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Evinacumab: Mechanism of action, clinical, and translational science

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Dingman, Robert, Bihorel, Sébastien, Gusarova, Viktoria, Mendell, Jeanne, Pordy, Robert·2024·Clinical and Translational Science
DOI 10.1111/cts.13836PMC PMC11157145
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Abstract

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low‐density lipoprotein cholesterol (LDL‐C). HoFH primarily results from loss‐of‐function (LOF) mutations in the LDL receptor (LDLR), reducing LDL‐C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL‐C; however, many patients with HoFH still fail to reach their target LDL‐C levels and many of these lipid‐lowering therapies are not indicated for pediatric use. Angiopoietin‐like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL‐C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low‐density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL‐C than non‐carriers and lower risk of coronary artery disease. Evinacumab is a first‐in‐class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL‐C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH.

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  1. [1]Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J. Clin. Invest. 2003; 111: 1795‐ 1803. doi: 10.1172/jci18925 12813012 PMC161432 · DOI
  2. [2]Cuchel M, Lee PC, Hudgins LC, et al. Contemporary homozygous familial hypercholesterolemia in the United States: insights from the CASCADE FH registry. J. Am. Heart Assoc. 2023; 12: e029175. doi: 10.1161/JAHA.122.029175 37119068 PMC10227232 · DOI
  3. [3]Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet A, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. McGraw‐Hill; 2001: 2863‐ 2913.
  4. [4]Kolansky DM, Cuchel M, Clark BJ, et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am. J. Cardiol. 2008; 102: 1438‐ 1443. doi: 10.1016/j.amjcard.2008.07.035 19026292 · DOI
  5. [5]Macchiaiolo M, Gagliardi MG, Toscano A, Guccione P, Bartuli A. Homozygous familial hypercholesterolaemia. Lancet. 2012; 379: 1330. doi: 10.1016/S0140-6736(11)61476-1 22285056 · DOI
  6. [6]Thedrez A, Blom DJ, Ramin‐Mangata S, et al. Homozygous familial hypercholesterolemia patients with identical mutations variably express the LDLR (low‐density lipoprotein receptor): implications for the efficacy of evolocumab. Arterioscler. Thromb. Vasc. Biol. 2018; 38: 592‐ 598. doi: 10.1161/atvbaha.117.310217 29284604 PMC5823753 · DOI · Paper page
  7. [7]Blom DJ, Harada‐Shiba M, Rubba P, et al. Efficacy and safety of Alirocumab in adults with homozygous familial hypercholesterolemia: the ODYSSEY HoFH trial. J. Am. Coll. Cardiol. 2020; 76: 131‐ 142. doi: 10.1016/j.jacc.2020.05.027 32646561 · DOI
  8. [8]Hegele RA, Tsimikas S. Lipid‐lowering agents. Circ. Res. 2019; 124: 386‐ 404. doi: 10.1161/CIRCRESAHA.118.313171 30702996 · DOI · Paper page
  9. [9]Rosenson RS. Existing and emerging therapies for the treatment of familial hypercholesterolemia. J. Lipid Res. 2021; 62: 100060. doi: 10.1016/j.jlr.2021.100060 33716107 PMC8065289 · DOI
  10. [10]Santos RD. Expression of LDLRs (low‐density lipoprotein receptors), dyslipidemia severity, and response to PCSK9 (Proprotein convertase Subtilisin Kexin type 9) inhibition in homozygous familial hypercholesterolemia: connecting the dots. Arterioscler. Thromb. Vasc. Biol. 2018; 38: 481‐ 483. doi: 10.1161/ATVBAHA.117.310675 29467219 · DOI
  11. [11]Luirink IK, Wiegman A, Kusters DM, et al. 20‐year follow‐up of statins in children with familial hypercholesterolemia. N. Engl. J. Med. 2019; 381: 1547‐ 1556. doi: 10.1056/NEJMoa1816454 31618540 · DOI
  12. [12]Stein EA, Dann EJ, Wiegman A, et al. Efficacy of rosuvastatin in children with homozygous familial hypercholesterolemia and association with underlying genetic mutations. J. Am. Coll. Cardiol. 2017; 70: 1162‐ 1170. doi: 10.1016/j.jacc.2017.06.058 28838366 · DOI
  13. [14]Shimamura M, Matsuda M, Yasumo H, et al. Angiopoietin‐like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler. Thromb. Vasc. Biol. 2007; 27: 366‐ 372. doi: 10.1161/01.ATV.0000252827.51626.89 17110602 · DOI · Paper page
  14. [16]Liu J, Afroza H, Rader DJ, Jin W. Angiopoietin‐like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases. J. Biol. Chem. 2010; 285: 27561‐ 27570. doi: 10.1074/jbc.M110.144279 20581395 PMC2934623 · DOI
  15. [17]Shimizugawa T, Ono M, Shimamura M, et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J. Biol. Chem. 2002; 277: 33742‐ 33748. doi: 10.1074/jbc.M203215200 12097324 · DOI
