Fremanezumab

Identification

Name
Fremanezumab
Accession Number
DB14041
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Fremanezumab is a genetically engineered humanized monoclonal antibody against human calcitonin gene-related peptide (CGRP) that is developed by Teva [1]. This therapy is given as a monthly subcutaneous injection and ongoing clinical trials for the agent are for episodic and chronic migraine as well as cluster headaches [3].

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
>fremanezumab|Heavy
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASAT
HYAEAVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQGTLVTV
SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
FRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK
>fremanezumab|Light
EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCSQSYNYPYTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
Not Available
External IDs
TEV-48125
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AjovyInjection225 mg/1.5mLSubcutaneousTeva Pharmaceuticals USA, Inc.2018-09-15Not applicableUs
Categories
UNII
PF8K38CG54
CAS number
1655501-53-3

Pharmacology

Indication

The ongoing trials for fremanezumab are for episodic and chronic migraine prevention and also for cluster headache [3].

Pharmacodynamics

Fremanezumab is experimentally administered as a monthly subcutaneous injection and targets the calcitonin gene-related peptide (CGRP) ligand [3]. During ongoing clinical trials, it was noted that among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3 to 1.5 day reduction in the mean number of monthly migraine days over a 12 week period [6]. Finally, the most commonly reported adverse events that led to discontinuation of the fremanezumab therapy included injection site erythema, injection site induation, diarrhea, anxiety, and depression [6].

Mechanism of action

Fremanezumab is a genetically engineered humanized monoclonal antibody that is specifically directed against calcitonin gene-related peptide (CGRP) alpha and beta [1, 3].

Studies since 1985 have demonstrated that CGRP levels increase during acute migraine attacks in migraine-suffering patients but normalize after efficacious sumatriptan therapy [4]. Moreover, research has also shown that intravenous administration of CGRP can induce migraine-like attacks in migraine-suffering patients [4]. For all these reasons, the binding of CGRP to interfere with its activity was specifically designed to be the form and mechanism of action for fremanezumab to take advantage of in reversing the migraine-inducing activity of natural CGRP. The binding of fremanezumab to natural endogenous CGRP subsequently interferes with its activities, such as its binding to CGRP receptors, for example.

Studies have also shown that humanized monoclonal antibodies against CGRP have proven successful in reducing the frequency of migraine headaches in early clinical trials as a preventative therapeutic [5].

TargetActionsOrganism
ACalcitonin gene-related peptide 1
antibody
Human
ACalcitonin gene-related peptide 2
antibody
Human
Absorption

Geometric mean ratios (GMRs) for Cmax for Japanese and Caucasian study subjects were 0.91, 1.04, and 1.14 for 225 mg, 675 mg, and 900 mg doses of fremanezumab [2]. GMRs for AUC (0-inf) were 0.96, 1.09, and 0.98, respectively [2]. Mean Tmax in a range of 5 to 11 days were similar across doses for both ethnicities as well [2].

Volume of distribution

Readily accessible data regarding the volume of distribution of fremanezumab is not available.

Protein binding

Readily accessible data regarding the protein binding of fremanezumab is not available.

Metabolism

Monoclonal antibody agents like fremanezumab are not expected to generate toxic metabolites as they generally undergo proteolysis to their constituent amino acids [7].

Route of elimination

Monoclonal antibody agents like fremanezumab are generally not eliminated via hepatic, renal, or biliary routes [7].

Half life

The mean half-life recorded for fremanezumab was similar across doses for Japanese and Caucasian study subjects at a range of 31-39 days [2].

Clearance

Readily accessible data regarding the clearance of fremanezumab is not available.

Toxicity

The most common adverse events that led to discontinuation of fremanezumab therapy in a clinical trial for the agent include injection site erythema, injection site induration, diarrhea, anxiety, and depression [6].

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 Fremanezumab.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Fremanezumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Fremanezumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Fremanezumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Fremanezumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Fremanezumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Fremanezumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Fremanezumab.
AmatuximabThe risk or severity of adverse effects can be increased when Amatuximab is combined with Fremanezumab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Fremanezumab.
Food Interactions
Not Available

References

General References
  1. Pellesi L, Guerzoni S, Pini LA: Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date. Clin Pharmacol Drug Dev. 2017 Nov;6(6):534-547. doi: 10.1002/cpdd.345. Epub 2017 Apr 14. [PubMed:28409893]
  2. Cohen-Barak O, Weiss S, Rasamoelisolo M, Faulhaber N, Yeung PP, Loupe PS, Yoon E, Gandhi MD, Spiegelstein O, Aycardi E: A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects. Cephalalgia. 2018 Jan 1:333102418771376. doi: 10.1177/0333102418771376. [PubMed:29667896]
  3. Vollbracht S, Rapoport AM: New treatments for headache. Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z. [PubMed:24867844]
  4. 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]
  5. Monteith D, Collins EC, Vandermeulen C, Van Hecken A, Raddad E, Scherer JC, Grayzel D, Schuetz TJ, de Hoon J: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers. Front Pharmacol. 2017 Oct 17;8:740. doi: 10.3389/fphar.2017.00740. eCollection 2017. [PubMed:29089894]
  6. JAMA Network: Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine [Link]
  7. Presentation on CGRP, MONOCLONAL ANTIBODIES AND SMALL MOLECULES (-GEPANTS) [File]
External Links
Wikipedia
Fremanezumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingPreventionPost-Traumatic Headaches1
2, 3RecruitingTreatmentMigraines2
3Active Not RecruitingTreatmentProphylaxis of migraine headaches1
3CompletedTreatmentMigraines1
3Enrolling by InvitationTreatmentCluster Headache1
3RecruitingTreatmentEpisodic Cluster Headache1
3RecruitingTreatmentMigraines1
3TerminatedTreatmentChronic Cluster Headache1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionSubcutaneous225 mg/1.5mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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
Yes
Actions
Antibody
General Function
Receptor binding
Specific Function
CGRP induces vasodilation. It dilates a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulato...
Gene Name
CALCA
Uniprot ID
P06881
Uniprot Name
Calcitonin gene-related peptide 1
Molecular Weight
13897.755 Da
References
  1. Vollbracht S, Rapoport AM: New treatments for headache. Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z. [PubMed:24867844]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antibody
General Function
Neuropeptide hormone activity
Specific Function
CGRP induces vasodilation. It dilates a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulato...
Gene Name
CALCB
Uniprot ID
P10092
Uniprot Name
Calcitonin gene-related peptide 2
Molecular Weight
13705.56 Da
References
  1. Vollbracht S, Rapoport AM: New treatments for headache. Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z. [PubMed:24867844]

Drug created on May 18, 2018 08:04 / Updated on November 02, 2018 07:49