Teprotumumab

Identification

Summary

Teprotumumab is a fully human monoclonal antibody directed against insulin-like growth factor-1 receptor for the treatment of thyroid eye disease.

Brand Names
Tepezza
Generic Name
Teprotumumab
DrugBank Accession Number
DB06343
Background

Teprotumumab is a fully human IgG1 monoclonal antibody directed against the human insulin-like growth factor-1 receptor.8 Following a clinical trial in which its efficacy in the treatment of thyroid eye disease (TED) was assessed, it received "breakthrough therapy" designation from the FDA in 20163 and was approved by the FDA in January 2020 for the treatment of TED.7 Thyroid eye disease is a potentially debilitating complication of Graves' Disease involving inflammation and tissue remodeling behind the eye, and previous treatment options typically involved multiple invasive surgeries - teprotumumab is the first drug ever approved for the treatment of TED and therefore represents a significant step forward in the treatment this disease.7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • Immunoglobulin G1, anti-(human insulin-like growth factor I receptor) (human monoclonal heavy chain), disulfide with human monoclonal light chain, dimer
  • Teprotumumab
  • teprotumumab-trbw
External IDs
  • R-1507
  • R1507
  • RG-1507
  • RG1507
  • RO-4858696
  • RO-4858696-000
  • RO-4858696000
  • RO4858696
  • RO4858696-000
  • RV-001
  • RV001

Pharmacology

Indication

Teprotumumab is indicated for the treatment of thyroid eye disease.8

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Teprotumumab inhibits the downstream effects of IGF-1R signaling, namely tissue inflammation and remodeling, which are responsible for the various symptoms of thyroid eye disease.8,5 Teprotumumab may cause disease flares in patients with pre-existing inflammatory bowel disease (IBD) - patients experiencing an exacerbation should discontinue therapy with teprotumumab. Significant hyperglycemia has been observed in patients receiving treatment with teprotumumab which may require antihyperglycemic medications. Based on its mechanism of action, it is likely that teprotumumab will cause fetal harm in pregnant woman - for this reason, females of child-bearing age should use effective contraception prior to initiation, during therapy, and for 6 months following the last dose of teprotumumab.8

Mechanism of action

Graves’ Disease is an autoimmune syndrome involving the thyroid, orbital connective tissues, and some regions of the skin.5 One manifestation of Graves’ Disease is thyroid-associated ophthalmopathy, or thyroid eye disease, which is characterized by orbital inflammation, tissue remodeling, and fibrosis. As the disease progresses, patients may develop proptosis, strabismus, corneal ulceration, and optic neuropathy.1 It has been demonstrated that insulin-like growth factor-1 receptors (IGF-1R) are overexpressed by orbital fibroblasts in patients with thyroid eye disease, in addition to being overexpressed on T-cells and B-cells in these patients.5 It was found that Graves’ Disease IgG molecules could mimic the principal ligand of IGF-1R, insulin-like growth factor-1 (IGF-1), and their binding of IGF-1R induces the expression of chemokines that play roles in tissue remodeling and inflammation. For these reasons, IGF-1R was sought after as a potential therapeutic target for the treatment of thyroid eye disease.5

Teprotumumab is a fully human IgG1 monoclonal antibody directed against IGF-1R. It binds to and induces internalization and degradation of these receptors,1 thus preventing their downstream effects and alleviating symptoms of thyroid eye disease.8

TargetActionsOrganism
UInsulin-like growth factor 1 receptor
binder
antibody
Humans
Absorption

In a population of 40 patients receiving standard dosing in two clinical trials of teprotumumab, utilizing a two-compartment pharmacokinetic model, the AUC and Cmax were estimated to be 138 ± 34 mg•hr/mL and 632 ± 139 mcg/mL, respectively.8

Volume of distribution

Following the standard dosing regimen, the mean central and peripheral volumes of distribution are approximately 3.26 ± 0.87 L and 4.32 ± 0.67 L, respectively.8

Protein binding

Data regarding teprotumumab serum protein binding is unavailable at this time.

Metabolism

The metabolism of teprotumumab has not been fully characterized. As a protein, its metabolism is expected to involve proteolysis to smaller proteins and peptides.8

Route of elimination

Data regarding specific route(s) of elimination are unavailable at this time.

