FIBROGEN

ROXADUSTAT [FG-4592] HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITOR FOR THE TREATMENT OF OF

CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE

MEETING DATE: 15 JULY 2021

ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee

TABLE OF CONTENTS TABLE OF CONTENTS ···················································································· 2 LIST OF TABLES ···························································································· 6 LIST OF FIGURES ··························································································· 9 LIST OF ABBREVIATIONS ············································································· 12 1. EXECUTIVE SUMMARY······································································· 14 1.1. Introduction ···················································································· 14 1.2. Disease Background and Unmet Need ····················································· 15 1.2.1. Overview of CKD Anemia ····························································· 15 1.2.2. Pathophysiology of CKD Anemia ····················································· 16 1.2.2.1. Hepcidin and Iron Metabolism ··················································· 16 1.2.3. Treatment of CKD Anemia ····························································· 18 1.2.4. Unmet Need ·············································································· 20 1.3. Efficacy of Roxadustat in Patients with NDD CKD Anemia ···························· 22 1.3.1. Study Design ············································································· 22 1.3.2. Patient Disposition and Demographics ··············································· 22 1.3.3. Efficacy Results ·········································································· 23 1.3.4. Supportive Phase 3 NDD Study 610 ·················································· 28 1.4. Efficacy of Roxadustat in Patients with DD CKD Anemia ······························ 31 1.4.1. Study Design ············································································· 31 1.4.2. Patient Disposition and Demographics ··············································· 31 1.4.3. Efficacy Results ·········································································· 32 1.4.4. Important Subgroups Across the Continuum of Patients with CKD ·············· 36 1.5. Hepcidin Reduction and Iron Mobilization ················································ 39 1.6. Safety Findings (NDD and DD Population) ··············································· 44 1.6.1. Cardiovascular Safety ··································································· 44 1.6.1.1. NDD Cardiovascular Safety Assessment ······································· 45 1.6.1.2. DD Cardiovascular Safety Assessment ········································· 57 1.6.1.3. Analysis of Pooled DD Studies With and Without Study 613 ··············· 61 1.6.1.4. Cardiovascular Safety Conclusions ············································· 63 1.6.2. Adverse Events ··········································································· 64 1.6.3. Safety Assessment of Specific Adverse Events ····································· 64 1.6.3.1. Thrombosis ········································································· 64 1.6.3.2. Seizures ·············································································· 69

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1.6.3.3. Serious and Fatal Infections ······················································ 70 1.7. Risk Management ············································································· 72 1.7.1. Risk Minimization ······································································· 72 1.7.2. Post-marketing Surveillance ··························································· 73 1.7.3. Starting Dose Reduction and Lowering Hb Target ································· 74 1.8. Benefit-Risk Summary ········································································ 77 SUPPLEMENTAL INFORMATION ··································································· 79 2. PRODUCT DESCRIPTION ····································································· 79 2.1. Dosage ·························································································· 79 2.2. Product Overview ············································································· 79 2.2.1. Pharmaceutical and Biological Properties of Roxadustat ·························· 79 2.3. Mechanism of Action ········································································· 80 3. REGULATORY AND DEVELOPMENT HISTORY ····································· 82 3.1. Regulatory Milestones ········································································ 82 4. CLINICAL PHARMACOLOGY ······························································ 83 4.1. Clinical Pharmacology Studies ······························································ 83 4.2. Pharmacokinetics ·············································································· 83 4.2.1. General Pharmacokinetic Properties ·················································· 83 4.2.2. Absorption, Distribution, Metabolism, and Elimination ··························· 83 4.2.3. Intrinsic Factors ·········································································· 84 4.2.4. Extrinsic Factors ········································································· 84 4.2.4.1. In Vitro Findings ··································································· 84 4.2.4.2. Effect of Other Drugs on Roxadustat ··········································· 85 4.2.4.2.1. Phosphate Binders ································································· 85 4.2.4.3. Effect of Roxadustat on Other Drugs ··········································· 85 4.3. Pharmacodynamics ············································································ 86 4.3.1. Pharmacodynamic Markers of Biologic Activity ··································· 86 4.3.1.1. ········································································· 86 4.3.1.2. ······································································ 86 4.3.1.3. Hepcidin ············································································· 86 4.3.1.4. Serum Iron Markers ······························································· 87 4.3.2. Pharmacodynamic Markers of Safety ················································· 87 4.3.2.1. Heart Rate and Pressure ··················································· 87 4.3.2.2. QT Intervals ········································································ 87

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5. CLINICAL EFFICACY ·········································································· 88 5.1. Pivotal and Supportive Phase 3 NDD Studies ············································· 88 5.1.1. Study Design ············································································· 88 5.1.1.1. Efficacy Endpoints in Pivotal NDD Studies ··································· 89 5.1.1.2. Patient Eligibility Criteria in Pivotal NDD Studies ··························· 89 5.1.1.3. Statistical Analyses in Pivotal NDD Studies ··································· 90 5.1.2. Demographic and Baseline Characteristics in Pivotal NDD Studies ············· 90 5.1.3. Efficacy Results in Pivotal NDD Studies ············································· 93 5.1.3.1. Primary Efficacy Endpoint Results ·············································· 93 5.1.3.2. Selected Secondary Efficacy Endpoint Results ································ 95 5.2. Pivotal and Supportive Phase 3 DD Studies ··············································· 99 5.2.1. Study Design ············································································· 99 5.2.1.1. Efficacy Endpoints in Pivotal Studies ·········································· 100 5.2.1.2. Patient Eligibility Criteria in Pivotal DD Studies ···························· 101 5.2.1.3. Statistical Analyses in Pivotal DD Studies ···································· 101 5.2.2. Demographic and Baseline Characteristics in Pivotal DD Studies ·············· 102 5.2.3. Efficacy Results in Pivotal DD Studies ·············································· 105 5.2.3.1. Primary Efficacy Endpoint Results ············································· 105 5.2.3.2. Selected Secondary Efficacy Endpoints Results ······························ 106 6. CLINICAL SAFETY············································································· 112 6.1. Overview of Safety Evaluation Plan ······················································· 112 6.2. Safety Data/Endpoints (NDD and DD) ···················································· 112 6.3. Clinical Safety–Overall Extent of Exposure (NDD and DD) ·························· 112 6.4. Cardiovascular Safety ········································································ 113 6.4.1. Cardiovascular Safety in NDD Population ·········································· 113 6.4.1.1. Placebo Evaluation Period Adjusted Analysis ································ 116 6.4.1.2. All-Cause Mortality in Pivotal Phase 3 NDD Studies: Cause of Death ··· 117 6.4.2. Cardiovascular Safety in DD Population ············································ 118 6.4.2.1. All-Cause Mortality in Pivotal Phase 3 DD Studies: Cause of Death ····· 122 6.5. General Safety Assessment of Roxadustat in NDD Population ························ 123 6.5.1. Exposure in Pivotal NDD Studies ···················································· 123 6.5.2. Safety Data from Pivotal NDD Studies ·············································· 124 6.5.2.1. Common Treatment-Emergent Adverse Events ······························ 125 6.5.2.2. Treatment-Emergent Adverse Events Leading to Discontinuation ········ 126

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6.6. General Safety Assessment of Roxadustat in DD Population ·························· 127 6.6.1. Exposure in Pivotal DD Studies ······················································ 127 6.6.2. Safety Data from Pivotal DD Studies ················································ 128 6.6.2.1. Common Treatment-Emergent Adverse Events ······························ 128 6.6.2.2. Treatment-Emergent Adverse Events Leading to Discontinuation ········ 130 7. DATA FROM SUPPORTIVE STUDY 610 ················································· 131 7.1. General Safety Data from Supportive Study 610 ········································ 131 7.2. Safety Assessment of Specific Adverse Events from Supportive Study 610 ········· 133 8. DATA FROM SUPPORTIVE STUDY 613 ················································· 134 8.1. Efficacy Data from Supportive Study 613 ················································ 134 8.2. Cardiovascular Safety Data from Supportive Study 613 ································ 134 8.3. General Safety Data from Supportive Study 613 ········································ 137 8.4. Safety Assessment of Specific Adverse Events from Supportive Study 613 ········· 138 9. SAFETY DATA FROM OTHER PHASE 3 CKD STUDIES ··························· 140 9.1. Japan Studies ·················································································· 140 9.1.1. Study 1517-CL-0310 (NDD) ·························································· 140 9.1.2. Study 1517-CL-0314 (NDD) ·························································· 140 9.1.3. Study 1517-CL-0302 (DD) ···························································· 141 9.1.4. Study 1517-CL-0307 (DD) ···························································· 141 9.1.5. Study 1517-CL-0308 (DD) ···························································· 141 9.1.6. Study 1517-CL-0312 (DD) ···························································· 142 9.2. China Studies ·················································································· 142 9.2.1. Study FGCL-4592-808 (NDD) ······················································· 142 9.2.2. Study FGCL-4592-806 (DD) ························································· 143 10. DISPOSITION TABLES ········································································ 145 11. DOSE MODIFICATION MODEL ···························································· 148 12. REFERENCES ···················································································· 149

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LIST OF TABLES Table 1: ...... Overview of NDD Study Designs ··························································· 22 Table 2: ...... Study 610: IV Iron Use During the First 36 Weeks ······································ 30 Table 3: ...... Overview of DD Study Designs ····························································· 31 Table 4: ...... ID-DD and SDD Populations: Mean Monthly IV Iron Use and Transfusion Requirement ····································································· 38 Table 5: ...... Mean Follow-up Time in Years, in On-treatment Plus 28 Days (OT+28) Analysis Set for MACE and ACM ····································································· 51 Table 6: ...... Mean Follow-Up Time in Years, in the On-treatment Plus 28 Days Analysis Set for MACE and ACM by Baseline eGFR ······················································· 52 Table 7: ...... Pooled NDD Studies: Cardiovascular Mortality and MACE+ Components ·········· 56 Table 8: ...... Pooled DD Studies: MACE+ Components ················································ 60 Table 9: ...... NDD and DD Studies: Overview of Adverse Events ····································· 64 Table 10: .... NDD and DD Studies: Adjudicated VAT Adverse Events ······························ 65 Table 11: .... NDD and DD Studies: DVT and PE Adverse Events (OT+28) ························· 68 Table 12: .... NDD and DD Studies: Clinical Impact in Patients with DVT/PE ······················ 69 Table 13: .... NDD and DD Studies: Seizure Adverse Events ··········································· 70 Table 14: .... NDD and DD Studies: Infection Adverse Events ········································· 71 Table 15: .... Pooled NDD Studies: Fatal Infection Adverse Events by Baseline eGFR ············ 72 Table 16: .... Key Characteristics of Roxadustat ·························································· 80 Table 17: .... Key Regulatory Milestones in Roxadustat Clinical Development ······················ 82 Table 18: .... Overview of Key Design Features of Pivotal and Supportive Phase 3 Studies in Patients with NDD CKD ····································································· 88 Table 19: .... NDD Studies: Demographic and Baseline Characteristics ······························ 91 Table 20: .... NDD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy ······························································· 94 Table 21: .... NDD Studies: Proportion of Patients Who Achieved Hb Response During the First 24 Weeks of Treatment, Censoring for Rescue Therapy ································· 95 Table 22: .... NDD Studies: Proportion of Patients with Hb ≥ 10.0 g/dL Averaged Over Weeks 28 to 36 Censoring for Rescue Therapy ························································ 96 Table 23: .... NDD Studies: Mean Change from Baseline in LDL Cholesterol to Mean Over Weeks 12 to 28 ················································································· 97 Table 24: .... NDD Studies: Patients Receiving Rescue Therapy in the First 52 Weeks ············· 98 Table 25: .... NDD Studies: Patients Receiving RBC Transfusions in the First 52 Weeks ·········· 99 Table 26: .... Overview of Key Design Features of Pivotal and Supportive Phase 3 Studies in Patients with DD CKD ······································································· 100 Table 27: .... DD Studies: Demographic and Baseline Characteristics ································ 103 Table 28: .... DD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy ······························································ 105 Table 29: .... DD Studies: Hb Response with Roxadustat Compared with Epoetin Alfa Over Weeks 28 to 36 in DD Patient Censoring for Rescue Therapy ························· 106

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Table 30: .... DD Studies: Mean Change in Hb From Baseline to Mean Over Weeks 18 to 24 Regardless of Rescue Therapy in Patients with Baseline hsCRP > ULN ············· 107 Table 31: .... DD Studies: Average Monthly IV Iron Usea Per Patient Exposure Month Over Weeks 28 to 52 ················································································ 108 Table 32: .... DD Studies: Mean Change in LDL Cholesterol from Baseline to Mean Over Weeks 12 to 28 ························································································ 109 Table 33: .... DD Studies: Proportion of Patients with RBC Transfusion in Roxadustat-Treated and Epoetin Alfa-Treated Patients with DD CKD ······································· 110 Table 34: .... ID-DD Subpopulation: Mean Change in Hb From Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy ······················································· 111 Table 35: .... Total Exposure to Study Drugs in Phase 3 Studies ······································ 113 Table 36: .... NDD Studies: Retention and Follow-up (% Based on Patients Who Were Randomized and Received at Least One Dose of Study Drug) ························ 113 Table 37: .... Pooled NDD Studies: Primary Analysis of MACE, MACE+, and All-Cause Mortality ······················································································· 114 Table 38: .... Study 001: Cardiovascular Safety Results ················································ 116 Table 39: .... Pooled NDD Pooled: All-Cause Mortality ················································ 118 Table 40: .... DD Studies: Retention and Follow-up (% Based on Patients Who Were Randomized and Received at Least One Dose of Study Drug) ························ 119 Table 41: .... Pooled DD Studies: Primary Analysis of MACE, MACE+, and All-Cause Mortality119 Table 42: .... Pooled DD Studies: All-Cause Mortality ················································· 123 Table 43: .... Pooled NDD Studies: Overall Drug Exposure (Safety Population) ··················· 124 Table 44: .... Pooled NDD Studies: Summary of Overall Treatment-Emergent Adverse Events in Roxadustat and Placebo Groups ···························································· 124 Table 45: .... Pooled NDD Studies: Summary of Treatment-Emergent Adverse Events (Incidence ≥ 5%) by Preferred Terms in Roxadustat and Placebo Groups ························ 126 Table 46: .... Pooled NDD Studies: Summary of Treatment-Emergent Adverse Events (≥ 0.3%) Leading to Discontinuation by Preferred Terms in Roxadustat and Placebo Groups127 Table 47: .... Pooled DD Studies (ID-DD and SDD-DD Subpopulations): Overall Drug Exposure127 Table 48: .... Pooled DD Studies: Summary of Overall Treatment-Emergent Adverse Events in Roxadustat- and Epoetin Alfa Groups ····················································· 128 Table 49: .... Pooled DD Studies: Summary of Treatment-Emergent Adverse Events (Incidence ≥ 5%) by Preferred Terms in Roxadustat and Epoetin Alfa Groups ··················· 129 Table 50: .... Pooled DD Studies: Summary of Treatment-Emergent Adverse Events (≥ 0.3%) Leading to Discontinuation by Preferred Terms in Roxadustat- and Epoetin Alfa Groups ························································································· 130 Table 51: .... Study 610: Overview of Treatment-emergent Adverse Events and Death (Safety Analysis Set) ·················································································· 131 Table 52: .... Study 610: Treatment-Emergent Serious Adverse Events (Safety Analysis Set) ···· 132 Table 53: .... Study 610: Summary of Specific Adverse Events ······································· 133 Table 54: .... Study 613: Demographics and Baseline Characteristics ································ 135 Table 55: .... Descriptive Statistics of MACE, MACE+, and ACM of Study 613 ··················· 136 Table 56: .... Study 613: Overview of Adverse Events and Death ····································· 137

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Table 57: .... Study 613: Roxadustat AEs (Incidence ≥ 5%) by Preferred Term Compared to Erythropoietin-Stimulating Agents ························································· 138 Table 58: .... Study 613: Summary of Specific Adverse Events ······································· 139 Table 59: .... Pooled NDD Studies: Reasons for Discontinuation ····································· 146 Table 60: .... Pooled DD Studies: Patient Disposition ··················································· 147

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LIST OF FIGURES Figure 1: ..... Phase 2 and 3 Clinical Studies for the Development of Roxadustat for Patients with CKD Anemia ··················································································· 15 Figure 2: ..... Direct and Indirect Regulation of Systemic Iron Homeostasis ·························· 17 Figure 3: ..... Most Common Treatments Used in Patients with NDD CKD Anemia ················ 20 Figure 4: ..... Pooled NDD Studies: Patient Disposition ·················································· 23 Figure 5: ..... Pooled NDD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy* ······················································ 24 Figure 6: ..... Pooled NDD Studies: Mean (±SE) Hb (g/dL) over Time up to Week 52 ············· 25 Figure 7: ..... Pooled NDD Studies: Roxadustat Treatment Effect by Study ·························· 25 Figure 8: ..... Pooled NDD Studies: Roxadustat Treatment Effect by Subgroup ······················ 26 Figure 9: ..... Pooled NDD Studies: LSMean Change from Baseline in Hb Levels in Patients Who Were Iron Replete* vs Iron Non-replete at Baseline ····································· 26 Figure 10: ... Pooled NDD Studies: Proportion of Patients with Hb Response ······················· 27 Figure 11: ... Pooled NDD Studies: Patients Receiving Any Rescue Therapy* or RBC Transfusion During the First 52 Weeks ···················································· 28 Figure 12: ... Pooled NDD Studies: LSMean Change from Baseline in Health-Related Quality of Life Scores at Week 12 ······································································· 28 Figure 13: ... Study 610 Design ·············································································· 29 Figure 14: ... Study 610: Mean Change in Hb Levels Over Time ······································· 30 Figure 15: ... Pooled DD Studies: Patient Disposition ···················································· 32 Figure 16: ... Pooled DD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy* ···················································· 33 Figure 17: ... Pooled DD Studies: Roxadustat Treatment Effect by Study ···························· 33 Figure 18: ... Pooled DD Studies: Mean Hb Change from Baseline by hsCRP Quintiles at Baseline ························································································· 34 Figure 19: ... Pooled DD Studies: Mean Weekly Study Drug Doses by Baseline hsCRP Quintiles 34 Figure 20: ... Pooled DD Studies: Average Monthly IV Iron Use Per Patient Exposure Month Over Weeks 28 to 52 (Full Analysis Set) ·················································· 35 Figure 21: ... Pooled DD Studies: Requirement for RBC Transfusion During Treatment ··········· 35 Figure 22: ... Pooled DD Studies: LSMean Change from Baseline in Health-Related Quality of Life Scores at Week 28 ······································································· 36 Figure 23: ... Pooled NDD Studies: Mean Hb and Weekly Roxadustat Dose During the Period of -3 to +6 Months Relative to Chronic Dialysis Initiation ································· 36 Figure 24: ... ID-DD Subpopulation: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy* ················································ 37 Figure 25: ... SDD Subpopulation: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy* ···················································· 38 Figure 26: ... DD Subpopulation: LSMean Change from Baseline in Hb to Mean Over Weeks 28 to 52 and Time to First RBC Transfusion in Patients Receiving Peritoneal Dialysis 39 Figure 27: ... Pooled NDD Studies: LSMean Change from Baseline to Week 20 in Iron, Ferritin, and Hepcidin Levels ·········································································· 40

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Figure 28: ... Pooled DD Studies: LSMean Change from Baseline to Week 20 in Iron, Ferritin, and Hepcidin Levels ·········································································· 41 Figure 29: ... Pooled DD Studies: Mean Hb Levels by Quintiles of Hepcidin at Baseline in the Epoetin Alfa Group ··········································································· 42 Figure 30: ... Pooled DD Studies: Mean Hb Levels by Quintiles of Hepcidin at Baseline in the Roxadustat Group ············································································· 42 Figure 31: ... Pooled DD Studies: Mean Hb Levels by Quintiles of Ferritin at Baseline in the Epoetin Alfa Group ··········································································· 43 Figure 32: ... Pooled DD Studies: Mean Hb Levels by Quintiles of Ferritin at Baseline in the Roxadustat Group ············································································· 44 Figure 33: ... Pooled NDD Studies: Proportion of Patients Without Early Study Drug Discontinuation over Time, by Treatment Group and Baseline eGFR ················· 46 Figure 34: ... Pooled NDD Studies: Proportion of Patients Without Dialysis Initiation over Time, by Treatment Group and Baseline eGFR ··················································· 47 Figure 35: ... Percent of Patients on Dialysis Among Patients Remaining on Treatment ············ 48 Figure 36: ... Treatment Completion Rate in Roxadustat and Historical Anemia of CKD Trials ·· 49 Figure 37: ... Study Completion Rate in Roxadustat and Historical Anemia of CKD Trials ········ 50 Figure 38: ... Pooled NDD Studies: Retention and Follow-up ·········································· 53 Figure 39: ... Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of MACE ········· 54 Figure 40: ... Pooled NDD Studies: Forest Plot of Primary Analysis of MACE, MACE+, and ACM ···························································································· 55 Figure 41: ... Pooled NDD Studies: Results for MACE Vary Due to Impact of Differential Treatment Discontinuation ··································································· 56 Figure 42: ... Study 610: Forest Plot of Primary Analysis of MACE, MACE+, and ACM ········· 57 Figure 43: ... Pooled DD Studies: Retention and Follow-up ············································· 58 Figure 44: ... Pooled DD Studies: Kaplan-Meier Curves of Primary Analysis of MACE ··········· 59 Figure 45: ... Pooled DD Studies: Forest Plot of Primary Analysis of MACE, MACE+, and ACM 59 Figure 46: ... ID-DD Subpopulation: Kaplan-Meier Curve of Primary Analysis of MACE ········ 60 Figure 47: ... SDD-DD Subpopulation: Kaplan-Meier Curve of Primary Analysis of MACE ······ 61 Figure 48: ... Analysis of Pooled Dialysis Studies With and Without Study 613 ····················· 62 Figure 49: ... MACE Results by Study for Pivotal DD Studies Including Study 613 ················ 62 Figure 50: ... Rate of Mortality Among US Patients by Dialysis Vintage ····························· 63 Figure 51: ... Pooled DD Studies: Adjudicated VAT Adverse Events by Time of Onset ············ 66 Figure 52: ... Pooled DD Studies: Incidence of VAT with Increasing Hb Rate of Increase ········· 67 Figure 53: ... Pooled DD studies: Proportion of Patients with First Occurrence of Hb Rate of Rise > 2 g/dL within Any 4-Week Period Over Time at Each Visit up to Week 52 ······· 67 Figure 54: ... Simulated Mean Hb Values with Roxadustat in Previously ESA-untreated Patients 75 Figure 55: ... Simulated Mean Hb Values in Patients Converting from ESA to Roxadustat ········ 75 Figure 56: ... Proportion of Roxadustat Patients (Previously Untreated with ESA) with Rapid Rate of Hb Rise, Phase 3 Dose Compared to Proposed Dose ··························· 76 Figure 57: ... Proportion of Patients Converting from ESA to Roxadustat with Rapid Rate of Hb Rise, Phase 3 Doses Compared to Proposed Doses ······································· 76 Figure 58: ... Structural Formula of Roxadustat ··························································· 79

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Figure 59: ... Circulating Erythropoietin Exposure with Roxadustat-Treated Patients with CKD and ESRD versus Reported ESA Dosing Patterns in ESRD (2005–2009) ············ 81 Figure 60: ... Plasma Endogenous EPO Concentration-Time Curve Profile in Healthy Subjects ·· 86 Figure 61: ... Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of MACE+ ······ 114 Figure 62: ... Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of ACM ·········· 115 Figure 63: ... Pooled NDD Studies: MACE Results in the OT+28 Analysis Set ···················· 115 Figure 64: ... Pooled NDD Studies: Forest Plot of Analyses of MACE, MACE+, and ACM Using the Placebo Evaluation Period Adjusted Method ········································ 117 Figure 65: ... Pooled DD Studies: Kaplan-Meier Survival Curves of MACE+ ······················ 120 Figure 66: ... Pooled DD Studies: Kaplan-Meier Curves of Primary Analysis of ACM ············ 120 Figure 67: ... Pooled DD Studies: Forest Plot of MACE, MACE+, and ACM (OT+28) ··········· 121 Figure 68: ... Pooled DD Studies: Forest Plot of MACE, MACE+, and ACM (On-Study) ······· 121 Figure 69: ... Pooled ID Studies: Forest Plot of MACE, MACE+, and ACM (On-Study Analysis)122 Figure 70: ... ESA Treatment Before, During, and After Treatment Discontinuation in the Roxadustat DD Program ····································································· 122 Figure 71: ... Study 613: Forest Plot of MACE, MACE+, and ACM ································· 136 Figure 72: ... Roxadustat Starting Dose Modifications ·················································· 148

