Dupilumab

Identification

Summary

Dupilumab is a monoclonal antibody used to treat moderate to severe atopic dermatitis, asthma, and nasal polyps accompanied by chronic rhinosinusitis in adolescents and adults.

Brand Names
Dupixent
Generic Name
Dupilumab
DrugBank Accession Number
DB12159
Background

Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass that binds to the interleukin-4 (IL-4) receptor, inhibiting the receptor signaling pathways.3 As an interleukin-4 receptor alpha antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, called interleukins (IL), that induce inflammatory and immunological reactions in several atopic or allergic conditions, such as eczema, allergic reaction, and rhinosinusitis.3 Dupilumab was generated by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.7

Dupilumab is commonly marketed as Dupixent®, which is available as a formulation for subcutaneous injection. It was first approved by the FDA in 2017 for patients 12 and older with eczema or atopic dermatitis. Dupilumab is also approved by Health Canada for the same indication and the European Commission for use in atopic dermatitis as well as severe asthma with type 2 inflammation.9 It is the first biologic therapy to have been approved for the treatment of adult patients with moderate-to-severe AD in the EU and USA.2 In 2018, FDA approved the use of dupilumab as an add-on maintenance treatment for patients 12 years and older with moderate-to-severe eosinophilic asthma or with oral corticosteroid-dependent asthma. In June 2019, dupilumab was also approved by the FDA as a treatment for inadequately controlled chronic rhinosinusitis with nasal polyps in adult patients.10 Dupilumab is currently under investigations for potential therapeutic use in diseases driven by allergic reactions or type 2 inflammation, such as pediatric atopic dermatitis, eosinophilic esophagitis, and chronic obstructive pulmonary disease. It is also being studied in combination with another antibody that which targets IL-33.9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6512H10066N1730O2052S46
Protein Average Weight
146896.9522 Da
Sequences
>Dupilumab Heavy Chain
EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTT
VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
>Dupilumab Light Chain
DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRA
SGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSV
FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Dupilumab [Link]
Download FASTA Format
Synonyms
  • Dupilumab
External IDs
  • REGN 668
  • REGN-668
  • REGN668
  • SAR 231893
  • SAR-231893
  • SAR231893

Pharmacology

Indication

Dupilumab indicated, as monotherapy or in combination with topical corticosteroids, for the treatment of patients aged 12 years and older with moderate-to­-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.7

Indicated as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. It is not indicated for the relief of acute bronchospasm or status asthmaticus.7

Indicated for the treatment of nasal polyps accompanied by inadequately controlled chronic rhinosinusitis in adult patients.10

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Dupilumab is an recombinant human IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies. In vivo, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed.8,9 Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling. It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy.8

While findings of some in vitro and in vivo studies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6).5

Mechanism of action

Type 2 inflammatory processes in various allergic and atopic conditions, such as asthma and atopic diseases, involve the type 2 helper T-cell (Th2) immunity.4 Upregulation of this Type 2/Th2 pathway is commonly observed in other inflammatory conditions 5 and the activation of Th2 cells is linked to the production of Th2-associated cytokines, such as interleukin (IL) 4, IL-5, IL-9, and IL-13.4 IL-4 and IL-13 play a central role in inducing inflammatory conditions such as allergic rhinitis, asthma, and atopic dermatitis,9 by regulating Type 2 inflammation and immune function. These inflammatory cytokines work by modulating gene expression downstream of receptor signalling,5 regulating Th2 cell differentiation, and activating inflammatory cells such as mast cells and macrophages.6

There are two types of receptors for IL-4: the type 1 receptor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1).4 Essentially, IL‐4Rα is a component shared by the IL‐4 and IL-13 receptor complexes 3 and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13.6 The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and myeloid cells.1 Dupilumab is a fully human monoclonal antibody directed against IL‐4Rα to inhibit the signalling of IL‐4 and IL‐13.5 Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα).8 It ultimately downregulates type-2 immunity.4

TargetActionsOrganism
AInterleukin-4 receptor subunit alpha
antagonist
Humans
Absorption

The Cmax following administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab were 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively. The Tmax ranged from 3 to 7 days following administration of a single subcutaneous dose ranging from 75 to 600 mg.7 Following a subcutaneous dose, the absolute bioavailability of dupilumab ranged between 61% and 64% in patients with atopic dermatitis or asthma.8

In clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. At these concentrations, the mean trough concentrations ranged from 60.3 ± 35.1 mcg/mL to 79.9 ± 41.4 mcg/mL for 300 mg dose and from 29.2 ± 18.7 to 36.5 ± 22.2 mcg/mL for 200 mg dose administered every other week.7

Volume of distribution

The estimated volume of distribution is 4.8 ± 1.3 L.3

Protein binding

There is limited data on the serum protein binding profile of dupilumab.

