Galcanezumab

Identification

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Name
Galcanezumab
Accession Number
DB14042
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

LY2951742/galcanezumab is a fully humanized monoclonal antibody against human calcitonin gene-related peptide (CGRP) that is developed by ELi Lilly and Company.1 This therapy is given as a single subcutaneous injection twice a month and ongoing clinical trials for the agent are for episodic and chronic migraine as well as cluster headaches.5

Although various small-molecule CGRP receptor antagonists have also been developed, humanized monoclonal antibodies like galcanezumab are specifically designed to potently and selectively bind to the CGRP entities directly.3 Given this target specificity, lack of off-target toxicity, and characteristic proteolysis profile of immunoglobulin antibodies to not undergo metabolism by liver enzymes, galcanezumab possesses favourable and promising safety and tolerability.3

Galcanezumab was given FDA approval on 27 September 2018.7

Protein chemical formula
Not Available
Protein average weight
147000.0 Da (Approximate)
Sequences
>galcanezumab|Heavy
QVQLVQSGAEVKKPGSSVKVSCKASGYTFGNYWMQWVRQAPGQGLEWMGAIYEGTGKTVY
IQKFADRVTITADKSTSTAYMELSSLRSEDTAVYYCARLSDYVSGFGYWGQGTTVTVSSA
STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN
VFSCSVMHEALHNHYTQKSLSLSLG
>galcanezumab|Light
DIQMTQSPSSLSASVGDRVTITCRASKDISKYLNWYQQKPGKAPKLLIYYTSGYHSGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQGDALPPTFGGGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
  • Galcanezumab-gnlm
External IDs
LY-2951742 / LY2951742
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EmgalityInjection, solution120 mg/1mLSubcutaneousEli Lilly and Company2018-09-27Not applicableUs
EmgalitySolution120 mgSubcutaneousEli Lilly & Co. Ltd.Not applicableNot applicableCanada
EmgalitySolution120 mgSubcutaneousEli Lilly & Co. Ltd.Not applicableNot applicableCanada
EmgalityInjection, solution100 mg/1mLSubcutaneousEli Lilly and Company2019-06-04Not applicableUs
EmgalityInjection, solution120 mg/1mLSubcutaneousEli Lilly and Company2018-09-27Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
55KHL3P693
CAS number
1578199-75-3

Pharmacology

Indication

Galcanezumab is a humanized monoclonal antibody that is indicated for migraine prophylaxis and treatment of episodic cluster headaches in adults by binding endogenous human calcitonin gene-related peptide (CGRP).3,Label

Associated Conditions
Pharmacodynamics

Galcanezumab is administered as a subcutaneous injection.3,5,Label During clinical trials, it was noted that galcanezumab therapy resulted in a significant reduction in the mean number of migraine headache days and a good tolerability profile.1 Additionally, post hoc efficacy analyses showed that 32% in the galcanezumab group versus 18% in the placebo group were complete responders.1 Finally, the most commonly reported adverse events associated with galcanezumab use are headache, nasopharyngitis, hematuria, dermatitis, diarrhea, toothache, and increased alanine aminotransferase (ALT).3

Mechanism of action

Galcanezumab is a fully humanized monoclonal antibody designed and manufactured specifically against calcitonin gene-related peptide (CGRP).1,Label It binds avidly to human CGRP, with a binding affinity (Kd) of 31 pM (4.5 ng/mL).

Studies since 1985 have demonstrated that CGRP levels increase during acute migraine attacks in migraine-suffering patients but normalize after efficacious sumatriptan therapy.6 Moreover, research has also shown that intravenous administration of CGRP can induce migraine-like attacks in migraine-suffering patients.6 For all these reasons, the binding of CGRP to interfere with its activity was specifically designed to be the mechanism of action for galcanezumab to take advantage of in reversing the migraine-inducing activity of natural CGRP. The binding of galcanezumab 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.3

TargetActionsOrganism
ACalcitonin gene-related peptide 1
antibody
Humans
ACalcitonin gene-related peptide 2
antibody
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

Following single dose subcutaneous administration, the time to maximum concentration was recorded as 5 days.Label The injection site location did not appear to significantly influence the absorption of galcanezumab.Label

The Cmax and the area under the concentration-time curve from dosing to infinity (AUC (0-∞)) are generally considered to be dose proportional over a dose range.3

Volume of distribution

The apparent volume of distribution of galcanezumab is documented to be 7.3 L, with 34% inter-individual variability.Label

Protein binding

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

Metabolism

Monoclonal antibody agents like galcanezumab are not expected to generate toxic metabolites as they generally undergo proteolysis to their constituent amino acids.8 In particular, after administration galcanezumab is specifically expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous immunoglobulins.Label Galcanezumab is also not believed to be metabolized by liver enzymes - making drug-drug interactions relatively unlikely.Label