Half-life

The half-life of teprotumumab is 20 ± 5 days.8

Clearance

The estimated mean clearance of teprotumumab is 0.27 L/day.8 The inter-compartment clearance is 0.74 L/day.8

Adverse Effects
Adverseeffects
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Toxicity

Toxicity information, including information regarding overdosage, is currently unavailable.8 Symptoms of teprotumumab overdose are likely to be consistent with its adverse effect profile.

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
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Teprotumumab.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Teprotumumab.
AlbiglutideThe therapeutic efficacy of Albiglutide can be decreased when used in combination with Teprotumumab.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Teprotumumab.
BromocriptineThe therapeutic efficacy of Bromocriptine can be decreased when used in combination with Teprotumumab.
CanagliflozinThe therapeutic efficacy of Canagliflozin can be decreased when used in combination with Teprotumumab.
ChlorpropamideThe therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Teprotumumab.
DapagliflozinThe therapeutic efficacy of Dapagliflozin can be decreased when used in combination with Teprotumumab.
DisopyramideThe therapeutic efficacy of Disopyramide can be decreased when used in combination with Teprotumumab.
DulaglutideThe therapeutic efficacy of Dulaglutide can be decreased when used in combination with Teprotumumab.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TepezzaInjection, powder, lyophilized, for solution500 mg/1IntravenousHorizon Therapeutics USA, Inc.2020-01-21Not applicableUS flag

Categories

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
  • Humans

Chemical Identifiers

UNII
Y64GQ0KC0A
CAS number
1036734-93-6

References

General References
  1. Wang Y, Patel A, Douglas RS: Thyroid Eye Disease: How A Novel Therapy May Change The Treatment Paradigm. Ther Clin Risk Manag. 2019 Nov 11;15:1305-1318. doi: 10.2147/TCRM.S193018. eCollection 2019. [Article]
  2. Hodgson NM, Rajaii F: Current Understanding of the Progression and Management of Thyroid Associated Orbitopathy: A Systematic Review. Ophthalmol Ther. 2019 Dec 10. pii: 10.1007/s40123-019-00226-9. doi: 10.1007/s40123-019-00226-9. [Article]
  3. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS: Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017 May 4;376(18):1748-1761. doi: 10.1056/NEJMoa1614949. [Article]
  4. Douglas RS: Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis. Eye (Lond). 2019 Feb;33(2):183-190. doi: 10.1038/s41433-018-0321-y. Epub 2018 Dec 21. [Article]
  5. Smith TJ: The insulin-like growth factor-I receptor and its role in thyroid-associated ophthalmopathy. Eye (Lond). 2019 Feb;33(2):200-205. doi: 10.1038/s41433-018-0265-2. Epub 2018 Nov 1. [Article]
  6. Mohyi M, Smith TJ: IGF1 receptor and thyroid-associated ophthalmopathy. J Mol Endocrinol. 2018 Jul;61(1):T29-T43. doi: 10.1530/JME-17-0276. Epub 2017 Dec 22. [Article]
  7. FDA News Release: Teprotumumab approval [Link]
  8. FDA Approved Drug Products: Tepezza (teprotumumab-trbw) for intravenous injection [Link]
RxNav
2274803
Wikipedia
Teprotumumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentThyroid Eye Disease1
4RecruitingTreatmentChronic (Inactive) Thyroid Eye Disease / Thyroid Eye Disease1
3CompletedTreatmentOrbitopathy, Graves / Thyroid Eye Disease1
3CompletedTreatmentThyroid Eye Disease1
2CompletedTreatmentThyroid Associated Ophthalmopathy1
2TerminatedTreatmentBreast Cancer1
2TerminatedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2TerminatedTreatmentNon-squamous Non-small-cell Lung Cancer (NSQ NSCLC)1
2TerminatedTreatmentSarcomas1
1CompletedBasic ScienceBreast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous500 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Antibody
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involv...
Gene Name
IGF1R
Uniprot ID
P08069
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da
References
  1. FDA Approved Drug Products: Tepezza (teprotumumab-trbw) for intravenous injection [Link]

Drug created on March 19, 2008 16:25 / Updated on July 02, 2021 03:58