Dupilumab

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Dupilumab
Dupilumab fab binding to IL-4.png
Dupilumab antigen binding fragment (orange and green) bound to a human IL-4 receptor alpha (purple)
Monoclonal antibody
Type Whole antibody
Source Human
Target Interleukin 4 (IL4) receptor alpha
Clinical data
Pronunciation /duˈpɪljumæb/ doo-PIL-yoo-mab
Trade names Dupixent
AHFS/Drugs.com Monograph
MedlinePlus a617021
License data
Pregnancy
category
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6512H10066N1730O2052S46
Molar mass 146898.98 g·mol−1

Dupilumab, sold under the brand name Dupixent, is a monoclonal antibody blocking interleukin 4 and interleukin 13, used for allergic diseases such as atopic dermatitis (eczema), asthma and nasal polyps which result in chronic sinusitis. [6] [7] [8] [4] It is also used for the treatment of eosinophilic esophagitis, [9] prurigo nodularis [10] and COPD. [11]

Contents

The most common side effects reported by the US Food 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 the European 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 by Regeneron Pharmaceuticals and Sanofi Genzyme. [12] [13] It received approval from the US Food 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 a first-in-class medication. [14]

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

A Dupixent auto-injector pen Dupixent Pen and Packaging.jpg
A Dupixent auto-injector pen

Dupilumab is indicated for the treatment of moderate-to-severe atopic dermatitis, moderate-to-severe asthma, and for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). [4] [5] [15] [16] [9] It has been shown to be effective at treating aspirin-exacerbated respiratory disease (AERD), a typically difficult to treat condition where aspirin intolerant patients have both CRSwNP and asthma. [17] [18]

In May 2022, the indication for dupilumab was updated to include the treatment of eosinophilic esophagitis in 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 with prurigo nodularis (PN). [10]

In March 2023, the EMA approved dupilumab for the treatment of severe atopic dermatitis in children aged six months to five years who are candidates for systemic therapy. [19] [20]

Side effects

Injection site reactions such as redness and pain are common, occurring in approximately 11.4% of cases. [21] Dupilumab can cause allergic reactions, conjunctivitis, and keratitis and, due to its immunosuppressive effects, reactivation of cold sores. [7] In clinical trials, people receiving dupilumab had decreased levels of T helper cells. [22]

Pharmacology

Mechanism of action

Dupilumab binds to the alpha subunit of the interleukin-4 receptor (IL-4Rα), making it a receptor antagonist. [23] Through blockade of IL-4Rα, dupilumab modulates signaling of both the interleukin 4 and interleukin 13 pathways. [22]

Pharmacokinetics

Dupilumab shows a non-linear rate in regard to the target. [22] Dupilumab is also reported to have a bioavailability of 64%, with the average concentration occurring one week after injection. [22]

History

Regeneron Pharmaceuticals and Sanofi Genzyme jointly developed dupilumab, [24] the latter of which provided 130 million dollars to Regeneron for research and development towards monoclonal antibodies. [25] Phase II trials for asthma treatment showed increased lung function with increased forced expiratory volume for patients. [22]

In October 2016, Regeneron completed a phase III trial comparing dupilumab with topical corticosteroids, in which subjects had a larger decrease in symptoms with both dupilumab and topical steroids than with steroids alone. [26] In these trials 38% and 36% of patients respectively, met the primary efficacy goal of the trial, compared to 8% and 10% under placebo. [22]

The US Food and Drug Administration (FDA) granted the application for dupilumab priority review designation [27] [28] 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

Dupilumab is under investigation for treating chronic obstructive pulmonary disease. [29] [30]

Related Research Articles

<span class="mw-page-title-main">Dermatitis</span> Inflammatory disease of the skin

Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can vary from small to covering the entire body. Dermatitis is also called eczema but the same term is often used for the most common type of skin inflammation, atopic dermatitis.

<span class="mw-page-title-main">Eosinophilia</span> Excess number of eosinophil cells in the blood

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merged with Aventis and renamed to Sanofi-Aventis, which were each the product of several previous mergers. It changed its name back to Sanofi in May 2011. The company is a component of the Euro Stoxx 50 stock market index. In 2023, the company’s seat in Forbes Global 2000 was 89.

