This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Garetosmab is a human IgG4κ anti-Activin A antibody under investigation for the management of fibrodysplasia ossificans progressiva.

Generic Name
Garetosmab
DrugBank Accession Number
DB16379
Background

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of episodic, progressive heterotropic ossification. FOP is characterized by episodic inflammatory episodes, which may be precipitated by trauma, including immunizations and minor tissue damage, which usually result in ossification of the lesion.1 Patients experience abnormal cartilage formation, growth plate dysplasia, and joint issues, resulting in progressive immobility and associated comorbidities.1,4 The discovery of an activating mutation in the ACVR1 receptor that renders it responsive to the (normally antagonistic) Activin A led to an interest in Activin A as a therapeutic target.3,4

Garetosmab is under investigation in clinical trial NCT04577820 (Study to Assess the Efficacy and Safety of Garetosmab in Japanese Adult Patients With Fibrodysplasia Ossificans Progressiva (FOP)).

Type
Biotech
Groups
Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • Garetosmab
External IDs
  • REGN-2477

Pharmacology

Indication

Not Available

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of episodic, progressive heterotropic ossification. Approximately 97% of FOP patients share the same c.617G > A; R206H mutation in the ACVR1 gene encoding a type I TGFβ/BMP family ligand-receptor that binds BMPs to signal through Smad1/5/8.1,2 This mutation is predicted to destabilize the intracellular glycine-serine (GS) activation domain.2 Activin A signals typically through a complex of the type I receptor ACVR1B and one of the type II receptors ACVR2A, ACVR2B, or BMPR2 that interfaces with Smad2/3. However, Activin A can also form a non-signalling complex (NSC) together with ACVR1 that sequesters both the ligand and cognate receptors resulting in an apparent inhibition of ACVR1-mediated BMP signalling.3

Surprisingly, the R206H ACVR1 mutation confers signalling sensitivity to the Activin A-ACVR1-type II receptor NSC, causing aberrant activation of Smad1/5/8 pathways and ossification of FOP lesions. At the same time, the mutant ACVR1 receptor retains its ability to signal through BMPs.3,4 Garetosmab is a human IgG4κ antibody specific for Activin A.5,6 By inhibiting Activin A signalling through the mutant R206H receptor, garetosmab will likely improve the course of heterotropic ossification in FOP while not interfering with normal TGFβ/BMP family functions.

TargetActionsOrganism
AInhibin beta A chain
binder
Humans
Absorption

Garetosmab, administered as a single intravenous dose to healthy females had a mean Cmax of between 8.10 ± 0.929 and 378 ± 39.7 mg/L for doses ranging between 0.3-10 mg/kg. The Cmax was achieved in a median of 0.06-0.10 days, regardless of dose. Over the same dose range, the AUC0-∞ ranged from 72.2 ± 15.4 to 7520 ± 809 mg*day/L.7

When administered as a single subcutaneous dose of 300 mg, garetosmab had a Cmax of 31.6 ± 7.94 mg/L, a Tmax of 20.9 (range 6.88-21.0) days, and an AUC0-∞ of 1334 ± 376 mg*day/L.7

Volume of distribution

Garetosmab had a steady-state volume of distribution between 41.4 ± 4.66 and 47.8 ± 4.70 ml/kg following a single IV dose of 0.3-10 mg/kg in healthy women.7

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

When administered as a single IV dose of 0.3-10 mg/kg in healthy women, Garetosmab clearance decreases with increasing dose from 4.35 ± 1.11 mL/day/kg at 0.3 mg/kg down to 1.34 ± 0.149 mL/day/kg at 10 mg/kg.7

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.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Not Available
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
KR9ZSKO5QE
CAS number
2097125-54-5

References

General References
  1. Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM: Fibrodysplasia ossificans progressiva (FOP): A disorder of osteochondrogenesis. Bone. 2020 Nov;140:115539. doi: 10.1016/j.bone.2020.115539. Epub 2020 Jul 27. [Article]
  2. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS: A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7. Epub 2006 Apr 23. [Article]
  3. Aykul S, Corpina RA, Goebel EJ, Cunanan CJ, Dimitriou A, Kim HJ, Zhang Q, Rafique A, Leidich R, Wang X, McClain J, Jimenez J, Nannuru KC, Rothman NJ, Lees-Shepard JB, Martinez-Hackert E, Murphy AJ, Thompson TB, Economides AN, Idone V: Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop. Elife. 2020 Jun 9;9. pii: 54582. doi: 10.7554/eLife.54582. [Article]
  4. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D'Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN: ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015 Sep 2;7(303):303ra137. doi: 10.1126/scitranslmed.aac4358. [Article]
  5. Wentworth KL, Masharani U, Hsiao EC: Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019 Jun;85(6):1180-1187. doi: 10.1111/bcp.13823. Epub 2019 Jan 6. [Article]
  6. Kaplon H, Reichert JM: Antibodies to watch in 2021. MAbs. 2021 Jan-Dec;13(1):1860476. doi: 10.1080/19420862.2020.1860476. [Article]
  7. Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD: Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study. J Clin Pharmacol. 2020 Nov;60(11):1424-1431. doi: 10.1002/jcph.1638. Epub 2020 Jun 18. [Article]
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
3WithdrawnTreatmentFibrodysplasia Ossificans Progressiva (FOP) / Heterotopic Ossification (HO)1
2CompletedTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
2WithdrawnTreatmentSporadic Inclusion Body Myositis (sIBM)1
1CompletedBasic ScienceHealthy Subjects (HS)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Curator comments
By binding to Activin A homodimers (and presumably Activin AB and AC heterodimers as well), garetosmab blocks aberrant ACVR1 R206H signalling.
General Function
Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition. Inhibins appear to oppose the functions of activins.
Specific Function
Cytokine activity
Gene Name
INHBA
Uniprot ID
P08476
Uniprot Name
Inhibin beta A chain
Molecular Weight
47441.915 Da
References
  1. Aykul S, Corpina RA, Goebel EJ, Cunanan CJ, Dimitriou A, Kim HJ, Zhang Q, Rafique A, Leidich R, Wang X, McClain J, Jimenez J, Nannuru KC, Rothman NJ, Lees-Shepard JB, Martinez-Hackert E, Murphy AJ, Thompson TB, Economides AN, Idone V: Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop. Elife. 2020 Jun 9;9. pii: 54582. doi: 10.7554/eLife.54582. [Article]
  2. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D'Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN: ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015 Sep 2;7(303):303ra137. doi: 10.1126/scitranslmed.aac4358. [Article]
  3. Wentworth KL, Masharani U, Hsiao EC: Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019 Jun;85(6):1180-1187. doi: 10.1111/bcp.13823. Epub 2019 Jan 6. [Article]
  4. Kaplon H, Reichert JM: Antibodies to watch in 2021. MAbs. 2021 Jan-Dec;13(1):1860476. doi: 10.1080/19420862.2020.1860476. [Article]

Drug created at December 21, 2020 19:36 / Updated at November 25, 2021 07:24