The oral Janus kinase (JAK) inhibitor baricitinib (Olumiant) improves signs and symptoms of moderate to severe atopic dermatitis (AD) in patients who fail or cannot tolerate cyclosporine, according to a phase 3 study published in the British Journal of Dermatology.

Baricitinib, recently approved in the United States for treating severe alopecia areata, is currently under US Food and Drug Administration review for AD.

Overall, said Peter Lio, MD, clinical assistant professor of dermatology and pediatrics at Northwestern University Feinberg School of Medicine in Chicago, its findings reinforce the evidence that JAK inhibitors, especially when paired with topical steroids, are extremely effective, even in very severe cases involving patients who fail or cannot tolerate conventional immunosuppressants such as cyclosporine. Lio was not involved with this study.

Patients who fail cyclosporine may be harder to treat, the study authors wrote, because of the chronic, severe, and/or refractory nature of their disease, which may explain why overall response rates in the BREEZE-AD4 trial were lower than in BREEZE-AD7, a previous baricitinib combination trial.

“While baricitinib is not FDA-approved in the US for AD at this time,” added Lio, “it is approved for AD in other parts of the world. And we have two other oral JAK inhibitors — upadacitinib and abrocitinib — that are comparable in many respects. Upadacitinib (Rinvoq) and abrocitinib (Cibinqo) were approved by the FDA in January for treating moderate to severe atopic dermatitis, the first oral JAK inhibitors approved in the US for this indication. A topical formulation of the JAK inhibitor ruxolitinib (Opzelura) was approved last September.

In the study, Breeze-AD4 investigators randomized 463 patients who had failed, could not tolerate, or had contraindications to cyclosporine to either placebo or baricitinib 1 mg, 2 mg, or 4 mg for 52 weeks. To mimic real-world conditions, patients also had to use background emollients daily and low- or moderate-potency topical corticosteroids (TCS) on active lesions.

Only baricitinib 4 mg met the study’s primary endpoint — superiority over placebo in achieving a 75% reduction in Eczema Area and Severity Index (EASI) scores at week 16. Among 92 patients at this dose, 32% achieved EASI 75 vs 17% for placebo plus TCS (P = .031). The corresponding figures for baricitinib 2 mg and 1 mg were 28% and 23% (P = 0.071 and 0.427, respectively, vs placebo). Among secondary endpoints at week 16, baricitinib 4 mg plus TCS proved significantly superior to placebo plus TCS regarding skin inflammation, pruritus, skin pain, and sleep disturbance.

Week 16 improvements generally persisted through week 52. All baricitinib doses maintained statistically significant superiority over placebo plus TCS in terms of EASI percentage change from baseline (PCFB). At week 52, baricitinib 4 mg showed significant superiority over placebo regarding most secondary outcomes, including EASI PCFB, Patient-Oriented Eczema Measure (POEM) scores, and at least four-point improvements in Itch Numeric Rating Scale (NRS) scores.

No new safety signals emerged. The proportions of baricitinib-treated patients reporting treatment-emergent adverse events (TEAEs) ranged from 73.1% with 1 mg to 89.1% with 4 mg vs 66.7% for placebo. However, most AEs were mild or moderate. In the 4 mg group, the most common TEAEs included nasopharyngitis (37%), herpes simplex (15.2%), influenza (15.2%), and headache (10.9%).

The most frequently reported serious adverse event was AD. Among adverse events of special concern, one myocardial infarction (deemed unrelated to baricitinib) and one basal cell carcinoma occurred in the 2 mg group.

Baricitinib-related AEs in BREEZE-AD4 mirror those observed in previous JAK inhibitor studies, Lio said. “My general sense is that the safety issues are significant but not insurmountable, especially for the right patient. For a patient who is really suffering and has truly climbed the therapeutic ladder to the JAK inhibitor class, the risk–benefit ratio looks very different from someone with more mild disease, and thus the JAK inhibitors are a critically important tool in our toolbox.”

Nevertheless, the supplemental New Drug Application for baricitinib in AD submitted by Lilly and Incyte in 2020 remains in limbo. In January, Lilly announced that disagreement over the indicated population might result in an FDA complete response letter (CRL).

The study was supported by Eli Lilly and Company, for which Lio has also been a speaker and consultant/advisor. Additionally, he has been a speaker and consultant/advisor for LEO Pharma and Galderma; a researcher, speaker, and consultant/advisor for Regeneron, Sanofi, and Genzyme; a researcher and consultant/advisor for AbbVie and AOBiome; a speaker for Hyphens Pharma, Incyte, and L’Oreal; and a consultant/advisor for Almirall, ASLAN Pharmaceuticals, Bristol-Myers Squibb, Dermavant, Exeltis, IntraDerm, Merck, Pfizer, UCB, and Verrica.

Br J Dermatol. Published online April 28, 2022. Full text

John Jesitus is a Denver-based freelance medical writer and editor.

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