Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study.

Abstract

To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842. This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800mg PF-04965842 (single ascending dose phase) and placebo or 30mg once daily (QD), 100mg QD, 200mg QD, 400mg QD, 100mg twice daily (BID) or 200mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842. Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n=13), diarrhoea (n=11) and nausea (n=11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2h after 10days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus kinase signalling inhibition. These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.