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LIST OF ABBREVIATIONS Abbreviation Definition ACM All-cause mortality AE Adverse event ANCOVA Analysis of Covariance AUC Area under the curve AVF Arteriovenous fistula AVG Arteriovenous graft BCRP Breast cancer resistance protein BMI Body mass index CI Confidence interval CKD Chronic kidney disease CLR Renal clearance

Cmax Maximum plasma concentration CV Cardiovascular CYP Cytochrome P450 DD Dialysis-dependent DVT Deep vein thrombosis eGFR Estimated glomerular filtration rate EPO Epoetin alfa ESA Erythropoiesis-stimulating agent ESRD End-stage renal disease FAS Full analysis set FDA Food and Drug Administration Hb Hemoglobin HIF Hypoxia-inducible factor HIF-PH Hypoxia-inducible factor prolyl hydroxylase HR Hazard ratio HRQoL Health-related quality of life hsCRP High-sensitivity C-reactive protein ID (or ID-DD) Incident dialysis IERC Independent Event Review Committee ITT Intent-to-treat IV Intravenous KDIGO Kidney Disease: Improving Global Outcomes LDL Low-density lipoprotein LSMean Least squares mean MACE Major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke) MACE+ MACE, plus hospitalization for unstable angina or congestive heart failure MCID Minimal clinically important difference MI Multiple imputation NDA New drug application NDD Non-dialysis-dependent OAT Organic anion transporter OATP Organic anion transporting polypeptide OT+7 On-treatment plus 7 days OT+28 On-treatment plus 28 days

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Abbreviation Definition PE Pulmonary embolism PEY Patient exposure year PK pharmacokinetic PRA Panel reactive antibody PY Patient year QoL Quality of life RBC Red blood cell SAE Serious adverse event SDD Stable dialysis-dependent SF-36 36-item short form questionnaire TIW 3 times per week TSAT Transferrin saturation UGT uridine diphosphate-glucuronosyltransferase ULN Upper limit of normal VAT Vascular access thrombosis

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1. EXECUTIVE SUMMARY

1.1. Introduction FibroGen, in global partnership with AstraZeneca and Astellas, is seeking approval of roxadustat (FG 4592) for the treatment of anemia in patients with chronic kidney disease (CKD) not on dialysis and on dialysis. Treatment with roxadustat is intended for the correction of anemia by increasing and maintaining hemoglobin (Hb) in patients with CKD. Roxadustat is a first-in-class, potent, orally active, and reversible inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes. By transiently inhibiting HIF-PH enzymes, roxadustat stimulates a coordinated erythropoiesis in a manner consistent with the natural physiologic response to hypoxia. Roxadustat presents a valuable option for the treatment of anemia to reduce the need for transfusion where the current standard of care leaves unmet needs. The clinical development program for roxadustat in patients with CKD anemia included 9 Phase 2 studies, 8 United States (US) and Global Phase 3 studies, and 8 additional Phase 3 studies in Japan and China (Figure 1). In agreement with the Food and Drug Administration (FDA), safety data from the 3 pivotal placebo-controlled studies in non-dialysis-dependent (NDD) patients (Studies 001, 060, 608) were pooled and data from the 3 pivotal active-controlled studies in dialysis-dependent (DD) patients (Studies 002, 063, and 064) were pooled in their respective indications as they shared key study design elements and were global studies. Two additional global Phase 3 studies—Study 610 and Study 613— had different trial designs compared to the pivotal Phase 3 studies and were not included in the respective study pools; however, results from these studies are included in this document. Unlike the other NDD studies, Study 610 was open-label and used an active comparator () instead of placebo, and the study was ongoing at the time of the New Drug Application (NDA) submission. In contrast to the other DD studies which used epoetin alfa (EPO) as a comparator, Study 613 used both EPO and darbepoetin alfa as active comparators. The additional Phase 3 Studies 302, 307, 308, 310, 312, and 314 were conducted only in Japan and Studies 806 and 808 were conducted only in China and were not included in the respective study pools. These studies were of shorter duration, may not have had comparator arms, and did not have safety events adjudicated. A brief summary of the safety data generated from the studies conducted in China and Japan is provided in Section 9.

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Figure 1: Phase 2 and 3 Clinical Studies for the Development of Roxadustat for Patients with CKD Anemia

The data from more than 8,000 patients from the 6 pivotal studies demonstrated that roxadustat has a positive benefit-risk profile across the spectrum of CKD anemia in patients who are NDD and DD. The overall cardiovascular (CV) safety of roxadustat was shown to be comparable to placebo in patients with NDD CKD and to EPO in patients with DD CKD based on a comprehensive assessment of the roxadustat safety data via independent adjudication review. These findings support the use of roxadustat to safely increase Hb levels for patients with CKD anemia who need additional treatment options. Roxadustat has been approved for DD and NDD CKD in China since 2018 and 2019, respectively, and in Japan since 2019 and 2020, respectively. Available post-marketing safety data have not shown any new unexpected risks.

1.2. Disease Background and Unmet Need

1.2.1. Overview of CKD Anemia Anemia is common in patients with CKD – occurring in approximately 15% of patients with CKD in the US – and becomes increasingly severe as CKD progresses (Fishbane and Spinowitz 2018; Stauffer and Fan 2014). Anemia most commonly begins to develop when patients have between 20% and 50% of normal kidney function, and the majority of patients with a near total loss of kidney function, such as those with end-stage renal disease (ESRD), have anemia (Nakhoul and Simon 2016; St Peter et al 2018; USRDS 2020). Accordingly, approximately 50% of patients with Stage 4 to 5 CKD and more than 90% of patients with DD CKD are anemic (Nakhoul and Simon 2016). Anemia is a condition marked by a deficiency in red blood cells (RBCs) (as measured by Hb levels) resulting in an inadequate oxygen-carrying capacity of blood to meet physiologic needs. The cause and extent of anemia may vary by age, sex, altitude, and smoking status (Stauffer and Fan 2014; WHO 2011). However, any disruption to erythropoiesis, such as that which occurs in CKD, has the potential to result in anemia.

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The Kidney Disease: Improving Global Outcomes (KDIGO) working group recommends that health care providers diagnose anemia in patients over 15 years old when Hb levels fall below 13 g/dL in males and 12 g/dL in females. Symptoms of anemia in patients with CKD often include low energy, fatigue, headache, impaired concentration, depression, impaired cognitive function, and overall reduced quality of life (QoL) (KDIGO Anemia Work Group 2012; Smith 2010). Additionally, anemia can reduce oxygen supply to the heart and cause increased heart rate and stroke volume, which may contribute to myocardial ischemia and lead to myocardial cell death. Anemia is associated with increased mortality and morbidity due to increased risk of CV hospitalization, all-cause- mortality (ACM), and progression of ESRD (Palaka et al 2020). Clinical changes due to acute anemia are generally reversible, but chronic anemia can lead to progressive and pathologic heart enlargement and left ventricular hypertrophy due to volume overload (Mozos 2015).

1.2.2. Pathophysiology of CKD Anemia While anemia is defined by a decrease in Hb, its frequency and severity are complicated not only by the high degree of inflammation that patients with CKD experience but also by the effect of inflammation on currently available therapies. The etiology of anemia of CKD is complex and involves multiple pathological factors that impact erythropoiesis including: inflammation, which negatively affects multiple erythropoietic processes; elevated hepcidin, which restricts iron availability; and impaired oxygen sensing by the kidneys, which results in insufficient erythropoietin production by renal erythropoietin producing cells (specialized fibroblasts located between the renal tubules and capillaries in the cortex and outer medulla) (Shahbazi et al 2019). Inflammation contributes to the disrupted erythropoiesis that occurs in patients with CKD (Brugnara and Eckardt 2020; Icardi et al 2013; Nemeth and Ganz 2014; Shahbazi et al 2019). Increased inflammatory cytokines in CKD impairs production of erythropoietin and yields a reduced responsiveness or “hyporesponsiveness” to EPO-mediated differentiation and maturation of RBCs. As CKD progresses, erythropoietin production from REP cells is decreased to a level that is inadequate to maintain a normal rate of erythropoiesis (Fu et al 2016; Locatelli et al 2017; Souma et al 2016). As a result, Hb levels are reduced, causing anemia and systemic tissue hypoxia, and renal fibrosis may ensue (Shahbazi et al 2019). Additional factors that contribute to CKD anemia include chronic blood loss; iron, , or folic acid deficiency; and shortened RBC survival (from 120 days to 60–90 days)

(Brugnara and Eckardt 2020).

1.2.2.1. Hepcidin and Iron Metabolism Several proteins, including ferritin and hepcidin, regulate iron levels in the body. Ferritin is an intracellular protein that stores iron and releases iron in a controlled fashion. Serum ferritin is elevated in patients with iron overload and decreased in patients with iron deficiency diseases (Jacobs et al 1972). Therefore, serum ferritin is used as an indirect marker of the total amount of iron stored in the body (Jacobs and Worwood 1975). However, factors such as inflammation, infection, and malignancy can elevate serum ferritin, which complicates the interpretation of serum ferritin levels (Wang et al 2010). Hepcidin is a liver-derived key regulator of the entry of iron into the circulation (Ganz 2003). The role of hepcidin in regulation of systemic iron homeostasis is depicted in Figure 2. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin, which is located on the surface of gut enterocytes, macrophages, and hepatocytes, leading to its internalization and degradation.

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee intracellular iron stores whose upper limit of normal [ULN] is frequently 300 mg/dL) is approximately 800 mg/dL according to the DOPPS Clinical Practice Monitor (Karaboyas et al 2020). Some patients with CKD have an absolute iron deficiency, which is characterized by severely reduced or absent iron stores in the bone marrow, liver, and spleen. Absolute iron deficiency can arise from an increased rate of blood loss during dialysis, gastrointestinal bleeding from the combination of gastritis and platelet dysfunction (Liang et al 2014), or decreased gastrointestinal iron absorption and malnutrition.

1.2.3. Treatment of CKD Anemia The objective of treatment for patients with NDD and DD CKD anemia includes increasing and maintaining Hb levels, reducing the risk of RBC transfusions, and enhancing QoL. Treatment of anemia in NDD and DD CKD is widely supported by worldwide guideline groups and regulatory approvals. Nephrologists typically diagnose anemia in patients with CKD, and the treatment has evolved significantly over the past 3 decades. In 1988, approximately 75% of dialysis patients in the US had a hematocrit of < 30%, indicative of severe anemia. During this time, patients undergoing dialysis routinely had Hb levels in the 5–6 g/dL range with marked symptomatology (Eschbach et al 1989; Eschbach et al 1987). The cumulative burden of associated symptoms led to the frequent administration of RBC transfusions. In 1989, this paradigm changed with the introduction of EPO, a first-in-class ESA that was approved via an orphan drug designation for the indication, “to elevate the red blood cell level […] and to decrease the need for transfusions […]” (Procrit Package Insert 2008). Subsequent uptake of ESAs was rapid and facilitated by a coverage determination from Medicare, and RBC transfusion became rescue therapy. ESA treatment that results in supraphysiologic erythropoietin levels and iron therapy remain the cornerstone of anemia treatment in patients with advanced CKD; nevertheless, rescue therapy with RBC transfusion is common. The results of several large studies raised concerns about the use of ESAs to treat anemia in patients with CKD and about target Hb concentrations. These studies include: • Normal Hematocrit Trial (1998) • Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) in 2006 • Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) in 2009 The results of these studies suggested that targeting higher Hb levels with higher doses of ESAs may contribute to CV adverse events (AEs). In 2011, the FDA published a safety announcement and implemented label changes for ESAs that included new warnings and called for more conservative ESA dosing in patients with CKD (FDA 2011). The new labels warned that, in controlled trials in CKD, patients experienced greater risks for death, serious CV AEs, and stroke when treated with ESAs to target a Hb level of > 11 g/dL. In addition, the labels warned that no trial had identified a Hb target level, ESA dose, or dosing strategy that did not increase these risks. Therefore, the recommendation was that healthcare providers should consider starting ESA treatment when Hb < 10 g/dL for patients with CKD. Dosing should be individualized, and the lowest dose of ESA sufficient to reduce the need for RBC transfusions should be used, after which dosing should be adjusted as appropriate. This recommendation did not define how far below 10 g/dL would be appropriate for an individual to initiate ESA treatment or the Hb level to target with treatment. Further, the recommendation was to reduce the dose or discontinue therapy when Hb rose above 10 g/dL in patients with NDD CKD. Page 18 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee

The KDIGO clinical practice guidelines for anemia in CKD were subsequently published in 2012, and these guidelines reflected the new FDA recommendations for ESAs. Each approved ESA product has a Boxed Warning for increased risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence. Whereas these 2012 guidelines have attempted to mitigate the mortality and morbidity of anemia treatment in CKD, there has been limited subsequent innovation within the ESA category. New treatments have primarily been related to convenience through reducing the frequency of ESA injections, mainly in the NDD and home dialysis settings. There remains a significant unmet need for additional treatments for patients with CKD anemia, as reflected by a high rate of RBC transfusions in this patient population. A further challenge in the treatment of CKD anemia is that many patients who are not on dialysis are not adequately treated for their anemia. Anemia treatment is initiated in a limited number of patients with NDD CKD, and treatment discontinuation is common in those who are treated due to the FDA labeled requirement to reduce or interrupt the ESA dose once a Hb level of 10 g/dL has been achieved (Davis et al 2020; St Peter et al 2018). In the US, fewer than 1 in 7 patients with NDD CKD were treated with an ESA in the 12 months prior to starting dialysis, and only 40% of patients with NDD CKD with Hb < 10 g/dL received any anemia medication within one year (St Peter et al 2018). Treatment with ESAs requires frequent clinic visits for many patients, from every week to monthly, depending on the prescribed ESA, as well as concurrent and not infrequent parenteral therapies. Particularly for patients who are not on dialysis, frequent travel to a healthcare facility is inconvenient or not even an option in underserved areas. A significant proportion of patients with NDD CKD are referred by their nephrologist to a hematologist due to the complexities and challenges of administering ESA and IV iron therapy, potentially impacting continuity of care. Accordingly, these patients are more likely than those without anemia to use healthcare resources, including hospitalizations and emergency department, hematologist, nephrologist, and outpatient (St Peter et al 2018). The unmet need in patients with NDD CKD anemia is illustrated by the significant transfusion burden despite more than 30 years of ESA availability. Despite efforts including glycation and pegylation to increase ESA half-life and decrease dosing intensity, 40% of patients with NDD CKD require 1 or more RBC transfusions in the 2 years prior to the initiation of dialysis (Winkelmayer et al 2014). These findings support the concept that anemia is sub-optimally managed among patients with NDD CKD anemia in the real-world setting with a lack of sustained and efficacious treatment and a greater number of patients treated with RBC transfusions than ESAs on an annual basis in the US (St Peter et al 2018).

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Figure 3: Most Common Treatments Used in Patients with NDD CKD Anemia

Abbreviations: CKD=chronic kidney disease; ESA=erythropoiesis-stimulating agent; IV=intravenous; NDD=non-dialysis-dependent; RBC=red blood cell. Source: St Peter et al 2018 Whereas RBC transfusions carry risks of volume overload, transfusion reactions, transmission of blood-borne infection, and iron overload, they only provide for a transient amelioration of anemia. Most importantly and of specific concern for patients with CKD, RBC transfusions are also associated with a decreased likelihood of receiving a kidney transplant, longer wait time prior to transplantation, and a higher risk of kidney rejection following transplantation due to allosensitization, the activation of the adaptive immune system to foreign antigens resulting in the generation of antibodies (Hickey et al 2016). This issue is critically important for patients with CKD, because kidney transplantation is associated with substantial improvements in survival and QoL (Gill et al 2005; Kostro et al 2016; Oniscu et al 2005; Wolfe et al 1999). The risk of allosensitization has been shown to increase with increasing number of transfusions, and allosensitization is associated with increased rejection and graft loss, as well as longer wait times to transplantation (Orandi et al 2016). In ESRD, panel reactive antibody (PRA) is commonly accepted as a routine practice in transplant centers and represents an estimate of alloimmunization. The incidence of rejection is significantly higher in patients with sensitization (ie, PRA ≥ 10%) than in patients without sensitization. Accordingly, the probability of receiving a kidney transplant is inversely related to the PRA percentage; for every percent increase in the PRA above 20%, the risk of not receiving a kidney transplant increased by 5% (Bostock et al 2013; Domingues et al 2010). Therefore, a therapy that reduces the complexities of anemia treatment and decreases the incidence of RBC transfusions, including in patients with NDD CKD who are not currently treated for their anemia with ESA therapy, would be an important advance.

1.2.4. Unmet Need Patients with CKD would benefit from an oral treatment for anemia that is safe, effective, and convenient and improves treatment across their entire clinical course. An ideal treatment would be efficacious across the spectrum of patients with NDD and DD CKD anemia including those with high levels of inflammation and inadequate clinical response to standard of care. The unmet need for

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee additional treatments for CKD anemia is particularly apparent in patients who are incident to dialysis who are often hyporesponsive to ESA treatment due to inflammatory conditions, and patients undergoing home dialysis. At the time of dialysis initiation in the US in 2018, patients had a mean Hb of 9.3 g/dL (USRDS 2018) due to limited use of ESAs, with less than 15% of patients treated for anemia of CKD contributing to the risk of transfusion that can affect their ultimate timing and success of transplantation. As would be expected in a population of patients who are generally untreated and who have low Hb at the time of dialysis initiation, rates of transfusion are highest in the 90 days following dialysis initiation, at nearly 150 transfusions/100 patient years (PY) (Wang et al 2016). Inadequate response to ESAs is common and often due to inflammation and/or functional iron deficiency (Ganz 2003). Hyporesponsiveness is common in DD CKD, and patients who are hyporesponsive to ESAs require higher doses than non-hyporesponsive patients. Such high ESA doses have been associated with CV and thrombotic risk. ESA underperforms in those individuals with increased ferritin and hepcidin levels, indicative of clinical scenarios consistent with inflammation and functional iron insufficiency. These patients at present are devoid of clinical options beyond higher ESA doses, increased iron administration, or reliance on blood transfusion. Clinicians are regularly confronted with difficult treatment decisions in these patients who are inflamed or hyporesponsive, either opting for higher ESA doses with increased CV risk or lower ESA doses and increased requirement for RBC transfusion, which has its own risks and inconveniences. Relevantly, chronic ESA hyporesponders have approximately 7-fold higher monthly burden of RBC transfusion compared with patients who respond to ESA (Fishbane and Nissenson 2010; Kilpatrick et al 2008; Luo et al 2016; McCullough et al 2013). The 2020 Advancing American Kidney Health Executive Order was a response to the challenges and barriers inherent in the care of individuals with CKD. The stated goal of this executive order is to “improve access to and quality of person-centered treatment options.” Specifically, the executive order states, “We need to provide patients who have kidney failure with more options for treatment, from both today’s technologies and future technologies such as artificial kidneys and make it easier for patients to receive care at home or in other flexible ways.” The initiatives in this executive order include a number of measures meant to improve care and QoL for patients with CKD. Payment model adjustments were enacted to promote more widespread use of in-home dialysis, which is more convenient for patients than going into a dialysis center. More than 500,000 patients were on dialysis in 2016 and many of them spend 12 hours a week in dialysis centers (USRDS 2020). In this context, the current standard of care with parenteral ESA therapy and regular administration of IV iron poses a burden for and a barrier to home hemodialysis and peritoneal dialysis. An oral therapy that can be self-administered in the home setting for hemodialysis and peritoneal dialysis patients will be a major advance in patient care, especially as more patients are treated in the home setting due to Centers for Medicare & Medicaid Services’ objective to transition patients from in-center to home dialysis. Moreover, a therapy that reduces the requirement for IV iron in these home-treated patients will be an important clinical advance. In summary, an ideal treatment for CKD anemia will be efficacious and IV iron mitigating or sparing and safe across the spectrum of NDD and DD CKD, including in patients with high levels of inflammation, inadequate iron mobilization, and inadequate clinical response to the current standard of care. An effective and convenient oral treatment can address the logistical challenges that many patients experience including IV access placement, need to travel to an infusion center, and increased Page 21 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee frequency of medical encounters; mitigate IV iron requirements and transfusion burden; and offer a more equitable access to therapy providing many patients on home dialysis and patients not on dialysis the opportunity to have appropriately managed anemia of CKD. Furthermore, a treatment with a novel mechanism of action that provides a “coordinated erythropoiesis,” better reduces hepcidin, and improves iron bioavailability would empower personalized care aligned with patients’ and healthcare providers’ goals and more effectively treat CKD anemia.

1.3. Efficacy of Roxadustat in Patients with NDD CKD Anemia

1.3.1. Study Design All 3 NDD studies (060, 608, and 001) were similarly designed, multicenter, randomized, double-blind, placebo-controlled trials (Table 1). Adult male and female patients with CKD Stage 3–5, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and Hb ≤ 10.0 g/dL at baseline were enrolled globally. Patients were randomized 2:1 to roxadustat and placebo in Studies 608 and 060 and 1:1 in Study 001. Target Hb with roxadustat treatment was 10–12 g/dL, and treatment duration was up to 4 years. The primary efficacy endpoint for all 3 studies was the mean change in Hb from baseline to mean over Weeks 28 to 52 regardless of rescue therapy (ie, RBC transfusion, ESA use, and intravenous [IV] iron supplementation). Secondary efficacy endpoints included the proportion of Hb responders (ie, Hb level of ≥ 11 g/dL with an increase of 1 g/dL for patients with baseline Hb > 8 g/dL and an increase of 2 g/dL for patients with baseline Hb ≤ 8 g/dL) without rescue, use of rescue therapy (ie, RBC transfusion, ESA use, and IV iron supplementation), RBC transfusion, change in hepcidin and iron parameters, and health-related quality of life (HRQoL). Given the similar study designs, the efficacy results for these studies were pooled for the NDA and are presented as such in this briefing document. Table 1: Overview of NDD Study Designs

Pivotal Phase 3 NDD Studies Study 001 Study 060 Study 608 Region Global Global Global Randomized, double-blind Yes Yes Yes Control Placebo Placebo Placebo Baseline Hb < 10.0 g/dL ≤ 10.0 g/dL ≤ 10.0 g/dL Randomization scheme 1:1 2:1 2:1 Duration (years) 1 – 4 1 – 4 1 – 2 Abbreviations: Hb=hemoglobin; NDD=non-dialysis-dependent.

1.3.2. Patient Disposition and Demographics A total of 4,270 eligible patients from the 3 pivotal Phase 3 studies were randomized to roxadustat (N=2,386) or placebo (N=1,884) and received at least 1 dose of study treatment. Overall, 82% of patients in the roxadustat group and 71% of patients in the placebo group completed study treatment to the period during which the primary efficacy endpoint could be assessed (Figure 4). Because the primary efficacy endpoint is change from baseline to Week 28–52, it is relevant to present information as to how many patients continued treatment to these timepoints.

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Figure 4: Pooled NDD Studies: Patient Disposition

Abbreviation: NDD=non-dialysis-dependent. Baseline demographics and disease characteristics were similar between groups and were reflective of patients with NDD CKD globally. The mean age was approximately 62 years old, and baseline disease characteristics were similar between treatment groups. Baseline Hb was 9.10 g/dL, and a similar proportion of patients had Hb levels < 8.0 at baseline. Baseline eGFR was < 15 mL/min/1.73 m2 in 42.5% of patients, and < 10 mL/min/1.73 m2 in 19.6% of patients. Additional details are provided in Section 5.1.2.

1.3.3. Efficacy Results The pre-specified primary efficacy endpoints were met in each individual study. Approval for efficacy is based on individual studies. To facilitate the presentation of efficacy, pooled results are presented rather than each of the individual studies where the results of individual studies were similar in terms of direction and magnitude. The reader should be reminded that while individual studies were controlled for multiplicity, this was not employed in the pooled analyses. In the pooled analysis, the roxadustat group showed an improvement in mean Hb levels regardless of rescue therapy (ie, RBC transfusion, ESA use, and IV iron supplementation) compared to placebo (Figure 5).

