Atopic dermatitis – dupilumab

Atopic dermatitis is a chronic inflammatory disease that is characterised by itchy, inflamed skin, and can occur on any part of the body. Although the symptoms are external, it is a form of eczema and results from an underlying systemic inflammation. It is thought to affect up to 3% of the population worldwide, and more than two-thirds of patients have a family history of other atopic diseases such as hay fever and asthma. The desire to scratch caused by the intense itching can lead to skin damage, which is prone to bacterial infections. It is commonly treated by topical steroids.

An alternative form of treatment is being developed by Regeneron and Sanofi. Dupilumab is a fully human monoclonal antibody that blocks interleukins 4 and 13, both of which are thought to be involved in the pathophysiology of allergic diseases. A collection of early stage trials indicated its potential in atopic dermatitis.¹ The randomised, double blind, placebo controlled trials recruited adults with moderate to severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors: two four-week trials and a 12-week trial as monotherapy, and a further four-week study in combination with topical glucocorticoids.

In the four-week monotherapy studies, the drug gave rapid and dose-dependent improvements in clinical indices, biomarker levels and the transcriptome. This was replicated and extended in the 12-week study, with 85% of those given the antibody having a 50% reduction in the eczema area and severity index (EASI) score, compared with 35% of the placebo group. In the combination study, this reduction was seen in all patients given both treatments, compared with 50% of those given topical treatment plus placebo.

In a randomised, placebo controlled, dose ranging Phase IIb trial, 380 patients with an EASI score of 12 or higher and an inadequate response to topical treatments were enrolled. Patients were assigned to one of six treatment groups, stratified by severity, to receive subcutaneous dupilumab in 300mg doses once a week, 200 or 300mg every two weeks, 300mg every four weeks, 100mg every four weeks, or weekly placebo, for 16 weeks.² Additional placebo was given to those subjects in non-weekly schedules in non-treatment weeks. EASI score improvements favoured all of the groups given dupilumab, in a dose dependent manner, ranging from a 74% improvement for those given the highest weekly dose to 45% for 100mg every four weeks. In contrast, placebo gave an 18% reduction. Nasopharyngitis was the most common side-effect, in about a quarter of all patients.

The companies published top-line results from two Phase III trials via press release at the beginning of April. Across the two identically designed trials, a total of 1,379 adult patients with moderate to severe atopic dermatitis were enrolled; either their disease was not adequately controlled by topical medications, or their use was not medically advisable. Subjects were given 300mg subcutaneous doses every week or every two weeks following an initial 600mg loading dose, or placebo.

In the two trials, 37 and 36% of patients on the weekly schedule, and 38 and 37% of those on the biweekly schedule, achieved a clearing or near clearing of skin lesions, compared with 10 and 8.5% with placebo. The improvements in EASI score were all around 70% with treatment, and below 40% with placebo. Further Phase III trials are underway.

References

1. L.A. Beck et al. N. Engl. J. Med. 2014, 371, 130

2. D. Thaçi et al. Lancet 2016, 387, 40