Clinical trial NCT03210961
Conditions: Plaque Psoriasis
Sponsor: Pfizer
Start date: 2017-07-14; Completion date: 2019-01-25
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This first in human study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06826647 in healthy subjects and subjects with plaque psoriasis.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: PF-06826647 tablet intervention 2: PF-06826647 oral suspension intervention 3: Placebo oral solution/suspension intervention 4: Placebo tablet
Intervention descriptions: intervention 1: PF-06826647 tablet for oral administration intervention 2: PF-06826647 suspension for oral administration (oral suspension to be administered to the 3mg starting dose cohort only) intervention 3: placebo oral solution for the single ascending dose, first cohort only intervention 4: Matching placebo tablet

Protocol documents:
Prot_000.pdf: 
PF-06826647
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Final Protocol Amendment 3, 05April 2018
Page 1
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-06826647 IN HEALTHY SUBJECTS AND SUBJECTS WITH PLAQUE 
PSORIASIS 
Investigational Product Number:
PF-06826647
Investigational Product Name:
Not Available (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C2501001
Phase:
1
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 3
05 April 2018
Section 1.3.2: updated the preliminary summary 
of clinical experience with PF-06826647.
Sections 1.3.2 and 1.3.4.1: dose rationale updated 
with preliminary pharmacokinetic (PK) 
parameters and starting dose selection rationale 
for psoriasis cohorts.
Section 3.1.1 and 3.1.2: introduction of optional 
cohort of Japanese subjects for PK comparability
to support the clinical development plan for 
PF-06826647.  
Section 3.1.2: added text indicating that 
PF-06826647 dose level may be adjusted for the 
second psoriasis cohort based on emerging 
clinical data from the planned interim analysis, at 
the discretion of the Sponsor.
Figure 1: Study Schematic updated with planned 
psoriasis cohort PF-06826647 dose level (based 
on recent psoriasis dose selection), dose level for 
the optional twice daily dose regimen cohort 
(BID), and optional Japanese cohort.
Figure 2: legend updated to add optional Japanese 
cohort.
Section 5.2: edits made to indicate that psoriasis 
cohorts will be sponsor-open, in order to allow 
sponsor review interim analysis results to inform 
dose decisions for psoriasis Cohort 2 
PF-06826647 dose level.
Section 4.1, Healthy Subject Inclusion Criteria: 
added single criterion for optional Japanese 
subject eligibility.
Section 6.1: expanded the maximum duration of 
the screening period from 28 to 45 days for 
psoriasis subjects, in order to accommodate 
potential recruitment delays in between cohorts, 
while Sponsor reviews results from the interim 


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analysis of psoriasis area and severity index 
scores.
Section 7, Table 7: added creatine phosphokinase 
laboratory test to the chemistry panel for psoriasis 
subjects, to help ensure adequate safety 
monitoring for subjects receiving longer duration 
of treatment (ie, 28 days). 
Section 9.7: added interim analysis of key 
secondary PASI endpoint for the 400 mg 
psoriasis cohort, to be conducted when 
21 subjects complete through study Day 28, to 
inform dose selection for subsequent psoriasis 
cohort and to support clinical development 
decisions for PF-06826647.
Section 9.7: changed the planned psoriasis 
cohorts from sponsor blind to sponsor-open, in 
order to permit review of interim analysis results 
by a designated, limited number of sponsor 
colleagues to facilitate dose selection 
adjustment/decisions for psoriasis Cohort 2. 
Several administrative edits and minor 
clarifications made. 
Amendment 2
20 December 2017
Schedule of Activities: Healthy Subject Single 
and Multiple Ascending Dose Periods.
Added a blood sample collection on Day 8 of the 
single asending dose period, in order to 
adequately characterize the pharmacokinetic (PK) 
profile (terminal half-life) of PF-06826647. 
Removed a PK blood sample on Day 1, 16 hours 
post dose to avoid increasing blood volume 
requirements for subjects. 
Added a study visit on Day 17 for extended PK 
sample collection (with corresponding vital sign 
collection and adverse event monitoring), in order 
to adequately characterize the terminal half-life of 
PF-06826647. Removed the Day 1 and Day 10,
16 hour post-dose blood collection for PK 
assessment to avoid increasing blood volume 
requirements for subjects.


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The rationale for the above changes is based on 
emerging PK data from the C2501001 trial, 
which indicates that the terminal half-life of 
PF-06826647 may be dose dependent.  The 
proposed PK sampling at approximately 
168 hours post dose will help to fully characterize 
the PK profile of PF-06826647. 
Section 1.3.2: Updated the preliminary summary 
of clinical experience.
Section 3.1.1 Study design- healthy subject single 
and multiple ascending dose period: extended the 
wash-out period between SAD and MAD dosing 
from 7 days to 14 days, based on preliminary 
assessment of the potential dose depenedent 
terminal half-life of PF-06826647.
Section 3.1.1 and 3.2 – added language to the 
dose escalation paradigm to state that the highest 
dose to be tested in MAD will not exceed the 
highest dose tested in SAD cohort, and that he 
highest dose MAD cohort will commence if 
adequate safety is demonstrated in SAD cohort at 
the same or higher dose level and the projected 
exposure at steady state does not exceed NOAEL. 
Amendment 1
06 November 2017
Various administrative changes.
Schedule of activities: removed the Day 28 blood 
collection for viral surveillance from the multiple 
ascending dose period, added additional blood 
collection for pharmacokinetic (PK) assessment 
on Day 1.
Schedule of activities: removed the Day 7 and 
Day 56 blood collection for viral surveillance 
from the Psoriasis Cohort schedule.
 
 
 
 
 
 
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Schedule of activities: added additional 
electrocardiogram (ECG) and vital sign 
assessment on Day 1 of the multiple ascending 
dose period, to coincide with the revised 
Day 1 PK collection.
Section 1.3.2 Preliminary Summary of Clinical 
Experience added to provide rationale for revised 
PF-06826647 dose levels in the single and 
multiple ascending dose periods.
Section 1.3.4 Updated Dose Rationale Based on 
Emerging Clinical Data added to provide 
rationale for revised PF-06826647 dose levels in 
the single and multiple ascending dose (MAD) 
periods.
Section 3.1.1 Healthy Subject Single and 
Multiple Ascending Dose Periods, updated 
PF-06826647 dose levels based on emerging PK 
data from the C2501001 study, and added 
optional cohorts to further explore higher 
PF-06826647 exposure ranges.
Figure 1 Study Schematic, updated to reflect 
amendment 1 PF-06826647 dose levels and 
addition of optional cohorts to further explore 
higher PF-06826647 exposure ranges.
Section 4.6.1 Meals and Dietary Requirements, 
updated to specify revised meal requirements for 
the multiple ascending dose period and psoriasis 
cohorts (dosing with food based on the emerging 
PK data from Study C2501001).
Section 5.5 Administration, harmonized with 
Protocol Section 4.6.1 to reflect the revised meal 
requirements for the trial.
Section 6.1 Screening, updated screening window 
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to allow eligible healthy subjects entry into the 
trial after lapse of the 28 day screening period, 
assuming study Day -1 paramters are within the 
limits of eligibility, as defined in Protocol 
Section 4.
Section 7.10 Blood Volume, updated blood 
volume table to reflect reduced viral surveillance 
testing, and added PK sample collection on 
Day 1 of the MAD period.
Section 7.11.1 
 
clarified process for 
management of subjects at Screening visit, in 
accordance with site Institutional Review Board 
(IRB) request.
Original 
protocol
16 May 2017
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................13
APPENDICES .........................................................................................................................13
SCHEDULE OF ACTIVITIES................................................................................................15
1. INTRODUCTION ...............................................................................................................25
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background .............................................................................................................25
1.2.1. Binding to the Pharmacological Target ......................................................25
1.2.2. Cellular Potency and Selectivity.................................................................26
1.2.3. Non-Clinical Pharmacokinetics and Metabolism.......................................28
1.2.4. Non-clinical Safety Studies ........................................................................29
1.2.5. Biopharmaceutics Properties ......................................................................32
1.3. Rationale..................................................................................................................32
1.3.1. Study Rationale...........................................................................................32
1.3.2. Preliminary Summary of Clinical Experience............................................33
1.3.3. Dose Rationale............................................................................................34
1.3.3.1. Dose Selection for FIH Study (Original Protocol Dose 
Rationale, 16 May 2017) ...................................................................34
1.3.4. Updated Dose Rationale Based on Emerging Clinical Data (Protocol 
Amendment 2, 20 December 2017).................................................................38
1.3.4.1. Dose Selection for Psoriasis Patients ........................................40
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................41
3. STUDY DESIGN.................................................................................................................44
3.1. Study Overview.......................................................................................................44
3.1.1. Healthy Subject Single and Multiple Ascending Dose Periods..................45
3.1.2. Psoriasis Multiple Dose Cohorts ................................................................47
3.2. Dose Escalation and Stopping Rules.......................................................................49
3.3. Individual Stopping Rules for the Healthy Subjects during the Single and 
Multiple Ascending Dose Periods.............................................................................51
3.4. Individual Stopping Rules for Psoriasis Subjects ...................................................52
3.5. Discontinuation/End of Treatment Monitoring for Adverse Events, 
Laboratory, Vital Signs and ECG Abnormalities......................................................54


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4. SUBJECT ELIGIBILITY CRITERIA.................................................................................54
4.1. Inclusion Criteria: Healthy Subject Single/Multiple Ascending Dose Cohorts......54
4.2. Exclusion Criteria: Healthy Subject Single/Multiple Ascending Dose 
Cohorts ......................................................................................................................55
4.3. Inclusion Criteria: Psoriasis Multiple Dose Cohorts...............................................59
4.4. Exclusion Criteria: Psoriasis Multiple Dose Cohort ...............................................60
4.5. Randomization Criteria ...........................................................................................65
4.6. Lifestyle Requirements ...........................................................................................66
4.6.1. Meals and Dietary Requirements................................................................66
4.6.2. Alcohol, Caffeine, and Tobacco .................................................................68
4.6.3. Activity .......................................................................................................68
4.6.3.1. Healthy Volunteer Single Ascending Dose Period ...................68
4.6.3.2. All Subjects ...............................................................................69
4.6.4. Contraception..............................................................................................69
4.6.4.1. Females – Childbearing Potential .............................................70
4.7. Sponsor’s Qualified Medical Personnel..................................................................70
5. STUDY TREATMENTS.....................................................................................................70
5.1. Allocation to Treatment ..........................................................................................71
5.2. Breaking the Blind ..................................................................................................71
5.3. Subject Compliance.................................................................................................72
5.4. Investigational Product Supplies.............................................................................72
5.4.1. Dosage Form and Packaging ......................................................................72
5.4.2. Preparation and Dispensing........................................................................72
5.5. Administration.........................................................................................................73
5.6. Investigational Product Storage ..............................................................................73
5.7. Investigational Product Accountability...................................................................74
5.7.1. Destruction of Investigational Product Supplies ........................................74
5.8. Concomitant Treatment(s).......................................................................................74
6. STUDY PROCEDURES .....................................................................................................75
6.1. Screening.................................................................................................................75
6.2. Treatment Period.....................................................................................................75
6.3. Follow-up/End of Study Procedures .......................................................................75


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6.3.1. Follow-up Contact ......................................................................................75
6.4. Subject Withdrawal/Early Termination ..................................................................76
7. ASSESSMENTS..................................................................................................................78
7.1. Safety.......................................................................................................................78
7.1.1. Laboratory Tests .........................................................................................78
7.1.2. Pregnancy Testing ......................................................................................80
7.1.3. Physical Examinations................................................................................81
7.1.4. Blood Pressure and Pulse Rate ...................................................................81
7.1.5. Temperature................................................................................................81
7.1.6. Electrocardiogram.......................................................................................81
7.1.7. Continuous Cardiac Monitoring by Telemetry...........................................82
7.1.8. Chest Radiograph........................................................................................83
7.1.9. Interferon Gamma Release Assay (IGRA) Tests........................................83
7.1.10. Urine Creatinine and 
............83
7.1.10.2. 24 Hour Urine Creatinine and 
 in 
Multiple Ascending Dose Period: Day -1 and Day 10......................84
7.1.10.3. 24 Hour Creatinine Clearance Calculation..............................84
7.1.11. Serum Creatinine and Serum Cystatin-C..................................................84
7.1.12. Estimated Glomerular Filtration Rate.......................................................85
7.2. Selection of IndexPlaques and Non-Lesional Skin for Skin Biopsies for 
Psoriasis Subjects ......................................................................................................85
7.3. Skin Biopsies (Psoriasis Subjects only) ..................................................................86
7.4. Psoriasis Clinical and Histological Assessments ....................................................87
7.4.1. Psoriasis Area and Severity Index (PASI) (Psoriasis subjects only)..........87
7.4.2. Linear-method Psoriasis Area and Severity Index (L-PASI) .....................88
7.4.6. Target Lesion and Regional Photography (Psoriasis subjects only) ..........89
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7.6. Pharmacokinetics ....................................................................................................91
7.6.1. Plasma for Analysis of PF-06826647.........................................................91
7.6.2. Urine for Analysis of PF-06826647 ...........................................................92
7.6.3. Shipment of Pharmacokinetic Samples ......................................................92
 
 
7.10. Blood Volume .......................................................................................................97
7.11. Assessment of Suicidal Ideation and Behavior.....................................................99
7.11.2. Patient Health Questionnaire – 8 items (PHQ-8) ...................................100
7.11.3. Suicidal Behaviors Questionnaire-revised (SBQ-R) ..............................100
7.12. Triggered Requirements......................................................................................100
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7.12.1. Potential Cases of Acute Kidney Injury .................................................100
7.13. Rater Qualifications.............................................................................................101
8. ADVERSE EVENT REPORTING....................................................................................101
8.1. Requirements.........................................................................................................101
8.1.1. Additional Details on Recording Adverse Events on the CRF.................103
8.1.2. Eliciting Adverse Event Information........................................................103
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) ...........................................103
8.1.4. Time Period for Collecting AE/SAE Information....................................103
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................103
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............104
8.1.5. Causality Assessment ...............................................................................104
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................104
8.2. Definitions.............................................................................................................104
8.2.1. Adverse Events.........................................................................................104
8.2.2. Abnormal Test Findings ...........................................................................105
8.2.3. Serious Adverse Events ............................................................................106
8.2.4. Hospitalization..........................................................................................106
8.3. Severity Assessment..............................................................................................108
8.4. Special Situations ..................................................................................................108
8.4.1. Potential Cases of Drug-Induced Liver Injury..........................................108
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................110
8.4.2.1. Exposure During Pregnancy....................................................110
8.4.2.2. Exposure During Breastfeeding ..............................................111
8.4.2.3. Occupational Exposure ...........................................................111
8.4.3. Medication Errors .....................................................................................112
8.4.3.1. Medication Errors....................................................................112
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................112
9.1. Sample Size Determination...................................................................................113
9.1.1. Healthy Subject Single Ascending and Multiple Dose.............................113
9.1.2. Psoriasis Multiple Dose............................................................................113
9.2. Efficacy Analysis ..................................................................................................113


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9.2.1. Analysis of Secondary Endpoints.............................................................113
9.3. Pharmacokinetic Analysis.....................................................................................114
9.3.1. Single and Multiple Dose Periods ............................................................114
9.6. Safety Analysis – Primary.....................................................................................116
9.6.1. Electrocardiogram Analysis......................................................................117
9.7. Interim Analysis ....................................................................................................117
9.8. Data Monitoring Committee .................................................................................118
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................118
11. DATA HANDLING AND RECORD KEEPING ...........................................................119
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record...................119
11.2. Record Retention.................................................................................................119
12. ETHICS............................................................................................................................120
12.1. Institutional Review Board/Ethics Committee....................................................120
12.2. Ethical Conduct of the Study ..............................................................................120
12.3. Subject Information and Consent........................................................................120
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................121
13. DEFINITION OF END OF TRIAL.................................................................................121
13.1. End of Trial in the United States.........................................................................121
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................121
15. PUBLICATION OF STUDY RESULTS........................................................................122
15.1. Communication of Results by Pfizer ..................................................................122
15.2. Publications by Investigators ..............................................................................122
16. REFERENCES ................................................................................................................124
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LIST OF TABLES
Table 1.
Preliminary Summary of Draft Plasma PK Parameters of PF-06826647 
Following Single Oral Dose Administration of PF-06826647 in Healthy 
Subjects (Fasted)...................................................................................................34
Table 2.
Preliminary Summary of Draft Plasma PK Parameters of PF-06826647 
Following Multiple Oral QD Dose Administration of PF-06826647 for 
10 Days in Healthy Subjects (Fed-Standard Meal) ..............................................34
Table 3.
Predicted Mean Human Total and Free Exposures and Associated Margins 
Following Single Dose Administration of PF-06826647.....................................36
Table 4.
Predicted Mean Human Total and Free Exposures and Associated Margins 
Following Once Daily Dosing of PF-06826647 for 10 Days...............................37
 
Table 7.
Laboratory Tests ...................................................................................................79
Table 8.
Blood Volume: Single Ascending Dose Period....................................................97
Table 9.
Blood Volume: Multiple Ascending Dose Period................................................98
Table 10.
Blood Volume: Psoriasis Multiple Dose Period...................................................99
LIST OF FIGURES
Figure 1.
Study Schema .......................................................................................................48
Figure 2.
Legend for Figure 1 ..............................................................................................49
APPENDICES
Appendix 1. Abbreviations....................................................................................................125
Appendix 2. Cockcroft-Gault Calculation.............................................................................132
Appendix 3. Prohibited Concomitant Medications................................................................133
Appendix 4. Estimated Glomerular Filtration Rate...............................................................135
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Appendix 8. Patient Global Assessment of Psoriasis ............................................................139
Appendix 10. Suicidal Behaviors Questionnaire-Revised (SBQ-R) .....................................146
Appendix 11. Patient Health Questionnaire – 8 items (PHQ-8)............................................148
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the subject. 
SCHEDULE OF ACTIVITIES Single Ascending Dose - Period 1: Healthy Subject Cohorts
Study Day
Screening
-28 to -2
Day
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 8a
Follow-up
/ET*
Hours Post Dose
Protocol Activity
0
0.5
1
2
4
6
8
12
16
24
36
48
72
168
Randomization
X
Informed Consent
X
Admission to CRU
X
Discharge from CRU
X
Outpatient Visitb
X
X
Inclusion/Exclusion Criteria
X
X
Drug/Alcohol/Tobacco History
X
X
Medical History 
X
X
Physical Examinationc
X
X
X
Demography
X
Body weight
X
X
X
Height
X
Interferon Gamma Release Assay 
(IGRA)
X
HIV, HepBsAg, HepBcAb, HCVAb
X
Blood Safety Labs 
(hematology & chemistry) (fasting)d
X
X
X
X
X
Fibrinogen
X
X
Lipid Panel (fasting)e
X
X
X
X
Urinalysis
X
X
X
X
X
X
FSHf
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Study Day
Screening
-28 to -2
Day
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 8a
Follow-up
/ET*
Hours Post Dose
Protocol Activity
0
0.5
1
2
4
6
8
12
16
24
36
48
72
168
Urine pregnancy test for females
X
X
Contraception Checkg
X
X
X
Urine Drug Test
X
X
ECGh (12-lead)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continous cardiac monitoring by 
Telemetryi
X
Monitored continuously through 8 hours 
post dose
Vital signs: Supine single PR, BP, 
and Oral Temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral Surveillance:
 
 
Study Treatment Administration
X
PK Blood Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious and non-serious adverse event 
monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
X
Prior/Concomitant treatments
X
X
→
→
→
→
→
→
→
→
→
→
→
→
X
Blood for mRNA analysis
X
X
X
X
X
X
X
X
X
Abbreviations: →= ongoing/continuous event; BP = blood pressure; 
;CRU = clinical research unit;
ECG = electrocardiogram; 
FSH = follicle-stimulating hormone; 
; HepBcAb = hepatitis B core 
antibody; HepBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus;
; PK = Pharmacokinetics; 
PR = pulse rate; 
.
a.
End of study visit (±1 day).
b.
Subjects will reside in the clinical research unit until the morning of Day 4 and return on Day 8 ±1 day for the end of the single dose period visit.
c.
A full physical examination may be done at screening or may be differed to Day -1 (prior to randomization) of Period 1 at the discretion of the investigator.  A limited 
physical exam may be completed on Day 8 (instead of a full exam) at the discretion of the investigator. 
d.
Chemistry and hematology labs are collected following fasting period of at least 8 hours (on Day 1, fasting applies to hour 0 labs only).
e.
Lipid Panel (Cholesterol, Triglycerides, HDL, and LDLc): Fasting requirement of at least 8 hours.
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f.
FSH test to be performed at screening to confirm postmenopausal status in females who are amenorrheic for at least 12 consecutive months.
g.
See protocol Section 4.6.4 (Contraception).  Investigator will discuss appropriate contraception methods with male subjects.
h.
ECGs will be collected in triplicate approximately 2-4 minutes apart except at screening and Day 8 where single ECG traces will be collected.
i.
To establish a baseline, telemetry should be recorded for at least 2 hours before dosing.  This may be done -2 hours immediately prior to dosing or at some 2 hour continuous 
interval in the 24 hours prior to dosing, as long as the recording is performed when the subject is awake.  Continous cardiac monitoring will be conducted -15 minutes 
pre-dose through the 8 hour post dose period.
 
*
ET: early termination – refer to Section 6.4 for additional guidance.  If a subject is withdrawn due to an adverse event, in addition to the early termination assessments 
included in the schedule of activities, a final PK sample should be collected when possible. 
Note: Time 0 on Day 1 is pre-dose. All assessments/samples at time 0 occur pre-dose, including PK sample collection. 
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SCHEDULE OF ACTIVITIES Multiple Ascending Dose - Periods 2: Healthy Subject QD and Optional BID and Japanese 
Subject Cohorts
The Schedule of Activities table provides an overview of the protocol visits and procedures.
Note: The below schedule assumes healthy subjects entering the multiple ascending dose (MAD) period have completed the single 
ascending dose period (SAD).  Prior to entering the MAD period, any subjects that have not completed the SAD period must complete 
the screening assessments listed in the SAD Schedule of Activities (including sample collection for Pharmacogenomic Sample 
Prep D1), and must meet eligibility requirements for healthy subjects outlined in the Inclusion Criteria: Healthy Subject 
Single/Multiple Ascending Dose Cohorts. 
Study Day
Day
-1
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day 
6
Day
7
Day 
8
Day
9
Day 10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
17
Day 28a
Follow-up
/ET*
Hours Post Dose
Protocol Activity
0 0.5
1
2
4
6
8
12
16
24
0 0.5 1 2 4 6
8 12 16 24
48
72
96
168
Confirm key eligibility 
criteria are met (safety 
labs, vitals, ECG)b
X
Contraception Checkc
X
Urine pregnancy test for 
females
X
Admission to CRU
X
Discharge from CRUd
X
Outpatient visit
X
X
Physical Examinatione
X
X
Body weight 
X
X
Blood Safety Labs 
(hematology & 
chemistry)(fasting)f
Xm
X
X
X
X
X
X
X
Fibrinogen 
X
X
Immunoglobulins: IgA, 
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Study Day
Day
-1
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day 
6
Day
7
Day 
8
Day
9
Day 10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
17
Day 28a
Follow-up
/ET*
Hours Post Dose
Protocol Activity
0 0.5
1
2
4
6
8
12
16
24
0 0.5 1 2 4 6
8 12 16 24
48
72
96
168
Lipid Panel (fasting)g
X
X
X
X
X
Urinalysis
X
X
X
X
X
X X
X
X
X
X
Urine Drug Test
X
ECGh
X
X
X
X
X
X
X
X
X
X
X
X
X X X X X X X X X X
X
X
X
X
X
Vital signs: Supine single 
PR, BP and Oral 
Temperaturei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X X X X X X X X X
X
X
X
X
X
X
24 hr Urine Collection for 
measurement, 
Creatinine Clearance, 
6-β-Hydroxycortisol/cortis
ol ratio and Urine PKj
0-24 
hr
0-24 hr
Study Treatment 
Administration
X
X
X
X
X
X
X
X
X X
PK Blood Samplingk
X
X
X
X
X
X
X
X
X
X
X
X
X X X X X X X X
X
X
X
X
X
 
 
Serious and non-serious 
adverse event monitoring
X
X
→
→
→
→
→
→
→
→→→→→→→→→→→
→
→
→
→
X
Prior/Concomitant 
treatment
X
→
→
→
→
→
→
→
→
→→
→
→
→
→
→
X
 
Abbreviations: →= ongoing/continuous event; BP = blood pressure; 
; CRU = clinical research unit; 
; ECG = electrocardiogram; 
; PK = Pharmacokinetics; 
PR = pulse rate; 
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a.
End of study procedures (±3 day).
b.
Prior to dosing on Day 1, confirm that safety labs, ECG, and vital sign results, contraception check and prior/concomitant treatments from Day -1 (or from Day 8 of SAD if 
obtained within 48 hours of MAD Day -1) meet eligibility requirements outlined in Section 4.2. If labs, vitals, or ECG results are not within limits as outlined in Section 4.2, 
the site will notify sponsor.  PI and sponsor will make the determination as to whether or not to allow the subject to continue into the MAD period.  If the out of range values 
meet individual stopping rules outlined in the protocol, the subject will not continue into the MAD period. 
c.
See protocol Section 4.6.4 (Contraception).  Investigator will discuss appropriate contraception methods with male subjects. 
d.
Subjects will reside in the clinical research unit until the morning of Day 14, returning on the morning of Day 28 ±3 days for the end of study procedures visit.
e.
Limited physical examination (at the discretion of the principle investigator, exam may be limited or full).
f.
Chemistry and hematology labs are collected following fasting period of at least 8 hours (on Day 10, fasting applies to hour 0 labs only).
g.
Lipid panel (Cholesterol, Triglycerides, HDL, and LDLc):Fasting requirement of at least 8 hours.
h.
ECGs will be collected in triplicate approximately 2-4 minutes apart on Days 1, 2, 4, 6, 8, 10 and Day 11.  Single ECGs will be collected at all other specified visits.
i.
Vitals taken on Day 1 will be performed prior to dosing and at approximately 2 hours post-dose; vitals taken on Days 2-9 will be performed approximately 2 hours post-dose; 
vitals taken on Days 12, 13, 14 will be performed in the morning.  Vital signs will also be collected at the Day 17 and Day 28 (follow up/ET) visit.
j.
An aliquot (urine blank) from the 0-24 hour period will be obtained from the urine collection for creatinine clearance on Day -1 for both the QD cohort and the BID cohort.
On Day 10, urine will be collected for the BID cohort over 2 time intervals: 0-12 hours and 12-24 hours. The Day 10 PK sample will be obtained from the 0-12 hour interval. 
k.
Blood samples collected for PK pre-dose on Days 1, 2, 4, 6, 8 and 10, and on the morning of Days 11-14 (following at least a 8 hour fasting period, before breakfast) and on 
study Day 17.
 
