Dupilumab
![]() Dupilumab antigen binding fragment (orange and green) bound to a human IL-4 receptor Alpha (purple) | |
Monoclonal antibody | |
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Type | Whole antibody |
Source | Human |
Target | Interleukin 4(IL4) receptor Alpha |
Clinical data | |
Pronunciation | /duˈpɪljumæb/doo-PIL-yoo-mab |
Trade names | Dupixent |
AHFS/Drugs | Monograph |
MedlinePlus | a617021 |
License data | |
Pregnancy category |
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Routes of administration | Subcutaneous |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider |
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UNII | |
KEGG | |
Chemical and physical data | |
Formula | C6512H10066N1730O2052S46 |
Molar mass | 146898.98g·mol−1 |
Dupilumab,sold under the brand nameDupixent,is amonoclonal antibodyblockinginterleukin 4andinterleukin 13,used forallergic diseasessuch asatopic dermatitis(eczema),asthmaandnasal polypswhich result inchronic sinusitis.[6][7][8][4]It is also used for the treatment ofeosinophilic esophagitis[9]andprurigo nodularis.[10]
The most common side effects reported by the USFood and Drug Administration(FDA) include injection site reactions, upper respiratory tract infections, joint pain, and herpes viral infections.[9]The most common side effects reported by theEuropean Medicines Agency(EMA) include injection-site reactions (such as redness, swelling including due to fluid build-up, itching and pain), conjunctivitis (redness and discomfort in the eye) including conjunctivitis due to allergy, joint pain, cold sores, and increased blood levels of a type of white blood cell called eosinophils.[5]It was developed byRegeneron PharmaceuticalsandSanofi Genzyme.[11][12]It received approval from the USFood and Drug Administration(FDA) for moderate-to-severe atopic dermatitis in 2017,[7]and for asthma in 2018.[4]The FDA considers it to be afirst-in-class medication.[13]
Dupilumab is the first treatment for eosinophilic esophagitis approved by the U.S.Food and Drug Administration(FDA).[9]Eosinophilic esophagitis is a chronic inflammatory disorder in which eosinophils, a type of white blood cell, are found in the tissue of the esophagus.[9]In adults and adolescents with eosinophilic esophagitis, common symptoms include difficulty swallowing, difficulty eating, and food getting stuck in the esophagus.[9]Dupilumab is a monoclonal antibody that acts to inhibit part of the inflammatory pathway.[9]Dupilumab is the first treatment for prurigo nodularis approved by the FDA.[10]Prurigo nodularis is a rare skin disease that causes hard, itchy lumps (nodules) to form on the skin.[10]
Medical uses
[edit]![Photo of a Dupixent (dupilumab) 300mg/2mL auto-injector pen and accompanying packaging. The pen is labeled in Japanese.](https://upload.wikimedia.org/wikipedia/commons/thumb/0/02/Dupixent_Pen_and_Packaging.jpg/261px-Dupixent_Pen_and_Packaging.jpg)
Dupilumab isindicatedfor the treatment of moderate-to-severeatopic dermatitis,moderate-to-severe asthma, and for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP).[4][5][14][15][9]It has been shown to be effective at treatingaspirin-exacerbated respiratory disease(AERD), a typically difficult to treat condition where aspirin intolerant patients have both CRSwNP and asthma.[16][17]
In May 2022, the indication for dupilumab was updated to include the treatment ofeosinophilic esophagitisin people aged twelve years of age and older weighing at least 40 kilograms (88 lb).[9]
In September 2022, the indication for dupilumab was updated to include the treatment of adults withprurigo nodularis(PN).[10]
In March 2023, theEMAapproved dupilumab for the treatment of severeatopic dermatitisin children aged six months to five years who are candidates forsystemic therapy.[18][19]
Side effects
[edit]Injection site reactionssuch as redness and pain are common, occurring in approximately 11.4% of cases.[20]Dupilumab can cause allergic reactions,conjunctivitis,andkeratitisand, due to its immunosuppressive effects, reactivation ofcold sores.[7]In clinical trials, people receiving dupilumab had decreased levels ofT helper cells.[21]
Pharmacology
[edit]Mechanism of action
[edit]Dupilumab binds to the Alpha subunit of theinterleukin-4 receptor(IL-4Rα), making it areceptor antagonist.[22]Through blockade of IL-4Rα, dupilumab modulates signaling of both theinterleukin 4andinterleukin 13pathways.[21]