Route of elimination

Monoclonal antibody agents like galcanezumab are generally not eliminated via hepatic, renal, or biliary routes.8

Half life

The mean serum half-life of galcanezumab is similar at all dose levels at about 25-30 days.3 The elimination half-life of galcanezumab was ultimately approximately 27 days.Label

Clearance

It is noted that the clearance of galcanezumab is by proteolysis.3 The apparent clearance of galcanezumab was recorded as 0.008 L/h.Label

Toxicity

Overdose and LD50 date are not readily available.Label

The most common adverse effects associated with galcanezumab during clinical trials include headache, nasopharyngitis, hematuria, and contact dermatitis 3. However, with the exception of hematuria which was not present in placebo treatment arms, the frequencies of these events were similar to placebo 3. Additional frequently reported adverse effects in subjects receiving galcanezumab were diarrhea, toothache, and increased alanine aminotransferase (ALT) 3.

The pharmacokinetics of galcanezumab were not affected by age, sex, race, or subtypes of migraine spectrum (episodic or chronic migraine), based on a population pharmacokinetic analysis Label. Body weight has no clinically relevant effect on the pharmacokinetics of galcanezumab Label.

Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab Label. Population pharmacokinetic analysis of integrated data from the galcanezumab clinical studies revealed that creatinine clearance did not affect the pharmacokinetics of galcanezumab in patients with mild or moderate renal impairment Label. Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied Label. Based on a population PK analysis, bilirubin concentration did not significantly influence the CL/F of galcanezumab Label.

Studies regarding the carcinogenic potential and genetic toxicology of galcanezumab have not yet been conducted Label.

When galcanezumab (0, 30, or 250 mg/kg) was administered to male rats by subcutaneous injection prior to and during mating, no adverse effects on fertility was observed Label. The higher dose tested was associated with a plasma exposure (Cave, ss) 8 times that in humans at the recommended human dose (RHD) of 120 mg Label. When galcanezumab was administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on fertility were observed Label. The highest dose tested (250 mg/kg) was associated with a plasma Cave, ss 38 times that in humans at the RHD Label.

Affected organisms
  • Humans and other mammals
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 Galcanezumab.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Galcanezumab.
AbrilumabThe risk or severity of adverse effects can be increased when Galcanezumab is combined with Abrilumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Galcanezumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Galcanezumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Galcanezumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Galcanezumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Galcanezumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Galcanezumab.
AmatuximabThe risk or severity of adverse effects can be increased when Amatuximab is combined with Galcanezumab.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
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  • Action
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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. Benemei S, Cortese F, Labastida-Ramirez A, Marchese F, Pellesi L, Romoli M, Vollesen AL, Lampl C, Ashina M: Triptans and CGRP blockade - impact on the cranial vasculature. J Headache Pain. 2017 Oct 10;18(1):103. doi: 10.1186/s10194-017-0811-5. [PubMed:29019093]
  3. 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]
  4. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J: Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014 Nov;13(11):1100-1107. doi: 10.1016/S1474-4422(14)70209-1. Epub 2014 Oct 5. [PubMed:25297013]
  5. 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]
  6. 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]
  7. FDA Label: Apadaz [Link]
  8. Presentation on CGRP, MONOCLONAL ANTIBODIES AND SMALL MOLECULES (-GEPANTS) [File]
External Links
Wikipedia
Galcanezumab
ATC Codes
N02CX08 — Galcanezumab
FDA label
Download (2.06 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic ScienceMigraine Disorders1
1CompletedOtherHealthy Volunteers1
1CompletedOtherMigraine1
1Not Yet RecruitingBasic ScienceHealthy Volunteers1
2CompletedTreatmentMigraine3
2TerminatedTreatmentKnee Osteoarthritis (Knee OA)1
3Active Not RecruitingTreatmentChronic Migraine1
3Active Not RecruitingTreatmentMigraine1
3CompletedTreatmentChronic Cluster Headache1
3CompletedTreatmentEpisodic Cluster Headache1
3CompletedTreatmentMigraine4
3Enrolling by InvitationTreatmentChronic Cluster Headache / Episodic Cluster Headache1
3RecruitingTreatmentEpisodic Migraine2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous100 mg/1mL
Injection, solutionSubcutaneous120 mg/1mL
SolutionSubcutaneous120 mg
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
Humans
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. 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]
Kind
Protein
Organism
Humans
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. 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]

Drug created on May 18, 2018 08:05 / Updated on September 02, 2019 20:11