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Serum dupilumab levels do not predict clinical response


 

FROM JAMA DERMATOLOGY

The finding that serum dupilumab levels in patients with atopic dermatitis (AD) do not predict long-term response levels or adverse events (AEs) suggests that factors beyond interpatient variability of the interleukin-4 receptor subunit-alpha (IL-4R-alpha) may drive response levels, according to a study published in JAMA Dermatology.

Dr. Jonathan I. Silverberg, director of clinical research in the department of dermatology at George Washington University, Washington

Dr. Jonathan I. Silverberg

The study results mean that researchers should continue exploring potential AD drugs with novel mechanisms to help patients who fail type 2 inflammatory inhibition, experts told this news organization. The search for accurate augurs of clinical performance also must continue.

Addressing inadequate response

Quantifying nonresponse and incomplete response levels with dupilumab is difficult, said Jonathan I. Silverberg, MD, PhD, MPH, offering perspective on the study. “True nonresponse is probably less than 20%, but many other patients are inadequate responders even if they are having partial response.” Dr. Silverberg, professor of dermatology and director of clinical research, at George Washington University, Washington, was not an investigator.

Dr. Robert Sidbury, division chief of dermatology at Seattle Children's

Dr. Robert Sidbury

Robert Sidbury, MD, MPH, added, “When a patient doesn’t respond to a medication that you expect they should, we always ask ourselves why.” Dermatologists have long assumed that, as with biologics for psoriasis, low blood levels were to blame for dupilumab nonresponse, said Dr. Sidbury, who is division chief of dermatology at Seattle Children’s Hospital and was not involved with the study. “This study showed that there was no correlation between response and blood levels.”

In the study, Lotte S. Spekhorst, MD, of National Expertise Center for Atopic Dermatitis, department of dermatology and allergology, University Medical Center Utrecht (the Netherlands) and coinvestigators prospectively followed 295 consecutive adult patients with moderate AD who were treated with dupilumab for 1 year. All patients received the same loading (600 mg) and biweekly (300 mg) doses.

The median dupilumab level at 16 weeks was 86.6 mcg/mL, which is higher than serum levels observed with other monoclonal antibodies used for other indications, such as psoriasis and inflammatory bowel disease, the authors noted. More importantly, researchers found no significant relationship between median week 16 dupilumab levels and 1-year clinical responses measured either discretely (Eczema Area and Severity Index [EASI] < 50, 50, 75, or 90; P = .18) or as quartiles (P = .06).

“It may be that response is dependent on target availability of the IL-4R-alpha, with an interpatient variability producing heterogeneity in response,” the authors wrote. But because serum dupilumab levels were relatively high, they said, all patients’ IL-4R-alpha “was likely fully saturated” at 16 weeks.

“This would explain why serum dupilumab levels were not related to effectiveness,” they noted, “although we cannot rule out differential effects in the tissue associated with heterogeneity in serum dupilumab levels.”

Dr. Eric Simpson, department of dermatology, Oregon Health & Sciences Center, Portland

Dr. Eric Simpson

The study helps explain why some patients do not fully respond to dupilumab, said Eric L. Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, who was not involved with the study.

“One hypothesis would be that drug serum levels differ due to metabolism or absorption reasons,” Dr. Simpson said in an interview. Results also suggest that heterogeneity in disease biology, such as other uninhibited cytokine pathways, might explain differences in clinical results. “Thus, more therapeutics that target different inflammatory pathways are needed to capture responses in patients not adequately responding to type 2 inflammatory blockade,” he said.

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