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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 (http://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.

SUBMITTER: Peeva E

PROVIDER: S-EPMC6046510 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Peeva Elena E Hodge Martin R MR Kieras Elizabeth E Vazquez Michael L ML Goteti Kosalaram K Tarabar Sanela G SG Alvey Christine W CW Banfield Christopher C

British journal of clinical pharmacology 20180524 8

<h4>Aims</h4>To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842.<h4>Methods</h4>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 800 mg PF-04965842 (single ascending dose phase) ...[more]

PMID: 29672897

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Project description:BACKGROUND:PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects. METHODS:Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000?mg and MR 30 to 300?mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750?mg twice daily, IR 1000?mg four times per day, IR 330?mg three times per day, and MR 300?mg QD. RESULTS:PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30?mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1?h versus 8?h for IR 100?mg and MR 100?mg formulations, respectively). Food had no effect on total exposure for MR 30?mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23?mL/min for IR <?750?mg and MR 300?mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ??250?mg and MR 300?mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed. CONCLUSIONS:PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases. TRIAL REGISTRATION:Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015.

Project description:ImportanceAn oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor.ObjectiveTo undertake safety testing of oral X-82 administered for the treatment of neovascular AMD.Design, setting, and participantsPhase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive.InterventionsParticipants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography.Main outcomes and measuresThe main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections.ResultsOf the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by -50 [97] μm, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1).Conclusions and relevanceX-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17% of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way.

Dataset Information

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

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

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