IL-31 Inhibitor Improves Atopic Dermatitis

Diana Phillips

March 02, 2017

The interleukin-31 (IL-31) inhibitor nemolizumab significantly improved pruritus in patients with moderate to severe atopic dermatitis in a phase 2, randomized, double-blind, placebo-controlled trial.

The results support the role of IL-31 — a cytokine produced by activated T cells — in the pathobiology of atopic dermatitis and suggest that targeting elevated levels of the protein may be an effective treatment strategy. Thomas Ruzicka, MD, from the Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany, and colleagues report their findings online March 1 in the New England Journal of Medicine.

Previously, a phase 1 clinical study showed that a single, subcutaneous dose of nemolizumab suppressed pruritus in adult patients with moderate to severe atopic dermatitis. As a result, these patients experienced less sleep disturbance related to skin discomfort, and they were able to reduce concomitant use of topical glucocorticoids.

In the current study, the investigators evaluated the safety, efficacy, and side effect profile of the drug over 12 weeks in a similar adult population.

The multicenter, multidose study included 264 adults with moderate to severe atopic dermatitis that was not adequately controlled with topical therapy. The researchers randomly assigned patients to receive subcutaneous nemolizumab (CIM331) at a dose of 0.1 mg, 0.5 mg, or 2.0 mg/kg body weight or placebo every 4 weeks or nemolizumab at 2.0 mg/kg every 8 weeks, with placebo given at week 4. The researchers included the latter group for an exploratory analysis.

Of the 264 patients, 82% completed the study. At 12 weeks, patients rated the severity of their pruritus relative to baseline by using a visual analog scale of 0 to 10, with 10 characterized as "the worst imaginable." Significant reductions in itch began as early as week 1 in the treatment groups, the authors write.

At 12 weeks, pruritus was reduced by 43.7% in patients treated with 0.1 mg/kg (95% confidence interval [CI], –53.4% to –34.0%; P = .002), 59.8% in those treated with 0.5 mg/kg (95% CI, –69.4% to –50.3%; P < .001), and 63.1% in those treated with 2.0 mg/kg (95% CI, –72.9% to –53.3%; P < .001), the authors report. Pruritus was reduced in patients in the placebo group by 20.9% (95% CI, –31.4% to –10.5%).

An analysis of the least-squares mean percentage change from baseline in the score on the pruritus visual analogue scale showed the 0.5-mg/kg dose was associated with the largest reduction in the primary outcome. "The apparent lack of incremental benefit of the higher dose is puzzling, since we might expect, at the very least, a faster onset of action," the authors write.

Among the secondary outcomes considered, the following reductions on the Eczema Area and Severity Index were observed in the 0.1-mg/kg, 0.5-mg/kg, 2.0-mg/kg, and placebo groups, respectively: –23.0%, –42.3%, and –40.9%, and –26.6%. The respective reductions in body surface area affected by atopic dermatitis were –7.5%, –20.0%, –19.4%, and –15.7%.

The rate of treatment discontinuation across groups was similar, as was the rate of adverse events, although the small patient sample precludes conclusions regarding adverse events, the authors note. The most common adverse events were exacerbation of atopic dermatitis and nasopharyngitis, and the risk for immune suppression appeared to be low, they write.

Although limited by its small size and short duration, the study "provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis," the authors write. The results, they conclude, "support future studies of the role of interleukin-31 and its inhibition for the control of pruritus."

The treatment effects observed in this study, as well as in other recently reported trials of subcutaneous dupilumab (a human monoclonal antibody against IL-4 receptor-α) reported by Medscape Medical News, provide hope for patients with moderate to severe atopic dermatitis, Lynda C. Schneider, MD, from the Division of Immunology at Boston Children's Hospital, Massachusetts, writes in an accompanying editorial.

However, the fact that some patients receiving the respective treatment drug in trials of both agents did not see an improvement in their symptoms suggests that "another immunologic mechanism may be prominent in their disease," she writes.

"Currently, we approach atopic dermatitis as one disease, even though the condition has many clinical phenotypes," Dr Schneider explains. "The development of biomarkers for different phenotypes of atopic dermatitis will be important in determining the most effective treatments."

For all of the new treatments, "[d]ata from larger long-term studies and pediatric trials are needed to fully understand how these new agents will fit into the management of atopic dermatitis," Dr Schneider stresses. "It will be important to evaluate how quickly patients have disease flares after stopping the agents and whether the addition of topical agents may provide more effective or longer remission."

In all cases, treatment for moderate to severe atopic dermatitis should be comprehensive, including not only drug therapy but also education, psychological support, and treatment of associated mental health and sleep disturbances, Dr Schneider concludes.

Chugai Pharmaceutical provided support for this study. Dr Ruzicka reports grant support and personal fees from Chugai Pharmaceutical during the conduct of the study and personal fees from Astellas outside the submitted work. The remaining coauthors report a variety of relationships with Chugai Pharmaceutical, including receipt of personal fees during the conduct of the study; personal fees and other support outside the submitted work; and grant support during the conduct of the study. In addition, one coauthor reports grant support and personal fees from Procter & Gamble, Sunster, and Maruho Co. Ltd. outside the submitted work, and one coauthor reports grant support and personal fees from Otsuka Pharmaceutical Company and Merck Inc; personal fees from Anacor Pharmaceuticals Inc, Dermira Inc, AbbVie, Hoffmann-La Roche, and Janssen/Johnson & Johnson; and nonfinancial support from LEO Pharma and Medimetriks Pharmaceuticals outside the submitted work. Dr Schneider reports personal fees from Anacor Pharmaceuticals and grant support from Astellas.

N Engl J Med. 2017;376:826-35. Abstract, Editorial

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