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Figure 5: Pooled NDD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy*

Abbreviations: CI=confidence interval; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; IV=intravenous(ly); LS=least square; NDD=non-dialysis-dependent; RBC=red blood cell. *Rescue therapy included RBC transfusion, ESA use, and IV iron supplementation. **P-value not controlled for multiplicity. Note: Intent-to-treat analysis set. Figure 6 compares the mean Hb over time, up to Week 52, between the pooled roxadustat and placebo groups in patients with NDD CKD. In the pooled roxadustat group, Hb increased starting from Week 2 through Week 12, following which the mean Hb level stabilized and was maintained close to 11.0 g/dL through the rest of the study period. By contrast, in the pooled placebo group, Hb levels remained relatively flat and close to baseline (approximately 9.0 g/dL) up to Week 52.

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Figure 6: Pooled NDD Studies: Mean (±SE) Hb (g/dL) over Time up to Week 52

Abbreviations: CI=confidence interval; Hb=hemoglobin; NDD=non-dialysis-dependent; SE=standard error. Note: Full analysis set. *p-value not controlled for multiplicity. Importantly, statistically and clinically significant improvements from baseline in mean Hb levels were seen across the 3 individual NDD studies. As shown by the placebo-adjusted treatment effect for roxadustat in Figure 7, the treatment effect for each of the pivotal studies in patients with NDD CKD was statistically significant compared to placebo. Figure 7: Pooled NDD Studies: Roxadustat Treatment Effect by Study

Abbreviations: CI=confidence interval; Hb=hemoglobin; ITT=intent-to-treat analysis set; NDD=non-dialysis-dependent; OT+7=on-treatment plus 7 days; Roxa=roxadustat. Note: Study 001 was analyzed using the ITT observational period; Studies 060 and 608 were analyzed using OT+7. Additionally, the treatment effect consistently favored roxadustat across a wide range of pre-specified subgroups including region, sex, baseline high-sensitivity C-reactive protein (hsCRP), and eGFR range (Figure 8). Patients with the lowest eGFR at baseline had the lowest Hb levels at baseline, and therefore had a greater change from baseline than patients with higher eGFR at baseline.

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Figure 8: Pooled NDD Studies: Roxadustat Treatment Effect by Subgroup

Abbreviations: CI=confidence interval; CRP=C-reactive protein; eGFR=estimated glomerular filtration rate; Hb=hemoglobin; NDD=non-dialysis-dependent; Roxa=roxadustat; ULN=upper limit of normal; US=United States. *mL/min/1.73 m2 **p-value not controlled for multiplicity. Note: Intent-to-treat analysis set. Patients treated with roxadustat demonstrated a consistent Hb response irrespective of iron repletion status at baseline (Figure 9). Patients who were not iron replete (ie, ferritin < 100 ng/mL or TSAT < 20%) at baseline had similar change from baseline in Hb levels as those who were iron replete while utilizing similar doses of roxadustat and without requiring more transfusions or IV iron. Figure 9: Pooled NDD Studies: LSMean Change from Baseline in Hb Levels in Patients Who Were Iron Replete* vs Iron Non-replete at Baseline

Abbreviations: Hb=hemoglobin; LS=least square; NDD=non-dialysis-dependent; TSAT=transferrin saturation. *Iron replete was defined as TSAT ≥ 20% and ferritin ≥ 100 ng/mL; mean change from baseline to mean of Weeks 28 to 52. **P-value not controlled for multiplicity.

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As shown in Figure 10, a higher percentage of roxadustat-treated patients achieved Hb response (defined as Hb ≥ 11.0 g/dL and increase by ≥ 1.0 g/dL in patients with baseline Hb > 8.0 g/dL, or Hb increase by ≥ 2.0 g/dL in patients with baseline Hb ≤ 8.0 g/dL) during the first 24 weeks compared to placebo, with a treatment difference of 71.5% without rescue. Figure 10: Pooled NDD Studies: Proportion of Patients with Hb Response

Abbreviations: CI=confidence interval; Hb=hemoglobin; NDD=non-dialysis-dependent. Note: Censored for rescue therapy. * P-value not controlled for multiplicity. Fewer patients from the roxadustat treatment group required any rescue therapy (ie, RBC transfusion, ESA use, or IV iron) or RBC transfusion compared to the placebo group during the first 52 weeks of treatment (Figure 11). A total of 124 patients (5.2%) in the roxadustat group required RBC transfusion compared to 288 (15.4%) in the placebo group, corresponding to an incidence rate of 6.1 patients with transfusion per 100 PY for roxadustat, and 20.4 per 100 PY for placebo.

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Figure 11: Pooled NDD Studies: Patients Receiving Any Rescue Therapy* or RBC Transfusion During the First 52 Weeks

Abbreviations: CI=confidence interval; ESA=erythropoiesis-stimulating agent; HR=hazard ratio; IV=intravenous(ly); NDD=non- dialysis-dependent; RBC=red blood cell. *Rescue therapy included RBC transfusion, ESA use, and IV iron supplementation. **P-value not controlled for multiplicity. Note: Full analysis set. HRQoL was assessed using patient-reported outcome measures. The physical functioning and vitality domains of the SF-36 v2 were included as secondary endpoints in the pooled analysis (Figure 12). Both roxadustat and placebo-treated patients reported least squares mean (LSMean) increases from baseline to Week 12 across all HRQoL endpoints. The difference between roxadustat and placebo- treated patients did not meet minimal clinically important difference (MCID) thresholds in any of the studies. Figure 12: Pooled NDD Studies: LSMean Change from Baseline in Health-Related Quality of Life Scores at Week 12

Abbreviations: CI=confidence interval; CFB=change from baseline; LS=least square; NDD=non-dialysis-dependent; SF-36=36-item short form survey. Note: Full analysis set. *p-value not controlled for multiplicity.

1.3.4. Supportive Phase 3 NDD Study 610 In addition to the 3 pivotal NDD CKD placebo-controlled studies, Study 610 was a Phase 3 study to evaluate the roxadustat efficacy and safety in patients with NDD CKD with an active control, Page 28 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee darbepoetin alfa (Figure 13). Study 610 was not pooled for analysis with the other NDD CKD studies because it used an active control and remains as a stand-alone study. Figure 13: Study 610 Design

Abbreviations: CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin. *Duration of correction phase is variable in length for each patient depending on when they reach Hb ≥ 11.0 g/dL and an Hb increase from baseline Hb ≥ 1.0 g/dL A total of 930 patients were screened and 616 were randomized to receive treatment, 323 to the roxadustat treatment group and 293 to the darbepoetin treatment group. Those patients are included in the Intent-To-Treat (ITT) and Safety Populations for statistical analysis. Baseline demographics were comparable between the roxadustat and darbepoetin treatment groups, with mean age (66.8 in roxadustat vs 65.7 in placebo), and mean body mass index (BMI) (27.95 vs 28.74). The majority of patients were White (95.3% overall) and were randomized in Central and Eastern Europe (70.1%). Median baseline Hb was 9.68 g/dL for the roxadustat treatment group and 9.70 g/dL in the darbepoetin treatment group. Median baseline eGFR (17.5 mL/min/1.73 m2 vs 18.5 mL/min/1.73 m2) was comparable between groups and was < 30 mL/min/1.73 m2 for 82.5% patients overall (81.7% roxadustat vs 83.3% darbepoetin). Treatment duration was considered comparable between treatment groups (median 103.71 weeks in the roxadustat treatment group vs 100.14 weeks in the darbepoetin treatment group). Total patient exposure years (PEY) on treatment was greater in the roxadustat treatment group (519.3 years) than the darbepoetin treatment group (472.5 years), because of the greater number of patients in the roxadustat treatment group. Primary Endpoint: Percentage of Hb Responders during the First 24 Weeks of Treatment Without Rescue Therapy In general, the efficacy data from Study 610 was consistent with other pooled pivotal studies. After 12 weeks, mean Hb levels stabilized and were comparable between treatment groups. In addition, mean Hb levels averaged over Weeks 28 to 36 demonstrated noninferiority of roxadustat to darbepoetin alfa (Figure 14).

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Figure 14: Study 610: Mean Change in Hb Levels Over Time

Abbreviations: CI=confidence interval; Hb=hemoglobin. Note: Per protocol analysis set. Hb Change from Baseline to Average Hb in Weeks 28 to 36 Without Rescue Therapy The LSMean change was 1.85 (95% confidence interval [CI]: 1.75, 1.96) g/dL for patients in the roxadustat group and 1.84 g/dL (95% CI: 1.73, 1.94) for patients in the darbepoetin alfa group. The LSMean difference for roxadustat vs darbepoetin alfa was 0.015 g/dL (95% CI: -0.13, 0.16), signifying noninferiority of roxadustat to darbepoetin alfa based on a margin for noninferiority of > -0.75 g/dL. Time to First IV Iron Use During First 36 Weeks Significantly fewer patients in the roxadustat treatment group required IV iron use during the first 36 weeks. The incidence rate per 100 PY at risk was lower in the roxadustat group (9.9) compared with the darbepoetin alfa group (21.2), and the hazard ratio (HR) was 0.45 (95% CI: 0.26, 0.78; p=0.004). Table 2: Study 610: IV Iron Use During the First 36 Weeks Roxadustat Darbepoetin Alfa N=322 N=292 Patients with IV Iron 20 (6.2%) 37 (12.7%) Cumulative Time at Risk (PY) 201.8 174.5 Incidence Rate (Per 100 PY) 9.9 21.2 Hazard Ratio (95% CI), p-value 0.45 (0.26, 0.78), P=0.004 Abbreviations: HR=hazard ratio; IV=intravenous(ly); PY=patient years.

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1.4. Efficacy of Roxadustat in Patients with DD CKD Anemia

1.4.1. Study Design The 3 pivotal DD studies (063, 064, and 002) were similarly designed, multicenter, randomized, open- label, clinical trials assessing the efficacy and safety of roxadustat compared with EPO (Table 3). Adult male and female patients with CKD on dialysis with threshold Hb < 10.0 g/dL at baseline (if not on ESA), and < 12.0 g/dL (if on ESA) were enrolled globally. Patients in these studies were randomized 1:1 to roxadustat and EPO. Target Hb was 10–12 g/dL with roxadustat treatment and as labeled for EPO, and the study durations were up to 4 years. These studies included a pre-specified subpopulation of incident dialysis (ID) patients (ie, patients who started dialysis within ≤ 4 months of study participation). The subpopulation of patients with ID-DD CKD consisted of all patients from Study 063 and a subset of eligible patients from Study 002 and Study 064 (14.1% and 9.6%, respectively). The primary endpoint in all 3 studies was the same as that in the NDD studies: mean change from baseline in Hb to mean over Weeks 28 to 52, regardless of rescue therapy (ie, RBC transfusion and ESA). Secondary endpoints included Hb change by baseline inflammatory status (hsCRP > ULN) – because of the known underperformance of EPO in patients who are inflamed – as well as RBC transfusion, and IV iron use. Hepcidin and serum iron storage parameters were investigated as exploratory endpoints. Table 3: Overview of DD Study Designs

Pivotal Phase 3 DD Studies Study 002 Study 063 Study 064 Region Global Global United States Design Open-label Open-label Open-label Control Epoetin alfa Epoetin alfa Epoetin alfa Randomization scheme 1:1 1:1 1:1 Duration (years) ≤ 4 years ≤ 4 years ≤ 4 years Baseline Hb (g/dL) < 12 if on ESA 9.0 – 12 (DD) ≤ 10 or < 10 8.5 – 12 (ID-DD) Abbreviations: DD=dialysis-dependent; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; ID-DD=incident dialysis- dependent.

1.4.2. Patient Disposition and Demographics A total of 1943 patients were randomized in the roxadustat group and 1947 in the EPO group for a total of 3,890 patients who were included in the ITT set (Figure 15). A total of 1940 patients in each group received at least 1 dose of study drug and were included in the Safety Analysis Set. The ID-DD subpopulation consisted of 1,530 patients, and the stable dialysis-dependent (SDD) subpopulation consisted of 2,360 patients. Overall, 79.4% of patients in the roxadustat group and 85.1% of patients in the EPO group completed treatment to the period during which the primary endpoint was assessed.

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Figure 15: Pooled DD Studies: Patient Disposition

Abbreviations: DD=dialysis-dependent. Baseline demographics were similar between the groups and are reflective of the underlying population of patients with DD CKD globally. The mean age of patients was approximately 55 years and ranged from 18 to 94 years. While globally, 61% of patients were White, approximately 18% were Black, and 14% were Asian, and among patients enrolled in the US, 40% were African American. Approximately half of patients had diabetes. More than 90% utilized hemodialysis as their modality and 10% utilized peritoneal dialysis. Mean baseline Hb was approximately 9.6 g/dL, and a similar proportion of patients had Hb levels of < 10 at baseline in each group. Among patients with baseline hsCRP (n=3,246), the mean hsCRP at baseline was also similar between the groups, with a similar proportion of patients with hsCRP above ULN. Mean baseline iron parameters including hepcidin, transferrin saturation (TSAT) and ferritin were also comparable between groups. Additional details on baseline demographics are provided in Section 5.2.2.

1.4.3. Efficacy Results The pre-specified primary efficacy endpoints were met in each individual study (Figure 17). To summarize these studies, pooled results are presented below. In the pooled analysis, the effect including the 95% CI of roxadustat was within the pre-specified non-inferiority margin (-0.75 g/dL), thereby demonstrating noninferiority compared to EPO on mean change from baseline in Hb over Weeks 28 to 52 regardless of rescue therapy (ie, RBC transfusion and ESA) (Figure 16).

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Figure 16: Pooled DD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy*

Abbreviations: CI=confidence interval; DD=dialysis-dependent; Hb=hemoglobin; LS=least square. *Rescue therapy consisted of red blood cell transfusion and erythropoiesis-stimulating agent. Note: Intent-to treat analysis set. Importantly, the Hb response with roxadustat was consistent across the DD studies, with a non-inferior treatment effect of roxadustat compared to EPO in each individual study (Figure 17). Figure 17: Pooled DD Studies: Roxadustat Treatment Effect by Study

Abbreviations: CI=confidence interval; DD=dialysis-dependent; Hb=hemoglobin; Roxa=roxadustat. Note: Intent-to treat analysis set; non-inferiority margin=-0.75. The ability of roxadustat to maintain Hb in the presence of inflammation likely related to its mechanism of action is an important clinical differentiator from ESA. While the treatment difference is clinically similar between roxadustat and EPO as quintiles of patients based on CRP are examined (Figure 18), roxadustat doses did not increase with increasing baseline hsCRP levels (Figure 19). In contrast, EPO dose requirements increased with increasing baseline hsCRP levels, reflecting the likely effect of inflammation on EPO dosing that is not affected in roxadustat dosing.

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Figure 18: Pooled DD Studies: Mean Hb Change from Baseline by hsCRP Quintiles at Baseline

Abbreviations: DD=dialysis-dependent; Hb=hemoglobin; hsCRP=high-sensitivity C-reactive protein; LS=least square. Note: Intent-to-treat analysis set.

Figure 19: Pooled DD Studies: Mean Weekly Study Drug Doses by Baseline hsCRP Quintiles

Abbreviations: DD=dialysis-dependent; hsCRP=high-sensitivity C-reactive protein; LS=least square. Note: Intent-to-treat analysis set As shown in Figure 20, roxadustat-treated patients received less monthly IV iron than patients treated with EPO (p < 0.0001). In the Phase 3 studies, IV iron supplementation was permitted if the investigator thought that the patient had not responded adequately while taking oral iron or could not tolerate oral iron and was considered iron deficient as determined by either ferritin < 100 ng/ml or TSAT < 20%. On average, roxadustat-treated patients required 52 mg of IV iron over Weeks 28 to 52 compared to 67 mg iron required by EPO-treated patients. The difference in IV iron needs to be Page 34 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee interpreted in the context of patients in the roxadustat arm achieving numerically higher Hb levels with fewer transfusions. This is supportive of the Phase 2 Study 053 in which patients receiving roxadustat treated with oral iron were able to achieve and maintain similar Hb levels and similar iron stores as compared to those treated with IV iron (Besarab and Szczech 2014). Figure 20: Pooled DD Studies: Average Monthly IV Iron Use Per Patient Exposure Month Over Weeks 28 to 52 (Full Analysis Set)

Abbreviations: DD=dialysis-dependent; IV=intravenous(ly); SE=standard error. Note: Full analysis set. Numerically fewer patients treated with roxadustat required RBC transfusions compared with EPO, demonstrating non-inferiority between roxadustat and EPO (Figure 21). Figure 21: Pooled DD Studies: Requirement for RBC Transfusion During Treatment

Abbreviations: CI=confidence interval; DD=dialysis-dependent; HR=hazard ratio; RBC=red blood cell. Note: Full analysis set. The physical functioning and vitality domains of the 36-item short form questionnaire (SF-36) v2 were included as secondary endpoints in one of the studies and were exploratory endpoints in the other

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee study (Figure 22). Both roxadustat and EPO-treated patients reported LSMean increases from baseline to Week 12 across all HRQoL endpoints in the pooled analysis. There was no clinically meaningful difference between patients on roxadustat compared to EPO in the pooled analysis. This finding is expected as patients in both treatment arms experienced corrected Hb levels, leading to improved HRQoL compared with baseline. LSMean treatment differences between roxadustat and EPO-treated patients did not meet MCID thresholds. Figure 22: Pooled DD Studies: LSMean Change from Baseline in Health-Related Quality of Life Scores at Week 28

Abbreviations: CI=confidence interval; CFB=change from baseline; DD=dialysis-dependent; LS=least square; SF-36=36-item short form survey. *P-value not controlled for multiplicity. Note: Full analysis set.

1.4.4. Important Subgroups Across the Continuum of Patients with CKD As patients were followed for up to 4 years, some patients initiated dialysis during the studies. As shown in Figure 23, roxadustat maintained Hb levels while patients transitioned to dialysis through at least 6 months. The figure shows continued maintenance of Hb through the transition to dialysis initiation. Figure 23: Pooled NDD Studies: Mean Hb and Weekly Roxadustat Dose During the Period of -3 to +6 Months Relative to Chronic Dialysis Initiation

Abbreviations: Hb=hemoglobin; NDD=non-dialysis-dependent; SE=standard error.

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For the primary endpoint of mean change in Hb from baseline to the mean over Weeks 28 to 52, roxadustat was non-inferior to EPO in both the ID-DD population (Figure 24) and SDD population (Figure 25). Figure 24: ID-DD Subpopulation: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy*

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; ID-DD=incident dialysis-dependent; RBC=red blood cell; SE=standard error. *Rescue therapy consisted of RBC transfusion and ESA.

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Figure 25: SDD Subpopulation: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Any Rescue Therapy*

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; RBC=red blood cells; SDD=stable dialysis-dependent; SE=standard error. *Rescue therapy consisted of RBC transfusion and ESA. The benefits of roxadustat compared to EPO were also observed across key secondary endpoints in both the ID-DD and SDD populations. Patients in the roxadustat group received a significantly lower monthly amount of IV iron than those in the EPO group (p=0.0001), and a similar number of patients treated with roxadustat and with EPO required RBC transfusions (Table 4). Table 4: ID-DD and SDD Populations: Mean Monthly IV Iron Use and Red Blood Cell Transfusion Requirement

Incident Dialysis (ID-DD) Stable Dialysis (SDD) Roxadustat Epoetin alfa Roxadustat Epoetin alfa N=756 N=759 N=1173 N=1169 Mean Monthly IV Iron Use over 53.6 70.2 51.4 64.89 Weeks 28 to 52, mg RBC Transfusion; Patients (%) 6.1% 6.7% 11.8% 16.7% Abbreviations: ID-DD=incident dialysis-dependent; IV=intravenous(ly); RBC=red blood cell; SDD=stable dialysis- dependent. It is also important to examine the results of roxadustat among the subgroup of patients in the DD studies utilizing peritoneal dialysis as their modality (n=372 [9.6%]). Roxadustat was non-inferior to EPO among patients on peritoneal dialysis in the primary endpoint of change from baseline in Hb (Figure 26). In addition, patients receiving roxadustat received fewer RBC transfusions during the treatment period.

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Figure 26: DD Subpopulation: LSMean Change from Baseline in Hb to Mean Over Weeks 28 to 52 and Time to First RBC Transfusion in Patients Receiving Peritoneal Dialysis

Abbreviations: CI=confidence interval; DD=dialysis-dependent; Hb=hemoglobin; LS=least square; RBC=red blood cell. *P-value not controlled for multiplicity. Note: A total of 372 patients (9.6% of the enrolled DD population) were on peritoneal dialysis.

1.5. Hepcidin Reduction and Iron Mobilization In patients with CKD undergoing ESA therapy, patients with systemic inflammation tend to have decreased response to ESA, requiring higher ESA doses to attempt to achieve target Hb. Whereas no singular definition of hyporesponse exists, studies show that patients have variable responsiveness to ESA longitudinally and 40% of patients enter the highest quintile of ESA dose at some point during a year. Inflammation also results in increased hepcidin and iron sequestration (Ganz 2003). The importance of iron availability is demonstrated in hemodialysis studies where higher ferritin values are achieved as an attempt to overcome iron restricted erythropoiesis and achieve target Hb levels without higher doses of ESAs. Unfortunately, patients with higher ferritin levels have the highest mortality rate (Bradbury et al 2009). While somewhat similar to absolute iron deficiency, the obvious difference between absolute and functional iron deficiency is that in the latter clinical scenario more than sufficient iron is present in the body. This iron is however sequestered by hepcidin and not available to the organs including the bone marrow that utilize it. A growing number of studies have demonstrated better outcomes among patients with heart failure when iron is repleted using the IV route (Anker et al 2018). A potential outcome of hepcidin reduction is similarly to have a new availability of sufficient iron to organs that need it by decreasing its sequestration. As shown in Figure 27, roxadustat increased serum iron compared to placebo in patients with NDD CKD. Importantly, this increase in serum iron occurred in the setting of less IV iron use in the roxadustat group compared to placebo likely due to increased absorption from the gastrointestinal tract as well as mobilization from previously sequestered stores. Patients receiving roxadustat also had a reduction in hepcidin and then ferritin. Hepcidin sequesters iron in the body where it cannot be delivered to the bone marrow. These findings support that roxadustat reduces hepcidin and increases iron availability to the bone marrow (as demonstrated by increasing serum iron and reduced ferritin). Page 39 of 154

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Figure 27: Pooled NDD Studies: LSMean Change from Baseline to Week 20 in Iron, Ferritin, and Hepcidin Levels

Abbreviations: CI=confidence interval; NDD=non-dialysis-dependent; LS=least square. *Week 20=the mean of Weeks 12–28; hepcidin data are mean change from baseline to Week 24. Note: Full analysis set. Similar results were seen in the DD population (Figure 28). While serum iron was decreased in patients receiving EPO, serum iron was increased in the roxadustat group, despite less IV iron administration, lower rates of transfusion, and slightly higher Hb levels. As seen in the NDD studies, the increases in iron and reduction in ferritin with roxadustat suggest increased iron mobilization from previously trapped stores.

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Figure 28: Pooled DD Studies: LSMean Change from Baseline to Week 20 in Iron, Ferritin, and Hepcidin Levels

Abbreviations: CI=confidence interval; DD=dialysis-dependent; LS=least square. *Week 20=the mean of Weeks 12–28; hepcidin data are mean change from baseline to Week 24. Note: Full analysis set. Inflammation is a common occurrence in patients with DD CKD and leads to increased hepcidin levels. In the presence of high hepcidin levels, iron stores are less accessible to be transported by the blood to the bone marrow. Under normal conditions, serum ferritin levels correlate with total body stores of iron. In the presence of inflammation, iron is sequestered in intracellular stores such as macrophages and the reticuloendothelial system, resulting in functional iron deficiency. The treatment of anemia in patients with functional iron deficiency requires the mobilization of this sequestered iron for it to be accessible by the bone marrow (Macdougall et al 1992). When examined by baseline quintiles of serum hepcidin, the Hb curves appeared to be clinically dissimilar among patients treated with EPO (Figure 29). Among patients with DD CKD treated with EPO, Hb levels in the patients in the 2 greatest hepcidin quintiles did not reach the same Hb levels as in the patients in the lower 3 hepcidin quintiles, despite higher EPO doses.

