PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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 CCI Drug (IND) Number: European Clinical Trials Database N/A (EudraCT) Number: Protocol Number: C2501001 Phase: 1 Page 1 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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 Page 2 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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. Page 3 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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. CCI Page 4 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 CCI 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 Page 5 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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 CCI clarified process for management of subjects at Screening visit, in accordance with site Institutional Review Board (IRB) request. Original 16 May 2017 N/A protocol 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). Page 6 PF-06826647 C2501001 Final Protocol Amendment 3, 05April 2018 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