Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. (Funded by AbbVie; ClinicalTrials.gov numbers, NCT01468207 and NCT01468233 for PIONEER I and PIONEER II, respectively.).

Background Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis. MethodsIn this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale [PP-NRS] score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.

BACKGROUNDThe oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited. METHODSIn a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16. RESULTSA total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively. CONCLUSIONSIn this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16.

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IMPORTANCE Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis. OBJECTIVE To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis. DESIGN, SETTING, AND PARTICIPANTS A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site. INTERVENTIONS Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients achieving an Investigator's Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12. RESULTS Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator's Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, −0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in Ն3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4. CONCLUSIONS AND RELEVANCE Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic de...