*
ET: early termination – refer to Section 6.4 for additional guidance.  If a subject is withdrawn due to an adverse event, in addition to the early termination assessments 
included in the schedule of activities, a final PK sample should be collected when possible.
Note: An optional BID cohort may be included based on emerging PK data.  Subjects participating in the BID cohort will follow the above schedule. 
Administration of blinded study medication occurs on study Days 1 through 10.  On study Days 1 through 9, all assessments listed occur pre-dose.  On study Days 1 through 9, at 
2 hours post dose, obtain vital signs including supine blood pressure, pulse rate (after at least 5 minutes of rest), and oral temperature.  Assess symptoms by spontaneous reporting 
of adverse events and by asking the subjects to respond to a non-leading question such as “How do you feel?”.  On study Day 10, the assessment time course depicted in the 
schedule of activities should be followed.  Assessments on Day 10, hour 0, occur pre-dose. 
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SCHEDULE OF ACTIVITIES: Psoriasis Cohorts 
Study Day
Screen
ing
-28 to 
-2
D 
-1
D 1 D2 D 3 D 4 D 5
D 
6
D 
7
D 8 D 9 D 
10
D 
11
D 
12
D 
13
D 14 D 21
D
28
Day 
29
D 
35
D
42
D 56/ETa
D 84
Hours Post Dose
Protocol Activity
0
0.5
1
2
4
6
8
12 16
24
Informed Consent
X
Drug/Alcohol/Tobacco 
History
X
Demography
X
Medical History
X
Prior/Concomitant 
treatment
X
X →→→→→→
→
→→→→→→
→
→
→
→
→→→→→→
→
→
→
→
→
X
FSHb
X
Urine pregnancy test for 
females
X
X
Contraception Checkc
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
Admission to CRU
X
Randomization
X
Discharge from CRU
X
Interferon Gamma 
Release Assay (IGRA)
X
Chest X-rayd
X
HIV, HepBsAg,
HepBcAb, HCVAb
X
 
Non lesional biopsy
X
Lesional biopsy of index 
lesion 
X
X
X
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Study Day
Screen
ing
-28 to 
-2
D 
-1
D 1 D2 D 3 D 4 D 5
D 
6
D 
7
D 8 D 9 D 
10
D 
11
D 
12
D 
13
D 14 D 21
D
28
Day 
29
D 
35
D
42
D 56/ETa
D 84
Hours Post Dose
Protocol Activity
0
0.5
1
2
4
6
8
12 16
24
Clinical Evaluation: 
Plaque Lesion 
Photographyf
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
Physical Examinationg
X
X
X
X
X
X
Body weight 
X
X
X
Height
X
 
Blood Safety Labs 
(chemistry and 
hematology) (fasting)h
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Lipid Panel (fasting)i
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X X
X
X
X
Urine Drug Test
X
X
ECGj
X
X
X
X
X
X
X
X
X
X X
X
X
X
Vital signs: Supine single 
PR, BP and Oral 
Temperaturek
X
X X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
Study Treatment 
Administrationl
X X X X X
X
X
X
X
X
X
X
X
X
X
X
PK Blood Samplingm
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
 
 
 
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Study Day
Screen
ing
-28 to 
-2
D 
-1
D 1 D2 D 3 D 4 D 5
D 
6
D 
7
D 8 D 9 D 
10
D 
11
D 
12
D 
13
D 14 D 21
D
28
Day 
29
D 
35
D
42
D 56/ETa
D 84
Hours Post Dose
Protocol Activity
0
0.5
1
2
4
6
8
12 16
24
Serious and non-serious 
adverse event monitoring
X →→→→→→
→
→→→→→→
→
→
→
→
→→→→→→
→
→
→
→
→
X
 
 
 
 
Patient Global 
Assessment
X
X
X
X
X
X
X
PHQ-8o
X
SBQ-Ro
X
Abbreviations: →= ongoing/continuous event; 
; BP = blood pressure; 
; CRU = clinical research unit; D=Day;
 
; ECG = electrocardiogram; 
; FSH = follicle stimulating hormone; HepBcAb = hepatitis B 
core antibody; HepBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus; 
 
; IGRA = interferon gamma release assay; 
 
 PK = Pharmacokinetics; PR = pulse rate; 
a.
End of study procedures (±3 days).  Note: the visit window (±3 days ) applies to outpatient visits on study Days 35, 42, 56, and 84. ET: early termination – refer to 
Section 6.4 for additional guidance.  If a subject is withdrawn due to an adverse event, in addition to the early termination assessments included in the schedule of activities, a 
final PK sample should be collected when possible. 
b.
FSH test to be performed at Screening to confirm postmenopausal status in females who are amenorrheic for at least 12 consecutive months.
c.
See protocol Section 4.6.4 (Contraception).  Investigator will discuss appropriate contraception methods with male subjects.
d.
Only required for psoriasis subjects with history of previously (adequately) treated TB, as described in the protocol eligibility criteria (see protocol Section 4.3).  Chest x-ray 
taken within 3 months of screening visit can be used to assess eligibility if available.
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f.
Target lesion and regional photography.
g.
A full physical examination may be done at screening or may be differed to Day -1 (prior to randomization) at the discretion of the investigator.  A full physical exam should 
also be performed at Day 28.  A limited physical exam can be performed at all other times if no findings during previous examination or new/open AE, at the discretion of the 
investigator.
h.
Safety labs (chemistry and hematology) are collected following at least 8 hours of fasting (on Day 28, fasting requirement applies to hour 0 only).
i.
Lipid panel (Cholesterol, Triglycerides, HDL, and LDLc): Fasting requirement of at least 8 hours.
j.
Triplicate ECGs will be collected on Day 1, Day 28, and Day 29.  Single ECGs will be collected at all other time points/visits.
k.
Vitals taken on Days 1-28 will be performed at approximately 2 hours post-dose; vitals will also be taken on Day 29, 35, 42 and 56/ET (follow-up) visits.
l.
Study treatment administration occurs once daily for 28 days, starting on Day 1 and ending on Day 28.
m.
Blood samples collected for PK predose on Days 1, 7, 14, 21, and 28 (time 0), and on the morning of Day 29 and Day 35.
o.
Subjects who have recent or active suicidal ideation or behavior will be excluded from the study (refer to Section 4.4).
 
Administration of blinded study medication occurs on study Days 1 through 28.  On study Days 1 through 21, all assessments listed in the schedule of activities occur pre-dose.  
On study Days 1 through 21, at 2 hours post dose, obtain vital signs including supine blood pressure, pulse rate (after at least 5 minutes of rest), and oral temperature.  Assess 
symptoms by spontaneous reporting of adverse events and by asking the subjects to respond to a non-leading question such as “How do you feel?”.  On study Day 28, the 
assessment time course depicted in the schedule of activities should be followed.  Assessments on Day 28, hour 0, occur pre-dose. 
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1. INTRODUCTION
The Janus kinase (JAK) family, including JAK1, JAK2, JAK3 and Tyrosine kinase 2 
(TYK2), is a group of cytoplasmic tyrosine kinases that mediate signal transduction via 
interactions with Type 1 and Type 2 cytokine receptors critical for leukocyte activation, 
proliferation, survival and function.5,6
PF-06826647 is a potent TYK2 inhibitor with a good selectivity profile over other human 
kinases.  Based on its cytokine inhibition profile, PF-06826647 is expected to target the
T-helper 1 (Th1) and T-helper 17 (Th17) pathways, and Types I and II interferon signaling, 
directly by inhibiting TYK2, and to provide therapeutic benefit in the treatment of 
inflammatory conditions driven by Th1/Th17 and interferon immune responses. 
This single- and multiple-ascending dose study is the first evaluation of PF-06826647 in 
humans.  The goal is to assess the safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) in healthy subjects and subjects with plaque psoriasis.  The 
inclusion of a psoriasis cohort will facilitate optimal assessment of TYK2 modulation in 
vivo, given that Th1 and Th17 pathways are not up regulated in the absence of inflammation.  
1.1. Mechanism of Action/Indication
PF-06826647 is a TYK2 inhibitor that is currently being developed for the treatment of
psoriasis and Crohn’s disease (CD).
TYK2 pairs with JAK1 to mediate type I interferon (IFN) signaling and with JAK2 to 
transmit interleukin (IL-12) and IL-23 signaling.  Additionally JAK1 pairs with JAK3 to 
mediate -common cytokine signaling and also with JAK2 and/or TYK2 to transmit the 
signals of additional cytokines important in inflammation and immune responses including 
IL-6, and IFN, JAK2 homodimers are critical for the signaling of hematopoietic cytokines 
and hormones including erythropoietin (EPO), IL-3, granulocyte-macrophage 
colony-stimulating factor (GM-CSF) and prolactin.  Key cytokines implicated in the 
pathophysiology of both Crohn’s disease and plaque psoriasis, such as IL-12 and IL-23, 
require TYK2 for signal transduction, indicating that inhibition of TYK2 mediated signaling
could be efficacious in the treatment of these inflammatory conditions.
1.2. Background 
1.2.1. Binding to the Pharmacological Target
PF-06826647 is an inhibitor of human TYK2.  The inhibitory potency of PF-06826647 on 
human TYK2 was determined by using a mobility shift microfluidic assay to monitor 
phosphorylation of a synthetic peptide by recombinant human TYK2.  When the assay was
performed under 1 mM adenosine triphosphate (ATP), PF-06826647 showed IC50 (half 
maximal inhibitory concentration) of 14.9 nM against human TYK2.  PF-06826647 was less 
active against human JAK1, JAK2 and JAK3, with IC50s of 383, 74.2 and >10,000 nM, 
respectively, at 1 mM ATP using the same assay technology.  PF-06826647 is less potent 
against mouse TYK2 in the kinase assays.  Sequence alignment of the TYK2 enzyme reveals 
that, within the ATP binding pocket, human TYK2 has an isoleucine at amino acid 960, 


PF-06826647
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while other species with known sequences bear a valine at the equivalent position, except in 
chimpanzee.  Mouse TYK2 and human TYK2 I960V mutant kinase domains were prepared 
to gain an understanding of species selectivity, relative to the wild-type human protein.  The 
IC50 of PF-06826647 measured in this assay at 1 mM ATP was 385 nM for mouse TYK2, 
and 344 nM for human TYK2 I960V mutant.  The results indicate that PF-06826647 binds 
more strongly to TYK2 with isoleucine at amino acid 960 than valine, and resulting in 
relatively lower potency in preclinical species when compared to human.
1.2.2. Cellular Potency and Selectivity 
The JAK family kinases mediate signal transduction via interactions with type I (eg, IL-2, 
IL-6, IL-23, GM-CSF) and type II (eg, type I IFNs, IL-10) cytokine receptors.  The JAK 
signaling pathways involves various hetero- or homodimer combinations (TYK2/JAK2, 
JAK1/JAK3, JAK1/JAK2, TYK2/JAK1, or JAK2/JAK2).  Upon binding of the cytokine to 
its receptor, the associated JAKs are activated, and phosphorylate each other and the 
receptor.  The phosphorylated receptors serve as docking sites for the signal transducer and 
activator of transcription (STAT) family (STAT1, STAT2, STAT3, STAT4, STAT5a, 
STAT5b, and STAT6) of transcription factors.  The STATs are then phosphorylated by the 
co-localized JAKs, which stabilizes homo- or heterodimeric STAT complexes that 
translocate to the nucleus where they bind to specific gene promoters and modulate 
transcription of a range of target genes. 
The cellular potency and selectivity of PF-06826647 was mainly evaluated using human 
whole blood (HWB).  HWB was pretreated with PF-06826647 and challenged with various 
cytokines to stimulate phosphorylation of STATs.  Inhibition of STAT phosphorylation by 
PF-06826647 was measured by flow cytometry using intracellular staining with specific 
phospho-STAT antibodies.
IL-12 and IL-23, both signaling through JAK2/TYK2, are important for the differentiation of 
Th1 and Th17, respectively.  Treatment of HWB with PF-06826647 led to inhibition of 
IL-12 induced STAT4 phosphorylation with an IC50 of 53 nM and IL-23 induced STAT3 
phosphorylation with an IC50 of 112 nM.  In human peripheral blood mononuclear cells
(PBMCs), PF-06826647 potently inhibited IL-12 induced pSTAT4 with an IC50 of 20 nM.
Treatment of HWB or human PBMCs with PF-06826647 resulted in inhibition of IFN
stimulated STAT3 phosphorylation (mediated via TYK2/JAK1) with an IC50 of 66 nM and 
23 nM, respectively.  Although IL-10 signaling is also mediated via the TYK2/JAK1 pair, 
PF-06826647 was less potent against IL-10 induced STAT3 phosphorylation with an IC50 of 
427 nM in HWB.  Signaling of the type II interferon, IFN, is controlled by JAK1/JAK2.  
PF-06826647 was shown to block IFNinduced pSTAT1 with an IC50 of 2,220 nM in HWB.
The common chain cytokines, such as IL-15 and IL-21, are dependent on JAK1 and JAK3 
to initiate signaling upon binding of their receptors.  PF-06826647 pre-incubation in human 
whole blood resulted in an inhibition of STAT5 phosphorylation induced by IL-15 with an 
IC50 of 4,840 nM and an inhibition of STAT3 phosphorylation induced by IL-21 with an 
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IL-6 signaling is thought to be dependent on JAK1/JAK2/TYK2.  The IC50 values in the IL-6 
assays were dependent on the STAT phosphorylated.  For example, IL-6 stimulated STAT1 
phosphorylation (IC50 = 566 nM) was more readily inhibited than STAT3 phosphorylation 
(IC50 = 4,370 nM) by PF-06826647 in CD3+ lymphocytes of human whole blood.  IL-27 
signaling is also mediated by the same JAK complex as IL-6.  PF-06826647 suppressed 
IL-27 induced pSTAT3 with an IC50 of 201 nM.
IL-4 initiates signal transduction through one of two different receptor complexes, a type I 
receptor expressed on hematopoietic cells or a type II receptor expressed mainly on 
non-hematopoietic cells.  The type I receptor is a heterodimer of IL-4 receptor (IL-4R) and 
the c chain, and the type II receptor is a heterodimer of IL-4Rand IL-13 receptor (IL-13R) 
1.  IL-13 only activates the type II IL-4R.  Following cytokine binding, the type I receptor 
(IL-4Rand the c chain) activates JAK1 and JAK3, while the type II receptor (IL-4Rand 
IL-13R1) stimulates mainly JAK1.  Activation of either type I or type II receptors leads to 
phosphorylation of STAT6.  In CD20+ B and CD3+ T cells, IL-4-induced pSTAT6, mediated 
via JAK1 and JAK3, was inhibited by PF-06826647 with IC50 values of 3,413 nM and 
1,227 nM, respectively.  In CD14+ monocytes, PF-06826647 showed an IC50 value of 
568 nM against IL-4 induced pSTAT6, which is controlled mainly by JAK1.  In HWB, IL-13 
induced pSTAT6 was detected in CD14+ monocytes and CD20+ B cells, but not in CD3+
T cells.  PF-06826647 pre-incubation in human whole blood resulted in an inhibition of 
STAT6 phosphorylation induced by IL-13 with IC50 values of 807 nM and 393 nM detected 
in CD14+ monocytes and CD20+ B cells, respectively.
Inhibition of JAK2/JAK2 homodimer was assessed through erythropoietin (EPO) induced 
STAT5 phosphorylation with an IC50 of 547 nM in human bone marrow CD34+ progenitor 
cells spiked into human whole blood.  PF-06826647 maintains a 10-fold selectivity over 
JAK2 as determined by comparing inhibition of JAK2 dependent EPO signaling in bone 
marrow CD34+ progenitor cells to the TYK2/JAK1dependent human whole blood IFN
assay.  These results demonstrate that PF-06826647 potently inhibits TYK2-dependent 
signaling pathways, while showing modest suppression of the JAK2/JAK2 driven pathway.
PF-06826647 was also assessed for its cellular activity in various cell types and settings.  
IL-12 is a critical cytokine that is required for the promotion of Th1 development as well as 
IFNproduction.  IL-12 synergizes with IL-18 in inducing IFNproduction.  IL-12 and 
IL-18 activate different transcriptional factors: the former activates STAT4, and the latter 
activates NF-κB and AP-1, which signaling is independent of the JAK family kinases.  IL-12 
upregulates expression of the IL-18 receptor to promote IL-18-driven signaling, and 
IL-12-activated STAT4 enhances the binding activity of IL-18-induced AP-1 to IFN
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PF-06826647 was tested for its inhibitory activity against IFNproduction which was 
triggered by a combination of IL-12 and IL-18 in human CD4+ T, CD8+ T, and CD56+ NK 
cells.  IL-12 signals via TYK2 and JAK2.  As expected, PF-06826647 abrogated IFN
production by blocking the IL-12 signaling that was necessary for the synergy of IL-12 and 
IL-18.  The inhibition by PF-06826647 was dose dependent with IC50 values of 177, 123, and 
217 nM in human CD4+ T, CD8+ T, and CD56+ NK cells, respectively. 
Type I IFNs have been shown to contribute to the progression of many autoimmune diseases.  
Numerous gene expression profiling studies have shown up-regulation of interferon induced 
genes.  In vitro, type I IFN release and the resulting gene expression pattern can be induced 
in PBMC using immune complexes constructed artificially by combining immunoglobulin 
G (IgG) purified from systemic lupus erythematosus patients with apoptotic cellular debris 
from U937 cells as a source of nuclear antigens.  The in vitro activity of PF-06826647 
inhibiting type I IFN induced genes in normal human PBMC stimulated with immune 
complexes was assessed.
IC50 curves were generated in PBMCs from 3 human volunteer blood donors for IFN induced 
genes quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).  
PF-06826647 potently blocked immune complex induced expression of 3 IFN induced genes, 
radical S-adenosyl methionine domain-containing protein 2 (RSAD2), ubiquitin specific 
peptidase 18 (USP18) and guanylate binding protein 1 (GBP1) with IC50s of 36.7, 44.1, and 
43.8 nM, respectively.
In summary, PF-06826647 potently inhibited TYK2-dependent cytokine receptors, such as 
receptors for IFN, IL-12 and IL-23, with selectivity against receptors that do not signal 
through TYK2, like receptors for IL-15 (signaling through JAK1/JAK3), IFN(signaling 
through JAK1/JAK2) or EPO (signaling through JAK2/JAK2).
1.2.3. Non-Clinical Pharmacokinetics and Metabolism
Single dose pharmacokinetic studies with PF-06826647 were conducted after oral and IV 
administration to mice and rats.  PF-06826647 had moderate oral bioavailability (26% to 
51%) utilizing a sprayed-dried dispersion (SDD) formulation versus 0.5% methyl cellulose 
(<1% to 12%).  After IV administration, PF-06826647 demonstrated a steady state volume of 
distribution (Vss) of approximately 0.9 to 1.4 L/kg and a low plasma clearance (CL [10 to 
18 mL/min/kg]), relative to mouse and rat liver blood flows.  Systemic exposures (maximum 
observed concentrations [Cmax] and area under the concentration time curve [AUC]) of 
PF-06826647 after repeat oral dosing in the pivotal toxicity studies increased with increasing 
dose in rats (up to 500 mg/kg/day) and monkeys (up to 300 mg/kg/day) in a less than 
dose-proportional manner.  No sex-related differences in exposure and no accumulation of 
PF-06826647 were observed over the dosing period in either species.  In vitro, PF-06826647 
showed high apparent passive permeability and may be a substrate for P glycoprotein (P-gp).  
PF-06826647 binding to plasma proteins ranged between 62% to 82%, and PF-06826647 
does not preferentially partition into red blood cells from nonclinical species and humans.


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Renal and biliary excretion of PF-06826647 was limited in the rat.  No unique human 
metabolites were observed in vitro compared to metabolite profiles in rat and monkey.  The 
major human clearance pathway for PF-06826647 is expected to be CYP450 mediated 
metabolism through CYP1A2, 2D6 and 3A.  PF-06826647 did not inhibit the major 
cytochrome CYP450 or UGT enzymes (IC50 >25 M).  PF-06826647 induced CYP3A4 
messenger Riboneucleic acid (mRNA) expression in 1 of 3 lots of hepatocytes (4.7-fold 
increase at 10 M), but no corresponding induction was seen in CYP3A4 enzymatic 
activity.  Induction of CYP1A2 enzyme activity occurred in 2 lots of hepatocytes 
(approximately 2-fold at 10 M), and PF-06826647 did not induce CYP2B6 mRNA levels 
or enzymatic activity.  Based on its in vitro profile, the potential for PF-06826647 mediated 
CYP450 or UGT drug interactions is low at clinically relevant concentrations (Cmax 355 nM; 
Cmax,u 135 nM).
PF-06826647 showed little to no inhibition of the multidrug and toxin extrusion protein 
(MATE1), multidrug resistant protein 1 (MDR1), multidrug resistance-associated protein 
(MRP2), MRP3, sodium/taurocholate co-transporting polypeptide (NTCP), organic anion 
transporting polypeptide (OATP) 1B1, OATP1B3 and organic cation transporter (OCT) 2.  
However, PF-06826647 did inhibit MATE2K with an estimated IC50 value of 0.53 M. 
Human pharmacokinetics of PF-06826647 were predicted using physiologically based 
pharmacokinetic modeling, scaling intrinsic clearance from human liver microsomes and 
hepatocytes.  Human blood clearance is predicted to be ~2 mL/min/kg, volume of 
distribution 1.3 L/kg, half-life 6 hours, and oral bioavailability of ~90%.  The once daily 
clinical dose predicted to achieve the average concentration resulting in approximately 
80% inhibitory effect (Cav80,ss) on IL-12 is 20 mg.  The target unbound AUC24,ss to achieve 
an 80% average daily inhibition of IL-12 (TYK2/JAK2) is approximately 587 ng*h/mL.  The 
corresponding PF-06826647 unbound Cmax is approximately 52 ng/mL (135 nM).
1.2.4. Non-clinical Safety Studies
PF-06826647 potently inhibited kinase activity of human TYK2 with relative selectivity over 
JAK1, JAK2 and JAK3 of 5x, as well as good specificity profile over the broader kinome.  
PF-06826647 blocked various TYK2-dependent cellular functions in vitro, including 
phosphorylation of STAT induced by TYK2-dependent cytokines such as IFN, IL-12 and 
IL-23, with selectivity against TYK2-independent cytokines like IL-15 (JAK1/JAK3 
dependent), IFN(JAK1/JAK2 dependent) or EPO (JAK2/JAK2 dependent) in HWB, 
IL-12-induced IFNproduction in human T and NK cells, and type I IFN gene signature 
induced by immune complexes in human PBMCs.  Treatment with PF-06826647 
significantly suppressed imiquimod induced skin inflammation in a mouse model as 
measured by ear thickness, gene expression of many inflammatory mediators, and induction 
of IL-17A and pSTAT3, demonstrating the in vivo anti-inflammatory effects of 
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PF-06826647 was profiled in vitro against a broad panel of receptors, kinases, transporters, 
ion channels, enzyme targets (at 10,000 nM), and phosphodiesterases (at 30,000 nM).  A 
50% inhibition was observed against Abl, AurA/Aur2, KDR (VEGFR2), and Src kinases 
with IC50 values of 1300, 710, 160, and 4300 nM, respectively.  These IC50 values 
correspond to approximately 9.6x, 5.3x, 1.2x, and 32x, respectively, the predicted human 
efficacious unbound Cmax.  In a functional cell-based assay, PF-06826647 inhibited Abl and 
VEGFR2 kinase less potently with IC50 values of ˃30,000 nM and 18,000 nM which are 
˃222x and 133x the projected human efficacious unbound Cmax, respectively. These results 
indicate that PF-06826647 has little potential for off-target pharmacology.
In safety pharmacology studies, PF-06826647 had no effect on the neurofunctional or 
pulmonary systems in rats up to the highest dose tested (500 mg/kg).  The unbound Cmax at 
500 mg/kg is 34x the predicted human steady-state unbound Cmax at a projected human 
efficacious dose of 20 mg.
In pivotal cardiovascular safety pharmacology and 1-month repeat-dose toxicity studies in 
cynomolgus monkeys, no PF-06826647-related changes were observed in any cardiovascular 
parameter measured up to the highest dose tested (300 mg/kg), corresponding to 
approximately 28x the projected human efficacious unbound Cmax.  In an exploratory 
cardiovascular safety pharmacology study in rats, PF-06826647-related increased diastolic 
and mean blood pressure (each +3 mmHg) from 0-2 hours postdose, and increased heart rate 
(+18 to +13 bpm) from 2-12 hours postdose, were observed at 500 mg/kg (the highest dose 
tested).  No PF-06826647-related effects were observed in any parameter measured at 
50 mg/kg, corresponding to 6.5x the predicted human efficacious unbound Cmax.
The hERG IC50 for PF-06826647 was >10,000 nM, which is >74x the predicted human 
efficacious unbound Cmax.
PF-06826647 was negative for mutagenicity in the GLP bacterial reverse mutation assay.  
Although PF-06826647 was positive in the in vitro micronucleus assay in TK6 cells by an 
aneugenic mechanism, it did not induce micronuclei in vivo in reticulocytes in the 1-month 
study in rats (at exposures 41x the predicted human unbound efficacious Cmax and AUC24).
PF-06826647 absorbs in the ultraviolet A (UVA) and ultraviolet B (UVB) range and could 
present potential risk for phototoxicity.  Therefore, PF-06826647 will be evaluated for 
phototoxicity prior to enrollment in large clinical trials.
PF-06826647 was evaluated in rats and cynomolgus monkeys in single- and repeat-dose
toxicity and/or toxicokinetic studies up to 1 month in duration.  The high dose selection in the 
1-month pivotal study was based on observed exposure plateau in exploratory studies.  Target 
organs and systems identified with PF-06826647 administration in rats and monkeys include 
the immune and hemolymphatic systems (thymus, spleen, lymph nodes, bone marrow, 
erythron, and leukon), bone, and liver. In addition, other PF-06826647-related findings 
occurred in clinical observations, body weights, and/or clinical pathology parameters.  In the 
immune and hemolymphatic system, decreased lymphoid cellularity within the lymphoid 
follicles of the thymus and spleen was observed in rats 30 mg/kg/day, and in the thymus, 


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spleen, and lymph node (mesenteric) in monkeys at 150 mg/kg/day.  This finding was 
associated with nondose-related lower or decreased lymphocyte, white blood count (WBC), 
and/or eosinophil counts in rats and monkeys at 30 mg/kg/day.  Additionally, lower 
reticulocyte numbers were observed in rats at 30 (15 twice a day (BID) mg/kg/day and not 
associated with any adverse effects in red blood cell (RBC) mass parameters.  Further 
observations included lower numbers of T cells, B cells, NK cells, and absolute lymphocyte 
counts in peripheral blood and/or spleen of rats at 30 (15 BID) mg/kg/day for cytotoxic 
T cells and NK cells in spleen or 200 (100 BID) mg/kg/day for all other 
PF-06826647-related immunophenotyping parameters.  In monkeys, decreased numbers of 
T cells in peripheral blood and NK cells in peripheral blood and spleen occurred at 
30 mg/kg/day, and decreased number of T cells, B cells, and absolute lymphocytes occurred
in the spleen at 300 mg/kg/day. Minimal decreased cellularity in all cell lineages was 
observed in the bone marrow (sternum) of monkeys at 150 mg/kg/day and corresponded 
with decreased RBC mass parameters (red blood cell (RBC), hemoglobin (HGB), and 
hematocrit (HCT)), reticulocytes, and WBC counts at 30 mg/kg/day.  The findings in the 
thymus, spleen, lymph nodes, bone marrow, erythron, and leukon observed in rats and 
monkeys are consistent with the pharmacological activity of PF-06826647, and were not 
adverse due to their low magnitude/severity of the effects and/or because they were not 
associated with any clinical or microscopic evidence suggestive of PF-06826647-related 
infections in these animals.
PF-06826647-related higher or increased alanine transaminase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), and/or triglycerides were observed in 
rats at 30 (15 BID) mg/kg/day and in monkeys at 30 mg/kg/day.  Additionally, higher 
cholesterol was observed in rats at 500 (250 BID) mg/kg/day. None of these alterations were 
adverse due to their minor magnitude and the absence of correlating microscopic findings.
PF-06826647-related nonadverse minimally higher femoral metaphyseal medullary
trabecular bone thickness was observed in the bone of the stifle joint in rats at 500 mg/kg/day 
after 14 days of repeated administration, but not at the same dose in the 1-month study.  The 
growth plate was within normal limits, and no evidence of inflammation, necrosis, or
hemorrhage of the medullary trabecular bone was noted.  This effect on bone was not 
observed in monkeys.
Other nonadverse PF-06826647-related findings included clinical observations, body 
weights, and/or clinical pathology parameters that lacked in-life or post-mortem correlates 
and/or were minor in magnitude.  These included higher mean fibrinogen in rats at 
200 (100 BID) mg/kg/day; higher mean total protein, consisting of both higher mean 
albumin and globulin, in rats at 500 (250 BID) mg/kg/day; dose-dependent, lower mean body 
weight gain and mean absolute body weight in rats at 30 (15 BID) mg/kg/day; decreased 
phosphorus in monkeys at 30 mg/kg/day; and pale/white discolored feces in monkeys at 
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The no-observed-adverse-effect-level (NOAELs) in the 1-month pivotal rat and monkey 
toxicity studies were 500 (250 BID) mg/kg/day in rats (unbound Cmax = 1870 ng/mL and 
AUC24 = 16,600 ng•h/mL) and 300 mg/kg/day in cynomolgus monkeys (unbound 
Cmax = 1790 ng/mL and AUC24 = 19,900 ng•h/mL).  Exposures at these doses were 
28x to 36x the predicted human efficacious unbound exposures (Cmax and AUC24).
The nonclinical safety profile of PF-06826647 has been adequately characterized to support 
progression into clinical trials of up to 4 weeks
1.2.5. Biopharmaceutics Properties
PF-06826647 is a basic compound.  The cLogP and permeability, as measured in cell lines, 
indicate that the molecule should readily permeate the intestinal membrane.  The solubility 
will be low across the physiological pH.  PF-06826647 has been formulated as a spray dried 
dispersion to improve solubility, and has shown improved bioavailability as compared to 
crystalline PF-06826647 in preclinical species.  Based on preclinical exposure data and 
modeling, we expect PF-06826647, formulated as a spray dried dispersion, to be moderately 
to well absorbed at the predicted dosing range in the first in human (FIH) study using a 
suspension or immediate release (IR) tablet of the spray dried dispersion.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigators Brochure (IB). 
1.3. Rationale 
1.3.1. Study Rationale 
This Phase 1 first-in-human (FIH) study will evaluate safety, tolerability, PK and 
 of 
PF-06826647 in healthy subjects and in subjects with plaque psoriasis.  The combined single 
ascending dose (SAD) and multiple ascending dose (MAD) design was selected because it 
provides the opportunity to shorten the time between completion of the SAD and MAD 
phases of early drug development, without compromising the safety of the subjects.  In 
addition, the dosing in MAD period will be done under fed condition and PK on Day 1 in 
MAD under fed condition would allow preliminary assessment of 
 on exposure of 
PF-06826647. 
 
