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

Abstract

Aims: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842.

Methods: 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 (https://ichgcp.net/clinical-trials-registry/NCT01835197" title="See in ClinicalTrials.gov">NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842.

Results: 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 ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2 h after 10 days 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 200 mg (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.

Conclusions: These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.

Keywords: JAK1 inhibitor; PF-04965842; inflammatory diseases; pharmacodynamics; pharmacokinetics; phase 1.

© 2018 The British Pharmacological Society.

Figures

Figure 1

Study design. Subjects in each cohort (n = ~8 per cohort) were randomized 3:1 to PF‐04965842:placebo. BID, twice daily; MAD, multiple ascending dose; QD, once daily; SAD, single ascending dose. *Japanese subjects

Figure 2

Plasma PF‐04965842 concentration vs. time profiles. (A) SAD phase. Data for 1 subject in the 800 mg (western) group were excluded due to vomiting. (B) MAD phase. Data shown are for day 10 predose (0 h) up to 72 h postdose. Data for 1 subject in the 400 mg QD group were excluded due to vomiting. BID, twice daily; MAD, multiple ascending dose; PK, pharmacokinetic; QD, once daily; SAD, single ascending dose

Figure 3

Median percent change from baseline in pharmacodynamic parameters over time (A) IP‐10 levels; (B) hsCRP levels; (C) neutrophil counts; (D) reticulocyte counts. BID, twice daily; hsCRP, high‐sensitivity C‐reactive protein; IP‐10, interferon gamma‐induced protein 10; MAD, multiple ascending dose; MD, multiple dose; QD, once daily; SAD, single ascending dose