A Maximum-Use Trial of Ruxolitinib Cream in Adolescents and Adults with Atopic Dermatitis

Abstract

Background: Ruxolitinib cream is a topical formulation of ruxolitinib, an inhibitor of Janus kinase 1 and Janus kinase 2.

Objective: We aimed to determine the safety, tolerability, and bioavailability of 1.5% ruxolitinib cream under maximum-use conditions in patients with atopic dermatitis. Efficacy was evaluated as an exploratory objective.

Methods: Eligible patients aged ≥ 12-65 years with atopic dermatitis, an Investigator's Global Assessment score ≥ 2, and ≥ 25% affected body surface area were enrolled in an open-label, maximum-use phase I study conducted in the USA and Canada. Patients applied 1.5% ruxolitinib cream twice daily to lesions identified at baseline for the first 28 days and continued use only on active lesions for an additional 28 days (extension period). Safety was assessed by frequency, duration, and severity of treatment-emergent adverse events. Plasma concentrations of ruxolitinib and pharmacokinetic parameters were assessed as secondary endpoints.

Results: Overall, 41 patients (median age, 17 years; 51% male) were enrolled and 37 (90.2%) entered the extension period, all of whom completed the study. Treatment-emergent adverse events were reported in 13 patients (31.7%). Treatment-related adverse events were reported in four patients (9.8%). The mean (standard deviation) steady-state plasma concentration was 104 (309) nM during the first 28 days, well below the half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in the bone marrow (281 nM), and decreased further during the extension period. Higher plasma concentrations were detected in a few patients who were treated for a very high affected body surface area. At day 56, 94.6% of patients achieved ≥ 75% improvement in the Eczema Area and Severity Index.

Conclusions: Under maximum-use conditions, ruxolitinib cream was generally well tolerated, with approximately one-third of patients experiencing treatment-emergent adverse events and few treatment-related adverse events. The mean steady-state plasma concentration of ruxolitinib was well below the level expected to affect bone marrow production of blood cells, with a small number of patients exhibiting higher plasma concentrations. In addition, ruxolitinib cream showed a high level of efficacy in patients with atopic dermatitis involving ≥ 25% affected body surface area.

Gov identifier: NCT03920852.

Fig. 1

Hematologic parameters. Boxes represent the interquartile range, the middle lines represent the median, and the “X” inside the boxes represents the mean. Bars represent data within 1.5× the interquartile range of either quartile 1 or quartile 3. Circles outside the bars represent outliers

Fig. 2

Boxplots of plasma trough concentrations and affected body surface area (BSA) in the (A, B) overall population and by (C, D) baseline BSA and (E, F) age groups. Boxes represent the interquartile range, the middle lines represent the median, and the bars indicate data within 1.5× the interquartile range of either quartile 1 or quartile 3

Fig. 3

Steady-state plasma concentrations of ruxolitinib from ruxolitinib cream (1.5% twice daily [BID]) on day 28 vs oral ruxolitinib (15 mg BID) on day 10. Error bars represent standard error of the mean. The data for oral ruxolitinib were included in the phase I publication [16]. AD atopic dermatitis, IC₅₀ half-maximal inhibitory concentration, TPO thrombopoietin