Evolocumab

Identification

Summary

Evolocumab is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody used as an adjunct to LDL cholesterol reducing therapies, aiding in the prevention of cardiovascular events and cardiovascular revascularization procedures.

Brand Names
Repatha
Generic Name
Evolocumab
DrugBank Accession Number
DB09303
Background

Evolocumab is a monoclonal antibody designed for the treatment of hyperlipidemia by Amgen. It is a subcutaneous injection approved by the FDA for individuals on maximum statin therapy who still require additional LDL-cholesterol lowering. It is approved for both homozygous and heterozygous familial cholesterolemia as an adjunct to other first-line therapies. Evolocumab is a human IgG2 monoclonal antibody that targets the proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation, therefore reducing the liver's ability to remove LDL-cholesterol (LDL-C), or "bad" cholesterol, from the blood. Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface, resulting in more LDL receptors on the surface of the liver to remove LDL-C from the blood. Evolocumab is the second PCSK9 inhibitor on the market, first being alirocumab.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db09303
Protein Chemical Formula
C6242H9648N1668O1996S56
Protein Average Weight
141800.0 Da
Sequences
Not Available
Synonyms
  • Evolocumab
External IDs
  • AMG-145

Pharmacology

Indication

For the treatment of heterozygous/homozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease in patients on maximum tolerated statin therapy requiring additional LDL-cholesterol lowering.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Evolocumab is a human IgG monoclonal antibody which targets PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 is a serine protease produced by the liver which binds LDL receptors and creates a complex to be targeted for lysosomal degradation. LDL receptors typically bind LDL-cholesterol ("bad" cholesterol) for cellular reuptake, therefore the formation of these complexes with PCSK9 inhibits LDL receptor recycling to the cell surface, resulting in decreased cellular reuptake of LDL-C and increased levels of free LDL-C in the plasma. Individuals with familial hypercholesterolemia often may have "gain of function" mutations in the PCSK9 molecules in their body, resulting in increased LDL-C plasma levels and a consequent cardiovascular risk. Evolocumab is able to bind both the normal PCSK9 and the "gain of function" mutant, D374Y. The exact mechanism of the binding has not been published, however the precursor molecule, mAb1, is indicative of the interaction. The mAb1 molecule binds on the catalytic site of PCSK9 next to the binding site for the LDL receptor and creates hydrogen bonds and hydrophobic interactions, resulting in the steric inhibition of binding between PCSK9 and the LDL receptor. Because the formation of complexes between LDL receptor and PCSK9 are prevented, the internalized LDL receptors are less likely to be degrated by lysosomes and may recycle to the surface of the cell to serve their function of removing LDL from the blood.

Absorption

Total bioavailability from subcutaneous injection was 82% in cynomolgus monkeys.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Evolocumab showed non-linear, dose-dependent clearance in healthy volunteers; clearance decreased with increasing dose.

Adverse Effects
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Toxicity

Not Available

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.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Evolocumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Evolocumab.
AducanumabThe risk or severity of adverse effects can be increased when Evolocumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Evolocumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Evolocumab.
AmivantamabThe risk or severity of adverse effects can be increased when Evolocumab is combined with Amivantamab.
AnsuvimabThe risk or severity of adverse effects can be increased when Evolocumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Evolocumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Evolocumab is combined with Antilymphocyte immunoglobulin (horse).
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Evolocumab.
Interactions
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Food Interactions
Not Available

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RepathaInjection, solution140 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
RepathaInjection, solution140 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
RepathaInjection, solution140 mg/1mLSubcutaneousAmgen USA Inc.2018-10-09Not applicableUS flag
RepathaInjection, solution140 mg/1mLSubcutaneousAMGEN INC2015-08-31Not applicableUS flag
RepathaInjection, solution420 mgSubcutaneousAmgen Europe B.V.2020-12-21Not applicableEU flag
RepathaInjection, solution140 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
RepathaInjection, solution140 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
RepathaInjection, solution140 mg/1mLSubcutaneousAmgen USA Inc.2018-10-09Not applicableUS flag
RepathaSolution120 mg / mLSubcutaneousAmgen2017-04-04Not applicableCanada flag
RepathaInjection, solution420 mgSubcutaneousAmgen Europe B.V.2020-12-21Not applicableEU flag

Categories

ATC Codes
C10AX13 — Evolocumab
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
Not Available

Chemical Identifiers

UNII
LKC0U3A8NJ
CAS number
1256937-27-5

References

General References
  1. Authors unspecified: Evolocumab (Repatha)--a second PCSK9 inhibitor to lower LDL-Cholesterol. Med Lett Drugs Ther. 2015 Oct 12;57(1479):140-1. [Article]
  2. Page MM, Watts GF: Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology. Expert Opin Drug Metab Toxicol. 2015;11(9):1505-15. doi: 10.1517/17425255.2015.1073712. [Article]
KEGG Drug
D10557
PubChem Substance
347910432
RxNav
1665684
ChEMBL
CHEMBL2364655
Drugs.com
Drugs.com Drug Page
Wikipedia
Evolocumab
FDA label
Download (1.18 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAtherosclerotic Cardiovascular Diseases1
4CompletedTreatmentHomozygous Familial Hypercholesterolemia (HoFH)1
4CompletedTreatmentType 2 Diabetes Mellitus1
4Not Yet RecruitingTreatmentFamilial Dysbetalipoproteinemia / Hyperlipoproteinemia Type III1
4Not Yet RecruitingTreatmentNon ST Segment Elevation Myocardial Infarction (NSTEMI) / ST Segment Elevation Myocardial Infarction (STEMI)1
4RecruitingBasic ScienceCoronary Artery Disease (CAD)1
4RecruitingDiagnosticDyslipidemia Associated With Type II Diabetes Mellitus / Hypertension Arterial / Type 2 Diabetes Mellitus1
4RecruitingPreventionAtherosclerosis / Coronary Artery Bypass Grafting (CABG) / Occlusions Vein1
4RecruitingPreventionCarotid Artery Diseases1
4RecruitingSupportive CareAtherosclerotic Vascular Diseases / Microvascular Dysfunction / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous
Injection, solutionSubcutaneous140 mg
Injection, solutionSubcutaneous140 mg/1mL
Injection, solutionSubcutaneous420 mg
KitSubcutaneous420 mg/3.5mL
SolutionSubcutaneous120 mg / mL
SolutionSubcutaneous140 mg / mL
InjectionSubcutaneous
Injection, solutionSubcutaneous
SolutionSubcutaneous140 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Very-low-density lipoprotein particle receptor binding
Specific Function
Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein recepto...
Gene Name
PCSK9
Uniprot ID
Q8NBP7
Uniprot Name
Proprotein convertase subtilisin/kexin type 9
Molecular Weight
74285.545 Da
References
  1. Page MM, Watts GF: Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology. Expert Opin Drug Metab Toxicol. 2015;11(9):1505-15. doi: 10.1517/17425255.2015.1073712. [Article]

Drug created on November 11, 2015 21:05 / Updated on July 29, 2021 06:27