Erenumab

Identification

Name
Erenumab
Accession Number
DB14039
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Erenumab (AMG-334) (INN; trade name Aimovig) is a human monoclonal antibody designed specifically to bind and antagonize the calcitonin gene-related peptide receptor (CGRPR) as a means to prevent migraines. Aimovig, as released and marketed by Novartis and Amgen, is in fact a novel therapeutic approach as the first and only FDA approved treatment specifically developed to prevent migraine by blocking the CGRP receptor, which is believed to play a critical role in migraine [3].

In particular, erenumab-aooe is a human immunoglobulin G2 monoclonal antibody that has high affinity binding to the CGRP receptor [Label]. The antibody is produced utlilizing recombinant DNA technology in Chinese hamster ovary cells [Label]. It is composed of 2 heavy chains, each containing 456 amino acids, and 2 light chains of the lambda subclass, each containing 216 amino acids, with an approximate molecular weight of 150 kDa [Label].

Protein chemical formula
C6472H9964N1728O2018S50
Protein average weight
Not Available
Sequences
> Erenumab (Heavy chain)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYS
VDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVW
GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV
HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP
APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP
REEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
> Erenumab (Light chain)
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIP
DRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGQPKANPTVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS
YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
Download FASTA Format
Synonyms
Not Available
External IDs
AMG 334 / AMG-334 / AMG334
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AimovigInjection70 mg/1mLSubcutaneousAmgen2018-05-22Not applicableUs
AimovigInjection70 mg/1mLSubcutaneousAmgen2018-05-22Not applicableUs
Categories
UNII
I5I8VB78VT
CAS number
1582205-90-0

Pharmacology

Indication

Erenumab is indicated for the preventative treatment of migraine in adults [Label].

Pharmacodynamics

As a human monoclonal antibody designed to specifically bind with and antagonize the calcitonin gene-related peptide (CGRP) receptor, there is the possibility that erenumab could interfere with natural activities of CGRP that may not be immediately or directly associated with migraines. For example, at peripheral synapses, CGRP released from trigeminal terminals results in vasodilation by way of CGRP receptor on smooth muscle cells of meningeal and cerebral blood vessels, making CGRP a potent general arterial vasodilator [1]. Antagonism of CGRP receptors responsible for such vasodilation could theoretically result in vasoconstriction and raises in blood pressure.

In a randomised, double-blind, placebo-controlled study in healthy volunteers, concomitant administration of erenumab (140 mg intravenous, single dose) with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) had no effect on resting blood pressure compared with sumatriptan alone, however [Label]. Please note that erenumab is indicated for subcutaneous use only, though [Label].

Mechanism of action

Erenumab is a human monoclonal antibody that has been designed to bind specifically to the calcitonin gene-related peptide (CGRP) receptor and antagonize the CGRP receptor function [Label].

Studies since 1985 have demonstrated that CGRP levels increase during acute migraine attacks in migraine-suffering patients but normalize after efficacious sumatriptan therapy [1]. Moreover, research has also shown that intravenous administration of CGRP can induce migraine-like attacks in migraine-suffering patients [1]. For all these reasons, the binding and antagonism of CGRP receptors was designed to be mechanism of action for erenumab to take advantage of in reversing the migraine-inducing activity of natural CGRP.

CGRP and its receptor are expressed in both the peripheral and the central nervous system [2]. In addition to playing a role in cranial nociception, CGRP is also a potent general arterial vasodilator [2]. At peripheral synapses, CGRP released from trigeminal terminals results in vasodilation via CGRP receptors on the smooth muscle cells of meningeal and cerebral blood vessels [1].

TargetActionsOrganism
UCalcitonin gene-related peptide type 1 receptorNot AvailableHuman
Absorption

Following a single subcutaneous dose of 70 mg or 140 mg erenumab administered to healthy adults, the median peak serum concentrations were attained in about 6 days, and the estimated absolute bioavailability was approximately 82% [Label].

Volume of distribution

After a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be approximately 3.86 (0.77) L [Label].

