Study Number: UX023-CL203 Statistical Analysis Plan Amendment 1 27 April 2016, Version 1.1 STATISTICAL ANALYSIS PLAN Title A Phase 2b, Open-Label, Long-Term Extension Study to Evaluate the Safety and Pharmacodynamics of KRN23 in Adult Subjects with X-Linked Hypophosphatemia (XLH) Protocol: UX023-CL203 Investigational Product: KRN23 (Recombinant human IgG1 monoclonal antibody to fibroblast growth factor 23 [FGF23]) Indication: X-linked Hypophosphatemia (XLH) IND/EudraCT Number: 076488 Author: PPD Consultant, Biostatistics Ultragenyx Pharmaceutical Inc. 60 Leveroni Court Novato, CA, USA 94949 Date: 27 April 2016 Version Number: 1.1 Proprietary and Confidential Page 1 Study Number: UX023-CL203 Statistical Analysis Plan Amendment 1 27 April 2016, Version 1.1 STATISTICAL ANALYSIS PLAN AMENDMENT SUMMARY OF CHANGES UX023-CL203 Amendment 1 27 April 2016 The UX023-CL203 statistical analysis plan (dated 15 January 2016) has been amended. Important changes in Amendment 1 are summarized below: 1. Interim Analysis Timing: Section 3.6 has been updated to reflect the timing of the interim analysis to support regulatory submission. 2. Events to Monitor: Section 8.6.1 has been updated so that the events to monitor categories are consistent with the product identified or potential risks. 3. Analysis of Vital Signs: Section 8.6.6 has been updated to reflect the standard descriptive analysis for vital signs. 4. Analysis of ECG: Section 8.7.2 has been updated to remove the normality or abnormality analysis of the ECG tracing because the overall interpretation of ECG is not collected for the study. 5. 6-Minute Walk Test: Section 8.8.2.3 has been updated to remove the graph display of 6-minute walk test data because there is only one post-baseline time point (Week 24). Proprietary and Confidential Page 2 Study Number: UX023-CL203 Statistical Analysis Plan Amendment 1 27 April 2016, Version 1.1 Table of Contents 1 INTRODUCTION ...............................................................................................................8 2 STUDY OBJECTIVES ........................................................................................................9 2.1 Primary Safety and Pharmacodynamics .....................................................................9 2.2 Efficacy .......................................................................................................................9 3 STUDY DESIGN...............................................................................................................10 3.1 Overall Study Design and Plan .................................................................................10 3.2 Study Duration ..........................................................................................................10 3.3 Randomization and Blinding Method of Assigning Subjects to Treatment Groups .......................................................................................................................10 3.4 Stratification Factors .................................................................................................10 3.5 Determination of Sample Size ..................................................................................11 3.6 Week 24 Analysis .....................................................................................................11 3.7 Data Monitoring Committee .....................................................................................11 4 STUDY CLINICAL OUTCOMES AND COVARIATES ................................................12 4.1 Safety Endpoints .......................................................................................................12 4.2 Pharmacodynamics Endpoints ..................................................................................12 4.3 Efficacy Endpoints ....................................................................................................12 5 DEFINITIONS AND DERIVED EFFICACY VARIABLES ...........................................13 5.1 Baseline .....................................................................................................................13 5.2 First KRN23 Dose Date ............................................................................................13 5.3 BPI ............................................................................................................................13 5.4 WOMAC ...................................................................................................................13 5.4.1. MPCI for WOMAC Scales and Responder definition ...................................14 5.5 SF-36 Health Survey version 2 .................................................................................15 5.5.1 MIC for SF-36v2 Scales and Responder definition ....................................16 5.6 Percent of Predicted 6-Minute Walk Test Distance ..................................................17 5.7 Events To Monitor ....................................................................................................17 Proprietary and Confidential Page 3 Study Number: UX023-CL203 Statistical Analysis Plan Amendment 1 27 April 2016, Version 1.1 6 ANALYSIS POPULATIONS ...........................................................................................18 6.1 Safety Analysis Set ...................................................................................................18 6.2 Pharmacodynamic Analysis Set ................................................................................18 6.3 Efficacy Analysis Set ................................................................................................18 7 DATA SCREENING AND ACCEPTANCE ....................................................................19 7.1 Handling of Missing and Incomplete Data ...............................................................19 7.2 Missing data in WOMAC questionnaire ...................................................................19 7.3 Missing data in SF36 questionnaire ..........................................................................19 7.4 Missing Date Imputation Rules.................................................................................19 7.5 Unscheduled or Early Termination Visits .................................................................20 7.6 Software ....................................................................................................................20 8 STATISTICAL METHODS OF ANALYSIS ...................................................................21 8.1 General Principles .....................................................................................................21 8.1.1 Repeated Measure Model: General Estimating Equations ..........................21 8.1.2 Graphic Displays and Study Results ...........................................................22 8.1.3 Direction of Effects for the PRO Endpoints ................................................22 8.2 Demographics and Baseline Characteristics .............................................................22 8.3 Disease Characteristics and Medical History............................................................22 8.3.1 Medical History / XLH Medical History ....................................................22 8.3.2 XLH Treatment History ..............................................................................22 8.4 Subject Accountability ..............................................................................................22 8.5 Dosing Summary.......................................................................................................23 8.6 General Safety ...........................................................................................................23 8.6.1 Adverse Events ............................................................................................23 8.6.2 Safety Lab Parameters .................................................................................24 8.6.3 Concomitant Medications ............................................................................24 8.6.4 Physical Examination ..................................................................................24 Proprietary and Confidential Page 4 Study Number: UX023-CL203 Statistical Analysis Plan Amendment 1 27 April 2016, Version 1.1 8.6.5 Pregnancy Test ............................................................................................24 8.6.6 Vital Signs ...................................................................................................25 8.7 Ectopic Mineralization Safety ...................................................................................25 8.7.1 Renal Ultrasound .........................................................................................25 8.7.2 ECG .............................................................................................................25 8.7.3 ECHO ..........................................................................................................25 8.8 Endpoints ..................................................................................................................26 8.8.1 Pharmacodynamic Endpoints ......................................................................26 8.8.2 Efficacy Endpoints ......................................................................................26 8.8.2.1 PRO Endpoints.............................................................................26 8.8.2.2 X-Ray Endpoints ..........................................................................27