 
 
 
 
PF-06826647 has demonstrated inhibition potential of MATE2K, and therefore, may have 
the potential to inhibit renal transport of creatinine.  In order to provide an additional 
assessment of renal function during this trial, serum cystatin C will be collected in order to 
estimate glomerular filtration rate (GFR).  Cystatin C is produced by all nucleated cells at a 
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constant rate and is 100% eliminated by glomerular filtration, without influence of renal 
transporters.  The blood concentration of cystatin C is not substantially affected by diet, 
nutritional status or inflammatory disease.  Therefore, serum cystatin C will serve as a 
nonbiased biomarker of GFR in addition to
 
 
 
 
 
 
 
 
 
 sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision.
1.3.2. Preliminary Summary of Clinical Experience
As of March 25, 2018, the one, on-going clinical trial is the current study, C2501001.  In this 
study, dosing of six single ascending dose cohorts and three multiple ascending dose cohorts  
has been completed, with 53 healthy adult subjects randomized and treated with 
PF-06826647 or placebo.  To date, preliminary safety and PK data indicate that the stopping 
criteria , as outlined in Protocol Section 3.3, have not been met.  
There have been no serious adverse events (including death) reported.  Based on preliminary 
review of data, all reported adverse events (AEs) have been of mild intensity. 
Preliminary pharmacokinetic data from the 3, 10, 30, 100, 400, and 1600 mg dose levels in 
SAD are summarized in Table 1. The results indicate that exposure (AUC and Cmax) is lower 
than predicted by GastroPlus simulations presented in Table 3, therefore, the safety margin 
based on observed exposure is larger than what was initially expected. The increase in 
exposure appears to be less than proportional between 10 mg and 400 mg cohort and linear 
between 400 and 1600 mg. The preliminary PK data suggest longer terminal half-life at 
higher dose, possibly due to the biphasic concentration time profile and increased ability to 
measure the concentration for longer period at higher dose. The terminal half-life at 10 mg 
was approximately 6 hours whereas at 400 mg it was approximately 15 hours. 
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Table 1.
Preliminary Summary of Draft Plasma PK Parameters of PF-06826647 
Following Single Oral Dose Administration of PF-06826647 in Healthy 
Subjects (Fasted)
Single 
Dose
(mg)
Cmax (ng/mL)
AUC24 (ng.hr/mL)
AUClast (ng.hr/mL)
t½
hr
3
8 (38)
40 (56)
40 (56)
NR
10
47 (35)
346 (64)
355 (67)
6 (33)
30
78 (34)
543 (49)
639 (58)
NR
100
167 (55)
1160 (55)
1378 (53)
NR
400
329 (28)
1933 (28)
2135 (26)
15 (33)
1600
1218 (25)
9321 (34)
9796 (34)
13 (56)
Geometric mean (%CV) for all except arithmetic mean (%CV) for t½ , Abbreviations: %CV = percent coefficient of 
variation; NR = Not Reportable; AUC24= Area under the concentration-time curve from time zero to 24 hours post single 
dose; Cmax = Peak plasma concentration.
Preliminary pharmacokinetic data on Day 1 and Day 10 following multiple oral 
administration of PF-06826647 with standard meal at 30, 100 and 400 mg once daily (QD)
are summarized in Table 2.  By contrast with the PK parameters reported in Table 1, single 
dose administration with standard meal modestly increased the exposure of PF-06826647 by 
approximately 1.6 and 1.5 fold for AUC and Cmax, respectively at 400 mg. The increase in 
exposure at steady state appears to be less than proportional with increase in dose. Multiple 
dosing over 10 days achieved steady state with modest accumulation (1.3 and 1.2 fold for 
AUC and Cmax at 400 mg, respectively). 
Table 2.
Preliminary Summary of Draft Plasma PK Parameters of PF-06826647 
Following Multiple Oral QD Dose Administration of PF-06826647 for 
10 Days in Healthy Subjects (Fed-Standard Meal)
Day 1
Day 10
Dose
(mg)
Cmax (ng/mL)
AUC24 (ng.hr/mL)
Cmax (ng/mL)
AUC24 (ng.hr/mL)
t½
hr
30
84 (24)
664 (25)
85 (27)
752 (32)
9 (67)
100
267 (20)
1811 (23)
263 (30)
1950 (34)
7 (38)
400*
520 (30)
3488 (58)
689 (14)
4919 (32)
4(13)
Geometric mean (%CV) for all except arithmetic mean (%CV) for t½; Abbreviations: %CV = percent coefficient of 
variation; NR = Not Reportable. AUC24= Area under the concentration-time curve from time zero to 24 hours post single 
dose; Cmax = Peak plasma concentration; *Partial data (only 4 subjects up to Day 11).
1.3.3. Dose Rationale
1.3.3.1. Dose Selection for FIH Study (Original Protocol Dose Rationale, 16 May 2017)
The data from in vitro pharmacologic and toxicologic studies on PF-06826647 and prior
clinical experiences with other JAK inhibiting drugs were considered in dose selection for 
the first-in-human study.
The efficacious concentration (Ceff) for PF-06826647 was derived as a concentration that is 
expected to achieve approximately 80% average daily inhibition of IL-12.  Based on the
unbound IC50 value of IL-12 (Unbound IC50=14 nM calculated based on total IC50=53 nM, 
fraction unbound in human of 0.38 and RBC partition ratio of 1.4) determined by pSTAT


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(phosphorylated signal transducer and activator of transcription proteins) modulation in 
in-vitro human whole blood and assuming Hill coefficient of 1, the calculated Ceff is 56 nM.  
The predicted Cav,24h at a dose of 20 mg QD as SDD formulation is expected to produce 
approximately 80% daily average inhibition of IL12, therefore, 20 mg is a projected 
efficacious dose.
The human PK of PF-06826647 was predicted using GastroPlus physiologically based 
pharmacokinetic modeling by scaling in vitro hepatic clearances obtained from human liver 
microsomes (HLM) and human hepatocytes (HEP).  HLM predicted a human clearance of 
2.3 mL/min/kg, while that by HEP was 1.5 mL/min/kg.  Given the confidence in CYP450s 
mediated metabolism as primary clearance mechanism and similarity between scaled 
clearances by HLM and HEP, 2 mL/min/kg was used for simulations of human PK 
concentrations.  GastroPlus predicted dose dependent bioavailability with SDD formulation, 
which was used to improve the solubility and bioavailability of PF-06826647. At lower 
doses (~ <100 mg), the predicted bioavailability is expected to be >80% (see Table 3 below) 
but it is expected to decrease considerably at higher doses (~ >100 mg).
The nonclinical safety profile of PF-06826647 has been adequately characterized in rats and 
cynomolgus monkeys to support progression into human clinical studies up to 1 month in 
duration (Section 1.2.4 Non clinical safety studies).  In cynomolgus monkeys, no observed 
adverse effect level (NOAEL) was established at 300 mg/kg/day while in rats, the NOAEL 
was established at 500 mg/kg/day and were the highest doses tested in both species.  The 
resulting combined male and female mean NOAEL exposures in rats based on free drug were 
16600 ng.hr/mL and 1870 ng/mL for the AUC24,ss and Cmax, respectively.  The corresponding 
values for the monkey were 19900 ng.h/mL and 1790 ng/mLfor AUC and Cmax, respectively.  
No clear differences in the species sensitivity were noted.  Since rat had lower free AUC24,ss, 
exposure limits were based on the NOAEL exposures observed in rats 
(AUC24,ss = 16600 ng.hr/mL and Cmax =1870 ng/mL). 
Human PK parameter estimates for PF-06826647 along with toxicokinetic data and predicted 
pharmacological effect based on in vitro inhibition of cytokines (IL12, IL23 and IFN-) were 
used to estimate the starting dose in this study.  Based on the predicted average 
concentrations over dosing interval (Cav,24 h) and in vitro IC50 in whole human blood (after 
accounting for fraction unbound of 0.38 and RBC partitioning of 1.4), the projected percent 
inhibitions of cytokines IL-12, IL-23 and IFN-(IL-12:Total IC50=53 nM,Unbound 
IC50=14 nM; IL-23:Total IC50=112 nM,Unbound IC50=30 nM; IFN:Total 
IC50=66 nM,Unbound IC50=18 nM; Unbound IC50 calculated based on fraction unbound in 
human 0.38 and RBC partition ratio=1.4) at the proposed starting single dose of 3 mg are 
approximately 43, 27 and 38%, respectively.  In the FIH study with TYK2/JAK1 inhibitor 
(PF-06700841) as a single dose of 200 mg, these cytokines were inhibited up to 
>95% without any safety concern.  The planned starting single dose of 3 mg is predicted to 
provide, relative to the exposures (based on free concentrations) on Day 29 observed from 
the highest dose (500 mg/kg/day) administered to rats, exposure margins of 260-fold for Cmax
and 185-fold for AUC24.  The maximum recommended starting dose based on human 
equivalent dose (HED) approach with safety factor of 10 is 225 mg.  The proposed starting 
dose of 3 mg is approximately 1/1880th of the HED based on the highest dose 


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(500 mg/kg/day) administered to rats.  The expected levels of inhibition of these cytokines 
will provide minimal pharmacological activity and no safety concerns at the starting dose of 
3 mg.
The proposed single ascending (SAD) doses for this study are 3, 10, 30, 100, 200 and 400 mg
to identify the expected clinically efficacious dose range in humans and to provide safety 
coverage for the expected clinically-relevant dose range. The margins for the highest
proposed single dose (400 mg) established on the free exposures in rat are projected to be 
approximately 4- fold for Cmax and 3- fold for AUC24 which are well within the NOAEL 
exposure.
The resulting mean total and free exposures and associated margins following the proposed 
single doses of PF-06826647 during the single ascending dose period are provided in
Table 3.
Table 3.
Predicted Mean Human Total and Free Exposures and Associated Margins 
Following Single Dose Administration of PF-06826647
Dosea
(mg)
Predicted 
Bioavailabilityb
(%)
Predicted Human Exposure of plasma 
PF-06826647b
Predicted Safety 
Margin based on 
free plasma 
PF-06826647d
Free Cmax
(ng/mL)
Total Cmax
c
(ng/mL)
Free AUC0-24
(ng•h/mL)
Total AUC0-24
c
(ng•h/mL)
Cmax
e
AUC0-24
f
3
88
7
19
90
237
260
185
10
87
23
61
296
778
80
56
30
84
66
174
846
2226
28
20
100
69
186
489
2287
6017
10
7
200
56
304
800
3686
9701
6
5
400
41
444
1168
5409
14233
4
3
AUC0-24 = Area under the concentration time curve from time zero to 24 hours after single dose; CL = Clearance; 
Cmax = Peak plasma concentration; NOAEL = No observed adverse effects level.
a.
Depending on the available safety and PK data, dose escalation may be adjusted to doses other than those 
outlined above with intermediate doses evaluated instead of or in addition to the planned dose levels while 
following dose escalation and stopping rules outlined in Section 3.2.
b.
GastroPlus predicted. Exposure prediction was based on scaled clearance (CL = ~2 mL/min/kg) from human 
liver microsome and human hepatocytes.
c.
Calculated using unbound values correcting for protein binding in humans (Human unbound fraction=0.38).
d.
Derived using Day 29 exposure of PF-6826647 at NOAEL (500 mg/kg/day) from 1 month rat toxicity study. 
Exposure on Day 29 in rats at 500 mg/kg/day (NOAEL): Total AUC24=92,100 ng.h/mL, free 
AUC24=16,600 ng.h/mL, Total Cmax=10,400 ng/mL, free Cmax = 1870 ng/mL; rat unbound fraction = 0.18.
e.
Cmax Margins=Cmax in Rat on Day 29/Predicted Cmax in human post single dose.
f.
AUC margins = AUC24 in Rat on Day 29/Predicted AUC0-24 in human post single dose.
The multiple dose period is planned to be initiated at the 10 mg QD dose level; however, the 
starting dose in MAD may be adjusted based on available PK, 
and safety data from the 
SAD cohorts.  Based on the predicted steady state exposures (Cmax,ss and AUC24,ss), 
10 mg QD is expected to provide margins of 71-fold for Cmax,ss and 50-fold for AUC24,ss
relative to the free exposure in rat on Day 29.  The proposed doses for the multiple ascending 
dose (MAD) period are 10, 30, 100 and 200 mg QD x10 days. All dose levels listed are 
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nominal since doses will be driven by exposure.  The highest proposed dose of 200 mg QD is 
predicted to have margins of 5-fold and 4-fold for Cmax,ss and AUC24,ss, respectively.
Listed in Table 4 are the mean exposure (total and free) and associated margins following the 
proposed QD dosing regimen for 10 days.
Table 4.
Predicted Mean Human Total and Free Exposures and Associated Margins 
Following Once Daily Dosing of PF-06826647 for 10 Days
Dosea
(mg)
QD
Predicted 
Bioavailabilityb
(%)
Predicted Human Exposure of plasma 
PF-06826647b
Predicted Safety 
Margin based on 
free plasma 
PF-06826647d
Free Cmax
(ng/mL)
Total Cmax
c
(ng/mL)
Free
AUC24,ss
(ng.h/mL)
Total AUC24,ss
c
(ng.h/mL)
Cmax
e
AUC0-24
f
10
87
26
69
332
874
71
50
30
84
76
199
962
2531
25
17
100
69
217
570
2664
7010
9
6
200
56
348
916
4249
11182
5
4
AUC24,ss= Area under the concentration-time curve from zero to 24 hours post dose at steady state; CL = Clearance; 
Cmax = Peak plasma concentration; Cmax,ss = Maximum concentration at steady state ; QD = Once daily
a.
Depending on the available safety and PK data, dose escalation may be adjusted to doses other than those 
outlined above with intermediate doses evaluated instead of or in addition to the planned dose levels while 
following dose escalation and stopping rules outlined in Section 3.2.
b.
GastroPlus predicted. Exposure prediction was based on scaled clearance (CL =~ 2 mL/min/kg) from human 
liver microsome and human hepatocytes.
c.
Calculated using unbound values correcting for protein binding in humans (Human unbound fraction=0.38).
d.
Derived using Day 29 exposure of PF-6826647 at NOAEL (500 mg/kg/day) from 1 month rat toxicity study. 
Exposure on Day 29 in rats at 500 mg/kg/day (NOAEL): Total AUC24=92,100 ng.h/mL, free 
AUC24=16,600 ng.h/mL, Total Cmax=10,400 ng/mL, free Cmax = 1870 ng/mL; rat unbound fraction = 0.18.
e.
Cmax Margins=Cmax in Rat on Day 29/Predicted Cmax in human post single dose.
f.
AUC margins = AUC24 in Rat on Day 29/Predicted AUC0-24 in human post single dose.
All the doses in SAD or MAD cohorts except starting dose of 3 mg in SAD cohort are 
nominal and may be adjusted, as the study progresses depending upon emerging PK,
safety, and tolerability data.  Other intermediate doses or lower doses may be administered 
instead of the planned doses, or changes in dosing frequency or titration schemes may be 
proposed for MAD cohorts if safety/tolerability issues become apparent, if evidence of 
nonlinear PK dictates the need to escalate more slowly, or if subsequent doses are predicted 
to result in exposures that exceed the target limits.  However, the projected exposure for the 
modified doses or additional cohorts will be equal to or less than a free AUC of 
16600 ng.h/mL or free Cmax of 1870 ng/mL following either single dose or multiple dose 
administration to ensure that the projected exposure of the altered planned dose scheme does 
not exceed the exposure limit.
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1.3.4. Updated Dose Rationale Based on Emerging Clinical Data (Protocol 
Amendment 2, 20 December 2017)
Based on the evaluation of the emerging human PK data, the observed exposure was lower 
than predicted and the increase in exposure appears to be less than dose proportional except 
at 3 mg SAD (dosed as suspension). Protocol amendment 1 updates the initially proposed 
dose levels with the aim to achieve exposure that will allow a full exploration of the clinical 
efficacy in future clinical studies. Also, the MAD cohort will be dosed under fed condition
in a hope to improve the bioavailability of PF-06826647
Under protocol amendment 1, the proposed dose of SAD Cohort 5 will be 400 mg. 
Accounting for the less than dose proportional increase in AUC24 and Cmax observed at 
100 mg, 400 mg is predicted to provide approximately ~2 fold higher exposure than 100 mg.  
The doses of Cohort 6 and two optional SAD cohorts (Cohort 7 and Cohort 8) will be based 
on the emerging PK, 
 and Safety data but in all cases will be selected to provide a 
projected exposure of no more than approximatelly 3 fold the previous highest dose cohort 
exposure and less or equal to the PK stopping limit. All dose levels listed in Table 5 are 
nominal and any of the listed or intermediate doses may be used based on emerging PK, 
 
and safety data. However, the maximum dose tested will not exceed 1600 mg 
(16 × 100 mg Tablets), based on practical limitations. The projected safety margin for 
AUC24 and Cmax at 1600 mg SAD is approximately 8 and 7 fold, respectively (Table 5). 
The projected PK parameters in Table 5 are based on preliminary exploratory population PK 
model from draft human PK data up to SAD Cohort 4, assuming nonlinear decrease in 
bioavailability with increase in dose. The projected geometric mean total and free exposures 
and the associated projected margins for doses (up to 1600 mg) are provided in Table 5.
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1.3.4.1. Dose Selection for Psoriasis Patients
Two cohorts of subjects with moderate to severe plaque psoriasis are proposed to be studied 
at two dose levels to be administered PF-06826647/placebo QD for 28 days. The initial 
psoriasis cohort will commence at 400 mg PF-06826647 (or placebo). The nominal dose for 
second psoriasis cohort dose level is planned to be 100 mg PF-06826647 (or placebo), which
may be adjusted based on results from the 400 mg psoriasis cohort. These dose levels are
selected based on preliminary PK,
safety and tolerability data up to 1600 mg single dose 
in SAD Period and up to 400 mg QD for 10 days in MAD Period in healthy subjects.
Dose selection for this part of the study is based on the observed PF-06826647 exposure in 
healthy subjects and in vitro potency data aiming to achieve high inhibition of TYK2 
dependent cytokines while maintaining selectivity over other JAK enzymes and modulation 
of associated genes. The Cav,24 at steady state at 100 and 400 mg dose in healthy subjects 
was approximately 81 and 205 ng/mL, respectively. Based on the IC50 value of IL-12 (total 
IC50=53 nM) determined by pSTAT modulation in in vitro human whole blood, RBC 
partition ratio of 1.4 and assuming Hill coefficient of 1, the average daily inhibition of IL-12 
at 100 and 400 mg will be approximately 85 and 93%, respectively. Similarly, IFNα (total 
IC50 = 66 nM) will have average daily inhibition of approximately 82 and 92% while the 
average inhibition of IL-23 (total IC50 = 112 nM) will be approximately 73 and 87% at 
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100 and 400 mg, respectively. These two doses are also supported by preliminary evidence 
of TYK2 pharmacology modulation of Type-I IFN genes.
In addition, based on data observed to date in healthy subjects (see Section 1.3.2) these doses 
are expected to be safe and well tolerated. Although, based on in vitro data, the average 
inhibition of EPO (total IC50 = 547 nM) is expected to be approximately 35% and 58% at 
100 and 400 mg respectively, no clinicially significant changes in hemoglobin were observed
in healthy subjects at the same dose. Based on the observed steady state free exposures 
(Cmax,ss and AUC24,ss), 400 mg QD is expected to provide margins of about 7-fold for Cmax,ss
and about 9-fold for AUC24,ss relative to the free exposure in rat on Day 29 (NOAEL). 
The initial psoriasis cohort will commence at 400 mg QD PF-06826647 for 28 days. Dosing 
of the second psoriasis cohort will occur after completion of 400 mg psoriasis Cohort 28 day 
dosing, while the follow up periods of the two cohorts may be parallel or staggered based on 
operational considerations.  Following interim analysis review of efficacy data from 
21 subjects (14 active and 7 placebo) completing through study Day 28 in the 400 mg 
psoriasis cohort, the PF-06826647 dose level for the next psoriasis cohort may be adjusted 
within the range of safe and well tolerated doses established in healthy subjects. 
The tablets administered in psoriasis subjects will be the same as the tablet administered to 
healthy subjects.  The subjects will be required to take the tablets in the morning with 
standard meal in order to achieve higher exposure.
2. STUDY OBJECTIVES AND ENDPOINTS
Objectives and Endpoints: Healthy Subject Single and Multiple Ascending Dose Cohorts
Primary Objective(s): 
Primary Endpoint(s) - Safety: 

To determine the safety and tolerability of 
escalating single and multiple doses of 
PF-06826647 administered to healthy subjects.

Vital signs (blood pressure, pulse rate, oral 
temperature).

Physical examination findings over time.

12-lead ECG parameters.

Incidence and severity of treatment emergent 
adverse events and withdrawals due to treatment 
emergent adverse events.

Incidence and magnitude of treatment emergent 
clinical laboratory abnormalities including 
hematology (with differentials), fibrinogen,
chemistry, fasting glucose, lipids, urinalysis.

Change in 24 hour creatinine clearance from 
Day -1 and Day 10 (MAD only).
Secondary Objective(s): 
Secondary Endpoint(s): 

To characterize the PK of PF-06826647 in plasma 
and urine (urine PK in multiple ascending dose 
period only) following oral administration of 

Systemic pharmacokinetics parameters (defined 
in Section 9.3.1) will include:


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escalating single and multiple oral doses to 
healthy subjects.
•
Single Dose: Cmax, Tmax, AUCinf, AUClast,
AUC24, Cmax(dn), AUCinf(dn), AUClast(dn), 
t½, MRT, Vz/F, and CL/F (if data permit).
•
Multiple Dose:
•
Day 1: Cmax, Tmax, AUCtau (tau=12 or 
24 hours), Cmax(dn), AUCtau(dn).
•
Day 10: Cmax, Tmax, AUCtau (tau=12 or 
24 hours), Cmax(dn), AUCtau(dn), t½, Cmin,
Cav, Rac, Rac,Cmax, PTR, MRT, Vz/F,CL/F (if 
data permit).
•
Urinary Pharmacokinetics (defined in 
Section 9.3.1;for healthy subjects, multiple 
ascending dose period only): Aetau and Aetau%, 
CLr (if data permit).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives and Endpoints: Psoriasis Multiple Dose Cohorts
Primary Objectives - Safety
Primary Endpoints - Safety
•
To determine the safety and tolerability of 
multiple dose administration of PF-06826647 in 
psoriasis subjects.
•
Vital signs (blood pressure, pulse rate, and oral 
temperature).
•
Physical examinations fndings over time.
•
12-lead ECG parameters.
•
Incidence and severity of treatment emergent 
adverse events and withdrawals due to treatment 
emergent adverse events.
•
Incidence and magnitude of treatment emergent 
clinical laboratory abnormalities including 
hematology (with differentials) chemistry, 
fasting glucose, lipids, urinalysis.
Secondary Objectives
Secondary Endpoints
•
To characterize the PK of PF-06826647 in plasma 
following oral administration of multiple oral 
doses to plaque psoriasis subjects.
•
To evaluate the efficacy of PF-06826647 in 
moderate to severe plaque psoriasis.
•
Multiple Dose (defined in Section 9.3.1): Cmax, 
Tmax, AUCtau, Cmax(dn), AUCtau(dn), t½, PTR, 
Cmin, Cav, MRT, Vz/F and CL/F (if data permit).
•
Change from baseline in psoriasis area and severity 
index (PASI) score at Day 28.
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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3. STUDY DESIGN
3.1. Study Overview
The study may be conducted at 1-3 study sites in the United States.
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This study is a Phase 1 combination, within cohort, randomized, double blind, third-party 
open, placebo-controlled, parallel group study with single- and multiple-dose escalation in 
healthy adult subjects, and multiple dosing in subjects with plaque psoriasis. 
Subjects will be screened within 28 days prior to administration of study drug to confirm that 
they meet the subject selection criteria for the study.  A summary of the schedule of study 
participation and procedures for the single- and multiple ascending dose periods of the study 
are provided in their respective Schedule of Activities.
3.1.1. Healthy Subject Single and Multiple Ascending Dose Periods
In the combined single ascending and multiple ascending dose (SAD/MAD) healthy subject 
cohorts there will be approximately 8 subjects per dose level; 6 subjects will receive 
PF-06826647 and 2 subjects will receive placebo per the randomization code. 
Healthy subjects will be randomized (once) into the SAD period, at which time, they will 
receive treatment assignment (active PF-06826647 dose level or placebo) for both the SAD 
and MAD periods.  Subjects will receive the same blinded treatment assignment (ie, the same 
dose level of active PF-06826647 or placebo) throughout in both the SAD (Period 1) and 
MAD (Period 2) periods. 
During the single ascending dose (SAD) period, healthy subjects in Cohort 1 to Cohort 6 will 
receive single doses of 3, 10, 30, 100, 400, or 1600 mg of PF-06826647 or placebo in a dose 
escalation format as shown in the Study Schema (Figure 1).  The doses and meal condition of
optional cohorts (Cohort 7 and Cohort 8) will be decided on emerging PK, 
and safety data from prior SAD and MAD cohorts. Dose escalation to subsequent cohorts 
will be based on a minimum of 3 days of safety data and PK over 24 hours in a minimum of 
6 subjects enrolled in a cohort.  Subjects will reside in the clinical research unit (CRU) for 
the single ascending dose phase from Day -1 until completion of protocol assessments on 
Day 4.  Dosing occurs on Day 1.  Subjects will return to the unit on Day 8 (±1) day for the 
end of single dose period assessment and PK sample.
At least 14 days (minimum wash-out period) will separate the beginning of the single and 
multiple dose periods (ie, at least 14 days will separate the single dose administered in the 
SAD and the first QD dose in the MAD); however, the minimum wash-out period may be 
adjusted based on emerging PK data.  Based on the PK predictions and emerging PK data 
from this study, the currently planned starting dose in the MAD period is 30 mg (previously, 
a PF-06826647 starting dose of 10 mg was planned for the MAD period under the original 
protocol) is not expected to provide pharmacologically relevant exposure.  In the multiple 
ascending dose (MAD) period, healthy subjects in Cohort 3 to Cohort 6 in Period 2 will 
receive doses of 30, 100, 400, or 1200 mg QD of PF-06826647 or placebo for 10 days (Day 1 
through Day 10) with standard meal. The dose of Cohort 6 in MAD (Period 2) may be 
adjusted based on emerging data from earlier MAD cohorts in the trial. Subjects will be 
housed for the duration of the multiple dosing period, discharged on the morning of Day 14. 
Subjects will return for outpatient visits on morning of Day 17 for PK sample collection and 
Day 28 (±3 days) for end of study procedures. Based on emerging PK data, subject may be 
asked to return between Day 17 and Day 28 for an additional outpatient visit for PK sample 
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collection. The additional PK sample will allow characterization of terminal half-lives at 
higher dose cohorts. 
The multiple ascending dose study is planned to be initiated in the same subjects who 
previously participated in the single dose period at the same dose level, when possible
(except for the optional twice daily, BID cohort and optional Japanese cohort).  The highest 
dose to be tested in MAD will not exceed the highest dose tested in SAD cohort. Except the 
highest dose cohort, dosing in the MAD period will commence at the intended dose level
(eg, 30 mg QD) if adequate single dose safety is demonstrated for next dose level 
(eg, 100 mg SAD). Subsequent MAD cohorts at higher dose levels (eg, 100 mg QD) will not 
be initiated until the single dose safety/tolerability has been established up to next dose level 
(eg, 400 mg), and a minimum of 10 days of safety and PK data from the preceeding multiple 
dose cohort (eg, 10 mg QD) from at least 6 subjects (with at least one subject on placebo) has 
been reviewed.  The remainder of the cohorts (except highest dose cohort) will follow a 
similar escalation paradigm.  Dosing in highest dose MAD cohort will commence if adequate 
safety is demonstrated in SAD cohort at the same or higher dose level and the projected 
exposure at steady state does not exceed NOAEL. 
Twice daily (BID) dosing (for 10 days) may be evaluated as a separate cohort based on 
emerging PK data from this FIH study. Dosing in the BID cohort will not commence until 
review of safety data from the equivalent QD MAD cohort (minimum review of 10 day 
safety and PK data in at least 6 subjects, with at least one subject on placebo).
An optional Japanese cohort may also be included. If conducted, the dose administered will 
be equal to or less than the maximum PF-06826647 dose level administered in the healthy 
volunteer MAD period.  Up to 8 subjects (including subjects on placebo) may be included in 
the optional Japanese cohort. 
Administration of investigational product will be in fasted state in the SAD period and under 
standard meal conditions in MAD and in psoriasis cohorts. Based on the emerging PK, 
 
and safety data, the meal condition requirement in SAD, MAD and psoriasis 
cohorts may be changed. 
During the single and multiple ascending dose periods the dose increments and planned 
doses may be adjusted, as the study progresses dependent upon emerging PK, safety, and 
tolerability data.  Other intermediate doses or lower doses may be administered instead of the 
planned doses, or changes in dosing frequency or titration schemes may be proposed for 
MAD cohorts if safety/tolerability issues become apparent, if evidence of nonlinear PK 
dictates the need to escalate more slowly, or if subsequent doses are predicted to result in 
exposures that exceed the target limits.  Any potential altered dose scheme will be equal to or 
less than a projected 3-fold increase in exposure from the previous highest dose if a higher 
dose is warranted to achieve exposure. The projected exposure will be equal to or less than a 
free AUC of 16600 ng.h/mL or free Cmax of 1870 ng/mL following either single dose or 
multiple dose administration to ensure that the projected exposure of the altered planned dose 
scheme does not exceed the exposure limit.
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3.1.2. Psoriasis Multiple Dose Cohorts
In the multiple dose psoriasis subject cohorts, approximately 42 subjects will be enrolled 
with approximately 14 subjects receiving placebo, and approximately 28 subjects receiving 
one of two possible PF-06826647 dose levels, for 28 days.  PF-06826647 dose range for the 
psoriasis cohorts will be selected based on emerging PK, 
 and safety data from the 
healthy subjects SAD/MAD periods. Refer to Protocol Section 1.3.4.1 for psoriasis dose 
selection rationale. QD dosing is planned for psoriasis subjects, however, daily dosing 
regimen (eg, QD, BID) may be adjusted based on emerging PK data from the SAD/MAD 
periods. Psoriasis subjects who discontinue early from the trial may be replaced at the 
discretion of the sponsor. PF-06826647 dose level in psoriasis may be adjusted based on 
emerging clinical data from the planned interim analysis, at the discretion of the Sponsor.
Any potential PF-06826647 dose adjustments for psoriasis Cohort 2 will be applied after 
review of PK, 
 and safety data up to 28 day in the 400 mg psoriasis cohort. 
Initiation of dosing in psoriasis subjects will be based on available safety data from the 
healthy subject MAD period.  Psoriasis subjects enrolled into the multiple dosing period will 
receive PF-06826647 or placebo (QD) for 28 days, with a 56 day follow-up period post last 
dose.  Doses will be selected based on emerging PK, PD and safety data from the study (not
to exceed Cmax and AUC0-24 limits of 1870 ng/mL and 16,600 ng·h/mL, respectively).  
Dosing in psoriasis subjects will commence if adequate safety is demonstrated in healthy 
subjects participating in the MAD period at the equivalent dose level. At a minimum, 10 day 
safety and PK data from at least 6 healthy subjects (with at least one subject on placebo) 
receiving the equivalent QD dose level will be reviewed to confirm that a given 
PF-06826647 dose is safe and well tolerated before administering PF-06826647 to psoriasis 
subjects. Subjects will be housed through Day 28 of the multiple dosing period, discharged 
on Day 28, to return for outpatient visits on the mornings of Days 35 (±3 days), 42 (±3 days), 
56 (±3 days) and 84 (±3 days)(end of study). The 28 day treatment duration is supported by 
preclinical toxicology data and will facilitate assessment of 
, as 
well as assessment of clinical endpoints (eg, PASI). 
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Figure 1.
Study Schema
Numbers 1 – 8 refer to subject cohorts.  Subjects completing the SAD period will continue into the MAD period
when applicable, after protocol defined washout and follow up. 
* Cohorts 7 and 8 are optional single dose cohorts that may be conducted at discretion of Sponsor and based on 
emerging PK data. If conducted, the dose and meal condition will be decided based on emerging PK, PD, and 
safety data from the multiple ascending dose period of the trial.
** Cohort 9 is an optional cohort for assessment of twice daily (BID) PF-06826647 dosing. BID dose level will 
be determined based on emerging PK, PD, safety and tolerability data. The planned PF-06826647 dose level to 
be administered in the BID cohort is 200 mg twice daily (total daily dose of 400 mg).
*** Based on interim analysis results from 400 mg psoriasis cohort, the PF-06826647 dose level for psoriasis 
Cohort 2 may be adjusted.  The maximum dose administered to psoriasis subjects will not be expected to 
exceed the exposure at the maximum tolerated dose in the healthy subject MAD period.
HVs = healthy volunteers
All cohorts are placebo controlled .
Note on optional Japanese subject cohort: if conducted, administration of PF-06826647 (or matching placebo) 
to Japanese subjects will occur once daily for 10 day duration, and subjects will follow the MAD period 
schedule of activities. 


