Identification

Summary

Evinacumab is a monoclonal antibody targeted against angiopoetin-like protein 3 (ANGPTL3) used as an adjunct with other lipid-lowering therapies for the treatment of homozygous familiar hypercholesterolemia.

Brand Names
Evkeeza
Generic Name
Evinacumab
DrugBank Accession Number
DB15354
Background

Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions - including involvement in the regulation of lipid metabolism - which have made them desirable therapeutic targets in recent years.2 Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.3

In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name "Evkeeza".8 Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
146000.0 Da
Sequences
Not Available
Synonyms
  • Evinacumab
  • evinacumab-dgnb
External IDs
  • REGN 1500
  • REGN-1500
  • REGN1500

Pharmacology

Indication

Evinacumab is indicated, as an adjunct with other lipid-lowering therapies, for the treatment of familial homozygous hypercholesterolemia (HoFH) in patients 12 years of age and older.7

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Evinacumab exerts its hypolipidemic and antiatherogenic effects via decreasing circulating levels of triglycerides, HDL-C, and LDL-C, apolipoprotein B, and total cholesterol.7 It is has a relatively long duration of action that allows for its administration via intravenous injection once-monthly.7

Animal studies have demonstrated embryo-fetal toxicity - administration to pregnant rabbits during organogenesis resulted in increases in fetal malformations at concentrations lower than those used in humans. For this reason, patients receiving therapy with evinacumab should obtain a pregnancy test prior to beginning therapy and use effective contraception throughout the duration of therapy and for 5 months following the administration of the last dose.7

Mechanism of action

Angiopoetin-like proteins (ANGPTL) are a diverse group of proteins involved in a number of physiological processes, including the regulation of lipoprotein metabolism. Loss-of-function mutations in ANGPTL3 and ANGPTL4 have been shown to result in hypolipidemia and a reduced risk of coronary artery disease, while increased levels of these proteins appear to be associated with cardiovascular risk.2,5 While these observations have made ANGPTLs as a class a desirable target in the treatment of hyperlipidemic disorders,2 ANGPTL3 is the first to be pharmacologically targeted for the purposes of lipid-lowering therapy.5 ANGPTL3 is expressed primarily in the liver and acts as an endogenous inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) which are responsible, in part, for metabolizing triglycerides (TG) and HDL-C, respectively.7

Evinacumab is monoclonal antibody that binds to and inhibits ANGPTL3, with the resulting disinhibition of LPL and EL reducing the levels of circulating TG and HDL-C. While the mechanism through which evinacumab reduces LDL-C is not entirely clear, this effect is independent of LDL receptor density and is therefore most likely due to the promotion of VLDL processing and upstream clearance of LDL formation.7

TargetActionsOrganism
AAngiopoietin-related protein 3
inhibitor
binder
antibody
Humans
Absorption

Following the recommended dosing regimen (15 mg/kg intravenously every 4 weeks), steady-state concentrations are reached after four doses. According to population pharmacokinetic modeling, the mean steady-state trough concentration is approximately 241 mg/L and the Cmax at the end of infusion is approximately 689 mg/L.7

Volume of distribution

The volume of distribution of evinacumab was estimated to be 4.8 L via population pharmacokinetic analysis.7

Protein binding

Not Available

Metabolism

The biotransformation of evinacumab has not been characterized.7 Monoclonal antibodies as a class are typically degraded via catabolic pathways into smaller peptides and amino acids.6

Route of elimination

Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions.6

Half-life

The elimination half-life of evinacumab is a function of its serum concentration and is therefore variable.7 This is because evinacumab is eliminated by two parallel pathways: at higher concentrations it is eliminated primarily through a non-saturable proteolytic pathway, while at lower concentrations its elimination occurs primarily via a saturable target-mediated pathway.7

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

There are no data regarding overdosage with evinacumab. Symptoms of overdose are likely to be consistent with evinacumab's adverse effect profile and may therefore include significant infusion reactions or dizziness.7 Patients experiencing an overdose should be treated with symptomatic and supportive measures.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

