SummaryBackground Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown. Objectives Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD. Methods In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored. Results The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0Á001) for tofacitinib (À81Á7%) vs. vehicle (À29Á9%). Patients treated with tofacitinib showed significant (P < 0Á001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib. Conclusions Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.

BackgroundTofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.ObjectivesThis phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.MethodsTwo tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm2 treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.ResultsThe primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) –54·4%] vs. vehicle 1 (LSM –41·5%), but not ointment 2 (LSM –24·2%) vs. vehicle 2 (LSM –17·2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.ConclusionsTofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

Downregulated Skin Biomarkers Upregulated Crisaborole Vehicle Crisaborole Day 15 Day 8 Day 1 Day 15 Day 8 Day 1 Vehicle Day 1 NL CRISABOROLE AND ATOPIC DERMATITIS SKIN BIOMARKERS: AN INTRAPATIENT RANDOMIZED TRIAL 2 AD lesions of identical severity were randomized intrapatient to crisaborole or vehicle and biopsied at days 1, 8, and 15 (including Th2 and Th17/Th22 axes) and improved barrier function NL skin biopsied at day 1 AD, atopic dermatitis; NL, nonlesional; Th, helper T cellBackground: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-tomoderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. Objective: 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 5 40) with mild-to-moderate AD. Methods: 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.

BackgroundMost psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis.MethodsThis was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2 % and 1 %) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician’s Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured.ResultsOverall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6 % for 2 % tofacitinib QD (80 % confidence interval [CI] for difference from vehicle: 3.8, 18.2 %) and 22.5 % for 2 % tofacitinib BID (80 % CI: 3.1, 18.5 %); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2 % tofacitinib QD and BID and 1 % tofacitinib QD (not BID) at Week 8, and with 2 % tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2 % and 1 % tofacitinib BID (starting Day 2), and 2 % tofacitinib QD (starting Day 3). Overall, 44.2 % of patients experienced AEs, 8.1 % experienced application site AEs, and 2.3 % experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group.ConclusionsIn adults with mild to moderate plaque psoriasis, 2 % tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile.Trial registrationNCT01831466 registered March 28, 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12895-016-0051-4) contains supplementary material, which is available to authorized users.

Background Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD).Objectives The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. Methods Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). Results Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was − 57.5%, and mean change in Patient-Oriented Eczema Measure total score was − 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years.Conclusions In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mildto-moderate AD with systemic exposures similar to patients aged ≥ 2 years. Clinical Trial Registration NCT03356977.William C. Ports: Affiliation at the time of this study. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4025 7-020-00510 -6) contains supplementary material, which is available to authorized users.