Protein binding

Readily accessible data regarding the protein binding of erenumab is not available, although it is reported that erenumab is capable of 50% to 99% total inhibition of calcitonin gene-related peptide receptors with dosages of 255 ng/mL and 1134 ng/mL, respectively [2].

Metabolism

Erenumab CGRP antibodies demonstrate a low risk for drug-drug interactions and hepatotoxicity since they are predominantly metabolized by degradation into peptides and single amino acids [1].

Route of elimination

Two elimination phases are observed for erenumab. At low concentrations, the elimination is mainly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of erenumab is primarily through a non-specific, non-saturable proteolytic pathway [Label]. These phases correspond to studies that demonstrated two parallel elimination pathways: (a) a slow non-specific elimination pathway through the hepatic reticuloendothelial system, and (b) a rapid saturable elimination pathway mediated by degradation or internalization of the erenumab-receptor complex [2].

Half life

Erenumab exhibits non-linear kinetics as a result of binding to the CGRP receptor [Label]. Lower than 2-fold accumulation was recorded in trough serum concentrations (Cmin) for episodic and chronic migraine patients following subcutaneous administration of 70 mg once-monthly and 140 mg once-monthly doses [Label]. Serum trough concentrations approached steady state by 3 months of dosing [Label]. The effective half-life of erenumab was observed to be 28 days [Label].

Clearance

Certain studies show that the population estimate of linear clearance is independent of erenumab concentrations and stays approximately constant at 0.214 L/day (95% CI: 0.191–0.243) [2]. In contrast, the nonlinear clearance is dependent on the target receptor density and the amount of erenumab bound to the receptors [2]. Nevertheless, the maximal nonlinear clearance was observed to be about 1.84L/day [2].

Toxicity

The most common side effects of erenumab include pain, redness, or swelling at the injection site, and constipation. Information regarding overdosage is not available [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Erenumab.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Erenumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Erenumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Erenumab.
Adenovirus type 7 vaccine liveThe risk or severity of adverse effects can be increased when Erenumab is combined with Adenovirus type 7 vaccine live.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Erenumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Erenumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Erenumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Erenumab.
AmatuximabThe risk or severity of adverse effects can be increased when Amatuximab is combined with Erenumab.
Food Interactions
Not Available

References

General References
  1. Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, Vigneri S, Edvinsson L, Maassen Van Den Brink A: Blocking CGRP in migraine patients - a review of pros and cons. J Headache Pain. 2017 Sep 25;18(1):96. doi: 10.1186/s10194-017-0807-1. [PubMed:28948500]
  2. Vu T, Ma P, Chen JS, de Hoon J, Van Hecken A, Yan L, Wu LS, Hamilton L, Vargas G: Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects. Pharm Res. 2017 Sep;34(9):1784-1795. doi: 10.1007/s11095-017-2183-6. Epub 2017 Jun 7. [PubMed:28593473]
  3. Press Release: Novartis and Amgen announce FDA approval of Aimovig(TM) (erenumab), a novel treatment developed specifically for migraine prevention [Link]
External Links
KEGG Drug
D10928
Wikipedia
Erenumab
FDA label
Download (1.57 MB)
MSDS
Download (35.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceMigrainous Headache1
1CompletedPreventionMigraines3
1CompletedPreventionVasomotor Symptoms; Hot Flashes1
1CompletedTreatmentHealthy Volunteers1
2Active Not RecruitingPreventionMigraines1
2CompletedPreventionTreatment for Prevention of Chronic Migraine1
2CompletedTreatmentStable Angina (SA)1
2CompletedTreatmentTreatment for Prevention of Chronic Migraine1
3Active Not RecruitingPreventionEpisodic Migraine1
3CompletedTreatmentMigraines2
3RecruitingPreventionMigraines1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionSubcutaneous70 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Specific Function
Adrenomedullin receptor activity
Gene Name
CALCRL
Uniprot ID
Q16602
Uniprot Name
Calcitonin gene-related peptide type 1 receptor
Molecular Weight
52928.98 Da

Drug created on May 18, 2018 07:55 / Updated on November 02, 2018 07:49