Evinacumab
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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". 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.8 In September and December 2023, evinacumab was also approved by Health Canada and EMA, respectively, for the same indication.11,13
- 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 5 years of age and older.9,10,12
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Homozygous familial hypercholesterolaemia (hofh) •••••••••••• •••••• ••••••••• •••••••••• ••••••••• ••••••••••• Adjunct therapy in treatment of Homozygous familial hypercholesterolaemia (hofh) •••••••••••• •••••• ••••••••• •••••••••• ••••••••• ••••••••••• Adjunct therapy in treatment of Homozygous familial hypercholesterolemia •••••••••••• •••••• ••••••••• ••••••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism AAngiopoietin-related protein 3 inhibitorbinderantibodyHumans - 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
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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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Evkeeza (Regeneron Pharmaceuticals, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Evkeeza Injection, solution, concentrate 150 mg/ml Intravenous Ultragenyx Germany Gmbh 2022-05-04 Not applicable EU Evkeeza Injection, solution, concentrate 150 mg/1mL Intravenous Regeneron Pharmaceuticals, Inc. 2021-02-11 Not applicable US Evkeeza Injection, solution, concentrate 150 mg/ml Intravenous Ultragenyx Germany Gmbh 2022-05-04 Not applicable EU Evkeeza Injection, solution, concentrate 150 mg/1mL Intravenous Regeneron Pharmaceuticals, Inc. 2021-02-11 Not applicable US Evkeeza Solution 150 mg / mL Intravenous Ultragenyx Pharmaceutical Inc. 2023-11-21 Not applicable Canada
Categories
- ATC Codes
- C10AX17 — Evinacumab
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Evkeeza (evinacumab-dgnb) for intravenous injection [Link]
- PR Newswire: FDA Approves First-in-class Evkeeza™ (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol [Link]
- EVKEEZA® (evinacumab-dgnb) injection, for intravenous use (March 2023) [Link]
- Health Canada Approved Drug Proucts: EVKEEZA (evinacumab) injection for intravenous use [Link]
- Ultragenyx Launches Evkeeza® (evinacumab for injection) in Canada for the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) [Link]
- EMA Approved Drug Products: Evkeeza (evinacumab) injection for intravenous use [Link]
- Ultragenyx Receives European Commission Decision for Evkeeza® (evinacumab) Expanded Indication in Children Aged 5 Years and Older with Homozygous Familial Hypercholesterolemia (HoFH) [Link]
- External Links
- 2478335
- Wikipedia
- Evinacumab
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Available Not Available Dysbetalipoproteinemia (DBL) / Pediatric Homozygous Familial Hypercholesterolemia (HoFH) / Severe Hypertriglyceridemia (HTG) 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Homozygous Familial Hypercholesterolaemia (HoFH) 1 somestatus stop reason just information to hide 3 Completed Treatment Homozygous Familial Hypercholesterolaemia (HoFH) 3 somestatus stop reason just information to hide 2 Completed Treatment High Cholesterol 1 somestatus stop reason just information to hide 2 Completed Treatment Homozygous Familial Hypercholesterolaemia (HoFH) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution, concentrate Intravenous 150 MG/ML Injection, solution, concentrate Intravenous 150 mg/1mL Solution Intravenous 150 mg / mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- InhibitorBinderAntibody
- 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
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Evkeeza (evinacumab-dgnb) for intravenous injection [Link]
Drug created at May 20, 2019 15:19 / Updated at February 15, 2024 07:14