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PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF PF-06700841 TO EVALUATE THE EFFICACY AT 16 WEEKS AND TO EVALUATE THE SAFETY AND EFFICACY UP TO 1 YEAR IN SUBJECTS WITH ACTIVE PSORIATIC ARTHRITIS Investigational Product Number: PF-06700841 Investigational Product Name: Tyk2/Jak1 United States (US) Investigational New Not applicable Drug (IND) Number: European Clinical Trials Database 2018-004241-16 (EudraCT) Number: Protocol Number: B7931030 Phase: 2b This document and accompanying materials contain confidential information belonging to Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in confidence and not copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. PFIZER CONFIDENTIAL Page 1 PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 Document History Document Version Date Summary of Changes and Rationale Amendment 2 22 October 2019 Schedule of Activities (SOA) and Section 7.2.8 Electrocardiogram (ECG) were updated to include the additional ECGs, and the requirements for centrally read ECG, alongside the locally read ECG. CCI Section 4.4.1. Contraception. Sexually active male subjects with female partners of child-bearing potential are no longer required to use a condom to prevent potential transfer to and exposure of partner(s) to drug through ejaculate. Rationale: Based on availability of new nonclinical developmental toxicity data that enabled assessment of the PF-06700841 systemic exposure risk of females resulting from male ejaculate, the requirements for condom use have been removed. Section 7.2.10. Events for Adjudication/Review Committee Submission, and Section 9.9. Safety Adjudication Committees (AC) were added to evaluate opportunistic infections, malignancy and cardiovascular events. Rationale: Based on emerging safety data across the Janus kinase (JAK) inhibitor class and regulatory feedback, a program level PFIZER CONFIDENTIAL Page 2 PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 Document Version Date Summary of Changes and Rationale decision has been made to include AC to more thoroughly investigate and interpret major safety events of interest. Appendix 6. Discontinuation Criteria. Additional discontinuation criterion added to clarify that study drug will be discontinued and the subject withdrawn from the study treatment in the event of any of the following: serious thromboembolic events, including venous thrombosis (including but not limited to deep vein thrombosis [DVT], pulmonary embolism [PE]), arterial thrombosis, and cerebrovascular events (thromboembolic stroke, transient ischemic attack [TIA], etc.) requiring hospitalization for treatment, or meeting other criteria that require the thromboembolic event to be classified as a serious adverse event (SAE). Rationale: The additional discontinuation criterion has been added based on regulatory feedback surrounding the emerging safety concerns across the JAK inhibitor product class. Appendix 6. Discontinuation Criteria. Additional discontinuation criteria added to clarify that study drug will be discontinued and the subject withdrawn from the study treatment in the event of any of the following: Two sequential AST or ALT elevation 3 times the upper limit of normal with at least one total bilirubin value 2 times the upper limit of normal; Two sequential AST or ALT elevation 3 times the upper limit of normal accompanied by signs or symptoms consistent with hepatic injury; Two sequential AST or ALT elevation 5 times the upper limit of normal, regardless of total bilirubin or accompanying signs or symptoms. Rationale: The additional clarification of PFIZER CONFIDENTIAL Page 3 PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 Document Version Date Summary of Changes and Rationale discontinuation criteria is similar to other ongoing studies with PF-06700841, and consistent with the laboratory changes expected at baseline and over time in subjects using background methotrexate. Amendment 1 29 April 2019 Section 4.4.1 Contraception was updated to include an instruction that male subjects should refrain from sperm donation during the study and for a period of at least 90 days after completion of active treatment. Rationale: to align with Regulatory request. Section 9. Data Analysis/Statistical Methods, on the timing of SAP finalization. It is stated that the SAP will be finalized prior to the study unblinding. Section 9.7. Interim Analysis, clarification added that the interim analysis, if performed, will not be used to drive any decisions for the current study. Rationale: to align with Regulatory request. Original protocol 31 October 2018 Not applicable (N/A) This amendment incorporates all revisions to date, including amendments made at the request of regulatory authorities and institutional review boards (IRBs)/ethics committees (ECs). PFIZER CONFIDENTIAL Page 4 PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 TABLE OF CONTENTS LIST OF TABLES...................................................................................................................10 LIST OF FIGURES .................................................................................................................10 APPENDICES .........................................................................................................................11 PROTOCOL SUMMARY.......................................................................................................12 SCHEDULE OF ACTIVITIES................................................................................................15 1. INTRODUCTION ...............................................................................................................20 1.1. Mechanism of Action/Indication.............................................................................20 1.2. Background and Rationale ......................................................................................20 1.2.1. Drug Development Rationale .....................................................................20 1.2.2. Study Rationale...........................................................................................22 1.2.3. Preclinical Safety Data ...............................................................................23 1.2.4. Clinical Experience with PF-06700841......................................................25 1.2.4.1. Summary of Clinical Safety with PF-06700841 .......................26 1.2.4.2. Summary of Pharmacokinetics (PK).........................................30 1.2.5. Dose Selection Rationale............................................................................31 1.2.6. Summary of Benefit Risk Assessment .......................................................32 CCI 2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................33 3. STUDY DESIGN.................................................................................................................35 4. SUBJECT ELIGIBILITY CRITERIA.................................................................................36 4.1. Inclusion Criteria.....................................................................................................37 4.2. Exclusion Criteria....................................................................................................40 4.3. Randomization Criteria ...........................................................................................46 4.4. Lifestyle Requirements ...........................................................................................46 4.4.1. Contraception..............................................................................................46 4.4.2. Fasting Visit Requirements.........................................................................47 4.4.3. Other Requirements....................................................................................47 4.5. Sponsor’s Qualified Medical Personnel..................................................................48 5. STUDY TREATMENTS.....................................................................................................48 5.1. Allocation to Treatment ..........................................................................................49 5.2. Breaking the Blind ..................................................................................................49 PFIZER CONFIDENTIAL Page 5 PF-06700841 B7931030 Final Protocol Amendment 2, 22 October 2019 5.3. Subject Compliance.................................................................................................49 5.4. Investigational Product Supplies.............................................................................50 5.4.1. Dosage Form(s) and Packaging..................................................................50 5.4.2. Preparation and Dispensing ........................................................................50 5.5. Administration.........................................................................................................50 5.6. Investigational Product Storage ..............................................................................51 5.7. Investigational Product Accountability...................................................................52