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Figure 29: Pooled DD Studies: Mean Hb Levels by Quintiles of Hepcidin at Baseline in the Epoetin Alfa Group

Abbreviations: DD=dialysis-dependent; Hb=hemoglobin; SE=standard error. However, in patients with DD CKD treated with roxadustat, the Hb levels achieved with were more similar across hepcidin quintiles (Figure 30). The data support that roxadustat efficacy was maintained across levels of hepcidin, whereas the efficacy of EPO was attenuated at the highest hepcidin levels. Figure 30: Pooled DD Studies: Mean Hb Levels by Quintiles of Hepcidin at Baseline in the Roxadustat Group

Abbreviations: DD=dialysis-dependent; Hb=hemoglobin; SE=standard error. While the mean Hb among quintiles was approximately 0.5 g/dL lower among patients with DD CKD treated with EPO in the groups with the highest hepcidin levels, it must be emphasized that one of the central goals of anemia treatment is to minimize or avoid transfusion. Therefore, the impact of this difference in Hb must be examined relative to its association with transfusion risk.

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Among patients with DD CKD who had the highest baseline levels of hepcidin, days with transfusions were reduced in the roxadustat vs EPO-treated patients: 11.6 per 100 PEY vs 21.3 per 100 PEY, respectively. As previously shown, hepcidin levels decreased among patients taking roxadustat. Consequently, there was more iron available making roxadustat a more effective treatment of anemia in these patients. Similar relationships were seen when quintiles of ferritin at baseline were examined. Serum ferritin levels reflect intracellular stores of iron. In addition, in inflammation ferritin can be elevated as an acute phase reactant and can therefore be used as a marker of inflammation similar to CRP. An elevation in serum ferritin in the presence of anemia can suggest the presence of a functional iron deficiency. Similar to the stratification of Hb levels by hepcidin quintiles, patients with DD CKD treated with EPO in the highest 2 quintiles of ferritin at baseline had the lowest Hb levels over time (Figure 31), despite being treated with the highest EPO doses. Figure 31: Pooled DD Studies: Mean Hb Levels by Quintiles of Ferritin at Baseline in the Epoetin Alfa Group

Abbreviations: DD=dialysis-dependent; Hb=hemoglobin; SE=standard error. Similar to stratification of Hb levels by hepcidin quintiles, Hb levels in patients with DD CKD treated with roxadustat were similar across quintiles of ferritin (Figure 32).

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Figure 32: Pooled DD Studies: Mean Hb Levels by Quintiles of Ferritin at Baseline in the Roxadustat Group

Abbreviations: DD=dialysis-dependent; Hb=hemoglobin; SE=standard error. While the difference between the Hb values among patients in the various quintiles of serum ferritin were roughly 0.5 g/dL, the clinical significance of this difference is apparent in the association between these different Hb levels and risk of transfusion. Among patients with DD CKD who had the highest baseline levels of ferritin, days with transfusions were reduced in the roxadustat vs EPO-treated patients: 12.5 per 100 PEY vs 21.5 per 100 PEY, respectively. This decrease is likely due to the availability of previously sequestered iron stores by reduction of functional iron deficiency. Inflammation is a significant contributor to the etiology of anemia of CKD. Higher levels of systemic inflammation can contribute to worse and potentially more “treatment-resistant” anemia. Hyporesponsiveness has no single definition in the clinical nephrology community. However, it is characterized by a persistently low Hb level below the desired clinical goal. The roxadustat Phase 3 trials demonstrate the critical role that iron sequestration and functional iron deficiency caused by inflammation plays in the clinical scenario of hyporesponsiveness. Both hepcidin and high ferritin levels are markers of this phenomenon. Hepcidin is likely the mediator of iron sequestration and ferritin is the marker of the iron being sequestered. Patients who have the highest values of both do not achieve the same Hb levels when treated with EPO despite higher doses. Roxadustat, in contrast, effectively treats anemia in this hyporesponsive patient population with less requirement for blood transfusions. Consequently, roxadustat will be an important option for this population of patients with DD CKD.

1.6. Safety Findings (NDD and DD Population)

1.6.1. Cardiovascular Safety The initial roxadustat Phase 3 program was designed to assess the efficacy and safety of roxadustat compared to placebo in NDD and compared to EPO in DD. Following the FDA’s recommendation to Page 44 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee use major adverse cardiovascular event (MACE) defined as ACM, myocardial infarction, and stroke as the primary safety endpoint and to power for non-inferiority, Studies 001 and 002 were added. From the outset, Studies 001 and 002 were intended to contribute to a pooled assessment of CV safety and included the most comprehensive follow-up among the pivotal studies, whereas the initial Phase 3 studies were initially designed to demonstrate efficacy and safety without contributing to a pooled assessment of CV safety. The CV safety of roxadustat was assessed using time to first adjudicated MACE, time to first MACE+ (MACE plus unstable angina requiring hospitalization and congestive heart failure requiring hospitalization) and time to ACM were also assessed, as well as time to CV mortality and the individual components of MACE+. Reported CV events and all deaths were sent to a blinded central Independent Event Review Committee (IERC) for adjudication. CV safety was assessed by pooling the pivotal studies for each population (001, 060, and 608 for NDD; 002, 063, and 064 for DD). The pooled population HR was estimated using the meta-analysis method to combine the HRs from the individual studies. The program was designed to have sufficient power to ensure an upper bound of the 95% CI of the HR for MACE of < 1.3 for roxadustat compared to placebo in the NDD population and compared to EPO in the DD population. The upper bound of the 95% CI of the HR of 1.3 was chosen based on precedent from and based on the consideration that HRs ≥ 1.3 were considered unacceptable in the Normal Hematocrit and CHOIR trials (Besarab et al 1998; Singh et al 2006). Indeed, the size of the roxadustat clinical program allowed for the generation of a large CV safety database, with more than 8,000 patients from 6 pivotal trials and approximately 1,500 total patients with MACE events in the primary analysis sets. As discussed further below, results for Study 610, an NDD study with an active control, are presented in order to assess the CV safety of roxadustat vs ESA in NDD patients and to assess the CV safety of roxadustat in NDD patients in a clinical trial setting not affected by informative censoring.

1.6.1.1. NDD Cardiovascular Safety Assessment As expected, given the intended treatment population of patients with Hb < 10 g/dL, the NDD population consisted largely of patients with severe CKD at baseline. Eighty percent of patients had baseline eGFR < 30 mL/min/1.73 m2 (consistent with CKD Stage 4 or 5), and 42% had baseline eGFR < 15 mL/min/1.73 m2 (consistent with CKD Stage 5). When assessed by quintiles, the 20% of patients with the lowest baseline eGFR had baseline values < 10 mL/min/1.73 m2, which corresponds with the mean eGFR at the time of dialysis initiation in the US (USRDS 2020). As expected, dialysis initiation was common in the Phase 3 NDD program, with 34.7% of patients starting dialysis during the study. • Placebo was selected as the comparator for the roxadustat NDD program due to the relative infrequency of ESA use in NDD CKD. However, given the severe CKD and high rates of dialysis initiation, many placebo patients required recurrent ESA rescue therapy, leading to large differences in treatment discontinuation between groups (Figure 33) with HR (95% CI) for early treatment discontinuation for roxadustat vs placebo of 0.49 (0.45–0.54). Although rates of discontinuation of placebo were consistently higher compared to roxadustat across subgroups, it was noted that differences were larger among patients with severe CKD, with placebo patients with baseline eGFR < 10 mL/min/1.73 m2 being nearly 2.5-times as likely to discontinue treatment early compared to corresponding roxadustat-treated patients (HR for early treatment discontinuation of roxadustat compared to placebo 0.41, 95% CI: 0.34–0.50). Page 45 of 154

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Figure 33 demonstrates this by showing the proportion of patients without early treatment discontinuation over time, including the patients with the lowest baseline eGFR (< 10 mL/min/1.73 m2) and those with baseline values ≥ 10 mL/min/1.73 m2. Because baseline eGFR < 10 mL/min/1.73 m2 was associated with increased risk for MACE regardless of treatment group (HR compared to baseline eGFR ≥ 10: 1.44, 95% CI: 1.22–1.69), these findings have important implications for the CV safety assessment of roxadustat compared to placebo by demonstrating that high-risk patients were retained in the roxadustat group in on- treatment analyses but more likely to be censored from on-treatment analyses in the placebo group. These findings were also noted among patients with more severe anemia, as patients with baseline Hb of < 9 g/dL were much less likely to discontinue roxadustat- treatment early (HR 0.45, 95% CI: 0.39–0.52) and had higher MACE risk regardless of treatment group (HR compared to baseline Hb ≥ 9 g/dL 1.47, 95% CI: 1.28–1.69) (Figure 34). In addition to the above, dialysis initiation was an important source of informative censoring (HR, 95% CI for early treatment discontinuation of roxadustat compared to placebo following dialysis initiation was 0.38, 0.32–0.46). As shown in Figure 34, dialysis initiation was common overall, particularly among patients with the lowest quintile of baseline eGFR. Figure 33: Pooled NDD Studies: Proportion of Patients Without Early Study Drug Discontinuation over Time, by Treatment Group and Baseline eGFR

Abbreviations: eGFR=estimated glomerular filtration rate; NDD-non-dialysis-dependent Note: Safety Population, NDD Pool: Studies 001, 060, 608

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Figure 34: Pooled NDD Studies: Proportion of Patients Without Dialysis Initiation over Time, by Treatment Group and Baseline eGFR

Abbreviations: eGFR=estimated glomerular filtration rate; NDD-non-dialysis-dependent. Note: Safety Population, NDD Pool: Studies 001, 060, 608 Cumulatively, these findings led to informative censoring of the highest CV risk placebo patients, with fewer high CV risk placebo patients remaining on treatment over time, leading to bias in favor of placebo. For example, over time, a substantially higher proportion of patients remaining on roxadustat treatment were patients who had initiated dialysis (Figure 35) due to placebo patients starting dialysis requiring ESA rescue therapy, compared to roxadustat patients generally having stable Hb values despite dialysis initiation. Because dialysis patients are at substantially higher risk for CV and other events including death, this is another important source of bias in on-treatment analysis. To address these biases, the Sponsor and FDA agreed to preferentially analyze NDD safety data using on-study analysis (also referred to as ITT analyses, including all MACE events accrued during the study, regardless of whether patients remained on treatment at the time of the event).

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Figure 35: Percent of Patients on Dialysis Among Patients Remaining on Treatment

The approach to follow-up of MACE events and vital status after treatment discontinuation varied among the clinical trials. In Study 608, patients that discontinued treatment prematurely were assessed every 6 months until the end of the study for vital status, SAEs, and CV and thromboembolic events, unless consent was withdrawn. Study 060 conducted telephone visits every 3–6 months to assess for CV events, and Study 001 continued study visits with no change to safety data collection but allowed for modified follow-up such as telephone visits when necessary to avoid withdrawal of consent. The by-study and overall percentage of patients with treatment completion and complete follow-up for MACE and mortality are shown in Figure 38. Reasons for treatment discontinuation are presented in Table 59 in Section 10; patient decision was the most common reason for treatment discontinuation. Long-term follow-up of patients was more difficult than in other populations due to the patients’ medical complexity and the high proportion of patients who started dialysis. These challenges have been observed with prior CKD anemia trials in both the NDD and DD populations, as shown in Figure 36 and Figure 37. Although the rates of treatment discontinuation in the roxadustat NDD pool were higher than most prior CKD anemia trials, it should be noted that the roxadustat NDD program differed from prior trials by enrolling a patient population with much more severe CKD who required dialysis initiation at higher rates; the rates of study discontinuation in the roxadustat NDD program were lower than most prior CKD anemia programs. Overall, 87.8% and 91.4% of patients had complete follow-up for MACE and vital status, respectively. Among the pivotal NDD trials, follow-up was most complete for Study 001 (Table 36 in Section 6.4.1).

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Figure 36: Treatment Completion Rate in Roxadustat and Historical Anemia of CKD Trials

Abbreviations: CHOIR=Correction of Hemoglobin and Outcomes in Renal Insufficiency trial; CKD=chronic kidney disease; CREATE=Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta; DD=dialysis- dependent; NDD=non-dialysis-dependent; TREAT=Trial to Reduce Cardiovascular Events with Aranesp Therapy. Source: Wanner et al 2005; Fellström et al 2009; Singh et al 2006; Drüeke et al 2006; Fishbane et al 2013; Evolve Trial Investigators 2012; Macdougall et al 2013; Macdougall et al 2019; Pfeffer et al 2009.

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Figure 37: Study Completion Rate in Roxadustat and Historical Anemia of CKD Trials

Abbreviations: CHOIR=Correction of Hemoglobin and Outcomes in Renal Insufficiency trial; CKD=chronic kidney disease; CREATE=Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta; DD=dialysis- dependent; NDD=non-dialysis-dependent; TREAT=Trial to Reduce Cardiovascular Events with Aranesp Therapy. Source: Wanner et al 2005; Fellström et al 2009; Singh et al 2006; Drüeke et al 2006; Fishbane et al 2013; Evolve Trial Investigators 2012; Macdougall et al 2013; Macdougall et al 2019; Pfeffer et al 2009. Another way to assess follow-up is to evaluate mean follow-up time on treatment, mean follow-up time for MACE, and mean follow-up time for ACM. Table 5 shows these analyses by treatment group overall and Table 6 shows by treatment group and baseline eGFR. As expected, follow-up time on- treatment was substantially longer for roxadustat compared to placebo; however, follow-up time for MACE and ACM was comparable by treatment group. Ninety percent of MACE follow-up for roxadustat occurred during the OT+28 period, compared to 72% for placebo. This difference suggests that any amount of incomplete ascertainment of CV safety data following the on-treatment- period would be expected to lead to bias in favor of placebo in the ITT/on-study analysis, and that additional analyses which include a more balanced proportion of observation time occurring on treatment could further reduce bias due to differential treatment discontinuation. On review of the data by baseline eGFR, it is noted that the proportion of overall on-study/ITT follow-up that occurred during the on- treatment period is more consistent in the roxadustat group, and that follow-up time on treatment (and proportion of on-study/ITT follow-up time which occurred on-treatment) was particularly low among placebo patients with baseline eGFR < 10 mL/min/1.73 m2. In sum, this analysis confirms the potential for informative censoring and bias favoring the placebo group in the OT+28 period, which will be attenuated in the ITT/on-study analysis.

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The overall on-study analysis includes time when patients from both treatment groups were on dialysis and time when a high proportion of placebo patients had converted to ESA. In order to focus on the clinical question of the CV safety of roxadustat compared to placebo in patients not on dialysis, “NDD-NDD” results are presented, which censor at dialysis initiation for patients who initiated dialysis during the study. It is acknowledged that this analysis has limitations due to censoring at a post-randomization event. Additionally, on-study results for patients with baseline eGFR ≥ 10 mL/min/1.73 m2 are presented as supportive analyses to focus on the 80% of patients most likely to remain dialysis independent and who are less affected by differences in treatment discontinuation. As shown in Table 6, differences in on-treatment vs off-treatment follow-up time were less pronounced in this subgroup. Finally, results from Study 001 are shown as well as the pooled results because this study had the most complete follow-up for CV safety and mortality events. Table 5: Mean Follow-up Time in Years, in On-treatment Plus 28 Days (OT+28) Analysis Set for MACE and ACM Follow-up Time/Patient, Roxadustat Follow-up Time/Patient, Placebo OT-28 MACE ACM OT-28 MACE ACM Pooled 1.7 1.9 2.0 1.3 1.8 2.0 Percent of overall follow-up 90% 84% 72% 66% time during OT+28 period Abbreviations: ACM=all-cause mortality, MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke)

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Table 6: Mean Follow-Up Time in Years, in the On-treatment Plus 28 Days Analysis Set for MACE and ACM by Baseline eGFR Follow-up Time/Patient, Roxadustat Follow-up Time/Patient, Placebo OT+28 MACE ACM OT+28 MACE ACM eGFR < 10* 1.5 1.7 1.8 1.0 1.7 1.9 Percent of overall follow-up 85% 79% 57% 51% time during OT+28 period eGFR < 10 – < 20* 1.7 2.0 2.1 1.2 1.8 1.9 Percent of overall follow-up 89% 83% 70% 64% time during OT+28 period eGFR 20 – < 30* 1.8 1.9 2.0 1.5 1.9 2.1 Percent of overall follow-up 92% 88% 79% 72% time during OT+28 period eGFR ≥ 30* 1.8 1.9 2.0 1.6 1.9 2.0 Percent of overall follow-up 93% 87% 82% 77% time during OT+28 period Abbreviations: ACM=all-cause mortality; eGFR=estimated glomerular filtration rate; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); OT+28=on-treatment plus 28 days. *mL/min/1.73 m2

1.6.1.1.1. NDD Cardiovascular Safety Results Figure 38 shows treatment discontinuation and ascertainment of MACE and ACM for the pooled NDD population. Sixty-two percent of roxadustat patients completed treatment compared to 40% of placebo patients, and a similar proportion of patients in each group had complete follow--up for MACE and ACM.

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Figure 38: Pooled NDD Studies: Retention and Follow-up

Abbreviation: NDD=non-dialysis-dependent. The Kaplan-Meier survival analysis plots for the endpoint of MACE shows the probability of remaining event-free over time for the pooled NDD program and for the largest study in the program (Study 001), which had the most comprehensive follow-up of CV safety. The HR (95% CI) for MACE for roxadustat compared to placebo was 1.10 (0.96–1.27), in the pooled NDD assessment, and the results for Study 001 were consistent with the pooled results (Figure 39).

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Figure 39: Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of MACE a. Pooled NDD Studies

b. Study 001

Abbreviations: CI=confidence interval; ITT=intent-to-treat analysis set; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); NDD=non-dialysis-dependent. Note: Safety Population; On-study analysis, NDD Pool: Studies 001, 060, 608, hazard ratio upper bound of 95% CI below reference margin of 1.3. Figure 40 shows risk for MACE, MACE +, and ACM for roxadustat compared to placebo. HR point estimates range from 1.07–1.10, with 95% CIs crossing 1.0 and with 95% CI upper bounds ranging from 1.21–1.27 (Figure 40, top panel). When the data are censored at dialysis initiation (NDD-NDD), HR point estimates were nearly 1.0 (Figure 40, middle panel) and 95% CI upper bounds ranged from 1.19–1.21. This analysis includes 568 patients with MACE events and is considered important for assessing the CV safety of roxadustat for patients not on dialysis. Upon evaluation of the approximately 80% of total patients with baseline eGFR ≥ 10 mL/min/1.73 m2, who were less affected by differences in treatment discontinuation and who were less likely to start dialysis during the program, HR point estimates were also close to 1.0 (Figure 40, bottom panel).

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Figure 40: Pooled NDD Studies: Forest Plot of Primary Analysis of MACE, MACE+, and ACM a. Pooled NDD Studies

b. NDD-NDD

c. eGFR ≥ 10 mL/min/1.73 m2

Abbreviations: ACM=all-cause mortality; CI=confidence interval; eGFR=estimated glomerular filtration rate; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=m MACE, plus hospitalization for unstable angina or congestive heart failure; NDD=non-dialysis-dependent. Note: Safety Population; On-study analysis (Studies 001, 060, 608; N=4,270); hazard ratio upper bound of 95% CI below reference margin of 1.3. Results for Study 001 were consistent with the pooled results, for on-study NDD, on-study NDD with censoring at dialysis initiation, and on-study NDD with baseline eGFR ≥ 10 mL/min/1.73 m2 (Table 38). The NDD program was not powered for the comparison of CV mortality or MACE+ components for roxadustat and placebo, and in particular there were relatively few myocardial infarction and stroke events during the program. HR point estimates varied by endpoint, however 95% CIs crossed 1.0 for all endpoints (Table 7).

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Table 7: Pooled NDD Studies: Cardiovascular Mortality and MACE+ Components Roxadustat Placebo N=2386 N=1884 HR (95% CI) Event n (%) n (%) Death (all-cause mortality) 400 (16.8%) 301 (16.0%) 1.08 (0.93, 1.26) Cardiovascular-related mortality 143 (6.0%) 102 (5.4%) 1.11 (0.86, 1.44) Myocardial infarction 86 (3.6%) 52 (2.8%) 1.29 (0.90, 1.85) Stroke 56 (2.3%) 36 (1.9%) 1.25 (0.82, 1.90) Hospitalization for Unstable angina 15 (0.6%) 12 (0.6%) 0.56 (0.22, 1.42) Hospitalization for Congestive heart 175 (7.3%) 151 (8.0%) 0.93 (0.75, 1.16) failure Abbreviations: CI=confidence interval; HR=hazard ratio; NDD=non-dialysis-dependent. Note: Safety Population; On-study analysis (Studies 001, 060, 608; N=4270) Figure 41 shows MACE results presented above, as well as overall on-treatment MACE and on‑treatment MACE in patients with baseline eGFR ≥ 10 mL/min/1.73 m2. The on-treatment analyses are heavily influenced by bias due to informative censoring in the placebo group and are not considered representative of the CV safety profile of roxadustat. The overall on-study/ITT HR for MACE was 1.10. On-study analyses with censoring at dialysis initiation, and of the subgroup of patients with baseline eGFR of ≥ 10 mL/min/1.73 m2 were less affected by differential treatment discontinuation and had MACE HR point estimates of 1.02 and 1.00, respectively. Figure 41: Pooled NDD Studies: Results for MACE Vary Due to Impact of Differential Treatment Discontinuation

Abbreviations: eGFR=estimated glomerular filtration rate; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); NDD=non-dialysis-dependent. Note: Safety Population; OT+28 analysis or On-study analysis (Studies 001, 060, 608; N=4270) Although ESAs are used infrequently in NDD CKD anemia, they are approved for use in the US, and the placebo-controlled NDD program does not directly address the question of the CV safety of roxadustat compared to ESAs in this population. Study 610 is considered informative due to its unique

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee design as an active-controlled (darbepoetin alfa) NDD study which is not affected by substantial differences in study drug discontinuation and informative censoring. The CV safety results for 610 showed MACE, MACE+, and ACM with HR point estimates ranging from 0.81–0.90 (Figure 42). Figure 42: Study 610: Forest Plot of Primary Analysis of MACE, MACE+, and ACM

Abbreviations: ACM=all-cause mortality; CI=confidence interval; MACE=major adverse cardiovascular event (all- cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure; NDD=non-dialysis-dependent; OT+28=on-treatment plus 28 days. Note: Safety Population, OT+28 analysis.

1.6.1.2. DD Cardiovascular Safety Assessment In agreement with FDA, the pooled CV safety assessment of roxadustat in patients with DD CKD anemia is based on Studies 063, 064, and 002. Each of these studies compared open-label roxadustat to open-label EPO. The Phase 3 study, Study 613, had a different design and is assessed separately. The DD population consisted of patients from Studies 063, 064, and 002. Study 063 was a study of ID patients randomized within 4 months following dialysis initiation. These patients were untreated with ESA at baseline, had low Hb levels, and required anemia correction followed by maintenance. Study 064 was a study of prevalent dialysis (mean 3.9 years) patients treated with stable doses of ESA at baseline, and with Hb values of 9–12 g/dL. These patients were randomized to either continued maintenance anemia treatment with ESA, or conversion to roxadustat followed by titration and maintenance. Study 002 was the largest study in the program and contained a mix of incident and prevalent dialysis patients, and a mix of patients treated and untreated with ESA at baseline. The ID subpopulation is considered to be a clinically relevant population because anemia treatment is most commonly initiated in conjunction with dialysis initiation, and because these patients were generally untreated with ESA at baseline or had recently been initiated on ESA. By contrast, most prevalent—or stable—dialysis patients had been on ESA treatment long-term, and these patients commonly had baseline Hb values within target ranges on low doses of ESA. The population of stable dialysis patients studied in the roxadustat program thus represents a population where transition to a different anemia therapy may not be clinically warranted for many patients. Therefore, the Sponsor considers that incident dialysis data are important for the assessment of the cardiovascular safety of roxadustat in patients with DD CKD.