<span class="mw-page-title-main">Atopic dermatitis</span> Long-term form of skin inflammation

Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. AD is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditions. AD results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which can thicken over time.

<span class="mw-page-title-main">Eosinophilic esophagitis</span> Allergic inflammatory condition of the esophagus

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn.

<span class="mw-page-title-main">Prurigo nodularis</span> Medical condition

Prurigo nodularis (PN), also known as nodular prurigo, is a skin disorder characterized by pruritic (itchy), nodular lesions, which commonly appear on the trunk, arms and legs. Patients often present with multiple excoriated nodules caused by chronic scratching. Although the exact cause of PN is unknown, PN is associated with other dermatologic conditions such as untreated or severe atopic dermatitis and systemic causes of pruritus including liver disease and end stage kidney disease. The goal of treatment in PN is to decrease itching. PN is also known as Hyde prurigo nodularis, or Picker's nodules.

<span class="mw-page-title-main">Regeneron Pharmaceuticals</span> American biotechnology company

Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to its name, the company branched out into the study of both cytokine and tyrosine kinase receptors, which gave rise to their first product, which is a VEGF-trap.

Reslizumab, sold under the brand names Cinqair and Cinqaero, is a humanized monoclonal antibody against human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5, a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. By binding to human IL-5, it blocks its biological function; consequently survival and activity of eosinophils are reduced. The benefits with reslizumab are its ability to reduce the exacerbation rate and improve lung function and asthma-related quality of life in patients with severe eosinophilic asthma and with at least one previous asthma exacerbation in the preceding year. The most common side effects are increased blood creatine phosphokinase, myalgia and anaphylactic reactions.

Mepolizumab, sold under the brand name Nucala by GlaxoSmithKline, is a humanized monoclonal antibody used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome (HES). It recognizes and blocks interleukin-5 (IL-5), a signalling protein of the immune system.

Lebrikizumab, sold under the brand name Ebglyss is a humanized monoclonal antibody used for the treatment of atopic dermatitis. It is an interleukin-13 antagonist. It is given by subcutaneous injection.

Benralizumab, sold under the brand name Fasenra, is a monoclonal antibody directed against the alpha chain of the interleukin-5 receptor (CD125). It was developed by MedImmune for the treatment of asthma.

<span class="mw-page-title-main">Tralokinumab</span> Monoclonal antibody

Tralokinumab sold under the brand names Adtralza (EU/UK) and Adbry (US) among others, is a human monoclonal antibody used for the treatment of atopic dermatitis. Tralokinumab targets the cytokine interleukin 13.

Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

<span class="mw-page-title-main">Crisaborole</span> Chemical compound

Crisaborole, sold under the brand name Eucrisa among others, is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema) in adults and children.

<span class="mw-page-title-main">Tezepelumab</span> Monoclonal antibody

Tezepelumab, sold under the brand name Tezspire, is a human monoclonal antibody used for the treatment of asthma. Tezepelumab blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine that has been suggested to be critical in the initiation and persistence of airway inflammation.

Nemolizumab, sold under the brand name Nemluvio, is a medication used for the treatment of prurigo nodularis. It is a monoclonal antibody that blocks the interleukin-31 receptor A.

Cemiplimab, sold under the brand name Libtayo, is a monoclonal antibody medication for the treatment of squamous cell skin cancer. Cemiplimab belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway.

<span class="mw-page-title-main">Abrocitinib</span> Chemical compound

Abrocitinib, sold under the brand name Cibinqo, is a medication used for the treatment of atopic dermatitis (eczema). It is a Janus kinase inhibitor and it was developed by Pfizer. It is taken by mouth.

Type 2 inflammation is a pattern of immune response. Its physiological function is to defend the body against helminths, but a dysregulation of the type 2 inflammatory response has been implicated in the pathophysiology of several diseases.