Metabolism

Being a monoclonal antibody, dupilumab is not expected to undergo significant hepatic metabolism.8 While the metabolism of dupilumab has not been characterized, it is speculated that dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, as often observed with endogenous IgG.3

Route of elimination

Being a monoclonal antibody, dupilumab is not expected to undergo significant renal elimination. It is proposed that dupilumab is eliminated via parallel linear and nonlinear pathways. At higher concentrations, dupilumab is primarily cleared through a non-saturable proteolytic pathway. At lower concentrations, it undergoes a non-linear saturable IL-4R α target-mediated elimination.8

Half-life

There is limited human data on the half-life of dupilumab.8 In single-dose pharmacokinetic studies, the mean half-life of dupilumab following intravenous or subcutaneous administration ranged from 4.8 to 7 days in rats and 11.7 to 20.5 days in cynomolgus monkeys.11,12 In these studies, the mean half-life was comparable was comparable following intravenous and subcutaneous administration.11

Clearance

There is limited data on the clearance of dupilumab.8

Adverse Effects
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Toxicity

There is limited data on the overdose of dupilumab. As there is no specific treatment for dupilumab, close monitoring of the patient with appropriate symptomatic treatment is advised in case of suspected overdosage.[]

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 Dupilumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Dupilumab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Dupilumab.
AducanumabThe risk or severity of adverse effects can be increased when Dupilumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dupilumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Dupilumab.
AmivantamabThe risk or severity of adverse effects can be increased when Dupilumab is combined with Amivantamab.
AnsuvimabThe risk or severity of adverse effects can be increased when Dupilumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Dupilumab.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Dupilumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DupixentInjection, solution300 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentSolution150 mg / mLSubcutaneousSanofi Aventis2018-02-06Not applicableCanada flag
DupixentInjection, solution200 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentInjection, solution200 mg/1.14mLSubcutaneoussanofi-aventis U.S. LLC2018-10-19Not applicableUS flag
DupixentInjection, solution300 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentInjection, solution300 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentInjection, solution200 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentInjection, solution300 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag
DupixentSolution150 mg / mLSubcutaneousSanofi Aventis2021-05-27Not applicableCanada flag
DupixentInjection, solution200 mgSubcutaneousSanofi Aventis Groupe2020-12-16Not applicableEU flag

Categories

ATC Codes
D11AH05 — Dupilumab
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 and other mammals

Chemical Identifiers

UNII
420K487FSG
CAS number
1190264-60-8

References

General References
  1. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub 2013 May 21. [Article]
  2. Frampton JE, Blair HA: Dupilumab: A Review in Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2018 Aug;19(4):617-624. doi: 10.1007/s40257-018-0370-9. [Article]
  3. D'Ippolito D, Pisano M: Dupilumab (Dupixent): An Interleukin-4 Receptor Antagonist for Atopic Dermatitis. P T. 2018 Sep;43(9):532-535. [Article]
  4. Sastre J, Davila I: Dupilumab: A New Paradigm for the Treatment of Allergic Diseases. J Investig Allergol Clin Immunol. 2018 Jun;28(3):139-150. doi: 10.18176/jiaci.0254. [Article]
  5. Davis JD, Bansal A, Hassman D, Akinlade B, Li M, Li Z, Swanson B, Hamilton JD, DiCioccio AT: Evaluation of Potential Disease-Mediated Drug-Drug Interaction in Patients With Moderate-to-Severe Atopic Dermatitis Receiving Dupilumab. Clin Pharmacol Ther. 2018 Dec;104(6):1146-1154. doi: 10.1002/cpt.1058. Epub 2018 Apr 2. [Article]
  6. Hurdayal R, Brombacher F: Interleukin-4 Receptor Alpha: From Innate to Adaptive Immunity in Murine Models of Cutaneous Leishmaniasis. Front Immunol. 2017 Nov 10;8:1354. doi: 10.3389/fimmu.2017.01354. eCollection 2017. [Article]
  7. DUPIXENT® (dupilumab) injection, for subcutaneous use - FDA Label [Link]
  8. Dupixent, INN-dupilumab - European Medicines Agency - Europa EU [Link]
  9. Dupixent® (dupilumab) Approved for Severe Asthma by European Commission - Regeneron [Link]
  10. FDA approves first treatment for chronic rhinosinusitis with nasal polyps [Link]
  11. Dupixent, INN - dupilumab -Public Assessment Report - European Medicines Agency - Europa EU [Link]
  12. Australian Public Assessment Report for Dupilumab - TGA [Link]
  13. DUPIXENT® (dupilumab) injection, for subcutaneous use - FDA Label (Revised: 06/2019) [Link]
PubChem Substance
347911292
RxNav
1876376
Wikipedia
Dupilumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAtopic Dermatitis (AD)2
4Not Yet RecruitingDiagnosticAD / Atopic Dermatitis (AD) / Dermatitis, Eczematous1
4Not Yet RecruitingTreatmentAsthma3
4Not Yet RecruitingTreatmentAtopic Dermatitis (AD)1
4Not Yet RecruitingTreatmentAtopic Dermatitis (AD) / Dermatitis, Eczematous1
4Not Yet RecruitingTreatmentChronic Rhinosinusitis With Nasal Polyps / Olfactory Disorders1
4RecruitingBasic ScienceAtopic Dermatitis (AD)1
4RecruitingTreatmentAERD - Aspirin Exacerbated Respiratory Disease1
4RecruitingTreatmentAllergic Contact Dermatitis1
4RecruitingTreatmentAsthma3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous
Injection, solutionParenteral; Subcutaneous
Injection, solutionSubcutaneous200 mg/1.14mL
Injection, solutionSubcutaneous200 mg
Injection, solutionSubcutaneous300 mg/2mL
Injection, solutionSubcutaneous300 mg
SolutionSubcutaneous150 mg / mL
SolutionSubcutaneous200 mg / 1.14 mL
SolutionSubcutaneous200 mg
Injection, solutionSubcutaneous
SolutionSubcutaneous300 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor signaling protein activity
Specific Function
Receptor for both interleukin 4 and interleukin 13. Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regu...
Gene Name
IL4R
Uniprot ID
P24394
Uniprot Name
Interleukin-4 receptor subunit alpha
Molecular Weight
89657.42 Da
References
  1. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub 2013 May 21. [Article]

Drug created on October 20, 2016 21:30 / Updated on July 24, 2021 14:58