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1.6.1.2.1. DD Cardiovascular Safety Results Figure 43 shows treatment discontinuation and ascertainment of MACE and ACM for the pooled DD population. Sixty-six percent of EPO-treated patients completed treatment compared to 58% of roxadustat-treated patients, and a similar proportion of patients by treatment group had complete follow-up for MACE and ACM. Reasons for treatment discontinuation, and treatment discontinuation in the ID and SDD subpopulations are presented in Table 60 in Section 10. Treatment discontinuation was more balanced by treatment group in the ID compared to the SDD subgroup. “Withdrawal by patient” was the most common reason for treatment discontinuation. As shown in Figure 36 and Figure 37, the incidence of early treatment discontinuation was comparable to prior large NDD and DD CKD anemia trials, and the rates of study discontinuation were generally lower in the roxadustat DD CKD program. Figure 43: Pooled DD Studies: Retention and Follow-up

Abbreviation: DD=dialysis-dependent. The Kaplan-Meier survival analysis plot for the endpoint of MACE shows the survival curves of the 2 groups tracking closely (Figure 44). Results for additional analysis sets are provided in Section 6.4.2 .

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Figure 44: Pooled DD Studies: Kaplan-Meier Curves of Primary Analysis of MACE

Abbreviations: CI=confidence interval; DD=dialysis-dependent; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); OT+7=on-treatment plus 7 days. Note: Safety Population; OT+7 analysis (Studies 002, 063, 064, N=3880). CV safety findings in the DD population were comparable between roxadustat and EPO. The forest plot presenting primary analysis of MACE, MACE+, and ACM shows HR point estimates ranging from 0.91–1.02, with 95% CIs crossing 1.0 and 95% CI upper bounds of 1.05–1.23 (Figure 45). Additional CV safety results in the DD population are presented in Section 6.4.2. Figure 45: Pooled DD Studies: Forest Plot of Primary Analysis of MACE, MACE+, and ACM

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure Note: Safety Population; OT+7 analysis (Studies 002, 063, 064, N=3880) Incidence rates of MACE+ individual components were generally similar for roxadustat and EPO, and numerically lower for hospitalization for congestive heart failure in roxadustat-treated patients (Table 8).

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Table 8: Pooled DD Studies: MACE+ Components Roxadustat Epoetin Alfa N=1940 N=1940 MACE+ Components n (%) n (%) HR (95% CI) All-Cause Mortality 207 (10.7%) 232 (12.0%) 1.02 (0.84, 1.23) Cardiovascular-Related Mortality 122 (6.3%) 136 (7.0%) 1.02 (0.80, 1.31) Myocardial infarction 103 (5.3%) 109 (5.6%) 1.07 (0.82, 1.40) Stroke 45 (2.3%) 50 (2.6%) 1.04 (0.69, 1.56) Unstable angina 18 (0.9%) 22 (1.1%) 0.89 (0.48, 1.67) Congestive heart failure 120 (6.2%) 166 (8.6%) 0.83 (0.66, 1.05) Abbreviations: CI=confidence interval; DD=dialysis-dependent; HR=hazard ratio; MACE+=major adverse cardiovascular event including hospitalizations for either unstable angina and/or congestive heart failure; OT+7=on- treatment plus 7 days. Note: Safety Population; OT+7 analyses (Studies 002, 063, 064, N=3880) To further evaluate the results in patients with ID and SDD CKD, pooled analyses were performed. It should be noted that these analyses were not powered for non-inferiority. Figure 46 shows the proportion of ID patients without MACE over time for roxadustat compared to EPO. Although the 95% CI crossed 1.0, the curves for the proportion of patients without MACE appeared to separate over time, and the HR point estimate for MACE was 0.82 for roxadustat compared to EPO. Figure 46: ID-DD Subpopulation: Kaplan-Meier Curve of Primary Analysis of MACE

Abbreviations: CI=confidence interval; ID-DD=incident dialysis dialysis-dependent; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); OT+7=on-treatment plus 7 days. Note: Safety Population; OT+7 analyses (Studies 002, 063, 064, N=1526 for patients on dialysis for ≤ 4 months at the time of randomization) The Kaplan-Meier survival analysis plot for MACE shows similar curves in MACE for roxadustat and EPO in SDD or prevalent dialysis patients (Figure 47). The HR point estimate was 1.11, with a 95% CI crossing 1.0.

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Figure 47: SDD-DD Subpopulation: Kaplan-Meier Curve of Primary Analysis of MACE

Abbreviations: CI=confidence interval; SDD=stable dialysis-dependent; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); OT+7=on-treatment plus 7 days. Note: Safety Population; OT+7 analyses (Studies 002, 063, 064, N=2354 for patients on dialysis for > 4 months at the time of randomization).

1.6.1.3. Analysis of Pooled DD Studies With and Without Study 613 Figure 48 shows CV safety results for the pooled DD studies with and without Study 613. Study 613 was a study of stable dialysis patients on ESA at baseline. Patients on short-acting ESAs were randomized to roxadustat or EPO, whereas patients on long-acting ESA were randomized to roxadustat or darbepoetin. In agreement with FDA, Study 613 was not pooled with the other 3 Phase 3 trials for the NDA because it randomized to roxadustat and 2 different ESAs, which may have different profiles. The results for Study 613 are shown in Figure 71, and the pooled DD analysis including Study 613 is presented below.

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Figure 48: Analysis of Pooled Dialysis Studies With and Without Study 613

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure OT+7=on-treatment plus 7 days; Roxa=roxadustat. Note: Safety Population; OT+7 analysis As expected, based on the effect of including Study 613 in the pooled analysis, Study 613 is an outlier compared to the pivotal DD studies (Figure 49; MACE+ and ACM are shown in Figure 71). Figure 49: MACE Results by Study for Pivotal DD Studies Including Study 613

Abbreviations: CI=confidence interval; DD=dialysis-dependent; ESA=erythropoietin-stimulating agent; Roxa=roxadustat. In addition to the differences in trial design as discussed above, analysis of demographic and baseline characteristics showed apparent baseline imbalances by treatment group design in Study 613 (Table 54). Such imbalances were not noted in the pivotal DD studies, and several of the noted imbalances in Study 613 were in baseline characteristics known to be associated with CV risk, suggesting that the treatment groups may not have had balanced CV risk at baseline. Notably, dialysis

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee vintage (time since initiation of dialysis) differed by treatment group. Dialysis vintage is important prognostically. As shown in Figure 50, there is a “U-shaped” association between mortality and dialysis vintage in US patients, with high mortality rates in the ID period, which decline sharply until ~2 years following randomization, then increasing to rates which approach rates in the ID period by ~5 years following dialysis initiation. These results demonstrate how the observed differences in mean dialysis vintage in Study 613 could lead to confounding in the assessment of CV safety for roxadustat versus the comparators (Table 54). Figure 50: Rate of Mortality Among US Patients by Dialysis Vintage

Abbreviation: ESRD=end-stage renal disease. Source: USRDS 2020

1.6.1.4. Cardiovascular Safety Conclusions The CV safety of roxadustat is comparable to placebo in NDD CKD and to EPO in DD CKD. The CV safety results of the roxadustat NDD program should be interpreted in the context of the use of the placebo comparator. By contrast, prior seminal ESA NDD trials have generally used ESA as comparator, with the notable exception of TREAT, which showed an increased risk of stroke for darbepoetin compared to placebo. Notably, the NDD Study 610 compared roxadustat to darbepoetin alfa. The CV safety results in the NDD program are affected by informative censoring of placebo patients, with higher-risk patients being more likely to prematurely discontinue placebo than corresponding roxadustat patients who were more likely to continue treatment. The pooled NDD on-study analyses showed HR point estimate of 1.10 with a 95% CI that crossed 1.0, with upper bound of 1.27. Supportive results in patients with baseline eGFR ≥ 10 mL/min/1.73 m2, and in patients censored at dialysis initiation, which the Sponsor considers to be less affected by informative censoring, showed HR point estimates close to 1.0, with 95% CIs crossing 1.0. In addition, CV safety results of Study 001, which was the largest pivotal NDD study that had the most complete follow-up for CV events after treatment discontinuation, were consistent with the pooled results.

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In patients with VAT, demographics and baseline disease characteristics were similar between treatment groups. In addition, VAT rates across treatment groups were proportionally greater in the subgroup of patients with known risk factors of VAT (eg, history of cardiovascular/cerebrovascular/ thromboembolic disease, diabetes, and obesity). Rates of VAT in the roxadustat group were highest, and the difference between treatment groups was largest, during the first 12 weeks of the study following randomization (Figure 51). The rates of VAT were noted to decrease over time in both treatment groups, but to a proportionally greater extent in roxadustat-treated patients, and differences in event rates were noted to be of a lesser magnitude, at later compared to earlier time points in the study. Figure 51: Pooled DD Studies: Adjudicated VAT Adverse Events by Time of Onset

Abbreviations: DD=dialysis-dependent; IR=incidence rate; OT+7=on-treatment plus 7 days; PEY=patient exposure year; VAT=vascular access thrombosis. Note: Safety Population, OT+7 analysis; DD Pool: Studies 002, 063, 064 VAT risk was highest with roxadustat treatment early in the studies (Figure 51) when Hb values rose most quickly. During this early study period, roxadustat treatment was associated with a higher Hb rate of rise compared to EPO, which may contribute to the higher observed VAT incidence in roxadustat compared to EPO. Supporting this contention, exploratory analyses indicated that a more rapid rate of Hb rise was associated with a higher risk of VAT events in both roxadustat and EPO groups (Figure 52). Consequently, the higher rate of Hb rise in roxadustat-treated patients may explain the higher VAT risk compared to EPO. Based on this assessment, adjustments to roxadustat starting dose are expected to lower the rate of Hb rise, which will mitigate the risk of VAT.

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Figure 52: Pooled DD Studies: Incidence of VAT with Increasing Hb Rate of Increase

Abbreviations: AE=adverse event; DD=dialysis-dependent; Hb=hemoglobin; IR=incidence rate; OT+7=on-treatment plus 7 days; PEY=patient exposure year; VAT=vascular access thrombosis. Note: Safety Population, OT+7 analysis; DD Pool: Studies 002, 063, 064

Figure 53: Pooled DD studies: Proportion of Patients with First Occurrence of Hb Rate of Rise > 2 g/dL within Any 4-Week Period Over Time at Each Visit up to Week 52

Abbreviation: DD=dialysis-dependent. Note: Full Analysis Set Population, DD Pool: Studies 002, 063, 064. With respect to the clinical impact in patients with VAT, no patients were reported to discontinue roxadustat due to a VAT event. In addition, the majority of patients with a VAT event did not have a recurrence of the event (71.0% and 70.6% with roxadustat and EPO, respectively).

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Medication Guide for healthcare providers and patients, respectively. The Sponsor also plans to communicate risks in educational materials for healthcare providers. Important safety information includes: • Thrombotic events (eg VAT and DVT): This risk can be mitigated by reducing starting doses in order to decrease the incidence of rapid Hb rates of rise (See Section 1.7.3 ). Monitor Hb during treatment (ie, when initiating or adjusting therapy, monitor Hb levels at least every 2 weeks until stable, then monitor every 4 weeks). Consider withholding for severe or life-threatening thrombosis and manage all thromboses promptly. Advise patients to contact their healthcare provider for signs and symptoms of thrombosis. • Seizures: Advise patients to promptly report new onset seizures, premonitory symptoms, or increase in seizure frequency or severity to their healthcare provider. Patients with a history of seizure should be treated with caution. • Serious Infections: Avoid starting roxadustat in patients with an active severe or serious infection. Monitor patients for signs and symptoms of infection and promptly treat. Advise patients to contact their healthcare provider for signs and symptoms of an infection.

1.7.2. Post-marketing Surveillance Safety risks will continue to be monitored and evaluated in the post-approval setting, and will include the following: • Adverse event reporting: All individual case safety reports from spontaneous sources will captured in a validated safety database and relevant cases (eg, SAEs) will be reported to FDA's Adverse Event Reporting System. For spontaneous reports, targeted follow-up questionnaires will be used to collect additional specific information for events of interest (ie, DVT, VAT, seizures, serious infections). • Safety signal management: Safety surveillance and signal detection activities, which includes a monthly screening and evaluation of the Sponsor’s global safety database assessing serious and non-serious AEs reported from all sources (eg, clinical trials, spontaneous) will be performed. In addition, monthly safety assessments evaluate the global medical and scientific literature with regards to non-clinical and clinical reports. Review of global health authority safety databases (eg, FDA's Adverse Event Reporting System and Vigibase) are also conducted when potential signals are evaluated. Any confirmed signals will be communicated with the FDA. • Aggregate Reports: Cumulative reviews of events of interest will be summarized in periodic reports (eg, Periodic Benefit-Risk Evaluation Report) and will be submitted to the FDA. In addition to the activities listed above, the Sponsor is evaluating potential activities to characterize thrombosis risk with roxadustat treatment in the real-world setting at the newly recommended dosing regimen. The Sponsor will continuously evaluate, communicate, and mitigate known risks associated with the use of roxadustat. The Sponsor is also committed to working with the FDA on the development and implementation of appropriate activities/measures.

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1.7.3. Starting Dose Reduction and Lowering Hb Target Dosing recommendations for ESAs were modified in the post-marketing setting following evidence of an increased CV risk associated with higher Hb targets. Revised Hb targets were subsequently lowered, and Hb values > 11 g/dL are no longer a target for ESAs, though this has not been rigorously tested in randomized-controlled trials. In the roxadustat program, in both the NDD and DD studies, roxadustat-treated patients were treated to Hb targets of 10.5–12 g/dL. Similar to the strategy employed for ESAs, the Sponsor proposes to lower Hb targets in roxadustat-treated patients to 10–11 g/dL, which will lead to a lower effective dose and maintain the reduction in the risk of transfusion risk. In addition, like for ESAs, the Sponsor is recommending that the number of sequential dose increases in non-responsive patients is limited, to 3. As noted in Section 1.6.3.1, rapid rise of Hb was more common in the first 12 weeks of treatment than in the later phases of the studies and was associated with a greater risk of thrombotic events. The Hb response in this early phase was mainly affected by the starting dose. As very few actual starting doses (non-randomized) were utilized in the Phase 3 program, the Sponsor conducted modeling and simulation to estimate the effect of a range of potential starting doses on Hb performance and rapid rise. A semi-mechanistic-pharmacodynamic longitudinal mixed-effect model previously used in Phase 3 planning was re-evaluated and re-estimated using the new Phase 3 data. The model describes the time-course of Hb changes after the administration of roxadustat and is represented schematically in Figure 72 in Section 11. Figure 54 displays simulated Hb over time for ESA-untreated patients starting roxadustat, and Figure 55 for patients switching to roxadustat from ESA treatment. The graphs compare Hb dynamics with the doses utilized in the Phase 3 program and with the lower recommended starting doses. The reduced starting doses decrease the initial peak in Hb and rate of rise in both populations without diminishing longer-term efficacy.

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Figure 54: Simulated Mean Hb Values with Roxadustat in Previously ESA-untreated Patients

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin. Note: Solid line is mean. Grey areas depict 5, 25, 75, 95% quantiles.

Figure 55: Simulated Mean Hb Values in Patients Converting from ESA to Roxadustat

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin. Note: Solid line is mean. Grey areas depict 5, 25, 75, 95% quantiles. Figure 56 and Figure 57 display the incidence of rate of rise > 2 g/dL over 4 weeks for the ESA-untreated patients and ESA converters, respectively. The Phase 3 doses and the recommended lower starting doses are shown. The modeling and simulation data show reduction in the initial incidence of rapid rate of rise of Hb by at least two-thirds in both ESA-untreated and ESA conversion patients.

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Figure 56: Proportion of Roxadustat Patients (Previously Untreated with ESA) with Rapid Rate of Hb Rise, Phase 3 Dose Compared to Proposed Dose

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin. *Rapid rise: 4-week increase > 2 g/dL.

Figure 57: Proportion of Patients Converting from ESA to Roxadustat with Rapid Rate of Hb Rise, Phase 3 Doses Compared to Proposed Doses

Abbreviations: ESA=erythropoiesis-stimulating agent; Hb=hemoglobin. *Rapid rise: 4-week increase > 2 g/dL. The Sponsor plans reduced starting doses to mitigate the risk of VAT and other thrombotic complications and is evaluating potential post-marketing activities to assess Hb rate of rise and Page 76 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee thrombosis risk with these changes. Additionally, the Sponsor recommends to lower Hb target in roxadustat-treated patients to 10–11 g/dL and to limit the number of successive dose increases in patients who are not responding to roxadustat. These changes are anticipated to reduce doses of roxadustat and improve the roxadustat safety profile, while retaining efficacy and the desired reduction in transfusion risk.

1.8. Benefit-Risk Summary Roxadustat is a first-in-class, oral therapy that provides treatment of CKD anemia with the benefit of a novel mechanism of action that consistently corrects and maintains Hb across the spectrum of NDD and DD CKD anemia with an acceptable safety profile. In contrast to parenteral ESAs, which exogenously replace erythropoietin, roxadustat is a small molecule, reversible inhibitor of HIF-PH that stimulates HIF mediated erythropoiesis in a way that mimics the body's natural response to low oxygen environments by inducing endogenous erythropoietin and increasing iron availability. The current paradigm and standard of care for anemia treatment in NDD CKD has limitations. By requiring frequent travel to a healthcare facility for many individuals, the standard of care over the last 30 years produces many barriers to effective anemia treatment. Standard treatment for NDD CKD anemia generally requires treatment in a healthcare setting every week to every 3 weeks, which is inconvenient and may preclude treatment for many patients. Due in part to these limitations, many patients are untreated, and rates of transfusions – which require substantial healthcare utilization, have significant risks, and can decrease access to kidney transplantation – are unacceptably high. Roxadustat offers patients with NDD CKD an oral, convenient, home therapy that provides a coordinated erythropoiesis involving both erythropoietin production and increased iron utilization, to benefit patients whose disease is sub-optimally managed in the current real-world setting. Roxadustat provides benefit as it mitigates the IV iron requirement and lowers the risk of RBC transfusions. In the roxadustat clinical development program, all pivotal studies met the primary efficacy endpoint. The NDD trials demonstrated statistically significant treatment differences favoring roxadustat compared to placebo, providing patients with consistent increases in Hb regardless of baseline iron repletion status or inflammation. Importantly, patients treated with roxadustat achieved clinically meaningful reductions in transfusions. In the DD clinical trials, roxadustat was comparable in efficacy and safety to EPO. Unlike ESAs, roxadustat achieved efficacy in patients with elevated hsCRP and those with normal hsCRP without a need for dose increase. In addition, roxadustat is an effective treatment for patients with markers of hyporesponsiveness to ESAs including increased ferritin and hepcidin. Outside of clinical trials, these patients are currently devoid of clinical options beyond higher doses of ESAs and additional IV iron or marked transfusion requirement. These individuals will benefit from a treatment with a different mechanism of action to raise their Hb levels. Roxadustat demonstrated comparable CV safety to placebo in patients with NDD CKD and to EPO in patients with DD CKD. Patients treated with roxadustat had increased rates of VAT and DVT compared to EPO. Increased thrombosis risk was observed with higher rates of Hb rise in both roxadustat and EPO-treated patients, supporting the notion that reductions in the incidence of rapid rates of Hb rise can lower thrombosis risk in roxadustat-treated patients. More roxadustat-treated patients had seizures versus comparators, and patients with a history of seizure should be treated with roxadustat with caution. Increased fatal infection was noted for roxadustat compared with placebo in the NDD population; fatal infection risk, however, was not observed compared to darbepoetin. In Page 77 of 154

Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee addition, this this finding was not duplicated in the DD population, where rates were generally similar between roxadustat and comparator. In order to improve roxadustat’s safety profile while maintaining efficacy and reducing transfusion risk, the Sponsor proposes plans to use lower starting doses, to treat to lower Hb targets, and to limit the number of consecutive dose increases in patients not responding to roxadustat. The Sponsor will continuously evaluate, communicate, and mitigate known and potential risks associated with the use of roxadustat. Overall, the roxadustat clinical program provided efficacy and safety data to support its use to increase and maintain Hb levels for patients across the continuum of CKD anemia. Roxadustat offers a novel mechanism of action for the treatment of CKD anemia with unique benefits compared to ESAs and the convenience of an oral treatment that can be used to support home hemodialysis, peritoneal dialysis, and non-dialysis patients. Based on the totality of the evidence, the benefit-risk is positive for roxadustat in patients with NDD and DD CKD who need correction of their anemia.

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SUPPLEMENTAL INFORMATION

2. PRODUCT DESCRIPTION

2.1. Dosage The roxadustat formulation is proposed in 5 dose strengths of 20, 40, 50, 70, and 100 mg tablets for oral administration. For ESA-naïve patients or those not currently receiving stable doses of ESA, the recommended starting dose of roxadustat is based on body weight. For patients converting from an ESA, the recommended starting dose of roxadustat is based on their prior ESA dose. The dose range is 20 mg to 400 mg per administration. Maximum Recommended Dose • Patients not on dialysis: Not exceed a dose of 3 mg/kg or 300 mg TIW, whichever is lower • Patients on dialysis: Not exceed a dose of 3 mg/kg or 400 mg TIW, whichever is lower

2.2. Product Overview

2.2.1. Pharmaceutical and Biological Properties of Roxadustat Roxadustat is a new chemical entity and the first in a new pharmacologic class of small molecule therapeutics (Kang et al 2015). As shown in Figure 58, roxadustat is an N-acyl glycine resulting from the formal condensation of the amino group of glycine with the carboxy group of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. The chemical classification/formula and other key characteristics of roxadustat are provided in Table 16. Figure 58: Structural Formula of Roxadustat

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Table 16: Key Characteristics of Roxadustat International Non-proprietary roxadustat (FG-4592) Name/ Alternative Names Chemical Name [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Chemical formula C19H16N2O5 Chemical Abstract Service 808118-40-3 Registry Number Molecular weight 352.34 g/mol Class Amide; antianemia; carboxylic acid; isoquinoline; small molecule Mechanism of action Binds to and potently inhibits HIF-PHD, reducing HIF breakdown and promoting its activity Pharmacokinetics Exposure increases dose-dependently (approximately proportional to dose) across 1– 4 mg/kg dose range; half-life was 8–12 h Pharmacodynamics Dose-dependently increase Hb levels, reduce hepcidin and cholesterol levels and transiently increase endogenous EPO levels within or near physiologic range

2.3. Mechanism of Action Roxadustat is a novel, orally bioavailable, potent and reversible HIF-PH inhibitor (HIF-PHI) that transiently induces HIF stabilization and leads to a functional HIF transcriptional response that mimics the erythropoietic response associated with exposure of humans to intermittent hypoxia. HIF induces expression of not only erythropoietin, but also the erythropoietin receptor and proteins that promote iron absorption and recycling from the macrophage iron storage system (Peyssonnaux et al 2008). Thus, roxadustat pharmacologically stimulates erythropoiesis via the HIF pathway and in a manner consistent with the physiologic response to hypoxia, but under normoxic conditions. Roxadustat also has the potential to effectively treat anemia caused by inflammation-induced functional iron deficiency, which is typically hyporesponsive to ESAs. In these conditions, iron availability for erythropoiesis is reduced due to a number of inflammatory mediators. Because HIF-PHIs such as roxadustat alter expression not only of the erythropoietin gene, but also of genes regulating iron metabolism, it is postulated that roxadustat may be effective in treating these as well (Siddiq et al 2005). Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF transcriptional activity, presumably because intermittent stimulation allows the restoration of HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes sustained gene expression and the induction of genes that are expressed late after HIF activation, as well as expression of additional genes that are secondary to activation of HIF- dependent genes. Both nonclinical and clinical studies of roxadustat have successfully used the intermittent dosing paradigm to induce selective erythropoiesis and to optimize the Hb dose response. Furthermore, roxadustat was selected for development over other HIF-PHI candidate molecules based on an optimal biodistribution profile that enhances its selective action (eg, kidney [erythropoietin production], bone marrow [increase in erythropoietin receptors], duodenum [iron transport], and liver [erythropoietin and transferrin production and down-regulation of hepcidin]).

