Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial.

Abstract

Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD. Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10^-15) that was sustained until day 15 (92.90% vs 49.59%, P < 10^-15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including T_H2 and T_H17/T_H22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.