Products2
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International/Other Brands
Evkeeza (Regeneron Pharmaceuticals, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
T8B2ORP1DW
CAS number
1446419-85-7

References

General References
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee IT, Liang KW, Guo X, Rotter JI, Chen YI, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Wulff AB, Nordestgaard BG, Tybjaerg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopoulos GD, Mellis SJ, Gromada J, Baras A: Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211-221. doi: 10.1056/NEJMoa1612790. Epub 2017 May 24. [Article]
  3. Ahmad Z, Banerjee P, Hamon S, Chan KC, Bouzelmat A, Sasiela WJ, Pordy R, Mellis S, Dansky H, Gipe DA, Dunbar RL: Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia. Circulation. 2019 Aug 6;140(6):470-486. doi: 10.1161/CIRCULATIONAHA.118.039107. Epub 2019 Jun 27. [Article]
  4. Harada-Shiba M, Ali S, Gipe DA, Gasparino E, Son V, Zhang Y, Pordy R, Catapano AL: A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis. 2020 Dec;314:33-40. doi: 10.1016/j.atherosclerosis.2020.10.013. Epub 2020 Oct 10. [Article]
  5. Surma S, Romanczyk M, Filipiak KJ: Angiopoietin-like proteins inhibitors: New horizons in the treatment of atherogenic dyslipidemia and familial hypercholesterolemia. Cardiol J. 2021 Jan 20. pii: VM/OJS/J/69566. doi: 10.5603/CJ.a2021.0006. [Article]
  6. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  7. FDA Approved Drug Products: Evkeeza (evinacumab-dgnb) for intravenous injection [Link]
  8. PR Newswire: FDA Approves First-in-class Evkeeza™ (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol [Link]
RxNav
2478335
Wikipedia
Evinacumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentHomozygous Familial Hypercholesterolaemia (HoFH)1
3CompletedTreatmentHomozygous Familial Hypercholesterolaemia (HoFH)1
3RecruitingTreatmentHomozygous Familial Hypercholesterolaemia (HoFH)1
2CompletedTreatmentHigh Cholesterol1
2CompletedTreatmentHomozygous Familial Hypercholesterolaemia (HoFH)1
2CompletedTreatmentSevere Hypertriglyceridemia (sHTG)1
2RecruitingTreatmentHypertriglyceridemias1
1CompletedBasic ScienceHealthy Subjects (HS)1
1CompletedTreatmentHypertriglyceridemias1
1CompletedTreatmentMetabolic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous150 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Binder
Antibody
General Function
Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
Specific Function
Enzyme inhibitor activity
Gene Name
ANGPTL3
Uniprot ID
Q9Y5C1
Uniprot Name
Angiopoietin-related protein 3
Molecular Weight
53637.105 Da
References
  1. Harada-Shiba M, Ali S, Gipe DA, Gasparino E, Son V, Zhang Y, Pordy R, Catapano AL: A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis. 2020 Dec;314:33-40. doi: 10.1016/j.atherosclerosis.2020.10.013. Epub 2020 Oct 10. [Article]
  2. Doggrell SA: Will evinacumab become the standard treatment for homozygous familial hypercholesterolemia? Expert Opin Biol Ther. 2020 Dec 14:1-4. doi: 10.1080/14712598.2021.1862083. [Article]
  3. Banerjee P, Chan KC, Tarabocchia M, Benito-Vicente A, Alves AC, Uribe KB, Bourbon M, Skiba PJ, Pordy R, Gipe DA, Gaudet D, Martin C: Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activity. Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2248-2260. doi: 10.1161/ATVBAHA.119.313051. Epub 2019 Oct 3. [Article]
  4. FDA Approved Drug Products: Evkeeza (evinacumab-dgnb) for intravenous injection [Link]

Drug created at May 20, 2019 15:19 / Updated at July 02, 2021 03:58