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The physiologic mechanisms underlying the effects of roxadustat on erythropoiesis are distinct from those of ESAs, and these differences result in several potential advantages over ESAs beyond the convenience of oral therapy. • Increase in the number of erythropoietin receptors in the bone marrow • Improved iron metabolism and bioavailability • Effective erythropoiesis at levels comparable to physiologic plasma erythropoietin concentrations (~10 to 20-fold lower than the supra-physiologic levels associated with parenteral ESA therapy) (Figure 59) • Effective erythropoiesis in the presence of inflammation • Reduction in total and low-density lipoprotein (LDL) cholesterol Figure 59: Circulating Erythropoietin Exposure with Roxadustat-Treated Patients with CKD and ESRD versus Reported ESA Dosing Patterns in ESRD (2005–2009)

Abbreviations: CKD=chronic kidney disease; Cmax=maximal serum concentration; EPO=epoetin alfa; ESA=erythropoiesis-stimulating agent; ESRD=end-stage renal disease; Hb=hemoglobin; Max=maximum; Min=minimum; TIW=3 times per week. 1 Cmax data for roxadustat estimated for a subset of 243 patients who achieved Hb response and were dosed 2 3 4 at expected therapeutic doses; Milledge and Cotes 1985; Goldberg et al 1993, Maeda et al 1992; Kato et al 1994; 5Based on Flaharty et al. (1990).

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3. REGULATORY AND DEVELOPMENT HISTORY

3.1. Regulatory Milestones Key regulatory milestones between FDA and FibroGen in the clinical development of roxadustat are summarized in Table 17. Table 17: Key Regulatory Milestones in Roxadustat Clinical Development Dates Discussion 04/17/2006 IND submitted under section 505 (b)(i) of the Food, Drug, and Cosmetic Act for roxadustat. 07/17/2012 End-of-Phase (EOP) 2 meeting: FDA requested that the roxadustat clinical development program be powered to assess CV safety for the NDD and DD CKD populations separately as a result of CV safety concerns for ESAs. To comply with this request, the sample size was increased in planned studies, new studies were added to the program, and study durations were extended. Independent CV endpoint adjudication was instituted, and FDA advised that while it would use MACE as its primary safety endpoint for analysis, the Sponsor could choose a different primary safety endpoint. 11/20/2012 FDA agreed that while placebo-controlled Phase 3 studies must be double-blind, open-label studies were acceptable for ESA comparator studies due to practical and ethical issues with a double-dummy design. FDA advised that open-label studies could contribute to the CV safety analysis since MACE is an objective endpoint that is not subject to ascertainment bias. 05/09/2014 FDA reiterated its preference for MACE as the primary safety endpoint. The choice of non- inferiority margin for the CV safety analysis was discussed, but no acceptable non- inferiority margin was agreed upon. 05/12/2014 Dosing regimens of once weekly, twice weekly, and TIW were initially investigated in the NDD Phase 3 program. At the May 2014 meeting, FDA recommended a single maintenance dosing regimen of TIW. Patients were converted to TIW dosing in Study 060 while patients were maintained on their original regimen in Study 608. 06/26/2017 FDA expressed concern that Study 1517-CL-0613 could be difficult to evaluate in pooled CV safety analysis as noted above and thus is not included in the DD pool. 07/30/2019 Pre-NDA meeting: The purpose of this meeting was to discuss the New Drug Application for roxadustat tablets for the treatment of anemia due to CKD. FDA advisement: The final Pooled Safety Analysis Plan safety pooling strategy in the NDD CKD population appears reasonable. The ITT analysis set for the MACE and MACE+ endpoints is preferred for analyses of the NDD CKD population. The final pooling strategy for analysis of CV safety (which removed Study 1517-CL-0613) in the DD CKD population appears reasonable. The OT+7 analysis set appears to be acceptable for analysis of the MACE and MACE+ endpoints in the DD CKD population, although sensitivity analyses should be done using the OT+28 analysis set. 12/20/2019 NDA submitted. Abbreviations: CV=cardiovascular; DD=dialysis-dependent; ESA=erythropoiesis-stimulating agent; FDA=Food and Drug Administration; IND=investigational new drug; ITT=intent-to-treat analysis set; MACE=major adverse cardiac event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure NDA=New Drug Application; NDD=non-dialysis-dependent; OT+7=on-treatment plus 7 days; OT+28=on-treatment plus 28 days; TIW=3 times per week.

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4. CLINICAL PHARMACOLOGY

4.1. Clinical Pharmacology Studies The global clinical pharmacology program to characterize roxadustat pharmacokinetic (PK) and pharmacodynamic parameters related to erythropoiesis and absorption, distribution, metabolism, and elimination/excretion includes: 1. Nonclinical pharmacology studies including 19 in vitro and ex vivo studies using human biomaterials. 2. Clinical pharmacology studies including 26 studies in healthy subjects, 1 study in patients with hepatic impairment, 3 studies in patients with severe renal impairment or ESRD, as well as clinical Phase 2/3 studies in patients with NDD CKD or DD CKD. A comprehensive summary of key clinical pharmacology findings is provided below.

4.2. Pharmacokinetics

4.2.1. General Pharmacokinetic Properties The PK and metabolic profile of roxadustat was evaluated in healthy subjects and patients with severely impaired renal function (eGFR < 30 mL/min/1.73 m2), including patients with ESRD requiring hemodialysis or hemodiafiltration. Roxadustat plasma exposure (area under the curve [AUC] and maximum plasma concentration [Cmax]) is dose-proportional from 20 to 280 mg (0.3 to 4.0 mg/kg, body weight); reaching a steady-state within one week with minimal accumulation. Roxadustat AUC is approximately 2-fold higher in patients with NDD or DD CKD than in healthy subjects, but Cmax is comparable.

4.2.2. Absorption, Distribution, Metabolism, and Elimination

Absorption: Roxadustat is rapidly absorbed and bioavailable with Cmax achieved at 2 h post- dose (fasted) in healthy subjects. Intake with food reduces the Cmax by 25% but does not affect roxadustat bioavailability. In vivo studies in healthy human subjects have demonstrated that ≥ 92% of the drug-related material in plasma is parent drug at 0.5 to 1 h post-dose from a single oral dose, suggesting that roxadustat is absorbed largely intact. In addition, recovery of Phase-1 oxidative and Phase-2 conjugated metabolites from urine and feces, accounting for 60% of the dose from a single oral dose is indicative of a high degree of absorption of roxadustat from the gastrointestinal tract. Distribution: Roxadustat is highly bound (~99%) to human plasma proteins, predominantly to albumin. In patients with severe renal impairment and ESRD on hemodialysis or hemodiafiltration, the mean unbound % of roxadustat in plasma is slightly increased compared with healthy subjects (1.1 % vs 0.9%) Dialysis does not appear to influence the in vivo protein binding of roxadustat but higher levels of unbound roxadustat have been seen in patients with moderate hepatic impairment. The distribution of roxadustat into RBCs is low, with a blood-to-plasma ratio of 0.5 after single-dose administration of radiolabeled roxadustat.

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Metabolism: Roxadustat is metabolized by cytochrome P450 (CYP)2C8 and uridine diphosphate-glucuronosyltransferase (UGT)1A9. Roxadustat is primarily metabolized through 2 main metabolic pathways: hydroxylation/oxidation followed by sulfation, producing metabolites 4’-hydroxy roxadustat and 4’-O-sulfate conjugates of 4’-hydroxy roxadustat, together accounting for 20% of the radioactive dose. The O-glucuronidation produces metabolite 4-O-β-glucuronide of roxadustat, representing 28% of the dose. Minor metabolic routes included glucosidation producing 4-O-β-glucoside of roxadustat (8.1% of the dose), acyl glucuronidation producing acyl-1-O-β-glucuronide of roxadustat (0.6% of the dose), and demethylation producing N-descarboxymethyl roxadustat oxide and N- descarboxymethyl roxadustat (together ~3.6% of the dose). Elimination/Excretion: The elimination and excretion of roxadustat and its metabolites involves multiple pathways including metabolism, biliary and/or intestinal clearance, and renal clearance (CLR). Roxadustat has an apparent total body clearance of 1.1 and 1.4 L/h in patients with NDD CKD and DD CKD respectively, compared with 2.3–2.6 L/h in healthy subjects. In feces, intact roxadustat was the major component (28%) of the dose, representing unabsorbed drug, biliary excretion of intact drug, and/or deconjugated (glucuronide) metabolites. The effective half-life of roxadustat is approximately 10 hours in healthy subjects, and 15 hours in patients with CKD.

4.2.3. Intrinsic Factors Based on a population PK analysis of 2,855 subjects from 4 Phase 3 studies, no clinically relevant differences in the PK of roxadustat were observed based on age, sex, race, body weight, renal function (eGFR), or dialysis status in patients with anemia due to CKD. Hepatic impairment: Following single-dose administration of 100 mg roxadustat in patients with moderate hepatic impairment (Child-Pugh Class B) and subjects with normal renal function, roxadustat AUC was increased by 23% and Cmax decreased by 16% relative to healthy subjects matched for age, sex, and BMI. Roxadustat unbound fraction was increased in patients with moderate hepatic impairment (1.1% vs 0.8%), resulting in an increase in mean unbound Cmax and AUCinf of 16% and 70%, respectively, compared with matched healthy subjects. Roxadustat PK has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). A lower starting dose is recommended when prescribing roxadustat to patients with moderate hepatic impairment. Renal Impairment: A positive correlation was observed between roxadustat PK parameters (CL/F, CLR, and unbound CL/F and CLR) and renal function (eGFR). Most patients (~70%) included in the analysis had an eGFR of ≤ 15 mL/min/1.73 m2.

4.2.4. Extrinsic Factors

4.2.4.1. In Vitro Findings Roxadustat is a substrate of CYP2C8 and UGT1A9 enzymes, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1, and organic anion transporter (OAT)1 and OAT3. Roxadustat inhibits CYP2C8, BCRP, OATP1B1, and OAT3,

Page 84 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee but showed no inhibition of other CYP metabolizing enzymes or transporters at clinically relevant concentrations, in vitro. Roxadustat does not induce CYP enzymes in vitro.

4.2.4.2. Effect of Other Drugs on Roxadustat Metabolism- and transporter-based drug interactions were studied with gemfibrozil (CYP2C8 and OATP1B1 inhibitor) and probenecid (UGT and OAT inhibitor) in healthy subjects. Results from these studies were used to extrapolate findings to other concomitant medications or products sharing the same drug-drug interactions properties. In addition, population PK analysis of data obtained from Phase 3 clinical studies was used to characterize the impact of observed or anticipated interactions with phosphate binders, oral iron, clopidogrel and perpetrators of CYP2C8, UGT1A9, or OATP1B1 in the target population.

4.2.4.2.1. Phosphate Binders Coadministration of phosphate binders and roxadustat decreased the absorption of roxadustat (excluding lanthanum carbonate hydrate). However, this effect can be mitigated by administering phosphate binders and roxadustat at least one hour apart.

4.2.4.2.2. Gemfibrozil Coadministration of roxadustat with gemfibrozil (CYP2C8 and OATP1B1 inhibitor) in healthy subjects increased roxadustat AUC by 2.3-fold and Cmax by 1.4-fold. The interaction between roxadustat and gemfibrozil or other inhibitors of CYP2C8 or OATP1B1 can be mitigated by regular monitoring of Hb levels in conjunction with dose adjustment according to roxadustat dose adjustment guidelines.

4.2.4.2.3. Probenecid Coadministration of roxadustat with probenecid (UGT1A9, OAT1, and OAT3 inhibitor) increased roxadustat AUC by 2.3-fold and Cmax by 1.4-fold and prolonged the half-life by 2.5 h. The interaction between roxadustat and probenecid or other inhibitors of OAT1, OAT3, or UGT1A9 or inducers of UGT1A9 can be mitigated by regular monitoring of Hb levels in conjunction with dose adjustment according to roxadustat dose adjustment guidelines. Probenecid is contraindicated for use in patients with severe renal impairment.

4.2.4.2.4. Other Drugs Without Clinically Meaningful Interactions Roxadustat exposure was not affected by coadministration with oral iron (from population PK analysis only), clopidogrel (from population PK analysis only), Kremenzin®, or lanthanum carbonate hydrate. Coadministration of omeprazole with roxadustat did not result in a clinically significant drug-drug interaction.

4.2.4.3. Effect of Roxadustat on Other Drugs Coadministration of roxadustat with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (simvastatin, rosuvastatin and atorvastatin) increased plasma exposure of simvastatin, simvastatin acid (active metabolite of simvastatin). Time-separated administration of simvastatin and roxadustat did not reduce the interaction observed with simultaneous administration. These results indicate that roxadustat moderately inhibit BCRP Page 85 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee and OATP1B1. Based on the observed interaction, it is recommended that the maximum daily dose of statins should be reduced. The PK exposure of bupropion, rosiglitazone, and S-warfarin (probe substrates for CYP2B6, CYP2C8 and CYP2C9, respectively) were not affected by coadministration with roxadustat.

4.3. Pharmacodynamics

4.3.1. Pharmacodynamic Markers of Biologic Activity

4.3.1.1. Hemoglobin The purpose of roxadustat treatment was to raise and/or maintain Hb concentrations within the target range of 10 to 12 g/dL. Hb data from Phase 3 studies are the primary efficacy endpoints and are discussed in Section 5.

4.3.1.2. Erythropoietin Data from the Phase 1 and Phase 2 studies have shown that single and repeated intermittent administration of roxadustat resulted in transient increases in EPO, which returned to baseline at approximately 48 h post-dose. Mean maximum EPO (EPOmax) levels increased more than proportionally with dose and were generally achieved approximately 8–12 h post- dose (Figure 60). Figure 60: Plasma Endogenous EPO Concentration-Time Curve Profile in Healthy Subjects

Abbreviation: EPO=erythropoietin.

4.3.1.3. Hepcidin Hepcidin, an iron metabolism regulating protein, is increased during inflammation and contributes to a lack of iron availability and therefore inadequate erythropoiesis. The principal mechanism of hepcidin is its inhibition of cellular iron efflux, blocking the effect of

Page 86 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee the transport protein, ferroportin; under these conditions, macrophages, hepatocytes, and enterocytes retain iron (Atanasiu et al 2007; Ganz 2006). As iron is not released into the circulation, the availability to erythroid precursors is reduced. High hepcidin concentrations cause cellular iron overload, as occurs in hemochromatosis, and contribute to the typical pattern of chronic anemia referred as “functional iron deficiency.” Roxadustat effects on hepcidin were studied in 6 Phase 1 studies and the Phase 2 and Phase 3 studies. Roxadustat was shown to cause a significant decrease in hepcidin levels from baseline in healthy subjects as well as patients with NDD CKD and DD CKD over a period of up to 24 weeks.

4.3.1.4. Serum Iron Markers Roxadustat effects on iron utilization (iron status: serum iron, ferritin, TSAT, and soluble transferrin receptor) were studied in patients concomitantly treated with iron products in main Phase 3 studies. The data indicate that in patients with NDD CKD who did not receive ESA, levels of serum ferritin and TSAT initially decreased after the start of roxadustat treatment compared to placebo, then gradually increased to plateau around Week 20 and remained generally constant to Week 52. Serum iron levels decreased after the start of roxadustat treatment, then increased above the baseline in the roxadustat arm and were greater at each treatment visit compared with the placebo arm. Those data suggests that with a fall in hepcidin, ferritin is released from its sequestration. Iron is utilized during the period of anemia correction and then the stores rise (likely through the increased availability through intestinal absorption) during the period of maintenance. Similar findings were observed in patients with DD CKD.

4.3.2. Pharmacodynamic Markers of Safety

4.3.2.1. Heart Rate and Blood Pressure Roxadustat treatment has been shown to produce a dose-dependent increase in heart rate in healthy subjects at doses greater than 2 mg/kg: a placebo-corrected heart rate increase of up to 9 to 10 beats per minute (bpm) at 8 to 12 h post-dose for the 2.75 mg/kg dose and 15 to 18 bpm at 6 to 12 h post-dose for the dose of 5 mg/kg. There was no clinically meaningful effect of roxadustat on blood pressure.

4.3.2.2. QT Intervals A thorough QT study in healthy subjects was conducted using a therapeutic dose of 2.75 mg/kg (up to 280 mg) and a single supratherapeutic dose of 5 mg/kg (up to 510 mg) of roxadustat. There was no meaningful prolongation.

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5. CLINICAL EFFICACY

5.1. Pivotal and Supportive Phase 3 NDD Studies

5.1.1. Study Design The pivotal NDD studies were double-blind, placebo-controlled studies with a randomization scheme of 2:1 to roxadustat or placebo in Studies 060 and 608, and 1:1 in Study 001. The primary efficacy objective of these studies was to evaluate the efficacy of roxadustat in correcting anemia and maintaining Hb levels at 11±1 g/dL for at least 52 weeks. The overall program was sized and was later extended up to 4 years to accumulate a sufficient number of adjudicated CV endpoints to evaluate CV safety. In the pivotal NDD studies, given that the majority of patients with NDD CKD do not currently receive ESA treatment for their anemia, the studies were designed to use an oral placebo comparator in a double-blind study design to minimize bias and maintain clinical equipoise comparing the treatment of anemia with roxadustat to the lack of effective treatment for anemia which in essence patients with CKD (not requiring dialysis) are currently receiving. From a safety perspective, use of a placebo comparator is considered the gold standard to evaluate causality to treatment rather than comparing against an active comparator from a different drug class. Key study design features are summarized in Table 18. Table 18: Overview of Key Design Features of Pivotal and Supportive Phase 3 Studies in Patients with NDD CKD ESA-controlled Supportive Phase Placebo-controlled Pivotal Phase 3 NDD Studies 3 NDD Study Key design features Study 608 Study 060 Study 001 Study 610 Number of Patients 594 922 2761 616 CKD stage III-V III-V III-V III-V Randomization 2:1 2:1 1:1 1:1 Planned Treatment 52–104 52 – up to 4 years 52 – up to 4 years 104 Duration (weeks) Baseline eGFR < 60 < 60 < 60 < 60 (mL/min/1.73 m2) Baseline Hb (g/dL) ≤ 10.0 ≤ 10.0 < 10.0 ≤ 10.5 Hb Aim (g/dL) – ≥ 11.0 and ≥ 1.0 ≥ 11.0 and ≥ 1.0 ≥ 11.0 and ≥ 1.0 11.0 ± 1.0† Correction Period from baseline from baseline from baseline Hb Aim (g/dL) – Maintenance 10.0–12.0 10.0–12.0 10.0–12.0 10.0–12.0 Period Abbreviations: CKD=chronic kidney disease, eGFR=estimated glomerular filtration rate, ESA=erythropoiesis-stimulating agent; Hb=hemoglobin, NDD=non-dialysis-dependent. †Treatment period was not split between correction and maintenance periods.

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5.1.1.1. Efficacy Endpoints in Pivotal NDD Studies

5.1.1.1.1. Primary Efficacy Endpoint The key primary efficacy endpoint for all 3 studies was the mean change in Hb (g/dL) from baseline to mean over Weeks 28 to 52 regardless of rescue therapy.

5.1.1.1.2. Selected Secondary Efficacy Endpoints The secondary efficacy endpoints included: • Proportion (%) of patients who achieved a Hb response at 2 consecutive visits during the first 24 weeks of treatment without rescue therapy (ie, RBC transfusion, ESA or IV iron) A Hb response is defined as a Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL in patients with baseline Hb > 8.0 g/dL, or a Hb increase from baseline by ≥ 2.0 g/dL in a patient with baseline Hb ≤ 8.0 g/dL. • Mean change from baseline in Hb to mean over Week 28 to 36 without rescue therapy within 6 weeks prior to and during this 8-week evaluation period • Proportion (%) of patients with Hb level ≥ 10 g/dL averaged over Week 28 to 36 without use of rescue therapy within 6 weeks prior to and during these 8-week evaluation periods • Mean change from baseline in Hb to mean over Week 28 to 52 regardless of rescue therapy in patients with baseline hsCRP>ULN • Mean change from baseline in LDL cholesterol to mean over Week 12 to 28 • Time to (and % of patients who received) first rescue therapy (composite of blood/RBC transfusion, ESA use, and IV iron) over the first 52 weeks of treatment • Time to first blood/RBC transfusion over the first 52 weeks of treatment

5.1.1.1.3. Exploratory Efficacy Endpoints • Serum Hepcidin change from Baseline to Week 24 in patients with NDD CKD • Serum Iron Markers: Assessment of mean serum iron, ferritin, and TSAT over time as indicators of iron status in patients with NDD CKD

5.1.1.2. Patient Eligibility Criteria in Pivotal NDD Studies All eligible patients in the pivotal Phase 3 program were adult patients with CKD anemia. Patient eligibility for all studies specified a Hb threshold as an important inclusion criterion as well as threshold criteria for minimal iron stores. Patients with or B12 deficiencies and other known causes of anemia were excluded. In the 3 pivotal NDD studies (Studies 060, 608 and 001), patients were to have CKD Stage 3–5, an eGFR < 60 mL/min/1.73 m2 and Hb < 10.0 g/dL at baseline. Study 060 and 608 excluded patients with ESA use within 12 weeks prior to randomization; in Study 001, the exclusion period was 6 weeks. Page 89 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee

All patients were required to have an average baseline Hb ≤ 10.0 g/dL based on the 2 or 3 most recent Hb values obtained during the screening period, except Study 610 which allowed an average Hb ≤ 10.5 g/dL. Baseline ferritin was required to be ≥ 30 ng/mL (for Studies 608 and 060), ≥ 50 ng/mL (for Study 001) or ≥ 100 ng/mL (Study 610). Patients could not have received any ESA treatment within 12 weeks (Studies 060 or 608) or 6 weeks (Study 001) in the global Phase 3 studies.

5.1.1.3. Statistical Analyses in Pivotal NDD Studies

5.1.1.3.1. Comparisons of Results from Individual Studies The observed results and estimates of treatment effect (eg, mean Hb change from baseline on roxadustat and placebo), as well as CIs and p-values from the treatment comparison analyses for each study were presented side by side to demonstrate substantial evidence of effectiveness for each indication.

5.1.1.3.2. Pooled Analyses The pooled analyses for the primary endpoint were performed on the ITT Population (which included all randomized patients). The rest of pooled analyses were performed on the Full Analysis Set (FAS) population (which included all randomized/enrolled patients who received at least one dose of study drug and had at least one post-dose Hb assessment). Overall analyses of dose safety were based on the Safety Analysis Set population (which included any randomized/enrolled patient with at least one dose of study drug). For the overall and subgroup analyses of the primary endpoint, the change from baseline Hb data from the multiple imputation (MI) datasets in each study were pooled and analyzed. The analysis model had terms for treatment, study, study*treatment interaction term and common randomization stratification factors as appropriate. Then, using the PROC MIANALYZE approach to summarize the results over the imputations. In the placebo-controlled global Phase 3 NDD CKD studies, the FDA primary efficacy endpoint of change from baseline in Hb to mean over Weeks 28 to 52 was evaluated using the MI Analysis of Covariance model (MI ANCOVA]), and superiority was established if p < 0.05 in Studies 060, 001, and 608. The pooled analysis methods for the same endpoints were analyzed following the same primary analysis method as specified in the individual study. In general, the missing data handling for the analyses in the pooled dataset followed the same approach as for the primary analysis described for the individual studies. For example, the missing data for the change from baseline in Hb primary endpoint were imputed using the PROC MI procedure.

5.1.2. Demographic and Baseline Characteristics in Pivotal NDD Studies Demographics and baseline characteristics in the ITT Population are provided in Table 19.

