Trial Finds Abrocitinib, Dupilumab Comparable for Atopic Dermatitis

Thomas Bieber, MD

Abrocitinib appeared superior to dupilumab in reducing itch of atopic dermatitis, while the agents were comparable and superior to placebo in other treatment outcomes, in the phase 3 JADE COMPARE trial sponsored by the abrocitinib manufacturer, Pfizer.

The orally-administered investigational Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces both interleukin-4 and interleukin-13 signaling, was compared to placebo and to the subcutaneously administered anti-interleukin-4-receptor α monoclonal antibody, dupilumab, which is currently approved for treatment of atopic dermatitis.

Thomas Bieber, MD, PhD, Chair, Department of Dermatology and Allergy, Christine Kühne-Center for Allergy Research and Education, University of Bonn, Germany and colleagues described the rationale for these agents in atopic dermatitis.

"When topical therapies are insufficient, treatment with systemic agents, including dupilumab and immunospressants, are recommended.JAK inhibitors, such as baricitinib, abrocitinib, and upadacitinib, are being investigated as systemic treatments for atopic dermatitis," the investigators explained.

Bieber and colleagues screened over 1,200 patients at multiple sites, and randomized 838 adult patients who had at least a 1-year history of atopic dermatitis that was moderate to severe at baseline and who had inadequate response to at least 4 weeks of topical medications; or who were deemed to require systemic therapy to control their disease.

Participants were eligible for the study with disease severity at baseline marked by the following measures:

• Score of 3 or higher on the Investigator's Global Assessment (IGA) 5-point scale where 0 is clear skin and 1 is almost clear to 4 severe
• Score of at least 16 on the Eczema Area and Severity Index (EASI) that measures from 0 to the greatest severity at 72
• At least 10% body-surface are involved
• Score or at least 4 on the Peak Pruritus Numerical Rating Scale (PP-NRS), in which 10 is most severe

Participants were randomly assigned in a 2:2:2:1 ratio to receive a 16-week regimen of either 200mg or 100mg of abrocitinib orally once daily; 300mg of dupilumab subcutaneously every other week, after a loading dose of 600mg; or placebo. Non-systemic treatments at baseline were continued throughout the study. Patients, investigators and representatives of the sponsor were blinded to the trial group assignments.

The primary endpoints were an IGA response (with score of 0 or 1) and an EASI-75 response (>75% improvement from baseline) at week 12. Key secondary endpoints were itch response (≥4-point improvement from baseline PP-NRS) at week 2; and IGA and EASI-75 responses at week 15.

Bieber and colleagues reported an IGA response at week 12 in 48.4% of patients in the 200mg abrocitinib group; 36.6% in the 100mg abrocitinib group, 36.5% in the dupilumab group; and 14% of those receiving placebo.The EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1% and 27.1%, respectively.

The investigators indicated that the 200mg dose, but not the 100mg dose of abrocitnib was superior to dupilumab with respect to itch response at week 2; but that neither abrocitinib dose differed statistically significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16.

In an accompanying review article on atopic dermatitis, Sonja Ständer, MD, Department of Dermatology and Center for Chronic Pruritus (KCP), University Hospital Münster, Münster, Germany concurred that the study had associated both agents with reductions in signs and symptoms relative to placebo, and that abrocitinib appeared superior to dupilumab in reduction of itch at 2 weeks. "...otherwise," she indicated, "the two drugs had similar outcomes."

While acknowledging the benefits of the treatments, particularly when symptoms have not responded to topical treatments,Ständer warned that the adverse effects can be significant.She noted, for example, that dupilumab therapy has been associated with long-term, functionally impairing conjunctivitis; and that JAK inhibitors carry a risk of thromboembolism and cancer, and have been associated with decreased white-cell counts and with respiratory tract infections and herpes zoster infection.

"Adverse effects such as skin infections or worsening of asthma necessitate careful evaluation of the future use of these new therapies in sensitive populations (children) and in patients with typical complications of atopic dermatitis," Ständer cautioned.

The trial, “Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis,” was published online in The New England Journal of Medicine.