A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.