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Figure 2.
Legend for Figure 1
SAD = Single ascending dose Period 1                 QD = once daily 
MAD=multiple ascending dose Period 2              BID=twice daily 
3.2. Dose Escalation and Stopping Rules
The following dose escalation rules apply to the single and multiple ascending dose healthy 
subject cohorts.  Individual stopping rules for healthy subjects (SAD/MAD) and psoriasis 
subjects are also outlined below.
Dose-escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained.  Dose escalation may be stopped if it is determined that the limits of safety 
and/or tolerability have been reached.  This decision will be made after a discussion takes 
place between the sponsor study team and the investigator.  The sponsor study team may not 
overrule the investigator’s decision to stop dose escalation.  If dose escalation is stopped 
because of any of these criteria, additional cohorts may receive the same or lower doses of 
the investigational product.
The dose escalation will be terminated based on the following criteria:

If 50% or more of the subjects receiving active drug at a given dose level (but not 
subjects receiving placebo) develop similar clinically significant laboratory, 
electrocardiogram (ECG), or vital sign abnormalities as described below in 
Section 3.3), or severe adverse events (AEs) in the same organ class, indicating 
dose-limiting intolerance.

Dosing will be paused for any serious adverse event (SAE) that occurs in a subject 
receiving active treatment until causality is fully assessed by the principal investigator 
(PI) and sponsor.  Dosing may resume if the SAE is determined to be not drug-related 


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by the PI and sponsor.  If the SAE is determined to be either drug-related or 
unknown, either dosing will cease or the SAE will be evaluated by the sponsor’s 
protocol review committee (or similar review group), which is independent of the 
study team and investigators.  If the protocol review committee determines that 
dosing may resume, a plan that mitigates risks to subjects with the resumption of 
dosing will be implemented.  Such a plan could include a revision of 
inclusion/exclusion criteria, repeating or reducing the dose, or adding appropriate 
safety monitoring.

It is determined that the limit of safety and/or tolerability has been reached.  This 
decision will be made following discussions between the study team and the 
investigator.

Other findings that, at the discretion of the study team and investigator, indicate that 
dose escalation should be halted.

If, at any dose level, the average exposure reaches or exceeds the pharmacokinetic 
(PK) stopping limits based on free Cmax and AUC0-24 values of 1870 ng/mL and 
16,600 ng.h/mL, respectively.

If, based on the observed data, the group mean maximum observed concentration 
(Cmax) or area under the curve (AUC) (based on total plasma concentration) of the 
next planned dose is projected to exceed the escalation limits, that dose will not be 
explored.  Modified doses may be explored if they are not expected to exceed PK 
stopping criteria.
Progression to the next single dose level will occur if the last dose was well tolerated and 
after satisfactory review of the available safety and PK data.  Minimum data required for 
dose escalation review includes 24 hour PK data, adverse event/serious adverse events, vital 
sign and ECG data, urinalysis, chemistry and hematology laboratory results through Day 3 in 
at least 6 subjects (with at least one subject on placebo)within a given dose cohort.
Initiation of the multiple ascending dose study will commence at the 10 mg dose level if 
adequate safety is demonstrated for single doses up to 30 mg. Similarly, the 30 mg dose 
level will not be initiated until the safety/tolerability has been established up to100 mg single 
dose and a minimum of 10 days of safety data (vital sign and ECG data, urinalysis, 
chemistry, hematology, adverse event data) and 10 day PK data from the preceding multiple
dose cohort from at least 6 subjects (with at least one subject on placebo). The remainder of 
the cohorts will follow a similar escalation paradigm (except for the highest MAD cohort 
dose level, which will be equal to or less than the maximum SAD dose level tested). Dosing 
in highest dose MAD cohort will commence if adequate safety is demonstrated in SAD 
cohort at the same or higher dose level and the projected exposure at steady state does not 
exceed NOAEL. Dose levels may be adjusted based on emerging PK data from this study, 
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3.3. Individual Stopping Rules for the Healthy Subjects during the Single and Multiple 
Ascending Dose Periods
Adverse Events:

Dosing will be discontinued for any treatment emergent serious adverse event (SAE) 
that occurs in a subject receiving active treatment unless the SAE is clearly unrelated 
to study drug (eg, subject is the victim of a motor vehicle accident).

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy or hospitalization.
Laboratory, Vital Sign, and ECG Abnormalities:
Individual stopping rules will be based on repeated measures (single repeat preferably 
performed within 24 hours of initial result) of the parameters outlined below. 

Grade 3 lymphopenia (<500 cells/mm3).

Grade 3 neutropenia (<1000 cells/mm3).

Grade 3 ALT/AST (>5x upper limit of normal (ULN) when not accompanied by an 
increase in bilirubin).

Grade 3 bilirubin (>2.0 x ULN when not accompanied by an increase in ALT/AST).

Changes in liver function tests that meet Hy’s Law criteria.

Serum creatinine 1.5 x ULN. 
Note: An increase of 0.3 mg/dL (or 26.5 mol/L) in serum creatinine relative to 
subjects’ own baseline measurement should trigger another assessment of SCr within 
24-hours from awareness.  See Potential Cases of Acute Kidney Injury for further 
guidance. 

Grade 2 Hemoglobin <10 g/dL.

Grade 2 Platelets <75,000/mm3 or >750,000/mm3.

12-lead ECG demonstrating QTc 500; or a QRS interval 140 msec or 50% 
increase from baseline; PR interval 300 msec or 25% increase over baseline when 
baseline >200 msec. 
Blood pressure or pulse rate measurements meeting criteria for individual stopping rules 
should be repeated at least twice, separated by at least 5 minutes, with the subject at rest, 
supine.  If confirmed to be abnormal and confirmed to be clinically significant by 
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periodically, as deemed appropriate by the investigator, until the blood pressure/pulse rate are 
returned to within normal limits or deemed acceptable by the investigator.

Vital sign abnormalities: 

Systolic blood pressure <90 mmHg or >160 mm Hg;

Diastolic blood pressure <50 mmHg or >100 mm Hg;

Pulse rate supine/sitting <36 or >120 beats per minute (bpm); standing <36 or 
>140 bpm.
Other:

Subjects non-compliant with study treatment.
3.4. Individual Stopping Rules for Psoriasis Subjects
Treatment with PF-06826647 will be discontinued and the subject withdrawn from this 
study for:
Adverse Events:

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy or hospitalization.

Other treatment emergent serious or severe AEs, after consultation with the Pfizer 
clinician.
Laboratory, Vital Sign, and ECG Abnormalities:
Individual stopping rules below will be based on repeated measures (single repeat preferably 
performed within 24 hours of initial result) of the parameters outlined below. 


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Laboratory Variable
Laboratory Value
Hematology
Absolute Neutrophil Count
<1000/mm3; <1.0 x109/L
Hemoglobin
<10.0 g/dL; <6.2 mmol/L; <100 g/L
Platelet count
<75,000/mm3; <75.0x0x109/L
WBC 
<3000/mm3; <3.0x109/L
Lymphocytes
<800/mm3; <0.8x109/L
Chemistry
AST
>2.5x ULN
ALT
>2.5x ULN
Creatinine (serum)
>1.5x ULN
Total bilirubin a
>1.5x ULN
a
Total bilirubin 1.5 x ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin is ULN.

Changes in liver function tests that meet Hy’s Law criteria.
Note: An increase of 0.3 mg/dL (or 26.5 mol/L) in serum creatinine relative to subjects’ 
own baseline measurement should trigger another assessment of SCr within 24-hours from 
awareness.  See Potential Cases of Acute Kidney Injury for further guidance.

12-lead ECG demonstrating QTc 500; or a QRS interval 140 msec or 50% 
increase from baseline; PR interval 300 msec or 25% increase over baseline when 
baseline >200 msec. 
Blood pressure measurements meeting criteria for individual stopping rules should be 
repeated at least twice, separated by at least 5 minutes, with the subject at rest, supine.  If 
confirmed to be abnormal, and confirmed to be clinically significant by investigator, dosing 
should be stopped and the blood pressure should be followed periodically, as deemed 
appropriate by the investigator, until the blood pressure are returned to within normal limits 
or deemed acceptable by the investigator.

Diastolic: recurrent or persistent (24 hrs) or symptomatic increase from baseline, in 
same posture, by >20 mmHg.

Systolic: recurrent or persistent (24 hrs) or symptomatic increase from baseline, in 
same posture, by >30 mm Hg. 
Other:

Subjects non-compliant with study treatment.


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3.5. Discontinuation/End of Treatment Monitoring for Adverse Events, Laboratory, 
Vital Signs and ECG Abnormalities
Any subject meeting discontinuation criteria will be followed up every 1 to 2 weeks, with 
retesting as appropriate, until the event has returned to normal or baseline levels or is deemed 
clinically stable.
Additional follow-up visits may occur as needed until any clinically relevant abnormalities or 
adverse events have resolved, returned to a baseline state, or are deemed clinically stable.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria: Healthy Subject Single/Multiple Ascending Dose Cohorts
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Healthy female subjects of non-childbearing potential and/or male subjectsbetween 
the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant 
abnormalities identified by a detailed medical history, full physical examination, 
including blood pressure and pulse rate measurement, 12-lead ECG and clinical 
laboratory tests).
2. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the post-menopausal state.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c.
Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations ) areconsidered to be 
of childbearing potential.
3. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg 
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4. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
6. No evidence of active or latent or inadequately treated infection with Mycobacterium 
tuberculosis (TB) as defined by the following:
a.
negative Interferon Gamma Release Assay (IGRA) (with the following acceptable 
assays: QuantiFERONR-TB Gold (QFT-G) test, T-SPOT TB, QuantiFERON-TB 
Gold In-Tube test (QFT-GIT)) performed during Screening or within 3 months 
prior to Day 1. 
AND
b. No history of either untreated or treated latent or active TB infection.
A subject who is currently being treated for either latent or active TB infection is to be 
excluded.
7. Additional criterion for subjects to be enrolled in Japanese cohort only: Japanese 
subjects who have four Japanese biologic grandparents born in Japan.
4.2. Exclusion Criteria: Healthy Subject Single/Multiple Ascending Dose Cohorts 
Subjects presenting with any of the following characteristics/conditions will not be included 
in the study:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy).
3. A positive urine drug screen.
4. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces 
(360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of screening.
5. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of investigational product, 
whichever is longer.


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6. Screening supine blood pressure 140 mm Hg (systolic) or 90 mm Hg (diastolic), 
following at least 5 minutes of supine rest.  If blood pressure (BP) is 140 mm Hg 
(systolic) or 90 mm Hg (diastolic), the BP should be repeated two more times and 
the average of the three BP values should be used to determine the subject’s 
eligibility.
7. 12-lead ECG demonstrating QTc >450, or a QRS interval >120 msec at Screening.  If 
QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two 
more times and the average of the three QTc (or QRS) values should be used to 
determine the subject’s eligibility.
8. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat, if deemed necessary:

Serum creatinine level above the upper limit of normal or an estimated 
Glomerular Filtration Rate (GFR) value 80 mL/min, based on the 
Cockcroft-Gault calculation, at Screening (see Appendix 2).

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transminase 
(SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transminase 
(SGPT) values more than 1.5 times the upper limit of normal.

Fasting glucose >110 mg/dL.

Total bilirubin 1.5 x ULN.

A white blood cell count below 4.5x103/mm3, including history of benign ethnic 
neutropenia.  Subjects with borderline clinical laboratory values outside the 
reference range may be included in the study if the investigator deems that the 
values are not clinically significant.

Absolute neutrophil count of <2 x 109/L (<2000/mm3).

Hematocrit below 38% for males and 33% for females.  Subjects with borderline 
clinical laboratory values outside the reference range may be included in the study 
if the investigator deems that the values are not clinically significant.

Red blood cell and reticulocytes outside the reference range at screening Subjects 
with borderline clinical laboratory values outside the reference range may be 
included in the study if the Investigator deems that the values are not clinically 
significant.

Platelet counts below LLN.  Subjects with borderline clinical laboratory values 
outside the reference range may be included in the study if the investigator deems 
that the values are not clinically significant.


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9. Any medical history of disease that has the potential to cause a rise in total bilirubin 
over the upper limit of normal (ULN).  Subjects with borderline clinical laboratory 
values outside the reference range may be included in the study if the investigator 
deems that the values are not clinically significant.
Note: Subjects with a history of Gilbert’s syndrome may have a direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin is ULN.
10. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential.
11. Fertile male subjects who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product.
12. Herbal supplements and and hormone replacement therapy must be discontinued 
28 days prior to the first dose of study medication.  As an exception, 
acetaminophen/paracetamol may be used at doses of 1 g/day.  Limited use of 
non-prescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. 
13. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to the first dose of study medication.  As an 
exception, acetaminophen/paracetamol may be used at doses of 1 g/day.  Limited 
use of nonprescription medications that are not believed to affect subject safety or the
overall results of the study may be permitted on a case by case basis following 
approval by the sponsor. 
14. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 56 days prior to dosing.
15. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
16. Unwilling or unable to comply with the Lifestyle Requirements (Section 4.6)
described in this protocol.
17. Other severe acute or chronic medical or psychiatric condition including recent 
(within the past year) or active suicidal ideation or behavior or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results and, in 
the judgment of the investigator, would make the subject inappropriate for entry into 
this study.


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18. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees including their family members
directly involved in the conduct of the study.
19. Will have vaccination with live virus, attenuated live virus, or any live viral 
components within the 6 weeks prior to the first dose of study drug or is to receive 
these vaccines at any time during treatment or within 8 weeks following completion 
of study treatment.
20. Have a history of any lymphoproliferative disorder (such as Epstein Barr Virus 
[EBV]-related lymphoproliferative disorder, as reported in some subjects on other 
immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative 
disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic 
disease.
21. Have a clinically significant infection currently or within 6 months of first dose of 
study drug (eg, those requiring hospitalization or parenteral antimicrobial therapy or 
opportunistic infections), or a history of chronic or recurrent infectious disease.
22. Have or have had symptomatic herpes zoster or herpes simplex within 12 weeks, 
more than one episode of local herpes zoster, or a history (single episode) of 
disseminated zoster.
23. Are known to be infected with human immunodeficiency virus (HIV) or hepatitis B 
or C viruses. 
24. Subjects with a history of cancer with the exception of adequately treated basal cell or 
squamous cell carcinoma of the skin.
25. Acute disease state (eg, nausea, vomiting, fever, or diarrhea) within 7 days of Day 1.
26. Have a first-degree relative with a hereditary immunodeficiency.
27. Have undergone significant trauma or major surgery within 4 weeks of Screening.
28. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day.
29. Consumption of grapefruit or grapefruit juice or citrus fruits eg, Seville oranges, 
pomelos within 7 days prior to the first dose of study medication until collection of 
the final pharmacokinetic blood sample.
30. Subjects who received (within 4 weeks of first dose of PF-06826647) or were likely 
to receive during the study any of the medications listed in protocol Appendix 3.


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4.3. Inclusion Criteria: Psoriasis Multiple Dose Cohorts
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Female subjects of non-childbearing potential and/or male subjects with a diagnosis 
of plaque psoriasis who are between the ages of 18 and 65 years, inclusive. 
2. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum FSH level confirming the post menopausal 
state.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c.
Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations) are considered to be 
of childbearing potential.
3. Body Mass Index (BMI) of 17.5 to 37.5 kg/m2; and a total body weight >50 kg 
(110 lbs).
4. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
6. Have a diagnosis of plaque psoriasis for at least 6 months prior to first study dose.
7. Have plaque-type psoriasis covering at least 15% of total BSA at Day -1 (prior to 
randomization in the study).
8. Have a PASI score of 12 or greater at Day -1 (prior to randomization in the study).
9. Be a candidate for phototherapy or systemic treatment of psoriasis (either naïve or 
history of previous treatment) in the opinion of the investigator.
10. Must agree to avoid prolonged exposure to the sun and avoid other ultraviolet light 
sources during the study (eg, tanning beds).


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11. No evidence of active or latent or inadequately treated infection with Mycobacterium 
tuberculosis (TB) as defined by the following:
a.
negative Interferon Gamma Release Assay (IGRA) (with the following acceptable 
assays: QuantiFERONR-TB Gold (QFT-G) test, T-SPOT TB, QuantiFERON-TB 
Gold In-Tube test (QFT-GIT)) performed during Screening or within 3 months 
prior to Day 1. 
AND
b. No history of either untreated or inadequately treated latent or active TB 
infection.
If a subject has previously received an adequate course of therapy for either latent 
(9 months of isoniazid in a locale where rates of primary multi-drug resistant TB 
infection are <5%) or active TB infection, a QFT Gold test need to be obtained, but a 
chest radiograph or other appropriate image negative for active TB infection, must 
still be obtained if not done so within the prior 3 months.
A subject who is currently being treated for either latent or active TB infection is to 
be excluded.
4.4. Exclusion Criteria: Psoriasis Multiple Dose Cohort
Subjects presenting with any of the following characteristics/conditions will not be included 
in the study:
1. Currently have non-plaque forms of psoriasis, eg, erythrodermic, guttate, or pustular 
psoriasis.
2. Have current drug-induced psoriasis, eg, a new onset of psoriasis or an exacerbation 
of psoriasis from beta blockers, calcium channel blockers, antimalarial drugs or 
lithium.
3. If planned initiation of, or changes to, concomitant medication that could affect 
psoriasis (eg, beta blockers, calcium channel blockers, antimalarial drugs or lithium) 
are to occur within 2 weeks prior to randomization and/or during the study.
4. Subjects with ANY of the following abnormalities in clinical laboratory tests at
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat, if deemed necessary:
a.
Hemoglobin:

If the hemoglobin level is greater than 5% below the lower limit of normal 
(LLN), subject is to be excluded;


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
If the hemoglobin level is within 5% below the LLN, iron and folate levels are 
to be measured: if iron and/or folate levels are below the LLN, subject is to be 
excluded.
b. Absolute neutrophil count of <2 x 109/L (<2000/mm3).
c.
Platelet count below the LLN.
d. Serum creatinine level above the upper limit of normal or an estimated 
Glomerular Filtration Rate (GFR) value 80 mL/min, based on the 
Cockcroft-Gault calculation, at Screening (see Appendix 2).
e.
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transminase 
(SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transminase 
(SGPT) values more than 1.5 times the upper limit of normal.
f.
Fasting glucose >140 mg/dL.
g. Total bilirubin 1.5 x ULN; subjects with a history of Gilbert's syndrome may 
have a direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin is ULN.
5. Any psychiatric condition including recent or active suicidal ideation or behavior that 
meets any of the following criteria:

Suicidal ideation associated with actual intent and a method or plan in the past
year: “Yes” answers on items 4 or 5 of the Columbia suicide severity rating scale 
(C-SSRS) (Appendix 9).

Previous history of suicidal behaviors in the past 5 years: “Yes” answer (for 
events that occurred in the past 5 years) to any of the suicidal behavior items of 
the C-SSRS.

Any lifetime history of serious or recurrent suicidal behavior. 

Suicidal behaviors questionnaire –revised (SBQ-R) (Appendix 10) total score 8.

Clinically significant depression: patient health questionnaire – 8 items (PHQ-8) 
(Appendix 11) when the total score 15.

The presence of any current major psychiatric disorder that is not explicitly 
permitted in the inclusion/exclusion criteria. 

In the opinion of the investigator or Pfizer (or designee) exclusion is required.


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6. Have current or recent history of severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, 
neurological or allergic disease (including drug allergies, but excluding untreated, 
asymptomatic, seasonal allergies at time of dosing).
7. Will have vaccination with live virus, attenuated live virus, or any live viral 
components within the 6 weeks prior to the first dose of study drug or is to receive 
these vaccines at any time during treatment or within 8 weeks following completion 
of study treatment.
8. Will have routine household contact with individuals who have received vaccination 
with live virus, or attenuated live virus, for 8 weeks following completion of study 
treatment.
9. Have a history of any lymphoproliferative disorder (such as Epstein Barr Virus 
[EBV]-related lymphoproliferative disorder, as reported in some subjects on other 
immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative 
disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic 
disease.
10. Have a clinically significant infection currently or within 6 months of first dose of 
study drug (eg, those requiring hospitalization or parenteral antimicrobial therapy or 
opportunistic infections), or a history of chronic or recurrent infectious disease.
11. Have or have had symptomatic herpes zoster or herpes simplex within 12 weeks, 
more than one episode of local herpes zoster, or a history (single episode) of 
disseminated zoster.
12. Any prior treatment with lymphocyte depleting agents/therapies (such as CamPath
[alemtuzab], alkylating agents [eg, cyclophosphamide or chlorambucil],total 
lymphoid irradiation, etc).
13. Have any condition possibly affecting oral drug absorption, gastrectomy, or clinically 
significant diabetic gastroenteropathy.
14. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces
(360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
15. 12-lead ECG demonstrating QTc >450, or a QRS interval >120 msec msec at 
Screening.  If QTc exceeds 450 msec or QRS exceeds 120 msec, the ECG should be 
repeated two more times and the average of the three QTc (or QRS) values should be 
used to determine the subject’s eligibility.


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16. Screening supine blood pressure 160 mm Hg (systolic) or 100 mm Hg (diastolic), 
following at least 5 minutes of supine rest.  If blood pressure (BP) is 160 mm Hg 
(systolic) or 100 mm Hg (diastolic), the BP should be repeated two more times and 
the average of the three BP values should be used to determine the subject’s 
eligibility.
17. Herbal supplements and and hormone replacement therapy must be discontinued 
28 days prior to the first dose of study medication.  As an exception, 
acetaminophen/paracetamol may be used at doses of 1 g/day.  Limited use of 
non-prescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor.
18. Donated blood in excess of 500 mL (excluding plasma donations) within 2 months 
prior to the first dose of study drug.
19. Acute disease state (eg, nausea, vomiting, fever, or diarrhea) within 7 days of Day 1.
20. Have a first-degree relative with a hereditary immunodeficiency.
21. Have any malignancies or have a history of malignancies with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin.
22. Have undergone significant trauma or major surgery within 4 weeks of Screening.
23. Are known to be infected with human immunodeficiency virus (HIV) or hepatitis B 
or C viruses. 
24. Have participated in any other studies with JAK inhibitors within 3 months prior to 
dosing.
25. In the opinion of the investigator or Pfizer, will be uncooperative or unable to comply 
with study procedures.
26. Have participated in other studies involving investigational drug(s) within 30 days or 
5 half-lives (whichever is longer) prior to study entry and/or during study 
participation.
27. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.


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28. Have any other condition which would make the subject unsuitable for inclusion in 
the study.
29. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members, 
directly involved in the conduct of the study.
30. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential.
31. Fertile males subjects who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product.
32. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day.
33. A positive urine drug screen.
34. Consumption of grapefruit or grapefruit juice or citrus fruits eg, Seville oranges, 
pomelos within 7 days prior to the first dose of study medication until collection of 
the final pharmacokinetic blood sample.
35. Require treatment with prohibited concomitant medication(s) listed in Appendix 3 or 
have received a prohibited concomitant medication in the 4 weeks prior to the first 
dose of study drug.  Subjects receiving non-prohibited concomitant medications for 
any reason must be on a stable regimen, which is defined as not starting a new drug or 
changing dosage within 2 weeks or 5 half-lives (whichever is longer) prior to first 
dose of study drug.
36. Have previously been treated with efalizumab (Raptiva).
37. Have previously been treated with secukinumab (Cosentyx) or ixekizumab (Taltz).
38. Have previously been treated with ustekinumab (Stelara).
39. Have received any of the following treatment regimens specified in the timeframes 
outlined below:
Biologic therapies for psoriasis (including brodalumab) have discontinuation periods 
determined from approximately 5x half-life of the respective biologic.
Within 12 weeks of first dose of study drug:

Any experimental therapy for psoriasis, psoriatic arthritis, or rheumatoid arthritis.


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Exception: Investigational biologics should be discussed with the Pfizer Medical 
Monitor (or designee) to confirm period of discontinuation required.

Apremilast (Otezla).
Within 10 weeks of first dose of study drug:

Adalimumab (Humira);

Certolizumab pegol (Cimzia);

Infliximab (Remicade);

Alefacept (Amevive).
Within 4 weeks of first dose of study drug:

etanercept (Enbrel).

Systemic treatments other than biologics that could affect psoriasis (eg, oral or 
injectable corticosteroids, retinoids, methotrexate, cyclosporine, fumaric acid 
derivatives, sulfasalazine, hydroxycarbamide (hydroxyurea), azathioprine).

Phototherapy and psoralens (PUVA).

Other – intramuscular gold, herbal medications.
Within 2 weeks of first dose of study drug:

Topical treatments that could affect psoriasis (eg, corticosteroids, tars, 
keratolytics, anthralin, vitamin D analogs, and retinoids).  Treatments allowed are: 
non-medicated emollients for use over the whole body, low or least 
potent(Class 6 or 7) topical corticosteroids for the palms, soles, face, 
andintertriginous areas only; tar and salicylic acid preparations for the scalp only, 
or shampoos free of corticosteroids for the scalp only.  More potent topical 
steroids (Class 5-2) could be considered on an as-needed basis on the face, scalp, 
and genital areas only after discussion with the Sponsor’s Medical Monitor.