Pharmacokinetics
[edit]Dupilumab shows a non-linear rate in regard to the target.[21]Dupilumab is also reported to have a bioavailability of 64%, with the average concentration occurring one week after injection.[21]
History
[edit]Regeneron PharmaceuticalsandSanofi Genzymejointly developed dupilumab,[23]the latter of which provided 130 million dollars to Regeneron for research and development towards monoclonal antibodies.[24]Phase II trials for asthma treatment showed increased lung function with increased forced expiratory volume for patients.[21]
In October 2016, Regeneron completed a phase III trial comparing dupilumab with topicalcorticosteroids,in which subjects had a larger decrease in symptoms with both dupilumab andtopical steroidsthan with steroids alone.[25]In these trials 38% and 36% of patients respectively, met the primary efficacy goal of the trial, compared to 8% and 10% under placebo.[21]
The USFood and Drug Administration(FDA) granted the application for dupilumabpriority reviewdesignation[26][27]and in March 2017, the FDA approved dupilumab injection to treat adults with moderate-to-severe eczema.[7]
The efficacy and safety of dupilumab in eosinophilic esophagitis was studied in a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial, that included two 24-week treatment periods (Part A and Part B) that were conducted independently in separate groups of participants.[9]In Part A and Part B, participants received either placebo or 300 milligrams of dupilumab every week.[9]The two primary measurements of efficacy were the proportion of participants who achieved a certain level of reduced eosinophils in the esophagus at week 24, as determined by assessing participants' esophageal tissue under a microscope, and the change in the participant-reported Dysphagia Symptom Questionnaire (DSQ) score from baseline to week 24.[9]The DSQ is a questionnaire designed to measure difficulty swallowing associated with eosinophilic esophagitis, with total scores ranging from 0 to 84; higher DSQ scores indicate worse symptoms.[9]
The efficacy and safety of dupilumab to treat prurigo nodularis among adults were evaluated in two clinical trials, EFC16459 (PRIME) and EFC16460 (PRIME2).[10]Each trial evaluated 300 mg of dupilumab administered every 2 weeks following an initial dose of 600 mg.[10]The treatment lasted for 24 weeks.[10]Effectiveness was mainly assessed by the proportion of subjects whose itchy skin (pruritus) improved by more than four points on the Worst Itch Numeric Rating Scale, the proportion of subjects who achieved score of 0 or 1 on Investigator's Global Assessment PN-stage scale (the equivalent of 0-5 nodules), and the proportion of subjects who achieved a response on both scales at week 24.[10]
Research
[edit]Dupilumab is under investigation for treatingchronic obstructive pulmonary disease.[28][29]
References
[edit]- ^ab"AusPAR: Dupilumab".Therapeutic Goods Administration (TGA).4 May 2022.Retrieved4 May2022.
- ^"Regulatory Decision Summary for Dupixent".Drug and Health Products Portal.14 April 2023.Retrieved2 April2024.
- ^"Skin health".Health Canada.9 May 2018.Retrieved13 April2024.
- ^abcd"Dupixent- dupilumab injection, solution".DailyMed.25 June 2020.Archivedfrom the original on 24 March 2021.Retrieved17 September2020.
- ^abc"Dupixent EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 28 December 2021.Retrieved23 September2021.Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^"Statement on a Nonproprietary Name Adopted By The USAN Council - Dupilumab"Archived21 May 2021 at theWayback Machine,American Medical Association.
- ^abcd"FDA approves new eczema drug Dupixent".U.S.Food and Drug Administration(FDA). 10 September 2019.Archivedfrom the original on 28 March 2017.Retrieved29 March2017.
- ^"FDA approves first treatment for chronic rhinosinusitis with nasal polyps".U.S.Food and Drug Administration(FDA). 26 June 2019.Archivedfrom the original on 29 December 2020.Retrieved27 June2019.
- ^abcdefghijkl"FDA Approves First Treatment for Eosinophilic Esophagitis, a Chronic Immune Disorder".U.S.Food and Drug Administration(FDA)(Press release). 20 May 2022.Archivedfrom the original on 5 August 2022.Retrieved20 May2022.
