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. 2024 Jan 30;149(5):343-353.
doi: 10.1161/CIRCULATIONAHA.123.065529. Epub 2023 Oct 20.

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia

Albert Wiegman  1 , Susanne Greber-Platzer  2 , Shazia Ali  3 , M Doortje Reijman  1 , Eliot A Brinton  4 , Min-Ji Charng  5 , Shubha Srinivasan  6 , Carissa Baker-Smith  7 , Seth Baum  3 , Julie A Brothers  8 , Jacob Hartz  9 , Patrick M Moriarty  10 , Jeanne Mendell  3 , Sébastien Bihorel  11 , Poulabi Banerjee  3 , Richard T George  3 , Boaz Hirshberg  3 , Robert Pordy  3
Affiliations

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia

Albert Wiegman et al. Circulation. .

Erratum in

  • Correction to: Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.
    Wiegman A, Greber-Platzer S, Ali S, Doortje Reijman M, Brinton EA, Charng MJ, Srinivasan S, Baker-Smith C, Baum S, Brothers JA, Hartz J, Moriarty PM, Mendell J, Bihorel S, Banerjee P, George RT, Hirshberg B, Pordy R. Wiegman A, et al. Circulation. 2025 Jul 8;152(1):e22. doi: 10.1161/CIR.0000000000001350. Epub 2025 Jul 7. Circulation. 2025. PMID: 40623081 Free PMC article. No abstract available.

Abstract

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study.

Methods: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks.

Results: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related.

Conclusions: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

Keywords: angiopoietin-like protein 3; atherosclerosis; evinacumab; homozygous familial hypercholesterolemia; lipids; lipoprotein; pediatrics.

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Conflict of interest statement

Disclosures A.W. reports payment or honoraria for lectures, presentations, speakers’ bureaus, article writing, or educational events from Novartis and Algorithm; participation in a data safety monitoring board or advisory board for Amryt Pharma; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Novartis; and research support for pharmaceutical trials from Amgen, Regeneron Pharmaceuticals, Inc, Novartis, Silence Therapeutics, Esperion, and Ultragenyx. S.G.-P. reports receiving research support from Amgen. S.A., J.M., S.B., P.B., R.T.G., B.H., and R.P. are employees of and stockholders in Regeneron Pharmaceuticals, Inc. E.A.B. is a steering committee member for the REDUCE-IT (Amarin) and PROMINENT (Kowa) trials, and receives research support from Regeneron Pharmaceuticals, Inc. He has received speaking or consulting honoraria from 89Bio, Amarin, Amgen, Amryt, Dalcor, Esperion, Immunovant, Ionis, Merck, New Amsterdam, and Pfizer. M.-J.C. reports honoraria from AstraZeneca, Merck Sharp & Dohme, Pfizer, Amgen, and Sanofi. C.B.-S. reports honoraria for presentations from the National Association of Continuing Medical Education and the Cardiometabolic Health Congress. S.B. reports funding or consulting fees from Amgen, Altimmune, Axcella, Regeneron Pharmaceuticals, Inc, Ionis Pharmaceuticals, Boehringer Ingelheim, Esperion, Lilly, Madrigal, Merck, and Novartis. J.B. reports funding or consulting fees from Regeneron Pharmaceuticals, Inc. P.M.M. reports receipt of research grants to his institution for the participation in the ODYSSEY OUTCOMES trial, as well as financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; consulting fees from Regeneron Pharmaceuticals, Inc, Amgen, Esperion, Kaneka, and Stage II Innovations; advisor fees from Novartis for serving on their advisory committee; and research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Evinacumab serum concentration over time after a single dose of evinacumab in part A. Six patients received a single dose of evinacumab (15 mg/kg intravenously). The observed (●) evinacumab serum concentrations were consistent with the model-based predictions (individual population predictions [IPRED]).
Figure 2.
Figure 2.
Percent change in calculated LDL-C from baseline to week 24 (intention-to-treat population). Raw data are shown, as there were no missing data at the primary efficacy time point (24 weeks). LDL-C was calculated using the Friedewald equation except when triglycerides were >400 mg/dL (4.52 mmol/L) or calculated LDL-C was <25 mg/dL (0.65 mmol/L), in which case LDL-C was determined by beta quantification. LDL-C indicates low-density lipoprotein cholesterol; and SE, standard error.
Figure 3.
Figure 3.
Mean (±SD) predose and postdose concentrations of total evinacumab and ANGPTL3 vs time in part B. Log-scaled evinacumab concentrations below the lower limit of quantification (LLOQ) (0.078 mg/L) were set to 1/2 LLOQ before computation of means (±SD). ANGPTL3 indicates angiopoietin-like 3; and SD, standard deviation.
See this image and copyright information in PMC

Comment in

References

    1. Vrablik M, Tichy L, Freiberger T, Blaha V, Satny M, Hubacek JA. Genetics of familial hypercholesterolemia: new insights. Front Genet. 2020;11:574474. doi: 10.3389/fgene.2020.574474 - PMC - PubMed
    1. Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, Bruckert E, Freiberger T, Gaudet D, Harada-Shiba M, et al. 2023 Update on European Atherosclerosis Society consensus statement on homozygous familial hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023;44:2277–2291. doi: 10.1093/eurheartj/ehad197 - PMC - PubMed
    1. Tromp TR, Hartgers ML, Hovingh GK, Vallejo-Vaz AJ, Ray KK, Soran H, Freiberger T, Bertolini S, Harada-Shiba M, Blom DJ, et al. ; Homozygous Familial Hypercholesterolaemia International Clinical Collaborators. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022;399:719–728. doi: 10.1016/S0140-6736(21)02001-8 - PMC - PubMed
    1. Brown MS, Goldstein JL. Familial hypercholesterolemia: a genetic defect in the low-density lipoprotein receptor. N Engl J Med. 1976;294:1386–1390. doi: 10.1056/NEJM197606172942509 - PubMed
    1. Brown MS, Kovanen PT, Goldstein JL, Eeckels R, Vandenberghe K, van den Berghe H, Fryns JP, Cassiman JJ. Prenatal diagnosis of homozygous familial hypercholesterolaemia. Expression of a genetic receptor disease in utero. Lancet. 1978;1:526–529. doi: 10.1016/s0140-6736(78)90552-4 - PubMed

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