  16. [18]Adam RC, Mintah IJ, Alexa‐Braun CA, et al. Angiopoietin‐like protein 3 governs LDL‐cholesterol levels through endothelial lipase‐dependent VLDL clearance. J. Lipid Res. 2020; 61: 1271‐ 1286. doi: 10.1194/jlr.RA120000888 32646941 PMC7469887 · DOI · Paper page
  17. [19]Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J. Lipid Res. 2015; 56: 1308‐ 1317. doi: 10.1194/jlr.M054890 25964512 PMC4479335 · DOI · Paper page
  18. [20]Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL‐triglyceride secretion. J. Lipid Res. 2015; 56: 1296‐ 1307. doi: 10.1194/jlr.M054882 25954050 PMC4479334 · DOI · Paper page
  19. [21]Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 2010; 363: 2220‐ 2227. doi: 10.1056/NEJMoa1002926 20942659 PMC3008575 · DOI · Paper page
  20. [22]Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 2017; 377: 211‐ 221. doi: 10.1056/NEJMoa1612790 28538136 PMC5800308 · DOI · Paper page
  21. [23]Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N. Engl. J. Med. 2020; 383: 711‐ 720. doi: 10.1056/NEJMoa2004215 32813947 · DOI · Paper page
  22. [24]Ishida T, Choi S, Kundu RK, et al. Endothelial lipase is a major determinant of HDL level. J. Clin. Invest. 2003; 111: 347‐ 355. doi: 10.1172/jci16306 12569160 PMC151857 · DOI
  23. [25]Broedl UC, Maugeais C, Millar JS, et al. Endothelial lipase promotes the catabolism of ApoB‐containing lipoproteins. Circ. Res. 2004; 94: 1554‐ 1561. doi: 10.1161/01.RES.0000130657.00222.39 15117821 · DOI
  24. [26]Boren J, Taskinen MR, Adiels M. Kinetic studies to investigate lipoprotein metabolism. J. Intern. Med. 2012; 271: 166‐ 173. doi: 10.1111/j.1365-2796.2011.02497.x 22142374 · DOI
  25. [27]Sosnowska B, Adach W, Surma S, Rosenson RS, Banach M. Evinacumab, an ANGPTL3 inhibitor, in the treatment of dyslipidemia. J. Clin. Med. 2022; 12: 168. doi: 10.3390/jcm12010168 36614969 PMC9821629 · DOI
  26. [29]Harada‐Shiba M, Ali S, Gipe DA, et al. A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis. 2020; 314: 33‐ 40. doi: 10.1016/j.atherosclerosis.2020.10.013 33130482 · DOI
  27. [30]Malik PRV, Temrikar ZH, Chelle P, Edginton AN, Meibohm B. Pediatric dose selection for therapeutic proteins. J. Clin. Pharmacol. 2021; 61(Suppl 1): S193‐ S206. doi: 10.1002/jcph.1829 34185910 · DOI
  28. [31]Pu X, Sale M, Yang F, Zhang Y, Davis JD, al‐Huniti N. Population pharmacokinetics and exposure‐response modeling for evinacumab in homozygous familial hypercholesterolemia. CPT Pharmacometrics Syst. Pharmacol. 2021; 10: 1412‐ 1421. doi: 10.1002/psp4.12711 34585515 PMC8592514 · DOI
  29. [32]Gaudet D, Saheb S, Iannuzzo G, et al. Long‐term efficacy and safety of Evinacumab in adult and adolescent patients with homozygous familial hypercholesterolemia. Circulation. 2021; 144: A12756.
  30. [33]Wiegman A, Greber‐Platzer S, Ali S, et al. Evinacumab for pediatric patients with homozygous familial hypercholesterolemia. Circulation. 2024; 149: 343‐ 353. doi: 10.1161/CIRCULATIONAHA.123.065529 37860863 PMC10814999 · DOI
  31. [34]Raal FJ, Rosenson RS, Reeskamp LF, et al. The long‐term efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. JACC: Advances. 2023; 2: 100648. doi: 10.1016/j.jacadv.2023.100648 PMC11198175 38938723 · DOI
  32. [35]Raal FJ, Rosenson RS, Reeskamp R, et al. The long‐term safety and efficacy of evinacumab in patients with homozygous familial hypercholesterolemia. Circulation. 2021; 144: A12066.
  33. [36]Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin‐like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation. 2019; 140: 470‐ 486. doi: 10.1161/CIRCULATIONAHA.118.039107 31242752 PMC6686956 · DOI

Cited by

Sorted by citations

Authors
Dingman, R., Bihorel, S., Gusarova, V., Mendell, J., & Pordy, R.
Affiliations
Regeneron (United States) (US)
Corresponding author
Dingman, Robert
ORCID
Venue
Clinical and Translational Science
Publisher
Wiley
Published
2024-06
Volume
17
Issue
6
Pages
e13836-e13836
ISSN
  • 1752-8054 (ISSN-L)
  • 1752-8062
DOI
10.1111/cts.13836
PMC
PMC11157145
OpenAlex
W4399441873
Cited by
23
References
2
Citations by year
2026: 9 · 2025: 11 · 2024: 3
FWCI
2.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical and Translational Science (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Regeneron Pharmaceuticals
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
evinacumab, homozygous familial hypercholesterolemia, ANGPTL3, LDL receptor, LDL cholesterol lowering, lipoprotein lipase, endothelial lipase, monoclonal antibodies, population pharmacokinetics, pediatric hypercholesterolemia, cardiovascular risk
MeSH terms
Broadly Neutralizing Antibodies, Angiopoietin-Like Protein 3, Animals, Antibodies, Monoclonal, Anticholesteremic Agents, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL, Receptors, LDL, Translational Research, Biomedical

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