Phototherapy with UVB (narrowband or broadband).
4.5. Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria.
Healthy subjects will be randomized (once) into the SAD period, at which time, they will 
receive treatment assignment (active PF-06826647 dose level or placebo) for both the SAD 
and MAD periods.  Subjects will receive the same blinded treatment assignment (ie, the same 


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dose level of active PF-06826647 or placebo) throughout in both the SAD (Period 1) and 
MAD (Period 2) periods. Optional BID cohort subjects may be directly randomized to the 
twice daily 10 day treatment regimen once confirmation of eligibility criteria occurs, without 
the need to participate in a single dose period. 
•
The randomization ratio for the cohorts in the healthy subject SAD/MAD segment
will be 3: 1 (PF-06826647:Placebo). 
•
The randomization ratio for the planned psoriasis multiple dose cohorts will be 
2:1 (PF-06826647:Placebo). 
4.6. Lifestyle Requirements
The following guidelines are provided:
4.6.1. Meals and Dietary Requirements
•
Administration of investigation product will be in fasted state in SAD period and 
under standard meal condition in MAD (QD and BID) period and in Psoriasis 
cohorts. Based on the emerging PK, 
and safety data, the meal 
condition requirement in SAD, MAD and Psoriasis cohorts may be adjusted.  
•
Under any meal condition, subjects will not be allowed to eat or drink grapefruit or 
grapefruit-related citrus fruits (eg, Seville oranges, pomelos) from 7 days prior to the 
first dose of study medication until collection of the final pharmacokinetic blood 
sample.
•
Except when the investigational product is dosed under high fat meal condition, the 
total daily nutritional composition should be approximately 55% carbohydrate, 
30% fat and 15% protein and the daily caloric intake per subject should not exceed 
approximately 3200 kcal while confined.
Dosing under fasted condition: 
•
Subjects must abstain from all food and drink (except water) at least 8 hours prior to 
any safety laboratory evaluations (as indiated in the study Schedule of Activities) and 
8 hours prior to the collection of the pre-dose pharmacokinetic sample.  Water is 
permitted until 1 hour prior to investigational product administration.
•
The investigational product should be administered with approximately 240 mL 
(8 fluid ounces) of ambient temperature water. Additional water may be allowed if 
needed to administer the entire dose.
•
Water may be consumed without restriction beginning 1 hour after dosing.  
Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices – see 
above) may be consumed with meals and the evening snack.
•
Lunch will be provided approximately 4 hours after dosing.
CCI


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
Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.
Dosing under standard meal condition:
Following an overnight fast of at least 8 hours, subjects should start breakfast approximately 
25 minutes prior to the morning administration of the investigational product when dosing in 
the fed condition.  In BID cohort, subjects should start dinner approximately 25 minutes prior 
to the evening administration of the investigational product, when dosing in the fed 
condition.  The breakfast and dinner (BID period only) will be consumed over approximately 
20 minutes with study drug administered within approximately 5 minutes after completion of 
the meal.  Subjects will be encouraged to eat the full standard meal on PK profile assessment 
days (Days 1 and 10) and are required to eat a minimum of approximately 80% of the meal
preceding dosing.  Subjects will be encouraged to eat the full standard meal and are required 
to eat a minimum of approximately 50% of the meal on all other dosing days.  Subjects 
should be encouraged to eat any snack that will precede dosing.  The study treatment should 
be administered with approximately 240 mL (8 fluid ounces) of ambient temperature water.
Additional water may be allowed if required to administer the entire dose.  No food will be 
allowed for at least 2 hours post-dose.

Water can be allowed as desired except for 1 hour after investigational product 
administration.  There are no water restrictions prior to dosing for subjects dosed 
under fed conditions.  

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.
Dosing under high fat meal condition (if needed):

Following an overnight fast of at least 8 hours, subjects should start a 
high-fat/high-calorie breakfast approximately 25 minutes prior to administration of 
the investigational product.  The breakfast will be consumed over approximately 
20 minutes with investigational product administered within approximately 5 minutes
after completion of the meal.  Subjects will be encouraged to eat the full meal on 
Day 1 and are required to eat a minimum of approximately 80% of the meal. 

The study treatment should be administered with approximately 240 mL 
(8 fluid ounces) of ambient temperature water. Additional water may be allowed 
if required to administer the entire dose.


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
The breakfast will be a high-calorie/high-fat test meal.  The following breakfast as 
a representative example of a high-fat, high-calorie meal: 2 eggs fried in butter, 
2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, 
8 fluid ounces (240 mL) of whole milk.

Water can be allowed as desired except for 1 hour after investigational product 
administration.  There are no water restrictions prior to dosing for subjects dosed 
under fed conditions. 

The investigational product should be administered with approximately 240 mL of 
ambient temperature water.

No food will be allowed for at least 2 hours post-dose.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.
4.6.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final pharmacokinetic sample 
of each study period.  Subjects may undergo an alcohol breath test or blood alcohol 
test at the discretion of the investigator.

Subjects will abstain from caffeine-containing products for 24 hours prior to the start 
of dosing until collection of the final pharmacokinetic sample of each study period.

Subjects will limit the use of tobacco- or nicotine-containing products for 24 hours 
prior to dosing and during confinement in the research unit to not exceed 5 cigarettes 
a day.
4.6.3. Activity
4.6.3.1. Healthy Volunteer Single Ascending Dose Period

Subjects will be confined to the procedure room after dosing on Day 1 during 
continuous cardiac monitoring, except to use the bathroom.  After this, if the 
equipment setup allows, subjects may be ambulatory during the ECG monitoring 
period, but should not engage in strenuous activities.  If equipment does not allow 
ambulation, appropriate accommodations will be made by the study site to facilitate 
continuous monitoring (ie, bedside urinals should be provided to accommodate 
subjects’ excretory needs).


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4.6.3.2. All Subjects 

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.

Subjects must avoid prolonged exposre to the sun and other ultravoilet light sources 
during this study (eg, tanning beds).
4.6.4. Contraception
All fertile male subjects who are, in the opinion of the investigator, sexually active and at risk
for pregnancy, with their partner(s), must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of investigational product.  The investigator or his/her 
designee, in consultation with the subject, will confirm the subject has selected the most 
appropriate method of contraception for the individual subject and his female partner from 
the permitted list of contraception methods (see below) and will confirm that the subject has 
been instructed in its consistent and correct use. At time points indicated in the Schedule of 
Activities, the investigator or designee will inform the subject of the need to use highly 
effective contraception consistently and correctly and document the conversation and the 
subject’s affirmation in the subject’s chart (subjects need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently.
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).


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All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of PF-06826647.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
4.6.4.1. Females – Childbearing Potential
Females of childbearing potential will be excluded from this study. 
4.7. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site.
http://ecf.pfizer.com/sites/crops/team/C2501001/default.aspx
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product(s) PF-06826647 and matching placebo will be
supplied as an extemperaneous preparation and tablets.


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5.1. Allocation to Treatment
The investigator will assign subject numbers sequentially to the subjects as they are screened 
for the study.  Pfizer will provide a randomization schedule to the investigator and, in 
accordance with the randomization numbers, the subject will receive the study treatment 
regimen assigned to the corresponding randomization number.  It will also appear on the 
study medication containers.
Randomization will occur for the SAD/MAD cohorts, and the Psoriasis cohorts. 
Healthy subjects will be randomized (once) into the SAD period, at which time, they will 
receive treatment assignment (active PF-06826647 dose level or placebo) for both the SAD
and MAD periods.  Subjects will receive the same blinded treatment assignment (ie, the same 
dose level of active PF-06826647 or placebo) throughout in both the SAD (Period 1) and 
MAD (Period 2) periods. 
5.2. Breaking the Blind
This study will be subject and investigator blinded, sponsor-open.  At the initiation of the 
study, the study site will be instructed on the method for breaking the blind.  The method will 
be manual.  Blinding codes should only be broken in emergency situations for reasons of 
subject safety.  Whenever possible, the investigator or sub investigator should consult with a 
member of the study team prior to breaking the blind.  When the blinding code is broken, the 
reason must be fully documented and entered on the case report form.
Blood specimens will be obtained from all subjects for pharmacokinetic analysis to maintain 
the study blind at the investigator site.  For the SAD/MAD cohorts only the investigator 
site(s) and the study monitor(s) will be blinded to study treatment.  A designated limited
number of sponsor colleagues within the study team will be unblinded to subject treatments 
in order to permit real-time interpretation of the safety and PK data; and provide information 
necessary to potentially alter the dose-escalation sequence.  The study monitor will remain 
blinded to treatment until all monitoring for the study has been completed.  Specimens from 
subjects randomized to placebo will not be routinely analyzed.  To minimize the potential for 
bias, treatment randomization information will be kept confidential by Pfizer personnel and 
will not be released to the investigator or investigator site personnel until the study database 
has been locked.  If an investigator would like to know the treatment assignment of a subject 
in the case of emergencyor in the event of a safety concern, in which case, the process for 
breaking the blind must be followed. 
The study will be double-blind (including site, investigator, subject), sponsor-open, for the 
Psoriasis cohorts. To minimize the potential for bias, treatment randomization information 
will be kept confidential and will not be released to the investigator or investigator site 
personnel until the study database has been locked. A designated limited number of Pfizer 
personnel will be unblinded to individual psoriasis subject treatment assignment to permit 
interpretation of interim analysis results, safety data, or management of subject’s safety. 


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Site pharmacy staff involved in dose preparation will be unblinded.  There may be one 
designated unblinded study monitor to perform drug accountability and site pharmacy 
monitoring activities.
5.3. Subject Compliance
Investigational product will be administered under the supervision of investigator site 
personnel.  The oral cavity of each subject will be examined following dosing to assure 
investigational product was taken. 
5.4. Investigational Product Supplies. 
5.4.1. Dosage Form and Packaging
PF-06826647 will be supplied by Pfizer as 5 mg, 25 mg, or 100 mg tablets, and will be 
administered to healthy volunteers during the SAD/MAD periods and to psoriasis subjects.
All tablets will be supplied to the CRU in bulk.  Individual dosing containers for unit dosing 
may be supplied, if needed.
There is no 3 mg tablet currently available.  Therefore, PF-06826647 spray dried dispersion 
suspension will be administered to the first SAD cohort.  Materials for PF-06826647 spray 
dried dispersion suspension and placebo dosages will be provided by Pfizer as bulk powders 
for extemporaneous preparation at the Clinical Research Unit (CRU), for administration to 
healthy subjects participating in the starting dose cohort (3 mg) of the Single Ascending Dose 
portion of the protocol.
5.4.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.
PF-06826647 and placebo oral dosing suspensions will be prepared in the CRU by 
2 qualified, unblinded operators, one of whom is a pharmacist.  Details of dose preparation 
will be given in a separate Extemporaneous Dispensing Record (EDR).  Prepared doses will 
be provided in unit dose containers and labeled in accordance with Pfizer regulations and the 
investigator site’s labeling requirements.
PF-06826647 and placebo tablets will be prepared for dosing at the CRU in the individual 
dosing containers by 2 qualified, unblinded operators, one of whom is a pharmacist. The 
tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 


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5.5. Administration
Following an overnight fast of at least 8 hours, subjects will receive study medication at 
approximately 08:00 hours (plus or minus 2 hours).  Investigator site personnel will 
administer study medication to subjects.
For subjects undergoing BID dosing, the second dose of study medication will be 
administered approximately 12 hours after the initial (morning) dose.  
Blinded PF-06826647 tablets and matching placebo will be provided as tablets for oral 
administration.  The PF-06826647 5 mg, 25 mg, and 100 mg tablets and their matching 
placebos will be supplied in bottles and labeled according to local regulatory requirements.
Subjects who receive tablet formulation of PF-06826647, will be instructed to swallow the 
study medication whole, and not to manipulate or chew the medication prior to swallowing.  
Subjects will be instructed to swallow with ambient water to a total volume of 240 mL. 
Additional water is allowed if needed to complete administration of the entire dose. No EDR 
will be provided for the tablet administration.
Administration instructions for the PF-06826647 suspension dose (3 mg single dose cohort 
only) will be provided in the extemporaneous dispensing record.
In order to standardize the conditions on pharmacokinetic sampling days, all subjects will be 
required to refrain from lying down (except when required for blood pressure, pulse rate, and 
ECG measurements). Meal and dietary requirements as described in Section 4.6.1 should be 
followed.
5.6. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including excipients, or drug substance are stored in a secured area 
with controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational products, excipients or drug substance should be stored in their original 
containers and in accordance with the labels.  See the EDR or label for storage conditions of 
the excipients, drug substance or product once constituted.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 


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evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site. 
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
Subjects will abstain from all concomitant treatments, except for the treatment of adverse 
events, as described in the Exclusion Criteria section and in Appendix 3 of this protocol. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at clinic visit as indicated in the Schedule of Activities.
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments.
Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. 


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6. STUDY PROCEDURES
6.1. Screening
For screening procedures, see Schedule of Activities and ASSESSMENTS section.
Subjects will be screened within 28 days prior to administration of the study medication to 
confirm that they meet the subject selection criteria for the study. The investigator (or an 
appropriate delegate at the investigator site) will obtain informed consent from each subject 
in accordance with the procedures described in the protocol. If the time between Screening 
and dosing for a healthy subject in the SAD period is anticipated to exceed 28 days as a result 
of unexpected delays (eg, delayed drug shipment), then subjects do not require re-screening 
if the Day -1 laboratory (including urine drug screen), ECG, vital sign results, contraception 
check and urine pregnancy test (if applicable), and review of prior/concomitant medications 
all confirm that the subject still meets the eligibility criteria, as outlined in Section 4 of 
Protocol C2501001.
A healthy subject who qualified for this protocol but did not enroll from an earlier cohort 
may participate in a subsequent cohort without re-screening provided the Day -1 laboratory 
(including urine drug screen), ECG, vital sign results, contraception check and urine 
pregnancy test (if applicable) and review of prior/concomitant medications all confirm that 
the subject still meets the eligibility criteria outlined in Section 4 of protocol C2501001. In 
addition, other clinical assessments or specimen collections may be used without repeat 
collection, as appropriate following discussion with Sponsor medical monitor.
If needed, eligible psoriasis subjects who have completed screening procedures but did not 
enroll due to scheduling related delays, site logistics, or Sponsor imposed delays (eg, due to 
protocol amendments or other), the screening window may be extended from 28 days as 
described above, to up to 45 days.
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
 
 
6.3. Follow-up/End of Study Procedures
For follow up and end of study procedures, see Schedule of Activities and ASSESSMENTS
section.
6.3.1. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
CCI


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appropriate contraception usage (see the Contraception section).  Contact with the subject 
may be done via a phone call.
6.4. Subject Withdrawal/Early Termination
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given investigator site.  The early termination visit applies only to subjects 
who are randomized and then are prematurely withdrawn from the study.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the early withdrawal 
visit, every effort must be made to complete the following assessments:

Physical examination;

Supine blood pressure and pulse rate measurements and oral temperature;

12-lead ECG measurement;

Blood and urine specimens for safety laboratory;

Blood sample for pharmacokinetic analysis *.
* For subjects who discontinue early during the treatment period due to an adverse event, a 
final PK sample should be collected when possible.  Subjects discontinuing early for other 
reasons may not be asked to provide a final PK sample, depending on when in the study 
discontinuation occurs. For such cases, please contact the study sponsor for further 
guidance.
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor (provided the nature of the safety event does not preclude 
dose escalation and exposure stopping limits are observed).
Replacement of psoriasis subject(s) who discontinue early may occur at discretion of the
sponsor in order to ensure adequate number of subjects completing through Day 28. 


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Withdrawal of consent: 
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate case report form (CRF) page.  In the event 
that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Lost to follow-up: 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return all unused investigational product(s), request that the subject 
return for a final visit, if applicable, and follow up with the subject regarding any unresolved 
AEs.
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the investigator 
may use a sponsor-retained third-party representative to assist site staff with obtaining the 
subject’s contact information or other public vital status data necessary to complete the 
follow-up portion of the study.  The site staff and representative will consult publicly 
available sources, such as public health registries and databases, in order to obtain updated 
contact information.  If, after all attempts, the subject remains lost to follow-up, then the 
last-known-alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.


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7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical labs may be obtained at any time during 
the study to assess any perceived safety concerns.


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Table 7.
Laboratory Tests
Hematology
Chemistry
*Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Reticulocytes (%)
BUN/urea and Creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Serum Cystatin C 
Creatinine phosphokinase 
(for psoriasis subjects 
only)
pH
Glucose 
(qualified)
Protein (qualified)
Blood (qualified)
Ketones
Nitrites
Leukocyte 
esterase
Urobilinogen
Urine bilirubin
Microscopya
FSHb
Urine drug screeningc
Fibrinogen
Lipids: TC, TG, LDLc, HDL
Interferon Gamma Release Assay 
(IGRA) (with the following 
acceptable assays: 
QuantiFERONR-TB Gold (QFT-G) 
test, T-SPOT TB, 
QuantiFERON-TB Gold In-Tube 
test (QFT-GIT)f
HIV, HepBsAg, HepBcAb, HCVAbf
 
 
PK
6β-hydroxy cortisol
 
 
 
Additional Testse
(Needed for Hy’s law)
Other :
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
Urine for 24 hour 
creatinine 
clearance and 
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
At Screening only, in females who are amenorrheic for at least 12 consecutive months. 
c.
At Screening and pre-dose only (see Schedule of Activities).  Minimum requirement for drug testing 
includes: cocaine, tetrahydrocannabinol (THC), opiates/opioids, benzodiazepines and amphetamines.
CCI
CCI
CCI
CCI
CCI
C
C


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e.
Additional testing for potential Hy's Law cases only.
f.
Screening only.  All subjects will be screened for HBsAg and HBcAb; subjects who are HBsAg 
positive will be screen-failed.  Subjects who are HBsAg negative but HBcAb positive will be 
reflex-tested for HBsAb and, if HBsAb positive, may enroll; if HBsAb negative, they will be 
screen-failed.  Subjects who are positive for HCV Ab or HIV will be screen-failed.
 
*.
Urinalysis sample may also be used to assess additional markers of renal function.
This table lists all protocol laboratory tests included in the study.  For a detailed description of 
laboratory tests required for a given subject cohort with specific collection time points, please refer to 
the Schedule of Activities. 
•
Minimum requirement for drug testing includes: cocaine, THC, opiates/opioids, 
benzodiazepines and amphetamines.
•
Subjects may undergo random urine drug screening at the discretion of the 
investigator.  Drug screening conducted prior to dosing must be negative for subjects 
to receive study medication. 
7.1.2. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  For female subjects of 
childbearing potential, 2 negative pregnancy tests are required before receiving 
investigational product/study treatment(s) (1 negative pregnancy test at screening and 1 at the 
baseline visit immediately before investigational product/study treatment administration).  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and the second negative pregnancy test result will then be required at the 
baseline visit and within 5 days after the first day of the menstrual period (counting the first 
day of the menstrual period as Day 1) before the subject may receive the investigational 
product/study treatment.  In the absence of regular menstrual bleeding, the study candidate 
should have used 2 forms of contraception for at least 1 month before the second pregnancy 
test.  Pregnancy tests will also be repeated at every visit and at the end of the study to 
confirm that the subject has not become pregnant during the study.  Pregnancy tests will also 
be done whenever 1 menstrual cycle is missed during the active treatment period and when 
potential pregnancy is otherwise suspected, and may be repeated if requested by institutional 
review boards (IRBs)/ethics committees (ECs) or if required by local regulations.  In the case 
of a positive confirmed pregnancy, the subject will be withdrawn from administration of 
investigational product and from the study.
C
C
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7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, trained physician assistant, or nurse 
practitioner as acceptable according to local regulation.  A full physical examination will 
include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, as well as towards subject reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 
7.1.4. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in Schedule of Activities
section of this protocol.  Additional collection times, or changes to collection times of blood 
pressure and pulse rate will be permitted, as necessary, to ensure appropriate collection of 
safety data.
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart and recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same 
arm (preferably the dominant arm) will be used throughout the study.  Subjects should be 
instructed not to speak during measurements. 
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time.  The use of an automated device for measuring BP and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for at least 30 seconds.  When the timing of these measurements coincides with a 
blood collection, blood pressure and pulse rate should be obtained prior to the nominal time 
of the blood collection.
For current smokers participating in this study, vital sign assessment (blood pressure and 
pulse rate) should not occur within 1 hour of smoking. 
7.1.5. Temperature
Temperature will be measured orally.  No eating, drinking or smoking is allowed for 
15 minutes prior to the measurement.
7.1.6. Electrocardiogram 
Electrocardiograms (ECGs) should be collected at times specified in the Schedule of 
Activities section of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 


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Triplicate 12-lead ECGs will be obtained approximately 2-4 minutes apart; the average of the 
triplicate ECG measurements collected predose on Day 1 will serve as each subject’s 
baseline QTc value.  When the timing of these measurements coincides with a blood 
collection, the ECG should be obtained prior to the nominal time of the blood collection, 
blood pressure and pulse rate. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Within a given study period (ie, SAD, MAD), 
baseline measurements from the current period will be used for comparison.  If the QTc 
interval is increased by 45 msec from the baseline, or an absolute QTc value is 500 msec 
for any scheduled ECG, then 2 additional ECGs will be collected, approximately 2-4 minutes 
apart, to confirm the original measurement.  If either of the QTc values from these repeated 
ECGs remains above the threshold value (45 msec from the baseline; or is 500 msec), then 
a single ECG must be repeated at least hourly until QTc values from 2 successive ECGs fall 
below the threshold value that triggered the repeat measurement. 
If the average of QTc values from the triplicate measurements remains above the threshold 
value (45 msec from the baseline; or is 500 msec), then a single ECG must be repeated at 
least hourly until QTc values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner at the discretion of the investigator); or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified physician’s interpretation determines that the QTc values are in the acceptable 
range.
For current smokers participating in this study, ECG assessments should not occur within 
1 hour of smoking. 
7.1.7. Continuous Cardiac Monitoring by Telemetry
Continous telemetry monitoring will be conducted in the single ascending dose period 
only.
All abnormal rhythms will be recorded and reviewed by the study physician for the presence 
of rhythms of potential clinical concern.  The time, duration, and description of the clinically 
significant event will be recorded in the case report form (CRF).  In addition, a printed record 
of the tracing(s) of the clinically significant rhythm(s) will be made and retained with other 
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Telemetry should be collected using a centralized system that also allows for the storage and 
advanced analysis of all recorded data in order to preserve important events for future 
evaluations.  Holter monitoring should not be used in parallel with continuous telemetry, 
unless it is the only means of data storage available at the investigator site, or verifiable 
arrhythmia quantification is required.  To establish a baseline, telemetry should be recorded 
for at least 2 hours before dosing in Period 1, single ascending dose period.  This may be 
done -2 hours immediately prior to dosing or at some 2-hour continuous interval in the 
24 hours prior to dosing, as long as the recording is performed when the subject is awake.  
Telemetry may be stopped within a reasonably short period of time prior to dosing, in order 
to avoid interference with study operations conducted immediately before dosing.  However, 
it is expected that the telemetry leads will be in place and the system connected prior to 
dosing. 
Continuous cardiac monitoring by telemetry will be conducted 15 minutes pre dose through 
the 8 hour post dose period, during the single ascending dose period.
7.1.8. Chest Radiograph
Potential psoriasis subjects will have a standard chest radiograph performed as part of
Screening if the individual previously received an adequate course of therapy for either latent 
(9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection 
are <5%) or active TB infection, and if there is no record and no report of having one 
performed in the prior 3 months.
7.1.9. Interferon Gamma Release Assay (IGRA) Tests
Interferon Gamma Release Assay (IGRA) will be performed at screening.  The following 
acceptable IGRA assays include: Interferon Gamma Release Assay (IGRA) (with the 
following acceptable assays: QuantiFERONR-TB Gold (QFT-G) test, QuantiFERON-TB 
Gold In-Tube test (QFT-GIT) and T-SPOT TB test).  A QFT-G test is recommended in 
subjects who have been previously vaccinated with BCG.
7.1.10. Urine Creatinine and 
 
 
  
 
 
 
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7.1.10.2. 24 Hour Urine Creatinine and 
 in Multiple Ascending Dose 
Period: Day -1 and Day 10
The same procedure outlined in Section 7.1.10.1 for urine collection in the single ascending 
dose period will be utilized in the multiple ascending dose period.  One aliquot of 10 mL
(“urine blank”) from the 0-24 hour period will be obtained from the urine collection for 
creatinine measurement on Day -1. Also, two 1-mL aliquots will be transferred to 
appropriately-labeled tubes and stored at -70°C within 2 hours of collection for 
 
After 24-hour collection on Day 10, two aliquots of 10 mL will be collected in appropriately 
labelled tubes for PK analysis and creatinine measurement. Also, two 1-mL aliquots will be 
transferred to appropriately-labeled tubes and stored at -70°C within 2 hours of collection for 
On Day 10, urine will be collected from the BID period over 2 time intervals: 0-12 hours and 
12-24 hours.  The PK sample will be collected from the 0-12 hour interval. 
 
7.1.10.3. 24 Hour Creatinine Clearance Calculation
Creatinine clearance (mL/min) = (Creatinine (urine)/Creatinine(serum)) x (Volume Urine 
(mL)/Time (hours) x 60)
 
 
7.1.11. Serum Creatinine and Serum Cystatin-C
Serum creatinine is the best known standard test for monitoring renal function. However, 
serum creatinine based estimates of glomerular filtration rate (eGFR) may be affected by 
factors other than renal function, including chronic and acute illness.  Cystatin C is a test that 
can be used either as an adjunct to or a replacement for serum creatinine.  The most reliable 
estimates of GFR use both test results.8
Cystatin C is a low molecular weight protein that is used as an alternative to serum creatinine 
for monitoring of renal function.  It seems to correlate more closely with GFR than does 
serum creatinine concentration and may be a more sensitive detector of early renal 
dysfunction.9,10 While use of cystatin C has been limited, its independence of demographic 
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factors (eg, race) has made it an interesting means of determining changes in renal function 
in clinical settings and it is included in the 2012 Kidney Disease: Improving Global 
Outcomes (KDIGO) guidelines.  Estimated GFR may be calculated via the 2012 Chronic 
Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine, cystatin C, or 
creatinine-Cystatin C equations.11
Serum creatinine and serum cystatin C will be measured from the  serum chemistry specified 
in the Schedule of Activities section of the protocol. Serum creatinine and cystatin C based 
eGFR will be calculated at baseline and end of treatment (EOT) at a minimum (additional 
time points may be assessed). 
When a subject has an increase in serum creatinine of 0.3 mg/dL relative to the subject’s 
baseline, and after that increase has been confirmed by a (single) repeat test obtained as soon 
as practically feasible, but within 24 hours of the initial result, this will trigger assessment of
serum cystatin-C in order to facilitate both cystatin C based and serum creatinine based 
eGFR calculations.
7.1.12. Estimated Glomerular Filtration Rate
Serum creatinine and serum cystatin-C based estimated GFR (eGFR) will be calculated at 
baseline and end of study treatment period at a minimum for all subjects, in order to facilitate 
calculation of eGFR at these time points.  When cystatin-C testing is performed during the 
treatment period, corresponding serum creatinine and cystatin-C based eGFR will be 
determined to support assessment of renal function.
The respective estimated GFR (eGFR) values will be calculated using the 2 sets of equations 
developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), which 
utilize serum creatinine (SCr) and serum Cystatin C (S Cystatin C) respectively.7
(Appendix 4).
7.2. Selection of IndexPlaques and Non-Lesional Skin for Skin Biopsies for Psoriasis 
Subjects
The index psoriatic plaque(s) to be used for skin biopsy should be selected pre-dose at the 
Day -1 visit.
Index lesion sites may be located on the torso (upper and mid back, chest), abdomen, 
buttocks, upper arms, and upper legs.  Index lesions may not be located on the scalp, face, 
elbows, knees, lower legs, genital area and inguinal area, intertriginous areas and lower back.
Ideally, a single target plaque, approximately the size of the palm of the subject’s hand, 
should be identified and the location and borders noted in the clinic chart; anatomical 
markers should be used as needed to describe the target plaque location.  A photograph of the 
site may also be used.  The plaque should be of sufficient size that the presence of multiple 
biopsy sites will not interfere with clinical evaluation of the lesion; potential biopsy sites 
should be pre-selected.  The plaque should also be large enough to perform the required 
number of biopsies specified in the protocol.  If a single index lesion meeting the above 
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at least 3 to 5 cm in diameter should be identified and the locations noted in the clinic chart.  
The index plaque(s) must have a total score of at least 5
 and a score of 
at least 2 for induration at the time of pre-dose assessment.  The plaques selected should have 
a similar appearance of severity, ie, plaques should be similar with regard to degree of 
erythema, induration and scaling.
An area of non-lesional skin anatomically similar in location to the target plaque should also 
be selected for biopsy.  The selected non-lesional skin area should be at least 3 cm from the 
target psoriatic plaque.  A biopsy of non-lesional skin will be obtained pre-dose at the Day -1
visit only.
7.3. Skin Biopsies (Psoriasis Subjects only)
The index plaque(s) selected for biopsy will be outlined using a black permanent marker on 
plastic transparency film.  An area will be marked on the transparency film for identification 
and biopsy.  The film will be identified with the study number and subject’s identification 
number and retained with subject’s clinic/site source documents.
Punch biopsies of the lesional skin will be obtained at each time point as specified in the 
Schedule of Activities.  At the discretion of the investigator and the subject, two 4 mm 
biopsies will be obtained.  At Day -1, two 4 mm biopsies of lesional skin and two 4 mm 
biopsies of non-lesional skin will be obtained.
Biopsy samples will be prepared and shipped following instructions in a separate manual 
provided by the sponsor.
Throughout the study period, the ‘punch’ biopsy instrument should be placed at least 3 mm 
from the target plaque’s edge as identified at the Day -1 Visit.
Any two biopsy sites will be at least the width of the biopsy punch instrument apart.
 
 
Punch biopsies from the index psoriatic plaque(s) will be obtained pre-dose on Day -1, at 
Day 14 and pre-dose at Day 28.  Punch biopsy sampling of normal non-lesional skin will be 
obtained pre-dose at the Day -1 visit only.  The biopsies may be used for RNA, protein and 
immunohistochemical analysis.
The shipment address and laboratory contact information will be provided to the investigator 
prior to initiation of the study.  Details on the procedure for skin biopsy and sample 
preparation will be provided to investigators in a separate manual.
 
