Identification

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Name
Dupilumab
Accession Number
DB12159
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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

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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DupixentSolution200 mgSubcutaneousSanofi AventisNot applicableNot applicableCanada
DupixentSolution150 mgSubcutaneousSanofi Aventis2018-02-06Not applicableCanada
DupixentInjection, solution200 mg/1.14mLSubcutaneoussanofi-aventis U.S. LLC2018-10-19Not applicableUs
DupixentInjection, solution300 mg/2mLSubcutaneoussanofi-aventis U.S. LLC2017-03-28Not applicableUs
DupixentInjection, solution300 mg/2mLSubcutaneoussanofi-aventis U.S. LLC2017-03-28Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
420K487FSG
CAS number
1190264-60-8

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

Associated Conditions
Associated Therapies
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
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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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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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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

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.[]

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 Dupilumab.
AbituzumabThe risk or severity of adverse effects can be increased when Dupilumab is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Dupilumab is combined with Abrilumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Dupilumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab 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.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Dupilumab.
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.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

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. [PubMed:23688323]
  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. [PubMed:30027349]
  3. D'Ippolito D, Pisano M: Dupilumab (Dupixent): An Interleukin-4 Receptor Antagonist for Atopic Dermatitis. P T. 2018 Sep;43(9):532-535. [PubMed:30186024]
  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. [PubMed:29939132]
  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. [PubMed:29498038]
  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. [PubMed:29176972]
  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]
External Links
PubChem Substance
347911292
Wikipedia
Dupilumab
ATC Codes
D11AH05 — Dupilumab
AHFS Codes
  • 84:92.00 — Misc. Skin and Mucous Membrane Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentRhinosinusitis Chronic / Sleep Apnea1
1Active Not RecruitingTreatmentAsthma, Allergic1
1CompletedBasic ScienceAtopic Dermatitis (AD)1
1CompletedTreatmentAtopic Dermatitis (AD) / Atopic disorders1
1CompletedTreatmentHealthy Volunteers4
1CompletedTreatmentSkin Inflammation1
1, 2CompletedTreatmentAtopic Dermatitis (AD)1
2Active Not RecruitingTreatmentAspirin-exacerbated Respiratory Disease1
2CompletedTreatmentAllergic Rhinitis (AR)1
2CompletedTreatmentAsthma4
2CompletedTreatmentAtopic Dermatitis (AD)6
2CompletedTreatmentOesophagitis, Eosinophilic1
2CompletedTreatmentPolyps, Nasal1
2Not Yet RecruitingTreatmentAllergies Food Milk1
2Not Yet RecruitingTreatmentChronic Hand Eczema1
2Not Yet RecruitingTreatmentEosinophilic Gastritis / Eosinophilic Gastroenteritis1
2Not Yet RecruitingTreatmentFood Allergy / Hypersensitivity / Hypersensitivity, Food / Peanut Allergies / Peanut Hypersensitivity1
2RecruitingTreatmentAlopecia Areata (AA)1
2RecruitingTreatmentAtopic Dermatitis (AD)1
2RecruitingTreatmentCholinergic Urticaria1
2RecruitingTreatmentChronic Spontaneous Urticaria / Recurrent Angioedema1
2RecruitingTreatmentPeanut Allergies2
2RecruitingTreatmentProstate Cancer1
2, 3CompletedTreatmentAsthma1
2, 3RecruitingTreatmentAtopic Dermatitis (AD)1
3Active Not RecruitingTreatmentAsthma1
3Active Not RecruitingTreatmentAtopic Dermatitis (AD)3
3CompletedTreatmentAsthma2
3CompletedTreatmentAtopic Dermatitis (AD)5
3CompletedTreatmentAtopic Dermatitis (AD) / Dermatitis, Dermatitis Atopic / Disease, Eczematous Skin / Diseases Genetic, Genetic / Diseases Inborn, Skin / Eczema, Skin Diseases, Skin / Hypersensitivity, Immediate / Hypersensitivity, Immune System Diseases / Moderate-to-Severe Atopic Dermatiti / Moderate-to-severe Atopic Dermatitis1
3CompletedTreatmentChronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP) / Polyps, Nasal2
3Enrolling by InvitationTreatmentAtopic Dermatitis (AD)1
3RecruitingTreatmentAsthma4
3RecruitingTreatmentAtopic Dermatitis (AD)1
3RecruitingTreatmentAtopic Dermatitis (AD) / Dermatitis, Eczematous / Genetic Diseases, Inborn / Hypersensitivity / Hypersensitivity, Immediate / Immune System Diseases / Skin Diseases / Skin Diseases, Eczematous / Skin Diseases, Genetic / Skin Inflammation1
3RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3RecruitingTreatmentOesophagitis, Eosinophilic1
4Not Yet RecruitingTreatmentAllergic Contact Dermatitis1
4Not Yet RecruitingTreatmentAsthma1
4RecruitingTreatmentAtopic Dermatitis (AD)2
4RecruitingTreatmentAtopic Dermatitis (AD) / Atopic Dermatitis Eczema1
4RecruitingTreatmentAtopic Dermatitis (AD) / Atopic Dermatitis and Related Conditions / Atopic Dermatitis Eczema / Dermatitis, Eczematous1
Not AvailableApproved for MarketingNot AvailableAsthma1
Not AvailableCompletedNot AvailableSevere Asthma1
Not AvailableEnrolling by InvitationNot AvailableAtopic Dermatitis (AD)1
Not AvailableNot Yet RecruitingBasic ScienceAtopic Dermatitis (AD)1
Not AvailableRecruitingNot AvailableAdverse Pregnancy Outcomes / Atopic Dermatitis (AD)1
Not AvailableRecruitingNot AvailableAtopic Dermatitis (AD)1
Not AvailableRecruitingNot AvailableAtopic Dermatitis (AD) / Psoriasis1
Not AvailableRecruitingNot AvailableDermatitis atopic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous200 mg/1.14mL
Injection, solutionSubcutaneous300 mg/2mL
SolutionSubcutaneous150 mg
SolutionSubcutaneous200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
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
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. [PubMed:23688323]

Drug created on October 20, 2016 15:30 / Updated on November 16, 2019 10:47