Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial

Abstract

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.

Systemic Tofacitinib Concentrations in Adult Patients With Atopic Dermatitis Treated With 2% Tofacitinib Ointment and Application to Pediatric Study Planning

“…Visual examination of predose and postdose concentrations indicated no trend of higher concentrations following dosing. This observation is consistent with previously reported data showing flat profiles following dosing with tofacitinib ointment in plaque psoriasis . The pre‐ and postdose pharmacokinetic collection had a median (range) time after last dose of 11.6 hours (8.4 to 23.6 hours) and 0.6 hours (0 to 1.8 hours), respectively.…”

“…The pharmacokinetic data collected in the phase 2a trial of topical tofacitinib ointment for treatment of patients with mild to moderate atopic dermatitis were analyzed using linear mixed‐effects models. The pharmacokinetic sampling times of 1 predose and postdose assessment in week 2 and week 4 were selected based on previous observations of flat pharmacokinetic profiles following topical administration of tofacitinib ointment in psoriasis patients . Because a typical pharmacokinetic profile characterized by absorption followed by an elimination phase was not observed, a practical pharmacokinetic sampling scheme maximizing patient convenience was adopted.…”

JAK inhibitors in dermatology: The promise of a new drug class

“…Ruxolitinib (INCB018424) 1.0% and 1.5% creams applied twice daily led to reduction in psoriasis lesion size over 4 weeks 35 . Improvement in psoriasis was also observed with tofacitinib 2% ointment; however, the degree of improvement relative to controls was modest and not always statistically significant 36,37 .…”

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies

“…Moreover, tofacitinib has been shown to directly inhibit cytokines, most importantly IL-4, thereby rapidly attenuating JAK-STAT signalling in keratinocytes [43,44]. While the results in psoriasis trials have shown quite varying results [45,46], the single published trial on topically administered tofacitinib in adults with mild to moderate AD revealed significantly better efficacy. Most importantly, for the primary analysis at week 4, the mean percentage change from baseline in the Eczema Area and Severity Index (EASI) total score was significantly greater (p < 0.001) for patients treated with tofacitinib (81.7%) versus patients treated with vehicle (29.9%).…”