First-in-Human Study to Evaluate Safety and Tolerability of Single and Multiple Ascending Doses of Janus Kinase-1 Inhibitor PF-04965842 in Healthy Western and Japanese Subjects

A Phase 1, Within Cohort, Randomized, Double Blind, Third-Party Open, Placebo-Controlled, Single- And Multiple Dose Escalation, Parallel Group Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-04965842 In Healthy Western and Japanese Subjects

This single- and multiple-ascending dose study is the first evaluation of PF-04965842, a Janus kinase1 (JAK1) inhibitor, in humans. The goal is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Western and Japanese subjects.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: PF-04965842; Drug: PF-04965842; Drug: PF-04965842; Drug: PF-04965842; Drug: PF-04965842; Drug: Placebo; Drug: Placebo; Drug: Placebo; Drug: Placebo; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive.
• Females must be of non-child bearing potential and either at least 1 year post menopausal (FSH ≥40 IU/L), or have documented hysterectomy (with or without bilateral oophrectomy) at least 6 months prior to study day
• Subjects willing to defer receiving prophylactic immunizations (e.g. influenza or pneumococcal vaccines) during the study.
• Absolute lymphocyte count must be greater than or equal to the lower limit of the laboratory reference range.
• Subjects enrolled in Cohort 8 must have four Japanese grandparents born in Japan.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, , pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
• History of hepatitis or positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab) or hepatitis C antibodies (HCV).
• Clinically significant abnormality on chest X-ray performed at screening or within 3 months of screening date; or history of tuberculosis or active or latent or inadequately treated infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAD Cohorts 1-8 Experimental Arm	Drug: PF-04965842; Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.; Drug: PF-04965842; Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.; Drug: PF-04965842; Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.
Placebo Comparator: SAD Cohorts 1-8 Placebo Arm	Drug: Placebo; Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.
Experimental: MAD Cohorts 3 through 5 Experimental Arm	Drug: PF-04965842; Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.; Drug: PF-04965842; Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.; Drug: PF-04965842; Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.
Placebo Comparator: MAD Cohorts 3 through 5 Placebo Arm	Drug: Placebo; Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.
Experimental: MAD Cohorts 6 and 7 Experimental Arm	Drug: PF-04965842; Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.; Drug: PF-04965842; Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.; Drug: PF-04965842; Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.
Placebo Comparator: MAD Cohorts 6 and 7 Placebo Arm	Drug: Placebo; Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.
Experimental: MAD Cohort 8 Experimental Arm	Drug: PF-04965842; Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.; Drug: PF-04965842; Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.; Drug: PF-04965842; Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.
Placebo Comparator: MAD Cohort 8 Placebo Arm	Drug: Placebo; Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.
Experimental: MAD Cohort 9 Experimental Arm	Drug: PF-04965842; Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.; Drug: PF-04965842; Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.; Drug: PF-04965842; Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.; Drug: PF-04965842; Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.
Placebo Comparator: MAD Cohort 9 Placebo Arm	Drug: Placebo; Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.; Drug: Placebo; Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events		6 weeks
Changes from baseline vital signs (blood pressure, pulse rate, oral temperature and respiration rate) and physical examinations		6 weeks
Changes from baseline in 12 lead ECG parameters	Quantitative changes in ECG intervals	6 weeks
Incidence and magnitude of treatment emergent clinical laboratory abnormalities including hematology (with white blood cell count differentials, platelets, PT and aPTT), chemistry, fasting glucose, urinalysis		6 weeks
Change from baseline in immunoglobulin levels	Quantitative IgG, IgA, IgM, and IgE levels	6 weeks
24-hour urine creatinine clearance (Single Ascending Dose Period)		Baseline, Day 1
24-hour urine creatinine clearance (Multiple Ascending Dose Period)		Baseline, Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complement Level: C3		6 weeks
Complement Level: C4		6 weeks
Complement Level: C3A	Cohorts 1-7 and Cohort 9	6 weeks
Complement Level: Bb	Cohorts 1-7 and Cohort 9	6 weeks
Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Infinity (AUCinf(dn))		8 days
Multiple Ascending Dose: Accumulation Ratio based on Cmax (Rac(Cmax))		6 weeks
Urinary Pharmacokinetics; for twice-a-day dosing, amount of PF-0496842 excreted unchanged in 12 hours (AE12)		6 weeks
Urinary Pharmacokinetics; for twice-a-day dosing, percent of PF-0496842 excreted unchanged in 12 hours (AE12%)		6 weeks
Multiple Ascending Dose: Apparent Volume of Distribution at Steady State (Vz/F)	Vz/F is the distribution of a drug between plasma and the rest of the body following oral adminstration.	6 weeks
Multiple Ascending Dose: Apparent Total Body Clearance (CL/F)		6 weeks
Urinary Pharmacokinetics; for once-a-day dosing, amount of PF-0496842 excreted unchanged in 24 hours (AE24)		6 weeks
Urinary Pharmacokinetics; for once-a-day dosing, percent of PF-0496842 excreted unchanged in 24 hours (AE24%)		6 weeks
Renal Clearance (CLr)		6 weeks
High-Sensitivity C-Reactive Protein (hsCRP)		6 weeks
Neutrophil counts		6 weeks
Reticulocyte counts		6 weeks
Complement Level: CH50		6 weeks
Single Ascending Dose: Apparent Total Body Clearance (CL/F)		8 days
Multiple Ascending Dose: Maximum Observed Plasma Concentration (Cmax)		6 weeks
Multiple Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)		6 weeks
Multiple Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))		6 weeks
Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau(dn))		6 weeks
Multiple Ascending Dose: Accumulation Ratio based on AUC predicted (Rss)		6 weeks
Multiple Ascending Dose: Accumulation Ration based on AUC observed (Rac)		6 weeks
Multiple Ascending Dose: Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one-half.	6 weeks
Multiple Ascending Dose: Peak to Trough Fluctuation (PTF)		6 weeks
Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn))		8 days
Single Ascending Dose: Area Under the Curve From Time Zero to Infinity (AUCinf)		8 days
Single Ascending Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)		8 days
Single Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))		8 days
Single Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)		8 days
Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn))	Dose-normalized area under the plasma concentration time-curve from zero to the last measured concentration (AUClast(dn))	8 days
Single Ascending Dose: Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	8 days
Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)		6 weeks
Single Ascending Dose: Apparent Volume of Distribution (Vz/F)		8 days
Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax)		8 days

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Wojciechowski J, Malhotra BK, Wang X, Fostvedt L, Valdez H, Nicholas T. Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis. Clin Pharmacokinet. 2022 May;61(5):709-723. doi: 10.1007/s40262-021-01104-z. Epub 2022 Jan 21. Erratum In: Clin Pharmacokinet. 2022 Apr;61(4):591.
• Peeva E, Hodge MR, Kieras E, Vazquez ML, Goteti K, Tarabar SG, Alvey CW, Banfield C. Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study. Br J Clin Pharmacol. 2018 Aug;84(8):1776-1788. doi: 10.1111/bcp.13612. Epub 2018 May 24.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: April 15, 2013
• First Submitted That Met QC Criteria: April 15, 2013
• First Posted (Estimate): April 18, 2013

Study Record Updates

• Last Update Posted (Estimate): June 20, 2014
• Last Update Submitted That Met QC Criteria: June 19, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Safety; PK; Randomized; Phase 1; Tolerability; Double Blind; Placebo-Controlled; PD; Single- & Multiple Dose Escalation; Pf-04965842
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Abrocitinib
• Other Study ID Numbers: B7451001