Summary Background Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. Objectives To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies. Methods In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. Results At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE‐AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. Conclusions Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns. Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.

IMPORTANCE Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. OBJECTIVE To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. RESULTS Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. CONCLUSIONS AND RELEVANCE A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD.

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Background Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late‐stage development for adult patients with moderate‐to‐severe AD. Objective To report pooled safety data for baricitinib in patients with moderate‐to‐severe AD in the clinical development program including long‐term extension (LTE) studies. Methods This analysis included patient‐level safety data from six double‐blinded, randomized, placebo‐controlled studies (one phase 2 and five phase 3), one double‐blinded, randomized, LTE study and one open‐label LTE study, reported in three data sets: placebo‐controlled, 2‐mg – 4‐mg extended and All‐bari AD. Safety outcomes include treatment‐emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. Results Data were collected for 2531 patients who were given baricitinib for 2247 patient‐years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo‐controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo‐controlled period in baricitinib‐treated patients. Frequency of herpes simplex was higher in the 4‐mg group (6.1%) vs. the 2‐mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2‐mg IR = 9.6; 4‐mg IR = 14.5) were lower vs. the placebo‐controlled data set (2‐mg IR = 12.4; 4‐mg IR = 21.3). In the All‐bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2‐mg group): two venous thrombosis events (4‐mg group) and one death. Conclusion This integrated safety analysis in patients with moderate‐to‐severe AD confirms the established safety profile of baricitinib.

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