Conference Coverage

IL-1 alpha is a new target in atopic dermatitis


 

REPORTING FROM EADV 2019

Interleukin-1 alpha has emerged as a novel and unexpected potential therapeutic target in atopic dermatitis (AD) on the basis of an encouraging phase 2, proof-of-concept study involving bermekimab, an investigational monoclonal antibody directed at that cytokine.

Dr. Alice B. Gottlieb, medical director of dermatology at Mount Sinai Beth Israel Campus, New York Bruce Jancin/MDedge News

Dr. Alice B. Gottlieb

The mechanism of benefit is unclear, although there are a number of plausible possibilities, all orbiting around the notion that AD is not only a Th2 immunity–mediated disease, but that Th1 immunity plays a role, too.

“The ultimate proof, as you will see, is that it works,” Alice B. Gottlieb, MD, PhD, observed in presenting the phase 2 study findings at the annual congress of the European Academy of Dermatology and Venereology.

Bermekimab is a monoclonal antibody cloned from human peripheral B lymphocytes. Sources of its target – IL-1 alpha – that are of therapeutic relevance include neutrophils, keratinocytes, platelets, and monocytes.

The study included 10 adults with moderate to severe AD who received a single subcutaneous injection of 200 mg of bermekimab and 28 who received 400 mg weekly for 8 weeks. Lumping together the various outcome measures employed in the study, the 400-mg dose was three times more effective than the 200-mg dose, a finding explainable by the 240% higher serum levels at 400 mg, according to Dr. Gottlieb, medical director of Mount Sinai Beth Israel Dermatology in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.

This was a small, uncontrolled, proof-of-concept study; at this early stage, results painted a favorable picture of efficacy and safety. For example, scores on the Eczema Area and Severity Index dropped by a mean of 65% from baseline at week 4 of bermekimab at 400 mg/week and by 80% at week 8. Scoring Atopic Dermatitis scores dropped by about 55% at week 4 and by nearly 70% at 8 weeks. Scores on the 0-4 Investigator Global Assessment improved by 1.2 points at week 4 and 1.4 points by week 8. Dermatology Life Quality Index scores improved by a mean of 70% by week 8, at which point 61% of patients had a DLQI of 0-1, indicating that AD had no or only a slight impact on quality of life. Scores on the Hospital Anxiety and Depression Scale improved by about 45% at 4 weeks and 65% at 8 weeks.

At baseline, most patients rated their pain as 7 out of 10. By week 8, pain scores had dropped by an average of 80%, and 80% of patients experienced a 4-point drop or greater. Similarly, 80% of patients had at least a 4-point drop in their self-rated worst itch scores on a 0-10 scale. The greatest improvement in both pain and itch scores occurred in the first 4 weeks, after which further improvement continued, albeit at a slower rate.

Adverse events consisted of grade 2 wheezing in two patients, grade 1 nausea in two patients, and a 3% rate of mild injection-site reactions.

An audience member rose to comment: “This is really interesting data, and it goes against everything that we think about atopic dermatitis. But we know from allergic contact dermatitis that IL-1 is a very early signal coming out of keratinocytes. It almost makes you wonder whether that’s not a primary problem in atopic dermatitis that we haven’t realized – that the keratinocytes are under stress because of damage to the skin barrier or other functions, and by alleviating that stress by blocking IL-1, you block the progression into what we previously thought was an Th2-mediated disease, atopic dermatitis.”

“I was thinking that, too – that the keratinocytes could be playing a role in atopic dermatitis through IL-1,” Dr. Gottlieb replied.

She noted that her Mount Sinai colleague Emma Guttman-Yassky, MD, PhD, and coinvestigators have demonstrated that a monoclonal antibody that blocks IL-17C is effective in treating AD, and that IL-17C causes keratinocytes to release proinflammatory IL-1 alpha. High levels of IL-1 alpha have been shown to drive leukocyte recruitment into the skin, promote breakdown of the skin barrier through production of matrix metalloproteinase, stimulate itch by a direct effect on nerves, and cause leaky vascular endothelium.

A phase 2 study of bermekimab for treatment of AD enrolled the first patient in mid-November. In addition, Dr. Gottlieb has led a positive phase 2 study of the monoclonal antibody in patients with hidradenitis suppurativa, with a phase 3 trial in the works.

She reported receiving research funding from and serving as a consultant without personal compensation to XBiotech, which sponsored the AD and hidradenitis suppurativa studies. She has similar financial relationships with numerous pharmaceutical companies developing psoriasis medications.

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