clearance, evinacumab and related agents may reduce the burden of TRLs and their atherogenic remnants, making them attractive candidates for addressing residual CVD risk [54, 55].”

    From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [54]

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Authors
Rosenson, R. S., Gaudet, D., Ballantyne, C. M., Baum, S. J., Bergeron, J., Kershaw, E. E., Moriarty, P. M., Rubba, P., Whitcomb, D. C., Banerjee, P., Gewitz, A., Gonzaga-Jauregui, C., McGinniss, J., Ponda, M. P., Pordy, R., Zhao, J., & Rader, D. J.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Université de Montréal (CA)
  • Baylor College of Medicine (US)
  • Florida Atlantic University (US)
  • Centre hospitalier universitaire de Québec (CA)
  • University of Pittsburgh (US)
  • University of Kansas Medical Center (US)
  • Federico II University Hospital (IT)
  • Regeneron (United States) (US)
  • University of Pennsylvania (US)
Corresponding author
Rosenson, Robert S.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-03
Volume
29
Issue
3
Pages
729-737
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-023-02222-w
PMC
PMC10033404
OpenAlex
W4323320185
Cited by
140
References
30
Citations by year
2026: 38 · 2025: 47 · 2024: 40 · 2023: 15
FWCI
27.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Regeneron Pharmaceuticals
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
evinacumab, severe hypertriglyceridemia, ANGPTL3, familial chylomicronemia syndrome, triglyceride lowering, acute pancreatitis, lipoprotein lipase, chylomicronemia
MeSH terms
Acute Disease, Antibodies, Monoclonal, Female, Humans, Lipoprotein Lipase, Hyperlipoproteinemia Type I, Male, Mutation, Pancreatitis, Triglycerides, Hypertriglyceridemia, Single-Blind Method

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