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As skin biopsies may be associated with risk of bleeding or infection, subjects will be 
instructed to contact the investigator or other designated site staff if they experience bleeding, 
warmth, swelling, tenderness, or erythema at the biopsy site; an unscheduled visit may be 
required for clinical assessment.
7.4. Psoriasis Clinical and Histological Assessments
Clinical and histological psoriasis assessments that will be collected throughout the study are 
outlined in this section.  These measures will be evaluated by an experienced physician, or 
qualified medical professional.  Detailed descriptions for the 
 
, 
, and Patient Global Assessment are 
provided in the Appendices. 
7.4.1. Psoriasis Area and Severity Index (PASI) (Psoriasis subjects only)
PASI should be collected at times specified in the Schedule of Activities section of this
protocol.
The Psoriasis Area and Severity Index quantifies the severity of a subject’s psoriasis based 
on both lesion severity and the percentage of body surface area affected.
Lesion severity: the basic characteristics of psoriatic lesions – erythema, induration and 
scaling – provide a means for assessing the severity of lesions.  Assessment of these three 
main signs is performed separately for four areas of the body: head, upper limbs, trunk, and 
lower limbs.  Average erythema, induration and scaling are rated for each body area 
according to a 5-point scale: 0, no involvement; 1, slight; 2, moderate; 3, marked; 
4, very marked.
 
 
Calculating PASI
In each area, the sum of the severity rating scores for erythema, induration and scaling is 
multiplied by the score representing the percentage of this area involved by psoriasis, 
multiplied by a weighting factor (head 0.1; upper limbs 0.2; trunk 0.3; lower limbs 0.4).  The 
sum of the numbers obtained for each of the four body areas is the PASI.1
PASI =
0.1Ah(Eh + Ih + Sh) + 0.2Au(Eu + Iu + Su) +
0.3At(Et + It + St) + 0.4Al(El + Il + Sl)
where A = area of involvement score; E = erythema; I =induration; S = scaling; h = head; u = upper limbs; 
t = trunk; l = lower limbs
The PASI score can vary in increments of 0.1 units from 0.0 to 72.0, with higher scores 
representing increasing severity of psoriasis.  The PASI score will be used for the primary 
analysis.
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7.4.2. Linear-method Psoriasis Area and Severity Index (L-PASI)
A second method of calculating PASI will also be performed.  A linear-scaling method will 
be applied to the Psoriasis Area and Severity Index calculation, adapting the classic 
calculation by using the actual percentage body surface area involved in psoriasis rather than 
categorizing the percentage involvement on a 7-point scale. 
The linear-scaling method will be calculated from the study database; investigator sites will 
only perform the classic PASI calculation during the study.  The L-PASI score will be used 
for a sensitivity analysis.
L-PASI Calculation
L-PASI =
0.1(6xBh)x(Eh + Ih + Sh) + 0.2(6Bu)x(Eu + Iu + Su) +
0.3(6xBt)x(Et + It + St) + 0.4(6xBl)x(El + Il + Sl)
where B = percentage area of involvement; E = erythema; I =induration; S = scaling; h = head; u = upper 
limbs; t = trunk; l = lower limbs
 
 
 
 
 
 
 
 
 
 
 
 
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7.4.6. Target Lesion and Regional Photography (Psoriasis subjects only)
Standardized digital photographs of target lesions and surrounding region photography will 
be taken at selected study sites using a professional quality digital camera.  These 
photographs are for illustrative purposes only. 
Target Lesion Photography: Two target lesions will be selected at the Day -1 visit.  
Anything extraneous to each lesion and its surrounding area are to be removed from the 
photographic field.  The camera/lens will be set at the appropriate magnification.  A close-up 
attachment scale attached to the camera system will help ensure that photographs are all 
taken at the same magnification and from the same set distance.  Photographs will be taken in 
duplicate with lighting, framing, and exposure held constant.
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Regional Photography: Regional photographs of each target lesion and surrounding area 
will also be taken.  Once the camera/lens is set at the appropriate magnification, proper 
focusing technique will help ensure that photographs are all taken from the same set distance 
from the camera.  Photographs will be taken in duplicate with lighting, framing, and 
exposure held constant.
Digital study images will be captured on memory cards.  The contents of those cards will be 
uploaded to Canfield Scientific, Inc. using Canfield’s secure, compliant website.  All study 
images received will be monitored and archived in a fully validated, 21 Code of Federal 
Regulations (CFR) Part 11 Food and Drug Administration (FDA) compliant system.  A copy 
of each subject's Day -1 photographs will be provided to the investigational sites for the 
subject file in order to confirm the location/field of view to be photographed at the end of 
treatment.  Photography will be performed at Day -1, Day 7, Day 14, and Day 28, as well as 
at the follow-up visits occurring at Day 42 and Day 56/Early Termination and Day 84.  
Additional instructions related to target lesion and Regional Photography can be located in 
the study manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.6. Pharmacokinetics
7.6.1. Plasma for Analysis of PF-06826647
During all study periods, blood samples (4 mL) to provide approximately 1.2-1.5 mL plasma 
for pharmacokinetic analysis will be collected into appropriately labeled tubes containing 
K2 EDTA at times specified in the Schedule of Activities section of the protocol. 
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF/DCT).
•
Samples will be centrifuged at approximately 1700 x g for about 10 minutes at 4°C.  The 
plasma will be stored in appropriately labeled screw capped polypropylene tube at 
approximately -20°C within 1 hour of collection. 
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the lab manual.
•
The PK samples must be processed and shipped as indicated to maintain sample 
integrity.  Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the sponsor.  On a case-by-case basis, the 
sponsor may make a determination as to whether sample integrity has been 
compromised.  Any sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation.
•
 
 
 
 
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7.6.2. Urine for Analysis of PF-06826647
Urine will be collected as outlined in the Schedule of Activities. 
Urine will be stored at approximately 4°C during each collection period.  At the end of each 
24 hour urine collection period, the urine will be mixed thoroughly and total volume will be 
measured and recorded.  A 7-8 mL aliquot will be withdrawn for measurement of drug 
concentrations and will be stored frozen at approximately -20°C within 1 hour of the end of 
the collection interval.  The urine blank for PK will be obtained from the 24-hour collection 
on Day -1 (0-24 hr) for subjects undergoing QD or BID dosing.  On Day 10, urine will be 
collected for the BID cohort over 2 time intervals: 0-12 and 12-24 hours.  The Day 10 PK 
sample will be obtained from the 0-12 hour urine time interval during the potential BID
cohort.
The PK samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PK processing steps, including any actions taken, must be 
documented and reported to the sponsor. On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation.
The preferred tubes for collection and storage will be identified and this information will be 
provided to the site prior to start of the study.  Samples will be analyzed using a validated 
analytical method in compliance with Pfizer standard operating procedures.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
 identification and/or evaluation of the bioanalytical method.  These data will be 
used for internal exploratory purposes and will not be included in the clinical report. 
7.6.3. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
 
 
 
 
 
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7.10. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
552.8 mL for the SAD and MAD cohorts and approximately 475 mL for the Psoriasis cohort.  
The actual collection times of blood sampling may change, but the total blood volume 
collected will not increase.  Additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 30 consecutive days.
Table 8.
Blood Volume: Single Ascending Dose Period
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Screening
Treatment 
Period
Follow-up 
Period
Total Volume 
(mL)
Interferon Gamma Release Assay 
(IGRA)
3
1
0
0
3
HIV, HepBsAg, HepBcAg, 
HCVAb
8.5
1
0
0
8.5
FSH
2
1
0
0
2
Blood Safety Labs (hematology & 
chemistry)
14.5
1
3
1
72.5
Fibrinogen
2.7
0
1
1
5.4
Lipid Panel
0
1
2
1
0
 
PK Blood Sampling
4
0
12
1
52
TOTAL
183.9
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Table 9.
Blood Volume: Multiple Ascending Dose Period
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Screening
Treatment 
Period
Follow-up 
Period
Total Volume 
(mL)
Blood Safety Labs (hematology 
& chemistry)
14.5
0
7
1
116
Fibrinogen
2.7
0
2
0
5.4
Lipid Panel
0
0
4
1
0
 
PK Blood Sampling
4
0
24
1
100
TOTAL
368.9
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Table 10.
Blood Volume: Psoriasis Multiple Dose Period
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Screening
Treatmen
t Period
Follow-up 
Period
Total Volume 
(mL)
Interferon Gamma Release Assay 
(IGRA)
3
1
0
0
3
HIV, HepBsAg, HepBcAg, 
HCVAb
8.5
1
0
0
8.5
FSH
2
1
0
0
2
Blood Safety Labs (hematology 
& chemistry)
14.5
1
9
3
188.5
Lipid Panel
0
1
5
1
0
 
PK Blood Sampling
4
0
14
1
60
TOTAL
475.0
Total volumes for the tables above do not include discarded blood from pre-draws used to 
remove fluid from flushed catheters, if applicable. 
7.11. Assessment of Suicidal Ideation and Behavior
 
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7.11.2. Patient Health Questionnaire – 8 items (PHQ-8)
Patient health questionnaire – 8 items (Appendix 11) is a patient-report questionnaire consists 
of 8 items to assess subject depression level. 
At Screening Visit, if PHQ-8 total score ≥15, the subject will not be included in the study.
7.11.3. Suicidal Behaviors Questionnaire-revised (SBQ-R)
Suicidal behaviors questionnaire- revised (Appendix 10) is a patient-report questionnaire 
consists of 4 items to assess suicidal ideation, suicide attempts, threat of suicidal behavior, 
and likelihood of suicidal behavior.
At Screening Visit, if SBQ-R total score ≥8, the subject will not be included in the study.
7.12. Triggered Requirements 
7.12.1. Potential Cases of Acute Kidney Injury
Abnormal values in serum creatinine (SCr) concurrent with decline in eGFR that meet the 
criteria described below in the absence of other causes of kidney injury, are considered 
potential cases of acute kidney injury and should be considered important medical events.  
An increase of ≥0.3 mg/dL (or ≥26.5 μmol/L) in serum creatinine relative to subjects’ own 
baseline measurement should trigger another assessment of SCr to confirm, within 24-hours 
from awareness.
If the second (repeat) result is still of ≥0.3 mg/dL (or ≥26.5 μmol/L) relative to subject 
baseline, assessment of serum Cystatin C (S Cystatin C) should be referenced.  Based on 
these measurements, estimated GFR using serum creatinine (2009 CKD-EPI eGFR7) and 
serum cystatin C (2012 CKD-EPI eGFR7) will be determined and reviewed, preferably 
within 72 hours and not later than 96 hours from the confirmed (repeat) elevated serum 
creatinine result.
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If an individual subject demonstrates CONCOMITANT sCr-based AND S Cystatin C-based 
eGFR decline of 30%compared to the subject’s baseline eGFR, then the subject should not 
be further dosed and adequate, immediate, supportive measures including immediate 
evaluation by a nephrologist (preferably within 24 hours) with appropriate 
management and treatment as clinically indicated.  Results should be repeated as indicated 
by the nephrologist or weekly at a minimum until the eGFR returns to baseline 15% or the 
renal parameters are deemed to be stable by the nephrologist and/or PI.
If the subject cannot be seen by a nephrologist within 24 hours (as described above), 
then the subject should be sent to a local emergency room for evaluation and treatment 
as clinically indicated.
Subjects should return to the investigational site and be evaluated as soon as possible, 
preferably within 24-48-hours from awareness of the abnormal eGFR result.  This 
evaluation should include laboratory tests, detailed history, and physical assessment.  In 
addition to evaluating eGFR as calculated by SCr and S Cystatin C, laboratory tests should 
include: serum blood-urea-nitrogen, serum creatine kinase, serum electrolytes (including at a 
minimum potassium, sodium, phosphate/phosphorus, calcium), in addition to urinary 
dipstick, urine microscopic examination, and urinary indices.  All cases confirmed on repeat 
testing as meeting the eGFR criteria for acute-kidney-injury, with no other cause(s) of 
laboratory abnormalities identified should be considered as potential cases of drug-induced 
kidney injury irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal SCr.  If 2 healthy subjects in a given cohort are noted to 
have 2 consecutive decreases from baseline in eGFR of -30%, based on both sCr AND 
S Cystatin C, an assessment of whether the finding may be considered adverse drug reaction 
should be undertaken.
This requirement applies to all subjects, all cohorts.  
7.13. Rater Qualifications 
Investigators participating in this study should be experienced in the conduct of psoriasis
clinical trials and have prior training and experience in the required protocol-specific
psoriasis subject clinical evaluations. The same rater should evaluate the same subject(s)
whenever possible.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal/Early Termination section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.


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SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 


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
Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or


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
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.


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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:


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
Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.


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A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 


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pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.


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8.4.3. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
are outlined here and further detailed in a Statistical Analysis Plan (SAP), which will be 
maintained by the sponsor.  The Statistical Analysis Plan may modify what is outlined in the 
protocol where appropriate; however, any major modifications of the endpoint definitions or 
their analyses will also be reflected in a protocol amendment.


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9.1. Sample Size Determination
9.1.1. Healthy Subject Single Ascending and Multiple Dose 
A sample size of 8 subjects in each SAD and MAD cohort (with 6 active and 2 placebo) with 
approximately 48 subjects (assuming 6 cohorts) and 24 subjects for optional cohorts 
MAD BID cohort, Cohort 7 and 8 is not based on any statistical considerations.  Sample size 
for optional Japanese subject cohort is not based on any statistical considerations, and may 
enroll up to 8 subjects in order to support characterization of the PF-06826647 PK profile in 
Japanese subjects. The sample size was based on the clinical consideration to provide safety 
and tolerability information and pharmacological considerations and on the need to minimize 
exposure to healthy subjects at each dose level.  No formal inferential statistics will be 
applied to the safety, pharmacodynamic or pharmacokinetic data.
9.1.2. Psoriasis Multiple Dose 
A sample size of approximately 42 subjects total is planned for the two psoriasis cohort(s).  
Psoriasis subjects will be randomized in each Psoriasis cohort to receive either active
PF-06826647 (or placebo) with a planned randomization ratio of 2:1 (PF-06826647:Placebo)
for each cohort.  The between-subject standard deviation of absolute PASI change from 
baseline to Day 28 (obtained from Sponsor data on file) is assumed to be 8. The true 
difference between PF-06826647 and placebo is assumed to -7.8 (derived from the 
meta-analysis of the Tofacitinib data).  Based on these assumptions the sample size is 
calculated to be 14 subjects per arm to provide approximately 80.7% power. This calculation 
assumes a one-sided alpha of 5%. The initial estimate of the total number of completers for 
the psoriasis cohort will be 42 with 21 (14 active +7 placebo) in each cohort. Based on the 
results from the planned interim analysis (described below in Section 9.7) PF-06826647 dose 
level or regimen may be adjusted for subsequent psoriasis subjects/cohorts enrolled after the 
interim analysis. 
9.2. Efficacy Analysis
All subjects who receive at least one dose of randomized study medication, and have a 
baseline and at least one post-baseline measurement (after taking randomized study 
medication) will be included in the efficacy data analyses for the psoriasis cohorts.
9.2.1. Analysis of Secondary Endpoints 
The change from baseline in PASI score at Day 28 in the psoriasis multiple dose segment is a
secondary endpoint. The treatment effect for each of the test dose groups is the treatment 
difference in the mean change from baseline of PASI score at Day 28 between the test dose 
and the placebo.  The estimates for treatment effect will be obtained by fitting a repeated 
measures linear model to the PASI change from baseline score.  The model will include 
treatment (active doses and placebo), week and treatment-by-week interaction as fixed 
effects and baseline PASI score as a covariate. Estimates and 90% confidence intervals for 
treatment effect will be presented.


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9.3. Pharmacokinetic Analysis
9.3.1. Single and Multiple Dose Periods 
The PK data set will include data from all subjects receiving active drug and having any 
measurable concentration of study drug.  Complete details will be provided in the study’s 
SAP.
The following PK parameters will be calculated for PF-06826647 (if possible) from the 
plasma concentration-time data using standard noncompartmental methods:
Matrix
Parameter
Definition
Method of Determination
Plasma
AUClast
Concentration-time profile from time zero 
to the time of the last
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUC
Area under the plasma
concentration-time profile over the dosing 
interval 
Linear/Log trapezoidal method
AUCinf
a
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point estimated from the 
log-linear regression analysis
Cmax
Maximum plasma concentration
Observed directly from data
Cmin
Lowest concentration observed during 
dosing interval, ; if measured at end of 
dosing interval, equivalent to Ctrough
Observed directly from data
Cav
Average concentration at steady state
Cav= AUC,ss/
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
t1/2
a
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only 
those data points judged to describe 
the terminal log-linear decline will 
be used in the regression
CL/Fa
Apparent clearance
Dose/AUCinf for SD 
Dose/AUCfor MD
Vz/Fa
Apparent volume of distribution
Dose/(AUCinf. kel) for SD 
Dose/(AUC. kel) for MD
Rac
Observed accumulation ratio based on 
AUC
AUC(ss)/AUC(sd)
Rac,Cmax
Observed accumulation ratio based on Cmax
Cmax (ss)/ Cmax (sd)
PTR
Peak to Trough ratio
Cmax,ss/Cmin,ss 
MRT
Mean residence time
AUMCinf/AUCinf, 
where AUMCinf is the area under 
the first moment curve from time
zero to infinity.
Cmax(dn)
Dose normalized Cmax
Cmax/Dose


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Matrix
Parameter
Definition
Method of Determination
AUClast(dn)
Dose normalized AUClast
AUClast/Dose
AUCinf(dn)a
Dose normalized AUCinf
AUCinf/Dose
Urine
Aeτ
Cumulative amount of drug recovered 
unchanged in urine from 0 to dose interval 
(τ) hours postdose
Sum of [urine concentration * 
sample volume] for each collection 
interval 
Aeτ%
Percent of dose recovered unchanged in 
urine from 0 to dose interval (τ) hours 
postdose
Aeτ/Dose*100
CLr
Renal clearance
Aeτ/AUCτ
a If data permit
The PK parameters will be summarized descriptively by dose, regimen and study population 
(healthy subject and psoriasis subject) in accordance with Pfizer data standards.  Summary 
statistics will also include the geometric mean and coefficient of variation for all parameters 
except Tmax.
Dose normalized (to 1 mg) AUC and Cmax values of PF-06826647 will be plotted against 
dose (using a logarithmic scale if dose range is greater than 10-fold) for single- and multiple 
dose phases, and will include individual subject values and the geometric means for each 
dose.  These plots will be used to help understand the relationship between the plasma PK 
parameters and dose.  Additional PK analyses may be performed if deemed appropriate.
Urine amounts of PF-06826647 and CLr will be listed and summarized descriptively, if data 
permits.
 
 Natural log 
transformed AUC24 and Cmax will be analyzed using a mixed effect model with treatment 
(Dose levels) and period as a fixed effect and subjects within a treatment as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidence intervals will be obtained from the model. The adjusted mean differences 
and 90% confidence for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios. Further details will be provided in statistical analysis plan (SAP).
 
 
 
CCI
CCI


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9.6. Safety Analysis – Primary
Adverse events, ECGs, blood pressure, pulse rate, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
subjects.  Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical 
concern will be described.  Safety data will be presented in tabular and/or graphical format 
and summarized descriptively, where appropriate.
Medical history and physical examination and neurologic examination information and 
continuous cardiac monitoring collected during the course of the study will not be captured 
for inclusion into the study database, unless otherwise noted.  However, any untoward 
findings identified on physical and/or neurologic examinations or on telemetry monitoring 
conducted after the administration of the first dose of study medication will be captured as an 
adverse event, if those findings meet the definition of an adverse event.  Data collected at 
Screening that is used for inclusion/exclusion criteria, such as laboratory data, ECGs and 
vital signs will be considered source data, and will not be captured for inclusion into the 
study database, unless otherwise noted.  Demographic data collected at Screening will be 
included in the study database.
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Data relevant to the assessment of suicidality will be mapped to the Columbia-Classification 
Algorithm of Suicide Assessment (C-CASA) codes.  Baseline and post-baseline 
 data 
(mapped to C-CASA scores) will be summarized descriptively by treatment group at baseline 
and each post-baseline visit.  The safety analyses will be carried out in the safety population, 
detailed analyses will be described in the SAP.
9.6.1. Electrocardiogram Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc
Borderline (msec)
Prolonged (msec)
Absolute Value
≥450 - <480
≥480
Absolute Change
30-<60
≥60
In addition, the number of subjects with corrected and uncorrected QT values ≥500 msec will 
be summarized.
If more than one ECG is collected at a nominal time post dose (for example, triplicate 
ECGs), the mean of the replicate measurements will be used to represent a single observation 
at that time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, 
but the mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing 
will be described in a safety section of the study report in order to place the ≥500 msec value 
in appropriate clinical context.  However, values from individual tracings within triplicate 
measurements that are ≥500 msec will not be included in the categorical analysis unless the 
average from the triplicate measurements is also ≥500 msec.  Changes from baseline will be 
defined as the change between QTc post dose from the average of the pre-dose triplicate 
values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a PK/PD 
relationship is found, the impact of subject factors (covariates) on the relationship may be 
examined. 
9.7. Interim Analysis
An interim analysis of the change from baseline at Day 28 in PASI score (psoriasis key 
secondary endpoint) will be conducted for the first psoriasis cohort (400 mg dose cohort). 
The analysis will be performed when 21 psoriasis subjects from the 400 mg cohort complete 
through study Day 28. Outcomes from this interim analysis may inform dose selection 
decisions/adjustments for later psoriasis subject cohorts to be enrolled in the study. The 
interim analysis is not planned to impact the conduct of the initial 400 mg psoriasis cohort. 
The analysis is planned to be performed after dosing of the full 400 mg psoriasis cohort 
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(n=21 subjects completing through study Day 28). Any decisions or dose adjustments that 
are taken, will be applied to the subsequent psoriasis cohort. A designated limited number of 
Sponsor colleagues will review the interim analysis results to support any dose related 
decisions. For the healthy SAD/MAD cohorts, this is a sponsor-open study, and the sponsor 
may conduct unblinded reviews of the data during the course of the study for the purpose of 
safety assessment, facilitating dose-escalation decisions, facilitating PK/PD modeling, and/or 
to support clinical development.  Unblinded results will be reviewed by a designated limited
number of sponsor colleagues within the study team.
The psoriasis multiple dose cohorts are double-blind with respect to investigator and subject. 
The psoriasis multiple dose cohorts will be sponsor-open (unblinded interim analysis results 
will be reviewed by a designated limited number of sponsor colleagues). In addition to the 
planned interim analysis from the 400 mg psoriasis cohort, the sponsor may analyze selected 
clinical endpoints at the end of the Psoriais treatment period (Day 28) before the follow-up 
period is completed for all cohorts.  For the purpose of safety assessment, select individuals
from sponsor may conduct unblinded reviews of individual subject safety data if needed to 
ensure proper management of subject safety. If needed, a designated limited number of 
sponsor colleagues may conduct unblinded reviews of the data during the course of the study 
to facilitate PK/PD modeling.
Refer to the study’s Data Blinding Plan and/or Statistical Analysis Plan for specific details 
including delineation of study team members who will be involved in these unblinded 
reviews as well as steps to be instituted ahead of initiation of any unblinded review to ensure 
study integrity is maintained.
9.8. Data Monitoring Committee 
This study will not use an external data monitoring committee (DMC).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs[/DCTs] are accurate.  The investigator and institution 
will allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 


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investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, it is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent[/assent] documents, copies of all CRFs, safety reporting forms, source 
documents, detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.


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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent[/assent] documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.


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The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06826647 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Fredriksson T, Pettersson U. Severe psoriasis – oral therapy with a new retinoid. 
Dermatologica 1978; 157 (4):238-44.
2.
Long CC, Finlay AY, Averill RW. The rule of hand: 4 hand areas = 2FTU = 1g. Arch 
Dermatol 1992; 128 (8) :1129-30.
3.
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical 
measure for routine clinical use. Clin Exp Dermatol 1994; 19 (3) :210-6.
4.
Mazzotti E, Picardi A, Sampogna F, et al.  Sensitivity of the Dermatology Life Quality 
Index to clinical change in patients with psoriasis. Br J Dermatol 2003; 149 (2) :318-22.
5.
Murray PJ.The JAK-STAT signaling pathway: input and output integration. J Immunol. 
2007;178:2623-9.
6.
O'Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
Jak-Stat-Socs pathway in disease. Mol Immunol. 2007;44:2497-506.
7.
Zhu Y, Ye X, Zhu B, et al. Comparisons between the 2012 New CKD-EPI (Chronic 
Kidney Disease Epidemiology Collaboration) Equations and Other Four Approved 
Equations. PLoS ONE 9(1): e84688. doi: 10.1371/journal.pone.0084688.
8.
Hoek FJ, Kemperman FAW, Krediet RT. A comparison between cystatin C, plasma
creatinine and the Cockcroft and Gault formula for the estimation of glomerular
filtration rate. Nephrology Dialysis Transplantation 2003; 18(10): 2024-31.
9.
Newman DJ, Thakkar H, Edwards RG, et al. Serum cystatin C measured by automated
immunoassay: A more sensitive marker of changes in GFR than serum creatinine.  
Kidney International 1995; 47(1): 312-8.
10.
Dharnidharka VR, Kwon c, Stevens G. Serum cystatin C is superior to serum creatinine
as a marker of kidney function: A meta-analysis. American Journal of Kidney Diseases
2002; 40(2): 221-6.
11.
Inker LA, Schmid CH, Tighiouart H, et al. Estimating Glomerular Filtration Rate from
Serum Creatinine and Cystatin C. New England Journal of Medicine 2012; 367(1):20-9.