Page 90 of 154 FibroGen Roxadustat Cardiovascular and Renal Drugs Advisory Committee Table 19: NDD Studies: Demographic and Baseline Characteristics NDD Population Study 608 Study 060 Study 001 Pooled NDD Population Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo (N=391) (N=203) (N=616) (N=306) (N=1384) (N=1377) (N=2391) (N=1886) Age, years Mean (SD) 60.6 (13.5) 61.7 (13.8) 64.9 (12.6) 64.8 (13.2) 60.9 (14.7) 62.4 (14.1) 61.9 (14.08) 62.7 (13.98) Male, n (%) 169 (43.2) 99 (48.8) 241 (39.1) 130 (42.5) 564 (40.8) 603 (43.8) 974 (40.7) 832 (44.1) Race, n (%) White 335 (85.7) 182 (89.7) 176 (28.6) 99 (32.4) 623 (45.0) 611 (44.4) 1134 (47.4) 892 (47.3) Black/African American 10 (2.6) 3 (1.5) 76 (12.3) 28 (9.2) 112 (8.1) 115 (8.4) 198 (8.3) 146 (7.7) Asian 9 (2.3) 0 310 (50.3) 151 (49.3) 544 (39.3) 538 (39.1) 863 (36.1) 689 (36.5) Other 37 (9.5) 18 (8.9) 46 (7.5) 23 (7.5) 81 (5.9) 82 (5.0) 196 (8.2) 159 (8.4) Region, n (%) x E -U.S. 391 (100) 203 (100) 209 (33.9) 101 (33.0) 1041 (75.2) 1037 (75.3) 1839 (76.9) 1445 (76.6) .S. U 0 0 407 (66.1) 205 (67.0) 343 (24.8) 340 (24.7) 552 (23.1) 441 (23.4) BMI, kg/m2 Mean (SD) 27.06 (5.5) 27.63 (5.5) 27.4 (6.3) 27.3 (6.0) 26.58 (6.0) 26.85 (6.1) 26.9 (6.0) 27.0 (6.0) Hb, g/dL Mean (SD) 9.1 (0.8) 9.1 (0.7) 9.1 (0.8) 9.1 (0.7) 9.1 (0.7) 9.1 (0.7) 9.1 (0.7) 9.1 (0.7) hsCRP, n (%) ≤ ULN 245 (63.1) 135 (66.8) 457 (74.2) 223 (72.9) 520 (37.6) 497 (36.1) 1222 (51.1) 855 (45.3) ≥ ULN 143 (36.9) 67 (33.2) 156 (25.3) 81 (26.5) 227 (16.4) 209 (15.2) 526 (22.0) 357 (18.9) Baseline eGFR (ml/min/1.73 m2)

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NDD Population Study 608 Study 060 Study 001 Pooled NDD Population Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo (N=391) (N=203) (N=616) (N=306) (N=1384) (N=1377) (N=2391) (N=1886) Mean (SD) 16.5 (10.2) 17.2 (11.7) 21.9 (11.5) 22.4 (11.4) 19.7 (11.7) 20.0 (11.7) 19.7 (11.6) 20.0 (11.8) < 10 119 (30.4) 57 (28.1) 71 (11.5) 19 (6.2) 291 (21.0) 283 (20.6) 481 (20.1) 359 (19.0) 10 – < 15 102 (26.1) 61 (30.0) 124 (20.1) 76 (24.8) 300 (21.7) 315 (22.9) 526 (22.0) 452 (24.0) 15 – < 30 128 (32.7) 58 (28.6) 292 (47.4) 146 (47.7) 534 (38.6) 520 (37.8) 954 (39.9) 724 (38.4) ≥ 30 42 (10.7) 26 (12.8) 129 (20.9) 65 (21.2) 259 (18.7) 259 (18.8) 430 (18.0) 351 (18.6) Iron Repletion Status, n(%) Ferritin < 100 ng/ml and TSAT 187 (47.8) 94 (46.3) 241 (39.1) 134 (43.8) 575 (41.5) 578 (42.0) 956 (40.0) 755 (40.0) < 20% Ferritin ≥ 100 ng/ml or TSAT 204 (52.2) 109 (53.7) 373 (60.6) 170 (55.6) 809 (58.5) 799 (58.0) 1433 (59.9) 1127 (59.8) ≥ 20% Diabetes Mellitus, n(%) 131 (33.5) 76 (37.4) 395 (64.6) 199 (65.2) 793 (57.3) 807 (58.6) 1337 (55.9) 1096 (58.1) Abbreviations: BMI=body mass index; eGFR=estimated glomerular filtration rate; Hb=hemoglobin; hsCRP=high-sensitivity C-reactive protein; Max=maximum; min=Minimum; NDD=non-dialysis-dependent; Roxa=roxadustat; SD=standard deviation; TSAT=transferrin saturation; ULN=upper limit of normal; US=United States of America. Note: Intent-to-treat analysis set.

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5.1.3. Efficacy Results in Pivotal NDD Studies

5.1.3.1. Primary Efficacy Endpoint Results The primary efficacy endpoint results from the pooled NDD studies are shown in Table 20. Roxadustat treatment of patients with NDD CKD met the pre-specified primary efficacy endpoint with a statistically significant (p < 0.001) improvement in mean Hb levels regardless of rescue therapy in the pooled ITT Population compared to the placebo.

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Table 20: NDD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy Hb (g/dL) Study 608 Study 060 Study 001 NDD Pool Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo n=391 n=203 n=616 n=306 n=1384 n=1377 n=2391 n=1886 Baseline Hb n 391 203 616 306 1384 1376 2391 1886 Mean (SD) 9.08 (0.76) 9.10 (0.72) 9.10 (0.75) 9.09 (0.69) 9.11 (0.733) 9.10 (0.742) 9.10 (0.743) 9.10 (0.732) Average Hb in Weeks 28 to 52 n 312 146 616 306 NA NA 2391 1886 Mean (SD) 11.16 (0.84) 9.60 (1.03) 11.10 (0.70) 9.25 (1.06) NA NA 10.95 (0.758) 9.23 (1.111) ANCOVA with Multiple Imputations LSMean Change (SE) 1.99 0.30 2.02 (0.036) 0.17 (0.051) 1.75 (0.033) 0.40 (0.034) 1.94 (0.022) 0.22 (0.030) 95% CI (1.82, 2.16) (0.09, 0.51) (1.947, 2.089) (0.066, 0.267) (1.68, 1.81) (0.33, 0.47) (1.898, 1.983) (0.159, 0.276) LSMean Difference (SE) 1.692 1.85 (0.059) 1.35 (0.041) 1.72 (0.036) 95% CI (1.52, 1.86) (1.735, 1.967) (1.27, 1.43) (1.653, 1.794) p-value < 0.001 < 0.001 < 0.001 < 0.001 Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; Hb=hemoglobin; ITT=intent-to-treat; LSMean=least squares mean; Max=maximum; Min=minimum; NDD=non-dialysis- dependent; Roxa=roxadustat; SD=standard deviation; SE=standard error. Note: ITT

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5.1.3.2. Selected Secondary Efficacy Endpoint Results

5.1.3.2.1. Proportion of Patients Achieving Hb Response During the First 24 Weeks of Treatment Without Rescue Therapy Table 21 shows the proportion of patients achieving a Hb response as defined in 5.1.1.1.2. In the pooled FAS population at the end of the 24-week treatment period, 80.2% of roxadustat- treated patients achieved a Hb response compared to 8.7% of placebo-treated patients; the difference in Hb response was statistically significant at p < 0.001. Table 21: NDD Studies: Proportion of Patients Who Achieved Hb Response During the First 24 Weeks of Treatment, Censoring for Rescue Therapy Study 608 Study 060 Study 001 NDD Pool Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo n=389 n=203 n=608 n=305 n=1371 n=1357 n=2368 n=1865

Patients Who 308 20 523 20 1055 115 1899 163 Achieved Hb Response (%) (79.2) (9.9) (86.0) (6.6) (77.0) (8.5) (80.2) (8.7)

95% CI a (74.8, 83.1) (6.1, 14.8) (83.0, 88.7) (4.1, 9.9) NR NR (78.5, 81.8) (7.5, 10.1)

Treatment Response Rate Difference 69.3 (63.7, 75.1) 79.5 (75.55, 83.38) 9.1 (7.63, 10.89) b 71.5 (69.40, 73.51) (95% CI) p-value < 0.001 < 0.001 < 0.001 < 0.001 Abbreviations: CI=confidence interval; NDD=non-dialysis-dependent; NR=not reported; Roxa=roxadustat. a 95% CI of response rate for each treatment group is based on the exact method of Clopper-Pearson. b Study 001 reported relative risk. Note: Full analysis set.

5.1.3.2.2. Proportion of Patients with Hb ≥ 10 g/dL Without Rescue Therapy As shown in Table 22, a significantly higher proportion of patients from the roxadustat group (72.8%) achieved a mean Hb level of ≥ 10.0 g/dL averaged over weeks 28 to 36 compared to the placebo group (18.9%; p < 0.001).

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Table 22: NDD Studies: Proportion of Patients with Hb ≥ 10.0 g/dL Averaged Over Weeks 28 to 36 Censoring for Rescue Therapy Study 608 Study 060 Study 001† NDD Pool Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo n=389 n=203 n=608 n=305 n=1384 n=1377 n=2368 n=1865 467 56 1725 352 n (%) NA NA (82) (33) (76.8) (18.4) (72.8) (18.9) (73.2, 95% CI a NA NA (14.2, 23.2) NA NA (71.0, 74.6) (17.1, 20.7) 80.1) Treatment Response Rate NA 58.4 (52.96, 63.94) 50 (47, 52) † 54.0 (51.45, 56.49) Difference (95% CI) Roxa/Placebo Odds Ratio (95% NA 15.47 (10.79, 22.19) NA 12.27 (10.50, 14.34) CI) b p-value NA < 0.001 < 0.001 < 0.001 Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; eGFR=estimated glomerular filtration rate; Hb=hemoglobin; NA=not available (endpoint not analyzed); NDD=non-dialysis-dependent; Roxa=roxadustat; US=United States. a the 95% CI of response rate for each treatment group is based on the exact method of Clopper-Pearson. b From Cochran-Mantel-Haenszel method adjusting for study, region (US, Europe, Other), baseline Hb (< 8 g/dL vs ≥ 8 g/dL), baseline eGFR (< 30 vs ≥ 30 mL/min/1.73 m2), and history of cardiovascular/ cerebrovascular/thromboembolic diseases (Yes vs No). †: in Study 001, this endpoint was defined as “proportion of total time of interpolated Hb (g/dL) values ≥ 10 g/dL, from Weeks 28 to 52 analyzed by ANCOVA in the intent-to-treat set.” Note: Full analysis set.

5.1.3.2.3. Mean Change from Baseline in LDL Cholesterol Patients treated with roxadustat had a 17% reduction in LDL cholesterol from baseline in the pooled NDD population compared to the placebo group (LSMean of the treatment difference [-19.8 mg/dL]) (p < 0.001) (Table 23).

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Table 23: NDD Studies: Mean Change from Baseline in LDL Cholesterol to Mean Over Weeks 12 to 28 Study 608 Study 060 Study 001† NDD Pool Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo LDL (mg/dL) n=389 n=203 n=608 n=305 n=1384 n=1377 n=2368 n=1865 Baseline LDL a (mg/dL) n 389 203 608 305 1272 1283 2256 1771 Mean (SD) 115.43 111.49 97.74 96.39 94.35 92.41 98.97 95.53 (49.69) (44.16) (39.09) (40.06) (43.39) (41.98) (44.151) (42.401) Median 108.28 105.18 92.00 89.00 86.62 87.00 92.00 89.33 Min, Max 26.30, 15.85, 15.0, 10.0, 1.16, 5.41, 1.2, 369.3 5.4, 466.0 369.30 259.86 363.0 252.0 356.54 465.97 Average LDL in Weeks 12–28 (mg/dL) n 342 185 564 269 1233 1214 1994 1430 Mean (SD) 93.27 117.60 79.25 96.84 81.14 93.98 81.83 97.55 (35.34) (47.87) (29.62) (37.69) (39.28) (43.51) (36.187) (43.793) Median 88.67 112.80 74.83 88.67 72.31 88.17 75.00 90.22 Min, Max 21.27, 20.88, 14.3, 14.0, 10.1, 14.0, 10.1, 14.0, 220.03 336.43 230.0 249.0 298.1 491.1 298.1 491.1 ANCOVA b LSMean (SE) -25.14 1.97 -18.41 -1.15 -14.69 -0.77 -17.26 2.57 (1.45) (1.82) (1.08) (1.04) (0.735) (0.969) 95% CI (-29.39, (-3.09, (-21.27, (-4.73, (-16.63, (-2.71, (-18.70, - (0.67, -20.88) 6.96) -15.56) 2.42) -12.37) 1.55) 15.82) 4.47) LSMean -27.11 ‡ -17.26 (1.73) -13.92 (1.28) -19.83 (1.186) Difference (SE) 95% CI (-32.10, -22.04) (-20.65, -13.87) (-16.24, -11.21) (-22.16, -17.51) p-value < 0.001 < 0.001 < 0.001 < 0.001 Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; eGFR=estimated glomerular filtration rate; FAS=full analysis set; Hb=hemoglobin; ITT=intent-to-treat; LDL=low-density lipoprotein; LSMean=least squares mean; Max=maximum; Min=minimum; NDD=non-dialysis-dependent; Roxa=roxadustat; SD=standard deviation; SE=standard error; US=United States. a : Baseline is defined as the last available value prior to the first dose of study treatment. b : Treatment comparison was made using an ANCOVA model with baseline Hb, baseline eGFR, baseline LDL as covariates, and study, treatment, study-by-treatment interaction, history of cardiovascular/cerebrovascular/ thromboembolic diseases (Yes vs No) and region (US, Europe, Other) as fixed effects. †: in Study 001, this endpoint was defined as mean change in LDL (mmol/L) from baseline to Week 24 analyzed by ANCOVA in ITT set. ‡: No SE available. Note: Full analysis set.

5.1.3.2.4. Proportion of Patients Receiving Any Rescue Therapy During the First 52 Weeks of Treatment

The proportion of patients who received any rescue therapy (RBC transfusion, ESA use, and IV iron) in the first 52 weeks of treatment was significantly lower in the roxadustat group (8.9%) than in the placebo group (31.1%; p < 0.001) (Table 24). Page 97 of 154

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Table 24: NDD Studies: Patients Receiving Rescue Therapy in the First 52 Weeks Rescue Therapy Study 608‡ Study 060 Study 001† NDD Pool Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo n=389 n=203 n=608 n=305 n=1384 n =1376 n=2368 n=1865 Patients with events a, 64 93 54 88 254 574 211 580 n (%) (16.5) (45.8) (8.9) (28.9) (18.35) (41.72) (8.9) (31.1)

Patients censored b, 554 217 1130 802 2157 1285 NA NA n (%) (91.1) (71.1) (81.65) (58.28) (91.1) (68.9) Treatment Effect 0.238 0.19 0.26 0.19 (roxa-placebo) HR c 95% CI c (0.17, 0.33) (0.138, 0.276) (0.23, 0.31) (0.164, 0.226) p-value c < 0.001 < 0.001 < 0.001 < 0.001 Total PEY d 438.5 155.9 527.3 230.9 2134.88 1443.49 2031.8 1414.3 Incidence rate of events 14.6 59.6 10.2 38.1 11.90 39.76 10.4 41.0 (per 100 PY) Abbreviations: CI=confidence interval; eGFR=estimated glomerular filtration rate; EOT=end of treatment; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; HR=hazard ratio; IV=intravenous(ly); NA=not available; NDD=non-dialysis-dependent; OT+28=on-treatment plus 28 days; PEY=patient exposure year; RBC=red blood cell; Roxa=roxadustat; US=United States. a Rescue therapy: Any use of RBC transfusion, ESA, or IV iron. b Patients with no event were censored at the date of minimum (last dose date, first dose date + 364 days, last visit date, death date). c From a Cox Proportional hazards model adjusting for baseline Hb, baseline eGFR, study, treatment, region (US, Europe, Other), and history of cardiovascular/cerebrovascular/thromboembolic diseases (Yes vs No). d: Total PEY was calculated as minimum (364 days, last dose date - first dose date +1). †: Endpoint was evaluated in the safety emergent period up to OT+28 in Study 001 ‡: Endpoint was evaluated in the efficacy emergent period (date of first dose intake up to 7 days after the date of last dose or EOT visit, whichever occurs first) in Study 608. Note: Full analysis set.

5.1.3.2.5. Proportion of Patients Receiving RBC Transfusions During the First 52 Weeks of Treatment

The proportion of patients who received RBC transfusion in the first 52 weeks of treatment was also significantly lower in the roxadustat group (5.2%) than in the placebo group (15.4%; p < 0.001) (Table 25).

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Table 25: NDD Studies: Patients Receiving RBC Transfusions in the First 52 Weeks Study 608‡ Study 060 Study 001† NDD Pool RBC Roxa Placebo Roxa Placebo Roxa Placebo Roxa Placebo Transfusion n=389 n=203 n=608 n=305 n=1384 n=1376 n=2368 n=1865 Patients with events a 33 39 34 47 176 320 124 288 n (%) (8.5) (19.2) (5.6) (15.4) (12.72) (23.26) (5.2) (15.4) Patients censored b 574 258 1208 1056 2244 1577 NA NA n (%) (94.4) (84.6) (87.28) (76.74) (94.8) (84.6) Treatment effect (Roxa- 0.343 0.26 0.37 0.26 placebo) HR c 95% CI c (0.21, 0.55) (0.165, 0.406) (0.30, 0.44) (0.206, 0.318) p-value c < 0.001 (nominal*) < 0.001 (nominal*) < 0.001 < 0.001 Total PEY d 455.2 181.0 527.3 230.9 2206.74 1631.69 2031.8 1414.3 Incidence rate of events 7.2 21.5 6.4 20.4 7.98 19.61 6.1 20.4 (per 100 PY) Abbreviations: CI=confidence interval; eGFR=estimated glomerular filtration rate; EOT=end of treatment; Hb=hemoglobin; HR=hazard ratio; NA=not available; NDD=non-dialysis-dependent; NE=not estimable; OT+28=on- treatment plus 28 days; PEY=patient exposure year; RBC=red blood cell; Roxa=roxadustat; US=United States. *: In Study 608 and Study 060, this endpoint fell below an endpoint in the hierarchical testing order that did not reach statistical significance and thus was considered nominal. a Rescue therapy: Any use of RBC. b Patients with no event were censored at the date of minimum (last dose date, first dose date + 364 days, last visit date, death date). c: From a stratified Cox Proportional hazards model adjusting for baseline Hb, baseline eGFR, and treatment, stratified by study, region (US, Europe, Other), and history of cardiovascular/cerebrovascular/thromboembolic diseases (Yes vs No). d: Total PEY was calculated as minimum (364 days, last dose date - first dose date +1). ‡: Endpoint was evaluated in the efficacy emergent period (date of first dose intake up to 7 days after the date of last dose or EOT visit, whichever occurs first) in Study 608. †: Endpoint was evaluated in the safety emergent period up to OT+28 in Study 001. Note: Full analysis set. One additional study in patients with NDD CKD comparing roxadustat to darbepoetin alfa was performed (Study 610). While Study 610 cannot be pooled with the 3 placebo- controlled studies in NDD due to the different comparator arms, a description of the results can be found in Section 1.3.4.

5.2. Pivotal and Supportive Phase 3 DD Studies

5.2.1. Study Design

The pivotal DD studies were open label with EPO as comparator with a randomization scheme of 1:1 to roxadustat or EPO (Table 26). The primary efficacy objective of these studies was to evaluate the efficacy of roxadustat in correcting anemia and maintaining Hb levels at 11±1 g/dL for at least 52 weeks. For the pivotal DD studies, a single ESA, EPO, was selected as the comparator to allow the comparison to only one agent and given that it is the standard of care treatment for anemia in this patient population. Because of its use of 2

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee comparators (EPO and darbepoetin alfa), Study 613 is not able to be pooled with the other 3 studies and is presented as supportive of efficacy. Table 26: Overview of Key Design Features of Pivotal and Supportive Phase 3 Studies in Patients with DD CKD ESA-controlled Supportive Phase 3 Epoetin Alfa-controlled Pivotal Phase 3 DD Studies DD Study Design Features Study 063 Study 064 Study 002 Study 613 Region Global US Global Europe Number of patients 1043 741 2106 836 Epoetin Alfa/Darbepoetin ESA Control Epoetin Alfa Epoetin Alfa Epoetin Alfa Alfa Planned Treatment up to 4 years up to 4 years up to 4 years 52–104 Duration (weeks) Dialysis Status ID SDD and ID SDD and ID SDD Baseline Hb (g/dL) ≤ 10.0 9.0†–12.0 < 10.0‡, < 12.0 9.5–12.0 Hb Correction or ESA Correction and Correction Conversion Conversion Conversion Conversion Hb Aim (g/dL) – 10.0–12.0 10.0–12.0 10.0–12.0 10.0–12.0 Maintenance Period Abbreviations: CKD=chronic kidney disease; DD=dialysis-dependent; ESA=erythropoieses-stimulating agent; ESRD=end-stage renal disease; Hb=hemoglobin; HD=hemodialysis; ID=incident dialysis; OL=open-label; SDD=stable dialysis-dependent; US=United States. †≥ 8.5 g/dL for ID patients. ‡For patients not on ESA treatment. Note: Stable dialysis comprises the initiation of dialysis ≥ 4 months at the time of randomization. Incident dialysis comprises the initiation of dialysis ≥ 2 weeks but ≤ 4 months at the time of randomization.

5.2.1.1. Efficacy Endpoints in Pivotal Studies

5.2.1.1.1. Primary Efficacy Endpoint The key primary efficacy endpoint for all global Phase 3 DD CKD studies was the mean change in Hb (g/dL) from baseline to mean over Weeks 28 to 52 regardless of rescue therapy.

5.2.1.1.2. Selected Secondary Efficacy Endpoints The key secondary efficacy endpoints were: • Mean change in Hb from baseline to mean over Week 28 to 36 without rescue therapy within 6 weeks prior to and during this 8-week evaluation period • Proportion (%) of patients with Hb level averaged ≥ 10 g/dL over Week 28 to 36 without use of rescue therapy within 6 weeks prior to and during these 8-week evaluation periods

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Other secondary efficacy endpoints included: • Hb change from baseline to the average in patients with DD CKD with baseline hsCRP > ULN between the pooled DD population and its constituent study populations. • Mean LDL cholesterol changes from baseline to mean over Weeks 12 to 28 • Average monthly IV iron use over Weeks 28 to 52 • Proportion of patients who received RBC transfusion during treatment

5.2.1.1.3. Exploratory Efficacy Endpoints • Serum Hepcidin change from Baseline to Week 24 in patients with DD CKD. • Serum Iron Markers: Assessment of mean serum iron, ferritin, and TSAT over time as indicators of iron status in pooled FAS ID and SDD populations.

5.2.1.2. Patient Eligibility Criteria in Pivotal DD Studies Adult male and female patients with CKD with anemia on hemodialysis or peritoneal dialysis with a Hb threshold as an inclusion criterion were eligible to participate. The ID and SDD populations were defined as patients who have been on dialysis for ≤ 4 months or > 4 months, respectively, at the time of randomization. Studies 064 and 002 had mostly stable dialysis patients and some ID patients. Study 063 consisted of only ID patients that had to be on dialysis for ≤ 4 months at the time of randomization. All patients in Study 063 were required to have an average baseline Hb < 10.0 g/dL. Study 063 excluded patients who had received more than 3 weeks of ESA treatment within 12 weeks prior to randomization. Study 064 required patients to have an average baseline Hb of 9.0–12.0 g/dL for stable dialysis patients and have been receiving IV or subcutaneous ESA (epoetin, darbepoetin, or methoxy polyethylene glycol-epoetin beta [Mircera®]) for ≥ 8 weeks prior to randomization, whereas required baseline Hb ≥ 8.5 g/dL for ID patients who have been on ESA for ≥ 4 weeks prior to screening. Study 002 required patients with baseline Hb < 12 g/dL for patients treated with ESA previously and with baseline Hb < 10 g/dL for ESA-naïve patients.

5.2.1.3. Statistical Analyses in Pivotal DD Studies The observed results and estimates of treatment effect (eg, mean Hb change from baseline on roxadustat and active control), as well as CIs from the treatment comparison analyses for each study were presented side by side to demonstrate substantial evidence of effectiveness. Similar as the pooled analyses performed in NDD population, the pooled analyses for the US primary endpoint in DD population were performed on the ITT Population. In the ESA- controlled global Phase 3 DD CKD studies, the FDA primary efficacy endpoint of change from baseline in Hb to mean over Weeks 28 to 52 was evaluated using MI ANCOVA with a non-inferiority margin of -0.75 g/dL. In general, the pooled analysis methods for the same endpoints were analyzed following the same primary analysis method as specified in the individual study. The missing data handling for the analyses in the pooled dataset followed the same approach for the primary analysis described for the individual studies.

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5.2.2. Demographic and Baseline Characteristics in Pivotal DD Studies

Demographics and baseline characteristics in the ITT Population are provided in Table 27.

