Dupixent
Dupilumab, brand name Dupixent, is a human IgG4 monoclonal antibody that was initially approved by the FDA in March of 2017. The initial approval was for the treatment of atopic dermatitis for patients with moderate-to-severe disease that is not adequately controlled with topical prescription therapies. Since its initial approval, it has been approved to be used in patients aged 6-11 years with atopic dermatitis as well as for the treatment of moderate-to-severe asthma for patients 12 years or older with an eosinophilic phenotype or who require an oral corticosteroid in their treatment.
Atopic dermatitis is a chronic skin condition that is characterized by a disturbed skin barrier and immune-mediated responses to environmental antigens. Th2 cytokines, interleukin-4 and interleukin-14, have been believed to play a role in the disease of atopic dermatitis but the clinical effect of blocking these interleukins had not been tested until the introduction of dupilumab. Dupilumab blocks signaling from both interleukins and shows positive response in atopic dermatitis patients. In addition, blockage of these Th2 interleukins showed efficacy in patients with moderate-to-severe asthma identifying that the blockage could aid in other Th2 related disease states. In a pivotal study for the approval of dupilumab in atopic dermatitis, the treatment was studied in two, 4-week monotherapy trials, a 12-week monotherapy trial, and a 4-week combination trial with topical glucocorticoids. Across all four studies, a positive correlation was found highlighting the significance of Th2 cytokines in the pathophysiology of atopic dermatitis. The blockade of these interleukins provided a reduction in skin lesions, as well as a decrease in pruritus which is a major complaint in patients with atopic dermatitis. Within the study groups, it was noted that the patients receiving placebo had higher rates of skin infection, indicating dupilumab aids in improving the skin barrier function.
As previously mentioned, Th2 cytokines play a role in the pathogenesis of asthma. Asthma presents in different phenotypes, meaning that the pathological process that produces asthma can slightly vary among patients. The inflammatory processes with these specific cytokines are present in about half of patients who are living with asthma. Despite several types of treatments on the market, 10-20% of patients with this diagnosis are not adequately controlled. The Th2 cytokines that are present in patients with atopic dermatitis are also present in patients with asthma but are signaled through different receptors. In one study, dupilumab was able to reduce asthma-exacerbation events by 87% compared to placebo.3. Dupilumab shows positive objective and subjective endpoints when it was added to previous mainstay therapies such as inhaled glucocorticoids and long-acting beta agonists. Compared to other monoclonal antibodies studied in asthma patients, such as lebrikizumab and tralokinumab, dupilumab also targets interleukin-4 and provides a reduction in asthma symptoms, beta-agonist drug use, and an increase in quality of life. These other treatments only improved lung function. Dupilumab is still in the pipeline to expand its indications to different age groups within its currently approved indications as well as a brand-new indication for the treatment of patients with peanut or grass allergies.
References:
1. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130-139. doi:10.1056/NEJMoa1314768
2. Barry K, Gorelik D. Dupilumab (Dupixent) for Asthma. Am Fam Physician. 2020;101(4):244-245.
3. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-2466. doi:10.1056/NEJMoa1304048
A Possible New Indication for Dupilumab
Dupilumab is an injectable prescription medication administered subcutaneously to treat severe and refractory forms of atopic dermatitis (AD). It was approved by the US Food and Drug Administration in April 2017 to treat moderate-to-severe, resistant, AD that is unresponsive to conventional therapy, including topical corticosteroids. Dupilumab is also used as maintenance treatment for asthma and chronic rhinosinusitis with nasal polyposis in both adults and children, in conjunction with other medications.
Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass designed to inhibit receptor signaling downstream of the JAK-STAT pathway by blocking interleukin-4/interleukin-13 (IL-4/IL-13) receptors.
As an IL-4Rα antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, or interleukins, that induce inflammatory and immunological responses in several conditions, including eczema, asthma, allergic reactions, and rhinosinusitis. Essentially, IL-4Rα is a component common to both IL-4 and IL-13 receptor complexes and is ubiquitously expressed on innate and adaptive immune cells to promote the signaling of IL-4 and IL-13. By blocking this pathway, dupilumab affects three integral disease mechanisms of AD: the decrease of skin barrier function, the class switch to IgE, and the Th2-differentiation.
As a treatment for asthma, dupilumab helps patients breathe and a new trial by Sanofi and Regeneron studied the use of dupilumab in chronic obstructive pulmonary disease (COPD) patients with type 2 inflammation. COPD is often associated with markedly reduced lung function and an increased risk of exacerbations. Exacerbations are also associated with an increased risk of subsequent exacerbations, accelerated lung-function decline, and an increased risk of death from any cause, despite the use of inhaled medications. Improving lung function and reducing exacerbations are therefore unmet needs in patients with COPD.
Although COPD has long been recognized as involving an amplified innate immune response, there is growing recognition that some patients with this disease have type 2 inflammation. Evidence of type 2 inflammation is present in 20 to 40% of patients with COPD and is associated with an increased risk of exacerbations. Cytokines and immune cells that are most commonly elevated in patients with type 2 inflammation include IL-5, IL-4, IL-13, type 2 innate lymphoid cells, and type 2 helper T cells, and increased levels of these cells can cause elevated eosinophil counts in sputum, bronchial tissue, and blood or elevated levels of fractional exhaled nitric oxide (FeNO).
The IL-5 pathway specifically drives eosinophil maturation and survival. The IL-4 and IL-13 pathways increase the FeNO level and, more broadly, promote eosinophil and type 2 inflammatory cell infiltrates in the lung. These infiltrates are believed to be involved in pathologic processes in COPD, including airway hyperreactivity, impairment of epithelial barrier function, fibrosis, and airway remodeling; lung-function decline; goblet-cell hyperplasia; mucociliary dysfunction; and mucus hypersecretion.
The phase 3, double-blind, randomized trial met its primary and secondary endpoints, setting dupilumab up to become the first biologic treatment for the disorder, which has seen few advancements over the last decade and is the world’s third leading cause of death.
The study compared dupilumab to placebo in 939 COPD patients with type 2 inflammation who were active or former smokers on maximal standard-of-care inhaled therapy. Dupixent showed a clinically significant 30% reduction in moderate or severe exacerbations over 52 weeks. Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo.
References:
Gade A, Ghani H, Rubenstein R. Dupilumab. [Updated 2023 Jan 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585114/
Napolitano M, Di Guida A, Nocerino M, Fabbrocini G, Patruno C. The emerging role of dupilumab in dermatological indications. Expert Opin Biol Ther. 2021 Nov;21(11):1461-1471. [PubMed]
Seegräber M, Srour J, Walter A, Knop M, Wollenberg A. Dupilumab for treatment of atopic dermatitis. Expert Rev Clin Pharmacol. 2018 May;11(5):467-474. [PubMed]
Bhatt, S. P., et al. (2023, May 21). Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. The New England Journal of Medicine. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2303951