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- ^abcdefgh"FDA approves first treatment for prurigo nodularis".U.S.Food and Drug Administration(FDA).29 September 2022.Archivedfrom the original on 29 September 2022.Retrieved30 September2022.
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- ^"Sanofi - Commercial collaboration".Sanofi. Archived fromthe originalon 8 November 2017.Retrieved9 March2017.
- ^"A powerful research and development engine".regeneron.Archivedfrom the original on 30 April 2019.Retrieved9 March2017.
- ^New Drug Therapy Approvals 2017(PDF)(Report). U.S.Food and Drug Administration(FDA). January 2018.Archivedfrom the original on 23 October 2020.Retrieved16 September2020.
- ^Kraft M, Worm M (April 2017). "Dupilumab in the treatment of moderate-to-severe atopic dermatitis".Expert Review of Clinical Immunology.13(4): 301–310.doi:10.1080/1744666X.2017.1292134.PMID28165826.S2CID3404484.
- ^Humbert M, Busse W, Hanania NA (January 2018). "Controversies and opportunities in severe asthma".Current Opinion in Pulmonary Medicine.24(1): 83–93.doi:10.1097/MCP.0000000000000438.PMID29059087.S2CID4433743.
- ^Buchheit KM, Sohail A, Hacker J, Maurer R, Gakpo D, Bensko JC, et al. (August 2022)."Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease".The Journal of Allergy and Clinical Immunology.150(2): 415–424.doi:10.1016/j.jaci.2022.04.007.PMC9378638.PMID35460728.
- ^Oykhman P, Paramo FA, Bousquet J, Kennedy DW, Brignardello-Petersen R, Chu DK (April 2022)."Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: A systematic review and network meta-analysis".The Journal of Allergy and Clinical Immunology.149(4): 1286–1295.doi:10.1016/j.jaci.2021.09.009.PMID34543652.
- ^EMA (17 September 2018)."Dupixent".European Medicines Agency.Retrieved22 March2023.
- ^Devarasetti H (22 March 2023)."Sanofi Dupixent receives EC approval for atopic dermatitis".Pharmaceutical Technology.Retrieved22 March2023.
- ^Kim PJ, Lansang RP, Vender R (July 2023)."A Systematic Review and Meta-Analysis of Injection Site Reactions in Randomized-Controlled Trials of Biologic Injections".Journal of Cutaneous Medicine and Surgery.27(4): 358–367.doi:10.1177/12034754231188444.PMC10486173.PMID37533141.
- ^abcdefShirley M (July 2017). "Dupilumab: First Global Approval".Drugs.77(10): 1115–1121.doi:10.1007/s40265-017-0768-3.PMID28547386.S2CID207489287.
- ^Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. (June 2013)."Dupilumab in persistent asthma with elevated eosinophil levels".The New England Journal of Medicine.368(26): 2455–66.doi:10.1056/NEJMoa1304048.PMID23688323.
- ^Spencer D (8 March 2020)."Sanofi Genzyme Head on Incredible Success of" Once-in-a-Career "Product Dupixent".Pharmaboardroom.Archivedfrom the original on 18 May 2021.Retrieved18 May2021.
- ^"SEC 10-Q Filing of Regeneron".SEC.gov.30 June 2017.Archivedfrom the original on 21 October 2017.Retrieved20 October2017.
- ^Hamilton JD, Ungar B, Guttman-Yassky E (2015). "Drug evaluation review: dupilumab in atopic dermatitis".Immunotherapy.7(10): 1043–58.doi:10.2217/imt.15.69.PMID26598956.
- ^"Novel Biologic Dupilumab Improves Eczema Symptoms".October 2016.Archivedfrom the original on 11 March 2017.Retrieved30 October2017.
- ^Walker J (30 May 2016)."New Eczema Treatments Could Be Available Soon".The Wall Street Journal.ISSN0099-9660.Archivedfrom the original on 5 January 2018.Retrieved31 May2016.
- ^Clinical trial numberNCT03930732for "Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients with Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD) with Type 2 Inflammation" atClinicalTrials.gov
- ^"Dupixent demonstrates potential to become first biologic to treat COPD by showing significant reduction in exacerbations in pivotal trial".Globe Newswire(Press release).Retrieved14 May2023.