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

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

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, Whitcomb, David C., Banerjee, Poulabi, Gewitz, Andrew, Gonzaga-Jauregui, Claudia, McGinniss, Jennifer, Ponda, Manish P., Pordy, Robert, Zhao, Jian, Rader, Daniel J.·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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Fig. 1 CONSORT diagram. *A total of 17 patients were randomized to placebo; however, one patient who failed screening was erroneously randomized and was withdrawn from the study.
Fig. 1 CONSORT diagram. *A total of 17 patients were randomized to placebo; however, one patient who failed screening was erroneously randomized and was withdrawn from the study.CC BY · PubMed Central
Fig. 2 Study design. *One patient was randomized but not treated.
Fig. 2 Study design. *One patient was randomized but not treated.CC BY · PubMed Central
Fig. 3 Median percent change in fasting triglycerides. a–c, Median (Q1 to Q3) percent change in fasting triglycerides from baseline to week 12 by cohort in the DBTP (exploratory end points). a, data for cohort 1; b, data for cohort 2; c, data for cohort 3.
Fig. 3 Median percent change in fasting triglycerides. a–c, Median (Q1 to Q3) percent change in fasting triglycerides from baseline to week 12 by cohort in the DBTP (exploratory end points). a, data for cohort 1; b, data for cohort 2; c, data for cohort 3.CC BY · PubMed Central
Extended Data Fig. 1 Patient disposition by cohort. aIn total, 17 patients were randomized to placebo. However, one patient who failed screening was erroneously randomized and was withdrawn from the study. DBTP, double-blind treatment period; SBTP, single-blind treatment period.
Extended Data Fig. 1 Patient disposition by cohort. aIn total, 17 patients were randomized to placebo. However, one patient who failed screening was erroneously randomized and was withdrawn from the study. DBTP, double-blind treatment period; SBTP, single-blind treatment period.CC BY · PubMed Central
Extended Data Fig. 2 Mean (SD) of total serum evinacumab concentrations by time and treatment group. The DBTP includes all measurements until week 12 pre-dose; the SBTP includes all measurements from week 12 EOI. During the SBTP, all patients received IV evinacumab 15 mg/kg Q4W. D, day; DBTP, double-blind treatment period; EOI, end of infusion; IV, intravenous; PRE, pre-dose; Q4W, every 4 weeks; SBTP, single-blind treatment period; SD, standard deviation; W, week.
Extended Data Fig. 2 Mean (SD) of total serum evinacumab concentrations by time and treatment group. The DBTP includes all measurements until week 12 pre-dose; the SBTP includes all measurements from week 12 EOI. During the SBTP, all patients received IV evinacumab 15 mg/kg Q4W. D, day; DBTP, double-blind treatment period; EOI, end of infusion; IV, intravenous; PRE, pre-dose; Q4W, every 4 weeks; SBTP, single-blind treatment period; SD, standard deviation; W, week.CC BY · PubMed Central
Extended Data Fig. 3 Individual log-scaled fold change from baseline in triglycerides versus log-scaled trough concentrations of total evinacumab. Fold change is derived as (individual TG value at each timepoint)/(baseline TG value). Concentrations below the LLOQ were set to LLOQ/2. BLQ, below the limit of quantification; LLOQ, lower limit of quantification; N, number of patients; TG, triglyceride.
Extended Data Fig. 3 Individual log-scaled fold change from baseline in triglycerides versus log-scaled trough concentrations of total evinacumab. Fold change is derived as (individual TG value at each timepoint)/(baseline TG value). Concentrations below the LLOQ were set to LLOQ/2. BLQ, below the limit of quantification; LLOQ, lower limit of quantification; N, number of patients; TG, triglyceride.CC BY · PubMed Central

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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 › Cardiology and Cardiovascular Medicine › 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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