A JAK inhibitor for atopic dermatitis: a randomised clinical trial

Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: A randomised clinical trial

Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al. JAMA Dermatology. 2020;156(8):863–873.

• When topical therapies for atopic dermatitis prove ineffective, or are overused, systemic therapies are recommended, but their use can be problematic and not all patients respond to treatment
• Janus kinase (JAK) inhibitors target cytokines involved in the pathogenesis of atopic dermatitis and show promise as alternative systemic treatments
• Abrocitinib, a small-molecule JAK1 inhibitor administered orally once daily, was effective in a previous phase 2b study¹ and a phase 3 trial (JADE MONO-1)²

This paper reports the findings of the JADE MONO-2 trial, a replicate phase 3 trial that evaluated the safety and efficacy of monotherapy with abrocitinib in patients 12 years or older with moderate-to-severe atopic dermatitis.

How was JADE MONO-2 conducted?

The design and results of the JADE MONO-2 trial are summarised in Figure 1.

Figure 1. JADE MONO-2 trial design and results. AD, atopic dermatitis; BSA, body surface area; CI, calcineurin inhibitor; CS, corticosteroid; EASI-50, 75, 90, Eczema Area and Severity Index, ≥50%, 75%, 90% improvement, respectively, from baseline; IGA, Investigator Global Assessment; JAK, Janus kinase; Pl, placebo; PP-NRS, Peak Pruritus Numerical Rating Scale.

In this multicentre, international, placebo-controlled, parallel-group, double-blind phase 3 trial, 391 patients 12 years or older with chronic atopic dermatitis (>1 year) and inadequate response to topical treatment were randomised to one of three treatment groups:

• 200 mg abrocitinib orally once daily (155 patients)
• 100 mg abrocitinib orally once daily (158 patients)
• placebo (78 patients)

Randomisation was stratified by baseline disease severity and age (under 18 years or 18 years and over). Patients received no topical therapy during the trial.

Multiplicity-controlled co-primary endpoints at Week 12 were:

• Proportion of patients achieving an Investigator Global Assessment (IGA) response, defined as a score of 0 (clear) or 1 (almost clear) on the IGA, with an improvement of ≥2 points from baseline
• Proportion of patients achieving an Eczema Area and Severity Index-75 (EASI-75) response, defined as ≥75% improvement from baseline in EASI score

Key secondary end points were:

• Proportion of patients achieving EASI-50 and/or EASI-90 response, defined as ≥50% or ≥90% improvement, respectively, from baseline in EASI score
• Proportion of patients achieving a Peak Pruritus Numerical Rating Scale (PP-NRS) response, defined as an improvement of ≥4 points in the score from baseline at Weeks 2, 4 and 12
• Change from baseline total score in Pruritus and Symptoms Assessment for AD (11-item questionnaire that measures daily symptoms of atopic dermatitis) at Week 12

What were the findings of the trial? 

For the co-primary end points, the efficacy analysis showed:

• A higher proportion of patients in both abrocitinib groups achieved an IGA response at Week 12 than those in the placebo group (P<0.001; Figure 2A)
• A higher proportion of patients in both abrocitinib groups achieved an EASI-75 response at Week 12 than those in the placebo group (P<0.001; Figure 2B)

Figure 2. IGA and EASI-75 responses. A: Percentage of patients with an Investigator Global Assessment (IGA) response during the trial. B: Percentage of patients with an Eczema Area and Severity Index (EASI-75) response during the trial. Error bars represent 95% confidence intervals. Note: Conclusion of statistical significance was controlled for multiplicity only at Week 12 (co-primary end points).  *P<0.05 vs placebo; b, **P<0.001 vs placebo.

For the key secondary end points:

• Proportions of patients achieving EASI-50 and/or EASI-90 responses at Week 12 were higher in both abrocitinib groups than in the placebo group (P<0.001)
• Proportions of patients achieving a PP-NRS response increased from Weeks 2 to 12 and were greater in both abrocitinib groups than in the placebo group (P<0.001)
• Decreases from baseline in Pruritus and Symptoms Assessment for AD were greater in both abrocitinib groups than in the placebo group at all time points (P<0.001)

Other findings:

• Patients treated with abrocitinib reported improvements in a range of outcomes, including quality of life, AD severity, global assessment, anxiety and depression

Adverse events:

• The most frequent treatment-emergent adverse events with abrocitinib were nausea in the 200-mg group (22 of 155), nasopharyngitis (20 of 158) and upper respiratory tract infection (14 of 158) in the 100-mg group, and headache (both groups); nausea was mostly transitory
• Most serious adverse events were unrelated to the treatment
• Dose-related increases of about 10% in high- and low-density lipoprotein levels, as well as increased creatine kinase levels, occurred in both abrocitinib groups

What can we conclude from the JADE MONO-2 trial?

• As measured by IGA or EASI-75 responses, 100 mg or 200 mg of abrocitinib once daily significantly improved signs and symptoms of moderate-to-severe atopic dermatitis in adults and adolescents
• At both doses, abrocitinib significantly reduced the severity of itch associated with moderate-to-severe atopic dermatitis
• Abrocitinib was well tolerated by most patients
• Similar results were obtained in the JADE MONO-1 trial; together, the findings support the efficacy and safety profile of abrocitinib for moderate-to-severe atopic dermatitis, but long-term efficacy and safety remain to be established.

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References

1. Gooderham MJ, Forman SB, Bissonnette R, Beebe JS, Zhang W, Banfield C, et al. Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinib for Patients With Atopic Dermatitis: A Phase 2 Randomized Clinical Trial. JAMA Dermatol. 2019;155(12):1371-1379.
2. Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-266.