Dupilumab as a Treatment for Atopic Dermatitis

Posted by • July 9th, 2014

For thousands of years, our knowledge of medications has largely been based on trial and error: we haphazardly used substances and learned from the effects. Within the last half a century, however, rational drug design slowly took to the forefront as scientific discoveries improved our understanding of the underlying pathogenesis of diseases. While there have not been many victories for rational drug design so far, dupilumab is a key one on a small but growing list. As a monoclonal antibody that targets cytokines involved in type 2 helper T cell (Th2) activation, dupilumab has already demonstrated preliminary efficacy for asthma, a disease which is known to be driven, at least in part, by Th2 activation. Furthermore, Th2 activation has also been implicated in the pathogenesis of atopic dermatitis, a disease characterized by skin barrier abnormalities, Th2 immune responses, and pruritis.

To evaluate the importance of Th2 activation in the pathogenesis of atopic dermatitis and the efficacy of dupilumab as a treatment, Beck and colleagues conducted four randomized, double-blinded, placebo-controlled clinical trials and reported their results in this week’s NEJM. Two of the trials (studies M4A and M4B) were originally designed primarily for safety analysis but the clinical effects were striking. The patients were randomly assigned to four weeks of treatment with either dupilumab or placebo. Another trial (study M12) followed 109 patients for 12 weeks after initiating monotherapy with either dupilumab or placebo. The primary objective was to assess clinical efficacy. Finally, a fourth trial (study C4) compared dupilumab in combination with topical glucocorticosteroids to placebo with topical glucocorticosteroids. The primary endpoints after four weeks of combination therapy were the incidence and severity of adverse events.

In studies M4A and M4B, patients treated with dupilumab showed rapid and dose dependent improvements in all clinical outcomes that were tested, such as pruritis scale rating and improvement in eczema area. This improvement was also seen in patients treated with dupilumab at the four-week point in study M12, and this treatment group continued to improve throughout the entire 12-week course. Similarly, in study C4, patients treated with dupilumab in combination with topical glucocorticosteroids had better improvements in clinical outcomes than those treated with placebo and topical glucocorticosteroids. Finally, in terms of safety measures, there were more mild to moderate adverse events in the patients treated with dupilumab (i.e. nasopharyngitis and headache), but there were more serious adverse events in the placebo group, mostly due to skin infections and atopic dermatitis.

Overall, the data provide solid evidence for the key role of Th2 activation in the pathogenesis of the disease; these trials cannot address the clinical utility of the treatment. This advance reflects the importance of studying the molecular underpinning of diseases, because if we can truly understand the biology, we will find effective therapies for even the most stubborn illnesses.

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