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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
Abs
Absolute
Ae12/24
amount of unchanged drug excreted into urine from time 0 to 
12 hours or 0-24 hours, respectively
Ae12/24%
percentage of dose excreted unchanged into urine from 0 to 12 hours 
or 0 to 24 hours, respectively
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate 
AUC
area under the curve
AUC0-24
area under the concentration time curve from time zero to 24 hours 
after single dose
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration
AUCtau
area under the concentration-time curve over the the dosing interval 
tau 
BA
Bioavailability
BBS
Biospecimen Banking System
BCG
bacille Calmette-Guérin 
BE
Bioequivalence
BID
Bis in die (twice a day)
BMI
body mass index
BP
blood pressure
BPM
beats per minute
BU
business unit
BUN
blood urea nitrogen
Cav
average concentration
C-CASA
Columbia-Classification Algorithm of Suicide Assessment
CD
Crohn’s disease
CDS
core data sheet
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Abbreviation
Term
Ceff
efficacious concentration
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CK
creatine kinase
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
plasma clearance
CL/F
Apparent total clearance of the drug from plasma after oral 
administration
CLr
renal clearance
Cmax
peak or maximum observed concentration
Cmin
Minimum plasma drug concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRP
C-reactive protein
CRU
Clinical Research Unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTC
Common Terminology Criteria
DAI
dosage and administration instructions
DCT
data collection tool
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
Electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
Extemporaneous Dispensing Record
CCI
CCI
CCI
CCI


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Abbreviation
Term
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eGFR
estimated glomerular filtration rate
EOT
end of treatment
EPO
erythropoietin
ET
early termination
EU
European Union
EIU
exposure in utero
ESoE
Early signal of efficacy
ERB
external review board
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FFPE
formalin-fixed paraffin-embedded 
FIH
first in human
FISH
Fluorescence in situ hybridization
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLDH
glutamate dehydrogenase
GLP
Good laboratory practice
GM-CSF
Granulocyte-Macrophage Colony Stimulating Factor
GBP1
Guanylate binding protein 1
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCT
Hematocrit
HCV
Hepatitis C virus
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol
HED
human equivalent dose
HEP
human hepatocytes
HepBcAb
hepatitis B core antibody
HepBsAg
hepatitis B surface antigen
hERG
human ether a-go-go gene
HGB
hemoglobin
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Abbreviation
Term
HIV
human immunodeficiency virus
HLM
human liver microsomes
HSV
herpes simplex virus
HVs
healthy volunteers
HWB
Human whole blood
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IC50
50% inhibitory concentration
ID
Identification
IEC
independent ethics committee
IFN
type I interferon
IGRA
interferon gamma release assay
IND
investigational new drug application
INR
international normalized ratio
IL
interleukin
IOBU-SDMC
Internal Oncology Business Unit -Safety Data Monitoring 
Committee 
IP
Investigational product
IR
Immediate release
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
IUS
Intrauterine system
IV
intravenous
JAK
Janus kinase
KDIGO
Kidney Disease: Improving Global Outcomes
KDR
kinase insert domain receptor
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LDLC
low density lipoprotein cholesterol
LFT
liver function test
LLN
lower limit of normal
L-PASI
Linear method Psoriasis Area and Severity Index
LPD
local product document
CCI
CCI
CCI
CCI


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Abbreviation
Term
LSLV
last subject last visit 
MAD
multiple ascending dose
MATE
multidrug and toxin extrusion protein
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDR1
multidrug resistant protein 1
MedDRA
medical Dictionary for Regulatory Activities
mRNA
messenger riboneuclic acid
MTD
maximum tolerated dose
MRP
multidrug resistance-associated protein
MRT
mean residence time
NAPAC
Neuropsychiatric and Abuse Potential Advisory Council
N/A
not applicable
NK
Natural Killer cell
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NRS
Numeric Rating Scale
NTCP
sodium/taurocholate co-transporting polypeptide
OATP
organic anion transporting polypeptide
OBU
Oncology Business Unit
OCT
organic cation transporter
OEB5
occupational exposure banding 5
PBMC
periperhal blood mononucleated cell 
PCD
primary completion date
PCRU
Pfizer Clinical Research Unit
PD
Pharmacodynamics
PGx
Pharmacogenomics
P-gp
P glycoprotein
PHQ-8
Patient health questionnaire
PI
principal investigator
PK
Pharmacokinetics
PR
pulse rate
PROs
patient reported outcomes
PT
prothrombin time
PUVA
Psoralen ultraviolet A 
QC
quality control
QD
Once daily
QFT
QuantiFERONR TB
QFT-G
QuantiFERONR TB Gold
CCI
CCI
CCI


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Abbreviation
Term
QFT-GIT
QuantiFERON TB Gold In Tube test
QTc
corrected QT
RBC
red blood cell
RNA
ribonucleic acid
RSAD2
radical S-adenosyl methionine domain-containing protein 2
S Cystatin C
serum Cystatin C 
SAD
ascending dose period
SAE
serious adverse event
SAP
statistical analysis plan
SBQ-R
Suicidal behaviors questionnaire
SCr
serum creatinine
sd
single dose
SDD
sprayed-dried dispersion
SGOT
serum glutamic oxaloacetic transminase
SGPT
serum glutamic pyruvic transminase
SIB
suicidal ideation and behavior
SLE
Systemic lupus erythematosus 
SOP
standard operating procedure
SRSD
single reference study document
ss
steady state
STAT
Signal Transducer and Activator of Transcription
T1/2
terminal half life
Tau
dosing interval of 12 or 24 hours
TB
tuberculosis
TBili
total bilirubin
TC
Total cholesterol
TG
Total triglycerides
Th1
T-helper 1
Th17
T-helper 17
Tmax
time to reach maximum concentration
THC
Tetrahydrocannabinol
UGT
UDP-glucuronosyltransferase 
ULN
upper limit of normal
US
United States
USP18
ubiquitin specific peptidase 18
USPI
United States package insert
UV
ultraviolet
UVA
ultraviolet A
UVB
ultraviolet B
VEGFR2
vascular endothelial growth factor receptor 2
Vss
Apparent volume of distribution at steady state
CCI
CCI


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Abbreviation
Term
Vz/F
apparent oral volume of distribution
WBC
white blood cell
CCI


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Appendix 2. Cockcroft-Gault Calculation
The Cockcroft-Gault formula may be used to calculate an Estimated Creatinine Clearance, 
which in turn estimates Glomerular filtration rate (GFR)
Est. Creatinine Clearance (mL/min) = ([140-Age(years)] x Weight(kg) x Factora)
(72 x Serum Creatinine [mg/dL])
a
Factor is equal to 0.85 in females, and 1.00 in males


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Appendix 3. Prohibited Concomitant Medications
CYP1A2, CYP3A4, CYP2D6 
Inhibitors 
CYP1A2, CYP3A4, 
Inducers
MATE substrates
CYP 1A2
CYP 1A2
Ciprofloxacin
Phenytoin
Dofetilide
Clinafloxacin
Rifampin
Metformin
Enoxacin
Ritonavir
Fluvoxamine
Teriflunomide
Oltipraz
Rofecoxib
Zafirlukast
Etintidine
Idrocilamide
Methoxsalen
Mexiletine
Oral contraceptive
Phenylpropanolamine
Pipemidic acid
Propafenone
Propranolol
Troleandomycin
Vemurafenib
CYP 2D6
Quinidine
Fluoxetine
Dacomitinib
Paroxetine
Buproprion
Cinacalcet
Terbinafine
Tipranavir
Moclobemide
Rolapitant
Mirabegron
Duloxetine
Eliglustat
Dronedarone
CYP3A4
CYP3A4
Viekira pak
Rifampin
Indinavir
Mitotane
Tipranavir
Avasimibe


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CYP1A2, CYP3A4, CYP2D6 
Inhibitors 
CYP1A2, CYP3A4, 
Inducers
MATE substrates
Ritonavir
Phenytoin
Cobicistat
Carbamazepine
Ketoconazole
Enzalutamide
Troleandomycin
St. John’s wort
Telaprevir
Rifabutin
Danoprevir
Phenobarbital
Elvitegravir
Saquinavir
Semagacestat
Lopinavir
Efavirenz
Itraconazole
Bosentan
Voriconazole
Genistein
Mibefradil
Thioridazine
Clarithromycin
Nafcillin
Posaconazole
Talviraline
Telithromycin
Lopinavir
Grapefruit Juice
Modafanil
Conivaptan
Etravirine
Nefazodone
Lersivirine
Nelfinavir
Saquinavir
Idelalisib
Boceprevir
Erythromycin
Fluconazole
Atazanavir
Darunavir
Diltiazem
Dronedarone
Crizotinib
Aprepitant
Casopitant
Amprenavir
Faldaprevir
Imatinib
Verapamil
Netupitant
Nilotinib
Tofisopam
Cyclosporine
Ciprofloxacin
Isavuconazole
Cimetidine


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Appendix 4. Estimated Glomerular Filtration Rate
The estimated GFR (eGFR) will be calculated using the 2 sets of equations developed by the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), which utilize serum 
creatinine (SCr) and serum Cystatin C (S Cystatin C) respectively.7
CKD-EPI2009Scr
If female and SCr is 0.7 mg/dL:

GFR (mL/min/1.73 m2) = 144 x (Scr/0.7) – 0.329 x 0.993age (x 1.159, if black)
If female and SCr is >0.7 mg/dL:

GFR (mL/min/1.73 m2) = 144 x (Scr/0.7) – 1.209 x 0.993age (x 1.159, if black)
If male and SCr is 0.9 mg/dL:

GFR (mL/min/1.73 m2) = 141 x (Scr/0.9) – 0.411 x 0.993age (x 1.159, if black)
If male and SCr is >0.9 mg/dL:

GFR (mL/min/1.73 m2) = 141 x (Scr/0.9) – 1.209 x 0.993age (x 1.159, if black)
CKD-EPI2012cys
If female and Scys is 0.8 mg/L:

GFR (mL/min/1.73 m2) = 133 x (Scys /0.8) –0.499 x 0.996age x 0.932
If female and Scys is >0.8 mg/L:

GFR (mL/min/1.73 m2) = 133 x (Scys /0.8) –1.328 x 0.996age x 0.932
If male and Scys is 0.8 mg/L:

GFR (mL/min/1.73 m2) = 133 x (Scys /0.8) –0.499 x 0.996age
If male and Scys is >0.8 mg/L:

GFR (mL/min/1.73 m2) = 133 x (Scys /0.8) –1.328 x 0.996age


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Appendix 8. Patient Global Assessment of Psoriasis
Clear (no psoriasis)
Almost Clear
Mild
Moderate
Severe
Clear (no psoriasis)
Almost Clear
Mild
Moderate
Severe
Overall, how would you describe your psoriasis right now?
Choose only ONE response.
My psoriasis is:


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Appendix 10. Suicidal Behaviors Questionnaire-Revised (SBQ-R)


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Appendix 11. Patient Health Questionnaire – 8 items (PHQ-8)

SAP_001.pdf: 
Protocol C2501001 (PF-06826647) Statistical Analysis Plan 
 
 
Page 1 of 40 
 
TMF Doc ID: 98.03 
 
 
 
 
Protocol C2501001 
 
 
 
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-06826647 IN HEALTHY SUBJECTS AND SUBJECTS WITH PLAQUE 
PSORIASIS  
 
 
Statistical Analysis Plan  
(SAP) 
Version: 
1.0 
Author:  
 
 – Cambridge, MA 02139) 
Date:  
12-June-2018 
 
PPD
PPD


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................5 
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6 
2. INTRODUCTION .................................................................................................................6 
2.1. Study Design .............................................................................................................6 
2.1.1. Healthy Subject Single and Multiple Ascending Dose Periods ....................6 
2.1.2. Psoriasis Multiple Dose Cohorts ..................................................................8 
2.2. Study Objectives .....................................................................................................10 
2.2.1. Objectives: Healthy Subject Single and Multiple Ascending Dose 
Segments ..........................................................................................................10 
2.2.1.1. Primary Objective .....................................................................10 
2.2.1.2. Secondary Objectives ................................................................10 
 
2.2.2. Objectives: Psoriasis Multiple Dose Segment ............................................11 
2.2.2.1. Primary Objective .....................................................................11 
2.2.2.2. Secondary Objectives ................................................................11 
 
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ................................12 
4. HYPOTHESES AND DECISION RULES .........................................................................13 
4.1. Statistical Hypotheses .............................................................................................13 
4.2. Statistical Decision Rules ........................................................................................13 
5. ANALYSIS SETS ...............................................................................................................13 
5.1. Full Analysis Set .....................................................................................................13 
5.2. Pharmacokinetic Analysis Set .................................................................................13 
5.2.1. Concentration Analysis Set .........................................................................13 
5.2.2. Parameter Analysis Set ...............................................................................13 
5.3. Pharmacodynamic Analysis Set ..............................................................................13 
5.4. Safety Analysis Set ..................................................................................................13 
5.5. Other Analysis Sets .................................................................................................13 
5.6. Treatment Misallocations ........................................................................................13 
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5.7. Protocol Deviations .................................................................................................14 
5.7.1. Deviations Assessed Prior to Randomization .............................................14 
5.7.2. Deviations Assessed Post-Randomization ..................................................14 
6. ENDPOINTS AND COVARIATES ...................................................................................14 
6.1. Endpoints: Healthy Subject Single and Multiple Ascending Dose Segments ........14 
6.1.1. Primary Endpoint(s) - Safety ......................................................................14 
6.1.2. Secondary Endpoint(s) ................................................................................15 
 
6.2. Endpoints: Psoriasis Multiple Dose Cohorts ...........................................................16 
6.2.1. Primary Endpoint(s) – Safety .....................................................................16 
6.2.2. Secondary Endpoints ..................................................................................16 
 
 
 
6.3. Safety Endpoints .....................................................................................................17 
6.3.1. Adverse Events ...........................................................................................18 
6.3.2. Laboratory Safety Tests ..............................................................................18 
6.3.3. Vital Signs ..................................................................................................18 
6.3.4. ECG ............................................................................................................18 
6.3.5. Other Safety Data .......................................................................................19 
6.4. Pharmacokinetic Endpoints .....................................................................................19 
 
7. HANDLING OF MISSING VALUES ................................................................................21 
7.1. Concentrations below the Limit of Quantification ..................................................21 
7.2. Deviations, Missing Concentrations and Anomalous Values .................................21 
7.3. Pharmacokinetic Parameters ...................................................................................21 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................22 
8.1. Sample Size Determination .....................................................................................22 
8.1.1. Healthy Subject Single Ascending and Multiple Dose ...............................22 
8.1.2. Psoriasis Multiple Dose ..............................................................................22 
8.2. Statistical Methods ..................................................................................................23 
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8.2.1. Statistical Method: Healthy Subject Single and Multiple Ascending 
Dose Segments .................................................................................................23 
8.2.2. Statistical Method: Psoriasis Multiple Dose Segment ................................23 
8.2.2.1. Method for Continuous Endpoints ............................................23 
8.2.2.2. Method for Binary and Ordinal Endpoints ................................23 
8.3. Statistical Analyses .................................................................................................24 
8.3.1. Pharmacokinetic Analysis ..........................................................................24 
8.3.1.1. Pharmacokinetic Parameters .....................................................24 
 
 
 
 
8.4. Safety Analysis ........................................................................................................26 
8.4.1. Treatment and Disposition of Subjects .......................................................27 
8.4.2. Demographic and Clinical Examination Data ............................................27 
8.4.3. Discontinuation(s) .......................................................................................27 
8.4.4. Adverse Events ...........................................................................................27 
8.4.5. Laboratory Data ..........................................................................................27 
8.4.6. Vital Signs Data ..........................................................................................27 
8.4.7. ECG Data ....................................................................................................28 
8.4.8. Other Safety Data .......................................................................................29 
8.4.9. Concomitant Treatments .............................................................................29 
8.4.10. Screening and Other Special Purpose Data ..............................................29 
9. APPENDICES .....................................................................................................................30 
9.1. Definition of Endpoints in Psoriasis Cohort ...........................................................30 
9.1.1. Psoriasis Area and Severity Index (PASI) ..................................................30 
 
 
 
 
 
 
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9.2. SAS Code ................................................................................................................38 
9.2.1. Continuous Data Analysis ..........................................................................38 
9.2.2. SAS Code for the Generalized Linear Mixed Model for Binary 
Longitudinal Data ............................................................................................38 
9.2.3. SAS Code for the Confidence Interval for Risk Difference using 
Chan and Zhang (1999)3 ..................................................................................39 
9.2.4. SAS code for the Confidence Interval of a Binomial Proportion 
(Blyth-Still-Casella) .........................................................................................39 
9.3. Assignment of Observations to the Visits ...............................................................39 
9.4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .........40 
10. REFERENCES ..................................................................................................................40 
 
LIST OF TABLES 
Table 1. 
PK Parameters to be Summarized Descriptively ..................................................24 
 
NOTE:  Italicized text within this document has been taken verbatim from the Protocol. 
 


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1. AMENDMENTS FROM PREVIOUS VERSION(S)  
None. 
2. INTRODUCTION 
The Janus kinase (JAK) family, including JAK1, JAK2, JAK3 and Tyrosine kinase 2 (TYK2), 
is a group of cytoplasmic tyrosine kinases that mediate signal transduction via interactions 
with Type 1 and Type 2 cytokine receptors critical for leukocyte activation, proliferation, 
survival and function (Murray PJ et al, 2007; O'Sullivan LA et al, 2007).  
PF-06826647 is a potent TYK2 inhibitor with a good selectivity profile over other human 
kinases.  Based on its cytokine inhibition profile, PF-06826647 is expected to target the 
T-helper 1 (Th1) and T-helper 17 (Th17) pathways, and Types I and II interferon signaling, 
directly by inhibiting TYK2, and to provide therapeutic benefit in the treatment of 
inflammatory conditions driven by Th1/Th17 and interferon immune responses.  
This single- and multiple-ascending dose study is the first evaluation of PF-06826647 in 
humans.  The goal is to assess the safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) in healthy subjects and subjects with plaque psoriasis.  The 
inclusion of a psoriasis cohort will facilitate optimal assessment of TYK2 modulation in vivo, 
given that Th1 and Th17 pathways are not up regulated in the absence of inflammation.  
2.1. Study Design 
The study may be conducted at 1-3 study sites in the United States. 
This study is a Phase 1 combination, within cohort, randomized, double blind, third-party 
open, placebo-controlled, parallel group study with single- and multiple-dose escalation in 
healthy adult subjects, and multiple dosing in subjects with plaque psoriasis.  
Subjects will be screened within 28 days prior to administration of study drug to confirm that 
they meet the subject selection criteria for the study, as described in Section 6.1 of the 
C2501001 clinical protocol.  A summary of the schedule of study participation and 
procedures for the single- and multiple ascending dose periods of the study are provided in 
their respective Schedule of Activities in the protocol. 
2.1.1. Healthy Subject Single and Multiple Ascending Dose Periods 
In the combined single ascending and multiple ascending dose (SAD/MAD) healthy subject 
cohorts (except the Japanese cohort) there will be approximately 8 subjects per dose level; 
6 subjects will receive PF-06826647 and 2 subjects will receive placebo per the 
randomization code.  The health subject in Japanese cohort may include approximately 6 
healthy subjects among which 4 subjects will receive PF-06826647 and 2 subjects will 
receive placebo. 


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Healthy subjects will be randomized (once) into the SAD period, at which time, they will 
receive treatment assignment (active PF-06826647 dose level or placebo) for both the SAD 
and MAD periods.  Subjects will receive the same blinded treatment assignment (ie, active 
PF-06826647 or placebo) throughout in both the SAD (Period 1) and MAD (Period 2) 
periods.  
During the single ascending dose (SAD) period, healthy subjects in Cohort 1 to Cohort 6 will 
receive single doses of 3, 10, 30, 100, 400, or 1600 mg of PF-06826647 or placebo in a dose 
escalation format as shown in the Study Schema (Figure 1) of the protocol.  The doses and 
meal condition of optional cohorts (Cohort 7 and Cohort 8) will be decided on emerging PK, 
 and safety data from prior SAD and MAD cohorts.  Dose escalation to 
subsequent cohorts will be based on a minimum of 3 days of safety data and PK over 
24 hours in a minimum of 6 subjects enrolled in a cohort.  Subjects will reside in the clinical 
research unit (CRU) for the single ascending dose phase from Day -1 until completion of 
protocol assessments on Day 4.  Dosing occurs on Day 1.  Subjects will return to the unit on 
Day 8 (r1) day for the end of single dose period assessment and PK sample.  
At least 14 days (minimum wash-out period) will separate the beginning of the single and 
multiple dose periods (ie, at least 14 days will separate the single dose administered in the 
SAD and the first QD dose in the MAD); however, the minimum wash-out period may be 
adjusted based on emerging PK data.  Based on the PK predictions and emerging PK data 
from this study, the currently planned starting dose in the MAD period is 30 mg (previously, 
a PF-06826647 starting dose of 10 mg was planned for the MAD period under the original 
protocol) is not expected to provide pharmacologically relevant exposure.  In the multiple 
ascending dose (MAD) period, healthy subjects in Cohort 3 to Cohort 6 in Period 2 will 
receive doses of 30, 100, 400, or 1200 mg QD of PF-06826647 or placebo for 10 days 
(Day 1 through Day 10) with standard meal.  The dose of Cohort 6 in MAD (Period 2) may 
be adjusted based on emerging data from earlier MAD cohorts in the trial.  Subjects will be 
housed for the duration of the multiple dosing period, discharged on the morning of Day 14.  
Subjects will return for outpatient visits on morning of Day 17 for PK sample collection and 
Day 28 (r3 days) for end of study procedures.  Based on emerging PK data, subject may be 
asked to return between Day 17 and Day 28 for an additional outpatient visit for PK sample 
collection.  The additional PK sample will allow characterization of terminal half-lives at 
higher dose cohorts.  
The multiple ascending dose study is planned to be initiated in the same subjects who 
previously participated in the single dose period at the same dose level, when possible 
(except for the optional twice daily, BID cohort and optional Japanese cohort).  The highest 
dose to be tested in MAD will not exceed the highest dose tested in SAD cohort.  Except the 
highest dose cohort, dosing in the MAD period will commence at the intended dose level 
(eg, 30 mg QD) if adequate single dose safety is demonstrated for next dose level (eg, 100 mg 
SAD).  Subsequent MAD cohorts at higher dose levels (eg, 100 mg QD) will not be initiated 
until the single dose safety/tolerability has been established up to next dose level 
(eg, 400 mg), and a minimum of 10 days of safety and PK data from the preceding multiple 
dose cohort (eg, 10 mg QD) from at least 6 subjects (with at least one subject on placebo) 
has been reviewed.  The remainder of the cohorts (except highest dose cohort) will follow a 
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similar escalation paradigm.  Dosing in highest dose MAD cohort will commence if adequate 
safety is demonstrated in SAD cohort at the same or higher dose level and the projected 
exposure at steady state does not exceed NOAEL.  
Twice daily (BID) dosing (for 10 days) may be evaluated as a separate cohort based on 
emerging PK data from this FIH study.  Dosing in the BID cohort will not commence until 
review of safety data from the equivalent QD MAD cohort (minimum review of 10 day safety 
and PK data in at least 6 subjects, with at least one subject on placebo). 
An optional Japanese cohort may also be included.  If conducted, the dose administered will 
be equal to or less than the maximum PF-06826647 dose level administered in the healthy 
volunteer MAD period.  Up to 8 subjects (including subjects on placebo) may be included in 
the optional Japanese cohort.  
Administration of investigational product will be in fasted state in the SAD period and under 
standard meal conditions in MAD and in psoriasis cohorts.  Based on the emerging PK, 
 
and safety data, the meal condition requirement in SAD, MAD and psoriasis 
cohorts may be changed.  
During the single and multiple ascending dose periods the dose increments and planned 
doses may be adjusted, as the study progresses dependent upon emerging PK, safety, and 
tolerability data.  Other intermediate doses or lower doses may be administered instead of 
the planned doses, or changes in dosing frequency or titration schemes may be proposed for 
MAD cohorts if safety/tolerability issues become apparent, if evidence of nonlinear PK 
dictates the need to escalate more slowly, or if subsequent doses are predicted to result in 
exposures that exceed the target limits.  Any potential altered dose scheme will be equal to or 
less than a projected 3-fold increase in exposure from the previous highest dose if a higher 
dose is warranted to achieve exposure.  The projected exposure will be equal to or less than 
a free AUC of 16600 ng.h/mL or free Cmax of 1870 ng/mL following either single dose or 
multiple dose administration to ensure that the projected exposure of the altered planned 
dose scheme does not exceed the exposure limit. 
2.1.2. Psoriasis Multiple Dose Cohorts 
In the multiple dose psoriasis subject cohorts, approximately 42 subjects will be enrolled 
with approximately 14 subjects receiving placebo, and approximately 28 subjects receiving 
one of two possible PF-06826647 dose levels, for 28 days.  PF-06826647 dose range for the 
psoriasis cohorts will be selected based on emerging PK, PD, and safety data from the 
healthy subjects SAD/MAD periods.  Refer to Protocol Section 1.3.4.1 for psoriasis dose 
selection rationale.  QD dosing is planned for psoriasis subjects, however, daily dosing 
regimen (eg, QD, BID) may be adjusted based on emerging PK data from the SAD/MAD 
periods.  Psoriasis subjects who discontinue early from the trial may be replaced at the 
discretion of the sponsor.  PF-06826647 dose level in psoriasis may be adjusted based on 
emerging clinical data from the planned interim analysis, at the discretion of the Sponsor.  
Any potential PF-06826647 dose adjustments for psoriasis Cohort 2 will be applied after 
review of PK, PD and safety data up to 28 day in the 400 mg psoriasis cohort.  
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Initiation of dosing in psoriasis subjects will be based on available safety data from the 
healthy subject MAD period.  Psoriasis subjects enrolled into the multiple dosing period will 
receive PF-06826647 or placebo (QD) for 28 days, with a 56 day follow-up period post last 
dose.  Doses will be selected based on emerging PK, PD and safety data from the study (not 
to exceed Cmax and AUC0-24 limits of 1870 ng/mL and 16,600 ng·h/mL, respectively).  Dosing 
in psoriasis subjects will commence if adequate safety is demonstrated in healthy subjects 
participating in the MAD period at the equivalent dose level.  At a minimum, 10 day safety 
and PK data from at least 6 healthy subjects (with at least one subject on placebo) receiving 
the equivalent QD dose level will be reviewed to confirm that a given PF-06826647 dose is 
safe and well tolerated before administering PF-06826647 to psoriasis subjects.  Subjects 
will be housed through Day 28 of the multiple dosing period, discharged on Day 28, to 
return for outpatient visits on the mornings of Days 35 (r3 days), 42 (r3 days), 56 (r3 days) 
and 84 (r3 days)(end of study).  The 28 day treatment duration is supported by preclinical 
toxicology data and will facilitate assessment of 
, as well as 
assessment of clinical endpoints (eg, PASI).  
Figure 1. Study Schema 
 
 
 
Numbers 1 – 8 refer to subject cohorts.  Subjects completing the SAD period will continue into the MAD period 
when applicable, after protocol defined washout and follow up.  
* Cohorts 7 and 8 are optional single dose cohorts that may be conducted at discretion of Sponsor and based 
on emerging PK data.  If conducted, the dose and meal condition will be decided based on emerging PK, PD, 
and safety data from the multiple ascending dose period of the trial.  
** Cohort 9 is an optional cohort for assessment of twice daily (BID) PF-06826647 dosing.  BID dose level will 
be determined based on emerging PK, PD, safety and tolerability data.  The planned PF-06826647 dose level to 
be administered in the BID cohort is 200 mg twice daily (total daily dose of 400 mg).  
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*** Based on interim analysis results from 400 mg psoriasis cohort, the PF-06826647 dose level for psoriasis 
Cohort 2 may be adjusted.  The maximum dose administered to psoriasis subjects will not be expected to exceed 
the exposure at the maximum tolerated dose in the healthy subject MAD period. 
HVs = healthy volunteers 
All cohorts are placebo controlled.  
Note on optional Japanese subject cohort: if conducted, administration of PF-06826647 (or matching placebo) 
to Japanese subjects will occur once daily for 10 day duration, and subjects will follow the MAD period 
schedule of activities.  
Figure 2. Legend for Figure 1 
SAD = Single ascending dose Period 1                 QD = once daily  
MAD=multiple ascending dose Period 2              BID=twice daily  
 
2.2. Study Objectives 
2.2.1. Objectives: Healthy Subject Single and Multiple Ascending Dose Segments 
2.2.1.1. Primary Objective
x To determine the safety and tolerability of escalating single and multiple doses of 
PF-06826647 administered to healthy subjects. 
2.2.1.2. Secondary Objectives 
x To characterize the PK of PF 06826647 in plasma and urine (urine PK in multiple 
ascending dose period only) following oral administration of escalating single and 
multiple oral doses to healthy subjects. 


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2.2.2. Objectives: Psoriasis Multiple Dose Segment 
2.2.2.1. Primary Objective 
x To determine the safety and tolerability of multiple dose administration of 
PF-06826647 in psoriasis subjects. 
2.2.2.2. Secondary Objectives 
x To characterize the PK of PF-06826647 in plasma following oral administration of 
multiple oral doses to plaque psoriasis subjects. 
x To evaluate the efficacy of PF-06826647 in moderate to severe plaque psoriasis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
Safety and pharmacokinetic (PK) data will be reviewed after each study cohort and period. 
This is a third party open study, with the investigator and subject blinded to study treatment.  
Specific Pfizer personnel (analytical staff, medical monitor, clinician, statistician, and 
pharmacokineticist) will be unblinded to subject treatments in order to permit real-time 
interpretation of the safety and pharmacokinetic data, and to provide information necessary 
to potentially alter the dose escalation sequence.  To minimize the potential for bias, 
treatment randomization information will be kept confidential by Pfizer personnel and will 
not be released to the investigator/study staff until the conclusion of the study.  Unblinding 
will not be performed until the final database has been locked for all cohorts.  Final analysis 
will follow the official database release. 
An interim analysis of the change from baseline at Day 28 in PASI score (psoriasis key 
secondary endpoint) will be conducted for the first psoriasis cohort (400 mg dose cohort).  
The analysis will be performed when approximately 21 psoriasis subjects from the 400 mg 
cohort complete through study Day 28.  Outcomes from this interim analysis may inform 
dose selection decisions/adjustments for later psoriasis subject cohorts to be enrolled in the 
study.  The interim analysis is not planned to impact the conduct of the initial 400 mg 
psoriasis cohort.  The analysis is planned to be performed after dosing of the full 400 mg 
psoriasis cohort (n=21 subjects completing through study Day 28).  Any decisions or dose 
adjustments that are taken, will be applied to the subsequent psoriasis cohort.  A designated 
limited number of Sponsor colleagues will review the interim analysis results to support any 
dose related decisions.  For the healthy SAD/MAD cohorts, this is a sponsor-open study, and 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or to support clinical development.  Unblinded results will be reviewed by a 
designated limited number of sponsor colleagues within the study team.  A separate 
document containing the list of designated unblinded sponsor colleagues for the interim 
analysis will be prepared (see the Data Blinding Plan for further details) and saved in the 
SharePoint. 
The psoriasis multiple dose cohorts are double-blind with respect to investigator and subject.  
The psoriasis multiple dose cohorts will be sponsor-open (unblinded interim analysis results 
will be reviewed by a designated limited number of sponsor colleagues).  In addition to the 
planned interim analysis from the 400 mg psoriasis cohort, the sponsor may analyze selected 
clinical endpoints at the end of the Psoriasis treatment period (Day 28) before the follow-up 
period is completed for all cohorts.  For the purpose of safety assessment, select individuals 
from sponsor may conduct unblinded reviews of individual subject safety data if needed to 
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ensure proper management of subject safety.  If needed, a designated limited number of 
sponsor colleagues may conduct unblinded reviews of the data during the course of the study 
to facilitate PK/PD modeling.  
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
No classical hypothesis testing will be performed. 
4.2. Statistical Decision Rules 
Not applicable.  
5. ANALYSIS SETS 
5.1. Full Analysis Set 
In general, the full analysis set is comprised of all randomized subjects.  Analysis sets for 
PK, pharmacodynamic and safety data are defined in Sections 5.2, 5.3 and 5.4. 
5.2. Pharmacokinetic Analysis Set 
5.2.1. Concentration Analysis Set 
The PK concentration population is defined as all enrolled subjects treated who have at least 
1 concentration in at least 1 treatment period. 
5.2.2. Parameter Analysis Set 
The PK parameter analysis population is defined as all enrolled subjects treated who have at 
least 1 of the PK parameters of interest in at least 1 treatment period. 
5.3. Pharmacodynamic Analysis Set 
The pharmacodynamic analysis population is defined as all enrolled subjects who receive at 
least 1 dose of study medication and have at least 1 pharmacodynamic parameter in at least 
1 treatment period. 
5.4. Safety Analysis Set 
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings. 
5.5. Other Analysis Sets 
None. 
5.6. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.  


