Biologic Agent Has Benefit for Skin Disease in Early Trials

Larry Hand

July 11, 2014

Patients with atopic dermatitis treated with the biologic agent dupilumab experienced rapid, significant improvements in disease signs, symptoms, and associated biomarker levels in early clinical trials, according to an article published online July 9 in the New England Journal of Medicine.

Lisa A. Beck, MD, from the Department of Dermatology, University of Rochester Medical Center, New York, and colleagues analyzed the results of 4 studies involving adult patients aged 18 years or older who have moderate to severe atopic dermatitis not controlled by topical treatments. Three studies were early phase, and 1 was a phase 2 study.

In 2 dose-escalation 4-week monotherapy US and multinational studies, 67 patients were randomly assigned to receive dupilumab or placebo subcutaneously once a week. The studies were designed primarily to assess safety, but the investigators also prespecified exploratory efficacy endpoints, including an Eczema Area and Severity Index (EASI) score and an itch score.

In another monotherapy trial in Europe, 109 patients were randomly assigned to receive either dupilumab 300 mg or placebo for 12 weeks. Finally, in a phase 2a study in Europe, 31 patients were randomly assigned to receive 4 weekly doses of either 300 mg dupilumab or placebo in combination with topical glucocorticoids.

Regeneron Pharmaceuticals and Sanofi funded the studies.

In the 4-week and 12-week monotherapy trials, 85% of the patients who received dupilumab compared with 35% of patients who received placebo showed a 50% reduction in EASI score (P < .001); 40% of patients in the dupilumab group and 7% of patients in the placebo group had significant clearing or near-clearing of skin lesions, as assessed by investigators (P < .001); and itch scores decreased 55.7% for the patients in the dupilumab group compared with 15.1% for the patients in the placebo group (P < .001).

In the combination study, all patients receiving dupilumab (vs 50% of placebo patients) had significant EASI score reductions (P < .002), and patients who received dupilumab used half the amount of topical glucosteroids compared with the patients in the placebo group.

Adverse events, most of which were mild or moderate, were similar between groups and included skin infection for patients in the placebo group and nasopharyngitis and headache for patients in the dupilumab group.

Rapid Improvement

"This study showed remarkable, consistent clinical improvements that were meaningful within a week or 2 of the injections," Dr. Beck told Medscape Medical News. "These improvements weren't just in the appearance and in magnitude but also with symptoms. At the same time we saw visual changes, we observed patients feeling that their itch improved across all studies and all sites."

Regeneron researchers designed dupilumab to attack 2 key cytokines involved in the pathogenesis of atopic dermatitis: interleukin 4 and interleukin 13.

Study patients' improvement "was highly linked to evidence that the drug did, in fact, seem to inhibit the biology of the proteins it targets," Dr. Beck said. "It targets proteins that have been observed now for over 20 years in the skin of eczema patients."

Significant Burden

An estimated 10% to 20% of American adults and children are living with atopic dermatitis, sometimes called eczema, according to Dr. Beck, and 15% to 30% of adults have moderate to severe disease, equivalent to 5.5 to 7 million Americans.

"At moderate levels of severity, this is clearly a systemic condition that topicals are not going to manage," she added. "That's a group of people that will typically have 40% to 50% body surface areas with skin lesions. They will have itch 24/7, and the itch will be severe enough that it affects their ability to focus at work and at school and to interact with others."

David Margolis, MD, PhD, a dermatologist at the University of Pennsylvania Perelman School of Medicine, Philadelphia, agrees about the burden of disease. "These people [in this treatment group] are really itchy and have a lot of skin breakdown. It keeps them from working, it keeps them from socializing, it can keep people from enjoying themselves," he told Medscape Medical News.

He characterized the results of the studies as "exciting. The downside to it, though, is that the disease in the US, while it's prevalent in adults and children, is often thought of as a childhood disease. The population you think about the most sometimes are kids, and this drug's not currently being evaluated in kids."

For the study patients and others like them, however, the results are positive, he said. "Almost every parameter that they looked at, there's some improvement. There's improvement in itch, there's improvement in redness, scaliness, and there's improvement in composite scores — everything you'd want to see from a drug that's going to treat atopic dermatitis."

At this time, "There's no approved systemic agent [to treat atopic dermatitis], and the burden of the adult disease is just beginning to be appreciated. Sometimes these people had it all their lives."

Dr. Beck said the study patients had had the disease for an average of 25 years.

On a related note, Regeneron and Sanofi issued a joint press release on results of a phase 2b trial of dupilumab simultaneously with the online publication of the other 4 trials. A company spokesperson said the release was coincidental and the results are being submitted for publication.

In that trial, patients receiving dupilumab showed significant improvement in clearing or near-clearing of skin lesions and in itching compared with patients receiving placebo.

Asthma Too

Last year, some of the same researchers coauthored another New England Journal of Medicine report showing a beneficial effect for dupilumab against persistent, moderate to severe asthma.

In the new article, the researchers conclude, "Our findings provide evidence that allergic asthma and atopic dermatitis might have related drivers — in particular, interleukin-4 and interleukin-13 — and that these diseases may benefit from the same therapeutic approach. Furthermore, this commonality suggests that other atopic diseases may share these drivers, providing a rationale for studying dupilumab in such conditions."

This research was funded by Regeneron Pharmaceuticals and Sanofi. Five coauthors report receiving consulting fees from Regeneron outside the submitted work; 9 coauthors are employees and stockholders of Regeneron; 2 coauthors report receiving grant funding and consulting fees from firms including Regeneron; 2 coauthors are current or past employees of Sanofi; and 2 coauthors report receiving consulting fees related to the study.

N Engl J Med. Published online July 9, 2014. Abstract

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