References

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  2. ↑ "Regulatory Decision Summary for Dupixent". Drug and Health Products Portal. 14 April 2023. Retrieved 2 April 2024.
  3. ↑ "Skin health". Health Canada . 9 May 2018. Retrieved 13 April 2024.
  4. 1 2 3 4 "Dupixent- dupilumab injection, solution". DailyMed. 25 June 2020. Archived from the original on 24 March 2021. Retrieved 17 September 2020.
  5. 1 2 3 "Dupixent EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 28 December 2021. Retrieved 23 September 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Statement on a Nonproprietary Name Adopted By The USAN Council - Dupilumab" Archived 21 May 2021 at the Wayback Machine , American Medical Association.
  7. 1 2 3 4 "FDA approves new eczema drug Dupixent". U.S. Food and Drug Administration (FDA). 10 September 2019. Archived from the original on 28 March 2017. Retrieved 29 March 2017.
  8. ↑ "FDA approves first treatment for chronic rhinosinusitis with nasal polyps". U.S. Food and Drug Administration (FDA). 26 June 2019. Archived from the original on 29 December 2020. Retrieved 27 June 2019.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 "FDA Approves First Treatment for Eosinophilic Esophagitis, a Chronic Immune Disorder". U.S. Food and Drug Administration (FDA) (Press release). 20 May 2022. Archived from the original on 5 August 2022. Retrieved 20 May 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 3 4 5 6 7 8 "FDA approves first treatment for prurigo nodularis". U.S. Food and Drug Administration (FDA). 29 September 2022. Archived from the original on 29 September 2022. Retrieved 30 September 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. ↑ "Dupixent approved in the US as the first-ever biologic medicine for patients with COPD". Archived from the original on 28 September 2024.
  12. ↑ "Sanofi - Commercial collaboration". Sanofi. Archived from the original on 8 November 2017. Retrieved 9 March 2017.
  13. ↑ "A powerful research and development engine". www.regeneron.com. Archived from the original on 30 April 2019. Retrieved 9 March 2017.
  14. ↑ New Drug Therapy Approvals 2017 (PDF) (Report). U.S. Food and Drug Administration (FDA). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
  15. ↑ 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. PMID   28165826. S2CID   3404484.
  16. ↑ 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. PMID   29059087. S2CID   4433743.
  17. ↑ 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. PMC   9378638 . PMID   35460728.
  18. ↑ 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 . PMID   34543652.
  19. ↑ EMA (17 September 2018). "Dupixent". European Medicines Agency. Retrieved 22 March 2023.
  20. ↑ Devarasetti H (22 March 2023). "Sanofi Dupixent receives EC approval for atopic dermatitis". Pharmaceutical Technology. Retrieved 22 March 2023.
  21. ↑ 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 . PMC   10486173 . PMID   37533141.
  22. 1 2 3 4 5 6 Shirley M (July 2017). "Dupilumab: First Global Approval". Drugs. 77 (10): 1115–1121. doi:10.1007/s40265-017-0768-3. PMID   28547386. S2CID   207489287.
  23. ↑ 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 . PMID   23688323.
  24. ↑ Spencer D (8 March 2020). "Sanofi Genzyme Head on Incredible Success of "Once-in-a-Career" Product Dupixent". Pharmaboardroom. Archived from the original on 18 May 2021. Retrieved 18 May 2021.
  25. ↑ "SEC 10-Q Filing of Regeneron". SEC.gov. 30 June 2017. Archived from the original on 21 October 2017. Retrieved 20 October 2017.
  26. ↑ 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. PMID   26598956.
  27. ↑ "Novel Biologic Dupilumab Improves Eczema Symptoms". October 2016. Archived from the original on 11 March 2017. Retrieved 30 October 2017.
  28. ↑ Walker J (30 May 2016). "New Eczema Treatments Could Be Available Soon". The Wall Street Journal . ISSN   0099-9660. Archived from the original on 5 January 2018. Retrieved 31 May 2016.
  29. ↑ Clinical trial number NCT03930732 for "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" at ClinicalTrials.gov
  30. ↑ "Dupixent demonstrates potential to become first biologic to treat COPD by showing significant reduction in exacerbations in pivotal trial". Globe Newswire (Press release). Retrieved 14 May 2023.
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