Dupilumab

A monoclonal antibody which binds to the alpha subunit of the interleukin-4 receptor and to the interleukin-13 receptor.

Dupilumab blocks the signal transduction on T cells triggered by IL-4 and IL-13.

In the pathogenesis of atopic eczema and bronchial asthma, the type-2 helper cell-mediated immune response plays an important role. Numerous cytokines are involved, including the cytokines interleukin-4 and interleukin-13. Dupilumab has already demonstrated its clinical efficacy in patients with bronchial asthma and elevated eosinophilic granulocytes.

Even in adult patients with extensive (infestation >10% of the skin surface), therapy-resistant atopic eczema, the skin condition was significantly improved in a dose-dependent manner in a Phase IIb study (reduction in the EASI score of 60-70%).

Dosage 300mg s.c. every 2 weeks/alternatively every 4 weeks

Several large studies are now available on atopic ekezm. A dose-dependent clinical outcome has been demonstrated. In 2 international phase 1 dose-finding studies, patients received placebo-controlled 75 mg /150 mg/300 mg s.c./1x per week for 4 weeks. In both studies, treatment with the monoclonal antibody improved clinical parameters. The results of a 12-week study showed that the effect was further enhanced with continued therapy. These initial results were essentially confirmed in 2 phase III studies (SOLO 1 and SOLOI 2). In SOLO 1, 38% of patients treated with Duplimab achieved virtual freedom from clinical manifestations (Simpson et al 2016).

With dupilumab, there is a significant decrease in serum total IgE.

Through a larger long-term study (n=178 pat.) was demonstrable that under the dupilumab in a monoclonal antibody does not affect the vaccination response (Blauvelt et al. 2019).

In another study (CHRONOS) dupilumab was used in 740 patients in a combination with an external glucocorticosteroid. Here, 70% of those treated achieved an EASI-75 response(Blauvelt A et al 2017). The itching improves under the therapy already after the 2nd day.

Bronchial asthma: In a large phase III study (n=1902 pat. with bronchial asthma aged 12 years or older) receiving 200/300mg dupilumab s.c. every 2 weeks for 52 weeks, there was a significantly lower exacerbation rate (Castro et al. 2018). Lung function and asthma control also improved significantly. Of note was the observation that pat. with initially higher eosinophil rates had better efficacy. In a second study (n=210 pat.) with a dosage of 300mg for 24 weeks, a decrease in glucocorticosteroid applications was detectable in addition to a reduction in exacerbation rates (Santer et al. 2018).

Prurigo nodularis: Very good success has been described in prurigo nodularis (Calugareanu A et al. 2019).

Most UAW`s were passager light to moderate. Dupilumab was associated with naso-laryngo-pharyngitis, conjunctivitis (28% of Pat. Aszodi N et al. 2019), headache, herpes simplex infections and inflammatory reactions at the injection site.

Dupixent®

Dupilumab has been approved for moderate to severe atopic dermatitis since September 2017. This was followed by a marketing authorisation extension for adolescents aged 12 years and over and children aged 6 years and over for severe atopic dermatitis.

Initially, 2 injections of 300mg or 200mg s.c. are injected. The maintenance dose is 300mg or 200 mg s.c. every 2 weeks. Dupilumab should be stored in the refrigerator at 2-8°C.

Efficacy has been demonstrated over 52 weeks.

The 2-weekly (maintenance) therapy costs 1,745€ per 4 weeks, about 10x as much as ciclosporin.

1. Aszodi N et al (2019) Management of dupilumab-associated conjunctivitis in atopic dermatitis. J Dtsch Dermatol Ges 17:488-491

2. Beck LA et al.(2014) Dupilumab treatment in adults with moderate to severe atopic dermatitis. N Engl J Med 371:130-139

3. Blauvelt A et al (2017) Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.Lancet 389: 2287-2303.

4. Blauvelt A (2019) Dupilumab does not affect correlates of vaccine-induced immunity: A randomized
   ,placebo-controlled trial in adults with moderate to severe atopic dermatitis. J Am Acad Dermatol 80:158-167.

5. Calugareanu A et al (2019) Dramatic improvement of generalized prurigo nodularis with dupilumab. J Eur Acad Dermatol Venereo 33:e303-e304.

6. Castro M et al.(2018) Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 378:2486-2496.

7. Hamilton JD et al (2014) Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 134:1293- 1300

8. Harskamp CTet al.(2013) Immunology of atopic dermatitis: novel insights into mechanisms and immunomodulatory therapies. Semin Cutan Med Surg 32:132-139Simpson EL et al. (2016) Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 375: 2335-2348.

9. Rabe KF et al.(2018) Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med 378:2475-2485.

10. Thaçi D et al (2016) Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 387:40-52.