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If a subject takes a treatment that is not consistent with the treatment they are randomized to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable. 
5.7. Protocol Deviations 
Subjects who experience events that may affect their PK profile (eg vomiting) may be 
excluded from the PK analysis.  At the discretion of the pharmacokineticist a concentration 
value may also be excluded if the deviation in sampling time is of sufficient concern or if the 
concentration is anomalous for any other reason.  
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure. 
5.7.1. Deviations Assessed Prior to Randomization 
At screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 – Section 4.4 of the protocol. 
5.7.2. Deviations Assessed Post-Randomization 
Any significant deviation from the protocol will be reviewed prior to database closure and a 
decision taken regarding evaluation for each analysis population. 
6. ENDPOINTS AND COVARIATES 
For the SAD/MAD and psoriasis cohorts, baseline is defined as the last pre-dose 
measurement from each period.  
6.1. Endpoints: Healthy Subject Single and Multiple Ascending Dose Segments 
6.1.1. Primary Endpoint(s) - Safety 
• Vital signs (blood pressure, pulse rate, oral temperature).  
• Physical examination findings over time. 
• 12-lead ECG parameters. 
• Incidence and severity of treatment emergent adverse events and withdrawals due to 
treatment emergent adverse events. 
• Incidence and magnitude of treatment emergent clinical laboratory abnormalities 
including hematology (with differentials), fibrinogen, chemistry, fasting glucose, 
lipids, urinalysis. 
• Change in 24 hour creatinine clearance from Day -1 and Day 10 (MAD only). 


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6.1.2. Secondary Endpoint(s) 
Systemic pharmacokinetics parameters (defined in Section 9.3.1 of the protocol) will include:  
x Single Dose: Cmax, Tmax, AUCinf, AUClast, AUC24, Cmax(dn), AUCinf(dn), AUClast(dn), t½, 
MRT, Vz/F, and CL/F (if data permit). 
x Multiple Dose:  
x Day 1: Cmax, Tmax, AUCtau (tau=12 or 24 hours), Cmax(dn), AUCtau(dn).  
x Day 10: Cmax, Tmax, AUCtau (tau=12 or 24 hours), Cmax(dn), AUCtau(dn), t½, Cmin, Cav, 
Rac, Rac,Cmax, PTR, MRT, Vz/F,CL/F (if data permit). 
x Urinary Pharmacokinetics (defined in Section 9.3.1 of the protocol; for healthy 
subjects, multiple ascending dose period only): Aetau and Aetau%, CLr (if data permit). 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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6.2. Endpoints: Psoriasis Multiple Dose Cohorts 
All subjects who receive at least one dose of randomized study medication, and have a 
baseline and at least one post-baseline measurement (after taking randomized study 
medication) will be included in the efficacy data analyses for the psoriasis cohorts. 
6.2.1. Primary Endpoint(s) – Safety 
x Vital signs (blood pressure, pulse rate, and oral temperature).  
x Physical examinations findings over time. 
x 12-lead ECG parameters. 
x Incidence and severity of treatment emergent adverse events and withdrawals due to 
treatment emergent adverse events. 
x Incidence and magnitude of treatment emergent clinical laboratory abnormalities 
including hematology (with differentials) chemistry, fasting glucose, lipids, urinalysis. 
6.2.2. Secondary Endpoints  
x Multiple Dose (defined in Section 9.3.1 of the protocol): Cmax, Tmax, AUCtau, Cmax(dn), 
AUCtau(dn), t½, PTR, Cmin, Cav, MRT, Vz/F and CL/F (if data permit). 
x Change from baseline in psoriasis area and severity index (PASI) score at Day 28. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
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6.3. Safety Endpoints 
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters): 
x adverse events, 
x laboratory data, 
x vital signs data, 
x ECG results. 
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6.3.1. Adverse Events 
Any events occurring following start of the treatment or increasing in severity will be 
counted as treatment emergent.  
Events that occur in a non-treatment period (for example, washout or follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken. 
6.3.2. Laboratory Safety Tests 
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
6.3.3. Vital Signs 
For subjects in study Periods 1 to 2, in each cohort, single supine measurements will be taken 
at times detailed in the Schedule of Activities given in the protocol. 
The following vital signs endpoints will be determined: 
• The maximum decrease and increase from baseline (pre-dose) over all measurements 
taken post-dose for supine systolic and diastolic blood pressures. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a subject does not show a 
decrease, the minimum increase should be taken. 
6.3.4. ECG 
12-lead ECGs will be recorded in triplicate for subjects in Periods 1 to 2 at times detailed in 
the Schedule of Activities given in the protocol. 
A single 12-lead ECG will be obtained on all subjects at screening and follow-up as well as 
on selected visits as detailed in Schedule of Activities section of the Protocol.  
The QT, QTc, PR, RR, QRS and heart rate will be recorded at each assessment time. 


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If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)1/3  
where RR = 60/HR (if not provided) 
If not supplied, QTcB will be derived using Bazett’s heart rate correction formula: 
QTcB = QT / (RR)1/2  
where RR = 60/HR (if not provided) 
The average of the triplicate readings collected at each assessment time will be calculated for 
each ECG parameter.  Baseline will be defined as the average of the triplicate predose 
recordings in each study period. 
The maximum absolute value (post-dose) and the maximum increase from baseline for 
QTcF, QT, heart rate, PR and QRS, will be determined over all measurements taken postdose 
for QTcF, PR and QRS. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken. 
6.3.5. Other Safety Data 
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database. 
6.4. Pharmacokinetic Endpoints 
Blood and urine samples for PK analysis of PF-06826647 will be taken according to the 
Schedule of Activities given in the protocol.  
The following PK parameters will be calculated for PF-06826647 (if possible) from the 
plasma concentration-time data using standard noncompartmental methods: 
 
Parameter 
Definition 
Method of Determination 
Plasma 
AUClast 
Concentration-time profile from time zero 
to the time of the last 
quantifiable concentration (Clast) 
Linear/Log trapezoidal method 
AUCτ 
Area under the plasma 
concentration-time profile over the dosing 
interval τ 
Linear/Log trapezoidal method 
AUCinf
a 
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time 
AUClast + (Clast*/kel), 
where Clast* is the predicted 
plasma concentration at the last 
quantifiable time point estimated 
from the log-linear regression 
analysis 
Cmax 
Maximum plasma concentration 
Observed directly from data 


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Parameter 
Definition 
Method of Determination 
Cmin 
Lowest concentration observed during 
dosing interval, τ; if measured at end of 
dosing interval, equivalent to Ctrough 
Observed directly from data 
Cav 
Average concentration at steady state 
Cav= AUCτ,ss/τ 
Tmax 
Time for Cmax 
Observed directly from data as time 
of first occurrence 
t1/2
 a 
Terminal elimination half-life 
Loge(2)/kel, 
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only 
those data points judged to describe 
the terminal log-linear decline will 
be used in the regression 
CL/Fa 
Apparent clearance 
Dose/AUCinf for SD  
Dose/AUCτ for MD 
Vz/Fa 
Apparent volume of distribution 
Dose/(AUCinf. kel) for SD  
Dose/(AUCτ. kel) for MD 
Rac 
Observed accumulation ratio based on 
AUC 
AUCτ (ss)/AUCτ (sd) 
Rac,Cmax 
Observed accumulation ratio based on Cmax Cmax (ss)/ Cmax (sd) 
PTR 
Peak to Trough ratio 
Cmax,ss/Cmin,ss  
MRT  
Mean residence time 
AUMCinf/AUCinf,  
where AUMCinf is the area under 
the first moment curve from time 
zero to infinity. 
Cmax(dn) 
Dose normalized Cmax 
Cmax/Dose 
AUClast(dn) 
Dose normalized AUClast 
AUClast/Dose 
AUCinf(dn)a 
Dose normalized AUCinf 
AUCinf/Dose 
Urine 
Aeτ 
Cumulative amount of drug recovered 
unchanged in urine from 0 to dose interval 
(τ) hours post-dose 
Sum of [urine concentration * 
sample volume] for each collection 
interval  
Aeτ% 
Percent of dose recovered unchanged in 
urine from 0 to dose interval (τ) hours 
post-dose 
Aeτ/Dose*100 
CLr 
Renal clearance 
Aeτ/AUCτ 
a If data permit 
The PK parameters will be summarized descriptively by dose, regimen and study population 
(healthy subject and psoriasis subject) in accordance with Pfizer data standards.  Summary 
statistics will also include the geometric mean and coefficient of variation for all parameters 
except Tmax. 
Dose normalized (to 1 mg) AUC and Cmax values of PF-06826647 will be plotted against 
dose (using a logarithmic scale if dose range is greater than 10-fold) for single- and multiple 
dose phases, and will include individual subject values and the geometric means for each 
dose.  These plots will be used to help understand the relationship between the plasma PK 
parameters and dose.  Additional PK analyses may be performed if deemed appropriate. 


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Urine amounts of PF-06826647 and CLr will be listed and summarized descriptively, if data 
permits. 
 (fasted) will be used as 
Reference and AUC24 and Cmax on Day 1 in MAD (QD) period (fed) as Test.  Natural log 
transformed AUC24 and Cmax will be analyzed using a mixed effect model with treatment 
(Dose levels) and period as a fixed effect and subjects within a treatment as a random effect.  
Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidence intervals will be obtained from the model.  The adjusted mean differences 
and 90% confidence for the differences will be exponentiated to provide estimates of the ratio 
of adjusted geometric means (Test/Reference) and 90% confidence intervals for the ratios.  
 
 
7. HANDLING OF MISSING VALUES 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
7.1. Concentrations below the Limit of Quantification 
In summary statistics for pharmacokinetic assayed values below the lower limit of 
quantification (LLOQ) will be set to zero.  The imputations (eg, ½ LLOQ) may be 
considered in other analyses (eg, Pop-PK, PK/
, and 
), if deemed 
appropriate.  In listings values below LLOQ will be reported as “<LLOQ” where LLOQ will 
be replaced with the numerical value for the lower limit of quantification.  The LLOQ for 
various PK and 
 concentrations will be noted in all tables and listings.  
7.2. Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true: 
1. A concentration has been collected as ND (ie not done) or NS (ie no sample), 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing. 
7.3. Pharmacokinetic Parameters 
Actual PK sampling times will be used in the derivation of PK parameters. 
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues). 
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In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with t3 evaluable measurements. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
While every effort has been made to pre-specify all analyses in this statistical analysis plan, 
should 
, the 
analyses and the reasons for them may be detailed in the clinical study report.  In all data 
presentations, results will be sorted by increasing dose level, starting with Placebo. 
8.1. Sample Size Determination 
8.1.1. Healthy Subject Single Ascending and Multiple Dose 
A sample size of 8 subjects in each SAD and MAD cohort (with 6 active and 2 placebo) with 
approximately 48 subjects (assuming 6 cohorts) and 24 subjects for optional cohorts 
MAD BID cohort, Cohort 7 and 8 is not based on any statistical considerations.  Sample size 
for optional Japanese subject cohort is not based on any statistical considerations, and may 
enroll up to 8 subjects in order to support characterization of the PF-06826647 PK profile in 
Japanese subjects.  The sample size was based on the clinical consideration to provide safety 
and tolerability information and pharmacological considerations and on the need to 
minimize exposure to healthy subjects at each dose level.  No formal inferential statistics will 
be applied to the safety, pharmacodynamic or pharmacokinetic data. 
8.1.2. Psoriasis Multiple Dose 
A sample size of approximately 42 subjects total is planned for the two psoriasis cohort(s).  
Psoriasis subjects will be randomized in each Psoriasis cohort to receive either active 
PF-06826647 (or placebo) with a planned randomization ratio of 2:1 
(PF-06826647:Placebo)  for each cohort.  The between-subject standard deviation of 
absolute PASI change from baseline to Day 28 (obtained from Sponsor data on file) is 
assumed to be 8.  The true difference between PF-06826647 and placebo is assumed to -7.8 
(derived from the meta-analysis of the Tofacitinib data).  Based on these assumptions the 
sample size is calculated to be 14 subjects per arm to provide approximately 80% power.  
This calculation assumes a one-sided alpha of 5%.  The initial estimate of the total number of 
completers for the psoriasis cohort will be 42 with 21 (14 active +7 placebo) in each cohort.  
Based on the results from the planned interim analysis (described in Section9.7 of the 
protocol) PF-06826647 dose level or regimen may be adjusted for subsequent psoriasis 
subjects/cohorts enrolled after the interim analysis.  
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8.2. Statistical Methods 
8.2.1. Statistical Method: Healthy Subject Single and Multiple Ascending Dose 
Segments 
Given the exploratory nature, descriptive statistics and graphic visualization will be provided 
for these segments.  No formal statistical hypothesis testing is planned.  
8.2.2. Statistical Method: Psoriasis Multiple Dose Segment 
8.2.2.1. Method for Continuous Endpoints 
The change from baseline in PASI scores at Day 28 in the psoriasis multiple dose segment is 
a secondary endpoint.  The treatment effect for each of the test dose groups is the treatment 
difference in the mean change from baseline of PASI score at Day 28 between the test dose 
and the placebo.  The estimates for treatment effect will be obtained by fitting a repeated 
measures linear model to the PASI change from baseline score.  The model will include 
treatment (active doses and placebo), week and treatment-by-week interaction as fixed effects 
and baseline PASI score as a covariate.  Estimates and 90% confidence intervals for 
treatment effect will be presented. 
For all other continuous endpoints except gene expression and histology data longitudinal 
analyses will be performed using a mixed model repeated measures (MMRM) analysis.  
  Endpoints 
may be transformed prior to analysis as needed.  
Each analysis will be performed with a restricted maximum likelihood (REML) MMRM 
analysis.  Change scores from baseline to the last post treatment visit will be calculated and 
used as dependent variable.  The model will include treatment and visit as fixed factors, 
along with the interaction of treatment and visit.  Baseline measurement will be used as a 
covariate.  An unstructured covariance structure will be used to model the within-subject 
variability.  In the event there are difficulties with initially fitting an unstructured covariance 
matrix, a variety of methods will be used to facilitate the computations.  The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom.  The model will 
be fit using SAS PROC MIXED.  Least squares (LS) means of the treatment groups at each 
available visit along with 90% CIs will be presented.  LS mean difference between treatment 
groups and between the current and baseline visit will be presented along with 90% 
confidence intervals.  Least squares means and confidence intervals will be back transformed 
to an appropriate scale when necessary. 
The sample SAS code for analysis of continuous data is presented in Section 9.2. 
8.2.2.2. Method for Binary and Ordinal Endpoints 
Binary and ordinal endpoints (such as 
 categories) will be summarized.  For a binary 
endpoint, the sample size, percentage, and corresponding 90% confidence intervals for each 
treatment arm, difference of proportions, corresponding confidence intervals and 2-sided 
p-value will be presented.  
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The exact confidence interval of a binomial proportion will be computed due to 
Blyth-Still-Casella (Casella (1986)).2  The estimated risk difference and the associated 
confidence interval of the risk differences will be computed based on the unconditional exact 
method proposed by Chan and Zhang (1999).3 
The sample SAS code for analysis of binary data is presented in Section 9.2. 
8.3. Statistical Analyses 
8.3.1. Pharmacokinetic Analysis 
8.3.1.1. Pharmacokinetic Parameters 
To assess the pharmacokinetics of PF-06826647, the PK parameters detailed in Section 6.4 
will be listed and summarized for subjects in the PK analysis set (as defined in Section 5.2).  
Missing values will be handled as detailed in Section 7.  Each PK parameter will be 
summarized by dosing regimen and period, and will include the set of summary statistics as 
specified in the table below: 
Table 1. 
PK Parameters to be Summarized Descriptively 
Parameter 
Summary Statistics 
AUClast, AUCinf, 
Cmax, AUClast(dn), 
AUCinf(dn), Cmin, Cav, 
AUCτ, Cmax(dn), Rac, 
Rac,Cmax, PTR, 
CL/F, and VZ/F, 
Aeτ, Aeτ% and CLr 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 
MRT and t1/2 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum. 
There will be 1 summary table presenting all PK parameters.  This will include data from all 
cohorts and will be paged by cohort.  The treatment subheading will include the cohort 
number and dosing regimen information.  
To assess the relationship between the PK parameters and dose, dose normalized AUCinf, 
AUClast and Cmax will be plotted against dose (using a logarithmic scale), and will include 
individual subject values and the geometric means for each dose.  Geometric means will have 
a different symbol than the individual values.  The values will be dose normalized (to a 1 mg 
dose) by dividing the individual values and raw geometric means by dose.  A footnote will be 
added to the plots to indicate that geometric means are presented and that data from both 
cohorts are presented on the plot. 
Natural log transformed AUCinf (if data permit),  AUClast and Cmax will be analyzed using a 
mixed effect model with dose as a fixed effect and subject as a random effect, for all cohorts 
in healthy volunteer; the similar exercise will be completed with patient cohort separately.  


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The purpose of these analyses is to obtain estimates of the intra-subject variation to assist in 
the planning of future studies.  No treatment contrasts will be provided. 
Supporting data from the estimation of t½ and AUCinf will be listed by analyte where 
applicable: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel.  This data may be included in the 
clinical study report. 
Presentations for PF-06826647 concentrations will include: 
• a listing of all concentrations sorted by subject ID, cohort, dose and nominal time 
post-dose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing. 
• a summary of concentrations by cohort, dose and nominal time post-dose, where the 
set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the 
lower limit of quantification. 
• median concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by cohort and dose (all treatments on the same plot per scale, based on 
the summary of concentrations by cohort, dose and time post-dose). 
• Median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by meal condition and dose for Day 1 (0-24 h post dose) for Cohort 3, 
4 and 5 (30, 100 and 400 mg cohorts). 
• Boxplot of dose-normalized AUC24 and Cmax on Day 1 in SAD and MAD separately 
by dose group and meal condition for Cohorts 3, 4 and 5. 
• mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by cohort and dose (all treatments on the same plot per scale, based on 
the summary of concentrations by cohort, dose and time post-dose). 
• individual concentration time plots by cohort and dose (on both linear and semi-log 
scales) against actual time post-dose (there will be separate spaghetti plots for each 
dose per scale). 
• individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time post-dose [there will be separate plots for each subject (containing 
all doses) per scale]. 
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PF-06826647 concentration is quantifiable in the matrix. 


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For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.  All statistical analyses related to the 
 will be performed as stated in 
Section 6.4. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
8.4. Safety Analysis 
For each of SAD/MAD (healthy volunteer cohort) and Psoriasis cohort a set of summary 
tables split by treatment will be produced separately to evaluate any potential risk associated 
with the safety and toleration of administering PF-06826647.  
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No formal analyses are planned for safety data.  The safety and other endpoints detailed in 
Section 6.2 will be listed and summarized in accordance with sponsor reporting standards, 
where the resulting data presentations will consist of subjects from the safety analysis set. 
8.4.1. Treatment and Disposition of Subjects 
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment. 
Data will be reported in accordance with the sponsor reporting standards. 
8.4.2. Demographic and Clinical Examination Data 
A breakdown of demographic data will be provided for age, race, weight, body mass index 
and height.  Each will be summarized by cohort and Overall in accordance with the sponsor 
reporting standards. 
8.4.3. Discontinuation(s) 
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment. 
Data will be reported in accordance with the sponsor reporting standards. 
8.4.4. Adverse Events 
Adverse events will be reported in accordance with the sponsor reporting standards. 
8.4.5. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. 
Mean change from baseline will be plotted against nominal time post dose.  On each plot 
there will be one line for each treatment.  The placebo data from all cohorts (for the 
SAD/MAD and Psoriasis cohorts) period will be plotted on the same figure using separate 
lines.  Individual plots of changes from baseline will also be produced for each cohort and 
treatment. 
8.4.6. Vital Signs Data 
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by cohort, treatment and time post-dose, according to 
sponsor reporting standards.  Tables will be paged by parameter.  Baseline is as defined in 
Section 6.3.3. 
Mean changes from baseline for supine systolic and diastolic blood pressure and pulse rate 
will be plotted against time post-dose.  On each plot there will be separate line for each 


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treatment.  Data from all cohorts will be plotted on the same figure using separate lines for 
different placebos.  Corresponding individual plots of changes from baseline will also be 
produced for each cohort and treatment. 
For supine systolic and diastolic blood pressure and pulse rate, the differences between each 
dose and placebo (dose – placebo) will be summarized (N, mean, 90% confidence interval) 
and plotted (mean) for each cohort, dose and timepoint (including baseline). 
Maximum absolute values and changes from baseline for vital signs (for supine) will also be 
summarized descriptively by treatment.  Numbers and percentages of subjects meeting the 
categorical criteria will be provided.  All planned and unplanned post-dose timepoints will be 
counted in these categorical summaries.  All values meeting the criteria of potential clinical 
concern will be listed. 
8.4.7. ECG Data 
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by cohort, treatment and time post-dose using sponsor reporting standards.  
Tables will be paged by parameter.  Baseline is as defined in Section 6.3.4. 
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
post-dose.  On each plot there will be 1 line for each treatment.  Data from all cohorts will be 
plotted on the same figure using separate lines for different placebos.  Corresponding 
individual plots of changes from baseline will also be produced for each cohort and 
treatment. 
Changes from baseline in QTcF will also be plotted separately against drug concentrations.  
This will be a scatter plot for all observations where QTcF and drug concentration are 
recorded.  Placebo data will also be included (with drug concentration set to zero).  Different 
symbols will be used for each treatment.  There will be 1 plot for each cohort. 
Maximum increase from baseline for QTcF, heart rate, QT, PR and QRS will be summarized 
by cohort and treatment, according to sponsor reporting standards.  
In addition for QTcF, heart rate and QT, the differences between each dose and placebo 
(dose – placebo) for each subject will be summarized and plotted (N, mean, 90% confidence 
interval) for each cohort, dose and timepoint (including baseline).  
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by cohort and treatment using categories as defined in Section 9.4 (for QTc 
these correspond to ICH E141).  Numbers and percentages of subjects meeting the categorical 
criteria will be provided.  All planned and unplanned post-dose timepoints will be counted in 
these categorical summaries.  All values meeting the criteria of potential clinical concern will 
be listed. 
Listings of subjects with any single post-dose value ≥500 msec will also be produced for 
QTcF. 


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QTcB will be listed only and not summarized. 
8.4.8. Other Safety Data 
None. 
8.4.9. Concomitant Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings. 
8.4.10. Screening and Other Special Purpose Data 
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine B-hCG for all females of childbearing potential, and urine or blood cotinine 
concentration will be obtained at Screening. 


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9. APPENDICES 
9.1. Definition of Endpoints in Psoriasis Cohort 
9.1.1. Psoriasis Area and Severity Index (PASI) 
The Psoriasis Area and Severity Index quantifies the severity of a subjects psoriasis based on 
both lesion severity and the percentage of body surface area affected.  Lesion severity: the 
basic characteristics of psoriatic lesions - erythema, induration and scaling - provide a 
means for assessing the severity of lesions.  Assessment of these three main signs is 
performed separately for four areas of the body: head, upper limbs, trunk, and lower limbs.  
Average erythema, induration and scaling are rated for each body area according to a 
5-point scale: 0, no involvement; 1, slight; 2, moderate; 3, marked; 4, very marked. 
Body surface area (BSA) involvement: the extent (%) to which each of the four areas of the 
body is affected by psoriasis is assigned a numerical score according to the following area 
scoring criteria: 0, no involvement; 1, >0 to 9%; 2, 10 to 29%; 3, 30 to 49%; 4, 50 to 69%; 
5, 70 to 89%; 6, 90 to 100%. 
Calculating PASI 
In each area, the sum of the severity rating scores for erythema, induration and scaling is 
multiplied by the score representing the percentage of this area involved by psoriasis, 
multiplied by a weighting factor (head 0.1; upper limbs 0.2; trunk 0.3; lower limbs 0.4).  The 
sum of the numbers obtained for each of the four body areas is the PASI. 
PASI = 0.1Ah(Eh + Ih + Sh) + 0.2Au(Eu + Iu + Su) + 0.3At(Et + It + St) + 0.4Al(El + Il + 
Sl) 
where A = area of involvement score; E = erythema; I =induration; S = scaling; h = head; 
u = upper limbs; t = trunk; l = lower limbs 
The PASI score can vary in increments of 0.1 units from 0.0 to 72.0, with higher scores 
representing increasing severity of psoriasis. 
PASI 50/75/90 response rate: At least 50/75/90% reduction in PASI relative to baseline 
PASI Score. 
Linear-method Psoriasis Area and Severity Index (L-PASI) 
A second method of calculating PASI will also be performed.  A linear-scaling method will 
be applied to the Psoriasis Area and Severity Index calculation, adapting the classic 
calculation by using the actual percentage body surface area involved in psoriasis rather 
than categorizing the percentage involvement on a 7-point scale.  The linear-scaling method 
will be calculated from the study database; investigator sites will only perform the classic 
PASI calculation during the study.  The L-PASI score will be used for a sensitivity analysis. 


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L-PASI Calculation 
L-PASI = 0.1(6xBh)x(Eh + Ih + Sh) + 0.2(6Bu)x(Eu + Iu + Su) + 0.3(6xBt)x(Et + It + St) + 
0.4(6xBl)x(El + Il + Sl)  
where B = percentage area of involvement; E = erythema; I =induration; S = scaling; 
h = head; u = upper limbs; t = trunk; l = lower limbs 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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CCI
CCI
CCI
CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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9.2. SAS Code 
9.2.1. Continuous Data Analysis 
Sample data set ds where for each subject and each visit the following information is stored 
in the row of the data set. 
Id 
Subject’s id 
Cbaseline 
Change from baseline 
visit  
Visit of interest (stored as a categorical) 
Trt 
Treatment group (stored as a categorical) 
Baseline 
Baseline observation of the outcome 
PROC MIXED DATA=<DATA>; 
           CLASS    ID TRT VISIT; 
           MODEL CBASELINE = TRT VISIT TRT*VISIT BASELINE /ALPHA=0.1 
DFM=KR; 
           REPEATED VISIT /SUBJECT= ID TYPE= UN; 
           LSMEANS TRT*VISIT /ALPHA=0.1 CI PDIFF; 
           ODS OUTPUT LSMEANS= LSM DIFFS=DIFF COVPARMS=COV; 
RUN; 
9.2.2. SAS Code for the Generalized Linear Mixed Model for Binary Longitudinal Data 
PROC GLIMMIX DATA =<DATA>   METHOD=RMPL; 
    CLASS SUBJID TRTPN VISIT; 
    MODEL RESPONSE (EVENT = "1") = TRTPN VISIT TRTPN * VISIT / ALPHA = 0.1 
DIST=BINARY LINK=LOGIT; 
    RANDOM VISIT /SUBJECT = SUBJID TYPE=UN RESIDUAL; 
    LSMEANS TRTPN * VISIT / ILINK COV DIFF CL; 
RUN; 
CCI


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9.2.3. SAS Code for the Confidence Interval for Risk Difference using Chan and Zhang 
(1999)3 
PROC BINOMIAL DATA=<DATASET> GAMMA=0 ALPHA=<Value>; 
PD/EX ONE STD; 
PO <POPULATION VARIABLE>; 
OU <OUTCOME VARIABLE>; 
RUN; 
9.2.4. SAS code for the Confidence Interval of a Binomial Proportion 
(Blyth-Still-Casella) 
PROC BINOMIAL DATA=<DATASET> ALPHA=<value>; 
BI/BS; 
OU <RESPONSE VARIABLE>; 
RUN; 
9.3. Assignment of Observations to the Visits 
Visit window (applicable for efficacy and PRO endpoints) will be assigned to the subjects in 
the Psoriasis cohorts.  The observations that are observed within the time window of 
(±3 days) around the target date will be assigned to the visit with the corresponding target 
date.  The resulting assignment of observations to the post-baseline and baseline visits is 
shown in the following table. 
Definition and Use of Visit Windows in Reporting 
Visit Label 
Targeted Day 
Analysis Window 
Screening 
28 days prior to Day 1 
1-30 days prior to Day 1 
Baseline* 
Day 1 (reference day) 
Day 1 (reference day) 
Week 1 
Day 7 
Days 4-10 
Week 2 
Day 14 
Days 11-17 
Week 3 
Day 21 
Days 18-24 
Week 4 
Day 28 
Days 25-31 
Week 5 
Day 35 
Days 32-38 
Week 6 
Day 42 
Day 39-45 
Week 8 
Day 56 
Day 53-59 
Week 12 
Day 84 
Day 81-87 
*In case Day 1 measurement is missing, the last available pre-dose will be considered as the baseline 


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If more than one observation from the same subject falls into the same window then the 
association of the observation with the visit will be done after the consultation with the study 
clinician and lead statistician.  
9.4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
Categories for QTcF 
QTcF (ms) 
450≤ max. <480 
480≤ max.<500 
max. ≥500 
QTcF (ms) 
increase from 
baseline 
30≤ max. <60 
max. ≥60 
 
Categories for PR and QRS 
PR (ms) 
max. ≥300 
 
 
PR (ms) 
increase from 
baseline 
Baseline >200 
and max. 
≥25% increase 
Baseline ≤200 and 
max. ≥50% 
increase 
QRS (ms) 
max. ≥140 
QRS (ms) 
increase from 
baseline 
≥50% increase 
Categories for Vital Signs 
Systolic BP (mm Hg) 
min. <90 
 
Systolic BP (mm Hg) 
change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
 
Diastolic BP (mm Hg) 
change from baseline 
max. decrease ≥20 
max. increase ≥20 
Supine pulse rate (bpm) 
min. <40 
max. >120 
Standing pulse rate (bpm) 
min. <40 
max. >140 
Measurements that fulfill these criteria are to be listed in report. 
10. REFERENCES 
1. 
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04. 
2. 
Casella G. Refining binomial confidence intervals. Can J Statist 1986; 14: 113–129.4. 
3. 
Chan ISF, Zhang Z.  Test-based exact conﬁdence intervals for the difference of two 
binomial proportions. Biometrics 1999, 55, 1201–1209.