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Table 27: DD Studies: Demographic and Baseline Characteristics DD Population Study 063 Study 064 Study 002 Pooled DD Population

Roxa Epoetin Alfa Roxa Epoetin Alfa Roxa Epoetin Alfa Roxa Epoetin Alfa (N=522) (N=521) (N=370) (N=371) (N=1051) (N=1055) (N=1943) (N=1947) Age, years Mean (SD) 53.8 (14.7) 54.3 (14.6) 57.6 (13.6) 58.4 (13.3) 53.5 (15.3) 54.5 (15.0) 54.3 (14.92) 55.2 (14.64) Min, Max 19, 87 18, 92 22, 92 23, 88 18, 93 20, 94 18, 93 18, 94 Male, n (%) 309 (59.2) 307 (58.9) 187 (50.5) 215 (58.0) 625 (59.5) 626 (59.3) 1121 (57.7) 1148 (59.0) Race, n (%) White 415 (79.5) 400 (76.8) 165 (44.6) 184 (49.6) 597 (56.8) 598 (56.7) 1177 (60.6) 1182 (60.7) Black/African American 44 (8.4) 50 (9.6) 158 (42.7) 156 (42.0) 148 (14.1) 158 (15.0) 350 (18.0) 364 (18.7) Asian 43 (8.2) 51 (9.8) 21 (5.7) 15 (4.0) 208 (19.8) 198 (18.8) 272 (14.0) 264 (13.6) Other 19 (3.6) 16 (3.1) 15 (4.1) 6 (1.6) 43 (4.1) 36 (3.4) 144 (7.4) 137 (7.0) Region, n (%) x E -U.S. 395 (75.7) 396 (76.0) 0 0 666 (63.4) 664 (62.9) 1061 (54.6) 1060 (54.4) .S. U 127 (24.3) 125 (24.0) 370 (100) 371 (100) 385 (36.6) 391 (37.1) 882 (45.4) 887 (45.6) BMI, kg/m2b Mean (SD) 26.73 (5.8) 27.01 (6.0) 30.2 (7.4) 30.5 (7.5) 27.0 (6.8) 26.9 (6.4) 27.55 (6.77) 27.63 (6.66) Min, Max 16.5, 47.7 15.2, 56.8 15.6, 58 17.3, 60.9 15.9, 64.9 14.7, 57.0 15.6, 64.9 14.7, 60.9 Hb, g/dL Mean (SD) 8.4 (1.0) 8.5 (1.0) 10.3 (0.7) 10.3 (0.7) 10.0 (1.2) 10.0 (1.2) 9.6 (1.3) 9.7 (1.3) Min, Max 5.3, 10.2 5.0, 10.3 (8.4, 11.9) (8.6, 12.0) 4.3, 12.0 5.4, 12.2 4.3, 12.0 5.0, 12.2 hsCRP, n (%) ≤ULN 289 (55.4) 289 (55.5) 178 (48.1) 192 (51.8) 421 (40.1) 427 (40.5) 889 (45.8) 912 (46.8)

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DD Population Study 063 Study 064 Study 002 Pooled DD Population

Roxa Epoetin Alfa Roxa Epoetin Alfa Roxa Epoetin Alfa Roxa Epoetin Alfa (N=522) (N=521) (N=370) (N=371) (N=1051) (N=1055) (N=1943) (N=1947) ≥ULN 228 (43.7) 226 (43.4) 189 (51.1) 177 (47.7) 303 (28.8) 311 (29.5) 723 (37.2) 722 (37.1) Ferritin, ng/mL Mean (SD) 441.4 (337.0) 437.4 (311.4) 1002.2 (459.1) 960.8 (414.8) NA NA 610.57 (467.8) 603.24 (467.0) Min, Max 33.0, 2852.8 38.9, 1896.0 107.3, 5184.5 92.3, 3229.0) NA NA 17.5, 5185.5 10.7, 4577.0 Hb n (%) ≤ 8.0 g/dL or ≤ 10 g/dL a 166 (31.8) 157 (30.1) 230 (62.2) 235 (63.3) 448 (42.6) a 435 (41.2) a 1083 (55.7) a 1058 (54.3) a > 8.0 g/dL or > 10 g/dL a 356 (68.2) 364 (69.9) 140 (37.8) 136 (36.7) 603 (57.4) a 620 (58.8) a 860 (44.3) 889 (45.7) TSAT (%) 27.02 (9.3) 27.56 (8.9) 33.6 (10.1) 33.6 (10.0) NA NA 33.03 (12.77) 32.66 (12.36) mean (SD) ESA-Naïve (%) 93.7 93.8 0 0 0 0 29.0 c 28.5 c ≤ 150 IU/kg/week, n(%) NA NA 298 (80.5) 301 (81.1) NA NA 1066 (54.9) c 1050 (54.1) c > 150 IU/kg/week, n(%) NA NA 72 (19.5) 70 (18.9) NA NA 209 (10.8) c 233 (12.0) c Diabetes n (%) 205 (39.3) 204 (39.2) 250 (67.5) 255 (68.8) 459 (43.7%)/ 454 (43.0%) 915 (47.1) 915 (47.0) Cardiovascular disease n (%) 141 (27.0) 149 (28.6) 140 (37.8) 134 (36.1) 372 (35.4) 383 (36.3) 947 (48.7) b 929 (47.7) b Cerebrovascular Disease n (%) 77 (14.8) 79 (15.2) 56 (15.1) 53 (14.3) 305 (29.0) 304 (28.8) Peritoneal Dialysis 53 (10.2) 58 (11.1) 16 (4.3) 17 (4.6) 111 (10.6) 117 (11.1) 180 (9.3) 192 (9.9) Abbreviations: BMI=body mass index; DD=dialysis-dependent; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; hsCRP=high-sensitivity C-reactive protein; Max=maximum; Min=minimum; Roxa=roxadustat; SD=standard deviation; TSAT=transferrin saturation; ULN=upper limit of normal; US=United States of America. a: Hb, n (%) in the Study 002 and pooled DD population were categorized by < 10 vs ≥ 10 g/dL. b: History of cardiac, cerebrovascular, or thromboembolic disease, n (%), were combined in the pooled DD population. c: ESA use at baseline in the pooled DD population is the Safety Analysis Set defined as randomized patients who took any dose of study medication Note: Intent-to-treat analysis set.

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5.2.3. Efficacy Results in Pivotal DD Studies

5.2.3.1. Primary Efficacy Endpoint Results

The pre-specified primary endpoint was met in the pooled DD studies. The effect including the 95% CI of roxadustat was within the pre-specified non-inferiority margin (-0.75 g/dL), thereby demonstrating non inferiority compared to EPO on mean change from baseline in Hb over Weeks 28 to 52 regardless of rescue therapy (ie, RBC transfusion and ESA) (Table 28). Table 28: DD Studies: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy Study 063 Study 064 Study 002 DD Pool Roxa EPO Roxa EPO Roxa EPO Roxa EPO Hb (g/dL) n=522 n=521 n=370 n=371 n=1051 n=1055 n=1943 n=1947 Baseline Hb n 522 521 370 371 1051 1055 1943 1947 8.43 8.46 10.30 10.31 9.99 10.02 9.63 9.66 Mean (SD) (1.044) (0.964) (0.661) (0.656) (1.195) (1.235) (1.300) (1.301) Median 8.60 8.60 10.29 10.33 10.20 10.30 9.80 9.80 Min, Max 5.3, 10.2 5.0, 10.3 8.4, 11.9 8.6, 12.0 4.3, 12.0 5.4, 12.2 4.3, 12.0 5.0, 12.2 Average Hb in Weeks 28 to 52 (Observed + Imputed) n 522 521 370 371 NA NA 1943 1947 11.00 10.83 10.69 10.22 NA NA 10.85 10.65 Mean (SD) (0.819) (0.876) (0.757) (0.681) (0.820) (0.908) Median 11.09 10.89 10.75 10.25 NA NA 10.95 10.66 Min, Max 8.0, 13.5 6.8, 13.2 7.7, 13.2 7.3, 14.8 NA NA 7.6, 13.5 6.8, 15.0 ANCOVA with Multiple Imputations 2.38 2.20 0.28 -0.19 0.77 0.68 1.21 0.95 LSMean (SE) (0.041) (0.041) (0.067) (0.063) (0.041) (0.040) (0.023) (0.022) (2.298, (2.115, (0.153, (-0.318, (0.69, (0.60, (1.167, (0.906, 95% CI 2.461) 2.278) 0.414) -0.071) 0.85) 0.76) 1.256) 0.992) LSMean 0.18 (0.053) 0.48 (0.058) 0.09 (0.044) 0.26 (0.032) Difference (SE) 95% CI (0.079, 0.287) (0.365, 0.591) (0.01, 0.18) (0.200, 0.325) Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; Hb=hemoglobin; ITT=intent-to-treat analysis set; LSMean=least squares mean; Max=maximum; Min=minimum; Roxa=roxadustat; SD=standard deviation; SE=standard error. Note: Intent-to-treat analysis set.

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5.2.3.2. Selected Secondary Efficacy Endpoints Results

5.2.3.2.1. Mean Change from Baseline to Mean Over Weeks 28 to 36 Without Rescue Therapy

Table 29 shows Hb response as mean change from baseline averaged over Week 28–36 without rescue therapy between pooled and its individual study populations. Table 29: DD Studies: Hb Response with Roxadustat Compared with Epoetin Alfa Over Weeks 28 to 36 in DD Patient Censoring for Rescue Therapy Study 063 Study 064 Study 002 DD Pool Roxa EPO Roxa EPO Roxa EPO Roxa EPO Hb (g/dL) n=490 n=468 n=334 n=352 n=842 n=869 n=1666 n=1689 Baseline Hb a n 490 468 303 324 842 869 1666 1689 8.43 8.43 10.33 10.35 9.60 9.66 Mean (SD) 9.98 10.04 (1.043) (0.963) (0.639) (0.614) (1.312) (1.303) Median 8.60 8.56 10.30 10.33 NA NA 9.73 9.80 Min, Max 5.3, 10.2 5.0, 10.3 8.8, 11.9 8.9, 12.0 NA NA 4.3, 12.0 5.0, 12.2 Average Hb in Weeks 28–36 n 433 418 263 293 NA NA 1435 1500 11.13 10.94 10.89 10.33 10.96 10.71 Mean (SD) NA NA (1.061) (1.024) (0.869) (0.766) (0.974) (1.036) Median 11.25 11.00 10.93 10.35 NA NA 11.05 10.70 Min, Max 5.9, 13.8 7.4, 13.6 7.8, 13.0 7.6, 15.4 NA NA 5.9, 13.8 5.0, 15.4 Mixed Model of Repeated Measures 2.59 2.39 0.63 0.09 0.88 0.74 1.32 1.03 LSMean (SE) (0.054) (0.055) (0.133) (0.131) (0.044) (0.043) (0.029) (0.028) (2.483, (2.283, (0.373, (-0.169, (1.261, (0.975, 95% CI NA NA 2.696) 2.500) 0.896) 0.347) 1.375) 1.087) LSMean 0.20 (0.076) b 0.55 (0.072) c 0.14 (0.056) d 0.29 (0.041) e Difference (SE) 95% CI (0.049, 0.346) (0.404, 0.687) (0.03, 0.25) (0.207, 0.366) Abbreviations: CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; Hb=hemoglobin; LSMean=least squares mean; Max=maximum; Min=minimum; MMRM=mixed model of repeated measures; Roxa=roxadustat; SD=standard deviation; SE=standard error of the mean; US=United States. a: Baseline Hb is defined as the mean of up to 4 last central lab values prior to the first dose of study treatment. b: In Study 063, treatment comparison was made using an MMRM with baseline Hb as covariate, and study, treatment, visit, visit-by-treatment interaction, study-by-treatment interaction, and history of cardiovascular/cerebrovascular/thromboembolic diseases (Yes vs No) as fixed effect. c: In Study 064, treatment comparison was made using a n MMRM with baseline Hb as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤ 4 months vs > 4 months of starting dialysis when randomized, and randomization stratification factors except mean qualifying screening hemoglobin (≤ 10.5 vs > 10.5 g/dL) as fixed effects. d: In Study 002, the averages and difference in averages of the LSMeans from Weeks 28 to 36 with the corresponding CI were calculated from an MMRM with terms for the baseline Hb measurement as covariate and treatment group, visit and treatment by visit interaction, cardiovascular/cerebrovascular/thromboembolic history, geographical region (US versus Ex-US), and incident versus stable dialysis (≤ 4 versus > 4 months) as fixed effects. The unstructured covariance matrix was used to model the covariate structure. e: Treatment comparison was made using an MMRM with baseline Hb as covariate and study, treatment, visit, visit-by- treatment interaction, study-by-treatment interaction, and history of cardiovascular/cerebrovascular/ thromboembolic diseases (Yes vs No) as fixed effects. Note: Hb values under the influence of a rescue therapy were censored up to 6 weeks in the analysis. Note: Per Protocol Set Page 106 of 154

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5.2.3.2.2. Hb Response with Roxadustat Compared to ESA in Patients with Inflammation at Baseline

Roxadustat demonstrated non-inferiority compared to ESA in increasing Hb levels in patients with DD CKD with evidence of inflammation at baseline (hsCRP > ULN) (Table 30). The analysis based on quintiles of hsCRP at baseline is presented in the Executive Summary of this document (Figure 18). Table 30: DD Studies: Mean Change in Hb From Baseline to Mean Over Weeks 18 to 24 Regardless of Rescue Therapy in Patients with Baseline hsCRP > ULN Study 002 Study 063 Study 064 DD Pool (ITT) Roxa EPO Roxa EPO Roxa EPO Roxa EPO Hb (g/dL) n=228 n=222 n=189 n=176 n=306 n=319 n=720 n=714 Baseline n 228 222 189 176 280 301 720 714 8.54 8.38 10.30 10.24 9.62 9.52 Mean (SD) 10.05 9.96 (0.968) (0.961) (0.616) (0.630) (1.221) (1.301) Median 8.73 8.43 10.28 10.25 NA NA 9.79 9.71 Min, Max 5.8, 10.1 5.6, 10.3 8.8, 11.8 8.6, 12.0 NA NA 5.8, 11.9 5.6, 12.1 Average Hb in Weeks 18–24 (Observed + Imputed) n 228 222 189 176 NA NA 720 714 10.87 10.85 10.91 10.21 10.90 10.61 Mean (SD) NA NA (1.043) (1.023) (0.927) (0.755) (0.981) (1.030) Median 10.99 10.97 11.06 10.22 NA NA 11.02 10.63 Min, Max 7.5, 13.1 7.6, 13.8 7.8, 12.8 8.2, 12.5 NA NA 7.5, 13.3 7.2, 14.8 ANCOVA with Multiple Imputations 2.29 2.27 0.55 -0.14 0.80 0.59 1.32 1.03 LSMean (SE) (0.073) (0.076) (0.110) (0.108) (0.077) (0.076) (0.039) (0.039) (2.150, (2.123, (0.332, (-0.350, (0.64, (0.44, (1.244, (0.954, 95% CI 2.438) 2.420) 0.764) 0.074) 0.95) 0.74) 1.398) 1.105) LSMean 0.02 (0.099) 0.69 (0.093) 0.20 (0.081) 0.29 (0.055) Difference (SE) 95% CI (-0.171, 0.217) (0.503, 0.869) (0.04, 0.36) (0.184, 0.400) Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; Hb=hemoglobin; ITT=intent-to-treat analysis set; LSMean=least squares mean; Max=maximum; Min=minimum; Roxa=Roxadustat; SD=standard deviation; SE=standard error. Note: Full analysis set.

5.2.3.2.3. Average Monthly IV Iron Use Over Weeks 28 to 52

Roxadustat patients required less monthly IV iron than EPO patients (52.2 mg vs 66.8 mg, respectively) to achieve the presented Hb response (Table 31).

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Table 31: DD Studies: Average Monthly IV Iron Usea Per Patient Exposure Month Over Weeks 28 to 52 Study 063 Study 064 Study 002 (ITT) DD Pool IV Iron Roxa EPO Roxa EPO Roxa EPO Roxa EPO (mg) n=522 n=513 n=369 n=370 n=1051 n=1055 n=1929 n=1928 n 437 438 286 319 885 920 1656 1716 59.08 63.99 17.07 37.02 58.71 91.37 52.16 66.82 Mean (SD) (145.179) (98.771) (53.375) (106.778) (236.12) (225.64) (226.293) (162.076) 0.0, 0.0, 0.0, 0.0, 0.0, Min, Max 0.0, 717.7 0.0, 515.8 0.0, 1400.0 1600.0 5600.0 2800.0 5504.0* 2800.0 p-Value 0.00028 b 0.00091 c < 0.0001 d < 0.0001 d Abbreviations: ANCOVA=analysis of covariance; DD=dialysis-dependent; EOS=end of study; EPO=epoetin alfa; FAS=full analysis set; ITT=intent-to-treat analysis set; IV=intravenous; Max=maximum; Min=minimum; Roxa=roxadustat; SD=standard deviation. a: Monthly iron use for each patient=Total IV iron in mg/ ([last visit date - first dose date of study medication in the period+1]/28). b: p-value is based on Koch et al (1982, 1990) stratified rank ANCOVA analysis, which was stratified by iron repletion status and randomization stratification factors except mean qualifying screening hemoglobin (≤ 8.0 g/dL versus > 8.0 g/dL) and considering baseline hemoglobin as covariates for the comparison between roxadustat and epoetin alfa. c: p-value is based on Koch et al. (1982, 1990) stratified rank ANCOVA analysis, which was stratified by iron repletion status and randomization stratification factors except mean qualifying screening hemoglobin (≤ 10.5 vs > 10.5 g/dL) and considering baseline Hb as covariates for the comparison between roxadustat and epoetin alfa. d: p-value is from Wilcoxon Rank-Sum Test. #: In Study 002, IV iron data were collected from Week 36 to EOS in the ITT Population. *:. The max in the pooled analysis was calculated as the weighted average IV iron use during Weeks 28–36 and Weeks 37–52. Note: Full analysis set.

5.2.3.2.4. Mean LDL Cholesterol Changes from Baseline to Mean Over Weeks 12 to 28

Treatment with roxadustat compared with the EPO was associated with a decrease in LDL cholesterol from baseline to the average over Weeks 12 to 28 (-17.2 mg/dL versus -1.4 mg/dL) (Table 32).

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Table 32: DD Studies: Mean Change in LDL Cholesterol from Baseline to Mean Over Weeks 12 to 28 Study 063 Study 064 Study 002 DD Pool LDL Roxa EPO Roxa EPO Roxa EPO Roxa EPO (mg/dL) n=522 n=513 n=369 n=370 n=1051 n=1055 n=1929 n=1928 Baseline LDL a n 522 513 369 370 991 1002 1870 1875 109.12 109.22 84.53 84.45 87.70 87.78 93.25 93.02 Mean (SD) (38.833) (35.914) (34.009) (34.124) (39.91) (40.63) (39.778) (39.359) Median 105.00 107.50 80.0 81.0 82.00 81.99 88.00 89.00 33.0, 26.0, 14.0, 13.0, 11.0, 11.0, Min, Max 9.0, 234.0 9.0, 361.9 271.0 229.5 186.0 361.9 314.0 314.0 Average LDL in Weeks 12–28 n 487 481 327 354 950 982 1650 1741 85.84 104.33 71.19 85.65 74.51 87.00 76.67 91.81 Mean (SD) (34.081) (36.377) (28.444) (33.768) (34.19) (39.97) (32.953) (38.540) Median 83.50 102.00 68.00 82.33 69.41 81.10 72.32 87.39 14.5, 10.0, 14.0, 17.0, Min, Max 5.0, 226.2 6.0, 268.0 7.3, 258.0 7.0, 268.0 258.0 252.0 195.7 252.0 ANCOVA -25.76 -7.42 -12.23 2.44 -14.54 -1.76 -17.22 -1.42 LSMean (SE) (1.220) (1.228) (1.485) (1.459) (1.00) (1.00) (0.634) (0.619) (-28.152, (-9.828, (-15.140, (-0.421, (-16.63, (-3.87, (-18.460, (-2.631, - 95% CI -23.362) -5.007) -9.310) 5.306) 12.37) 0.39) -15.974) 0.205) LSMean Difference (R - -18.34 (1.584) c -14.67 (1.514) -12.76 (1.16) -15.80 (0.885) Comparator) 95% CI (-21.448, -15.232) (-17.640, -11.695) (-15.08, -10.49) (-17.535, -14.063) p-value < 0.0001 < 0.0001 < 0.001 < 0.0001 Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; LDL=low-density lipoprotein; LSMean=least squares mean; Max=maximum; Min=minimum; Roxa=roxadustat; SD=standard deviation; SE=standard error. a: Baseline is defined as the last available value prior to the first dose of study treatment. Note: Full analysis set.

5.2.3.2.5. Proportion of Patients Who Received RBC Transfusions During Treatment

As shown in Table 33, 9.5% of patients in the roxadustat group required RBC transfusion compared to 12.8% in the EPO group.

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Table 33: DD Studies: Proportion of Patients with RBC Transfusion in Roxadustat- Treated and Epoetin Alfa-Treated Patients with DD CKD Study 063 Study 064 Study 002 (ITT) DD Pool RBC Roxa EPO Roxa EPO Roxa EPO Roxa EPO Transfusion n=522 n=513 n=369 n=370 n=1048 n=1053 n=1929 n=1928 Patients with events a 38 (7.3) 33 (6.4) 46 (12.5) 78 (21.1) 103 (9.8) 139 (13.2) 184 (9.5) 246 (12.8) n (%) Patients censored b 484 (92.7) 480 (93.6) 323 (87.5) 292 (78.9) NA NA 1745 (90.5) 1682 (87.2) n (%) Treatment Effect 1.26 0.67 0.83 0.82 (Roxa-ESA) HR c 95% CI c (0.791, 2.016) (0.466, 0.970) (0.64, 1.07) (0.679, 0.997) p-value c 0.3284 0.0337 0.151 0.0461 Abbreviations: CI=confidence interval; CKD=chronic kidney disease; DD=dialysis-dependent; EPO=epoetin alfa; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; HR=hazard ratio; ITT=intent-to-treat analysis set; NE=not estimable; NA=not available; PEY=patient exposure year; RBC=red blood cell; Roxa=roxadustat. a Any use of RBC transfusion. b Patients with no event were censored at the date of minimum (last dose date, last visit date, death date). c From a stratified Cox Proportional hazards model adjusting for treatment stratified by study, baseline Hb (< 10 g/dL vs ≥ 10 g/dL) and history of cardiovascular/cerebrovascular/thromboembolic diseases (Yes vs No). Note: In Study 002, patients who did not experience RBC transfusions were censored at the earliest occurrence of either 3 days after their last intake of study drug, or the date of withdrawal of consent or last study contact if the patient withdrew consent or was lost to follow-up, or at the date of death. Note: Full analysis set.

5.2.3.2.6. Primary Efficacy Endpoint Results in Patients with ID-DD CKD

The mean change from baseline in Hb averaged over Weeks 28 to 52 regardless of rescue therapy was non-inferior in the roxadustat group compared to the EPO group (Table 34).

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Table 34: ID-DD Subpopulation: Mean Change in Hb From Baseline to Mean Over Weeks 28 to 52 Regardless of Rescue Therapy Study 064 Study 002 Study 063 ID Pool (ID Subset) (ID Subset) Roxa EPO Roxa EPO Roxa EPO Roxa EPO Hb (g/dL) n=522 n=521 n=36 n=35 n=202 n=214 n=760 n=770 Baseline Hb N 522 521 36 35 202 214 760 770 8.43 8.46 10.23 10.09 9.56 9.62 8.82 8.86 Mean (SD) (1.044) (0.964) (0.795) (0.913) (1.158) (1.238) (1.215) (1.194) Median 8.60 8.60 10.27 10.23 9.60 9.72 8.88 8.87 Min, Max 5.3, 10.2 5.0, 10.3 8.4, 11.8 8.6, 11.9 6.4, 12.0 6.0, 12.0 5.3, 12.0 5.0, 12.0 Average Hb in Weeks 28 to 52 (Observed + Imputed) n 522 521 36 35 202 214 760 770 11.00 10.83 10.60 10.20 10.82 10.74 10.94 10.77 Mean (SD) (0.819) (0.876) (0.785) (0.782) (0.896) (1.010) (0.842) (0.919) Median 11.09 10.89 10.63 10.23 10.92 10.77 11.03 10.82 Min, Max 8.0, 13.5 6.8, 13.2 8.9, 12.2 8.0, 11.9 7.8, 13.0 8.0, 13.3 7.7, 13.5 6.8, 13.3 ANCOVA with Multiple Imputations 2.38 2.20 0.51 0.07 1.23 1.15 1.90 1.67 LSMean (SE) (0.041) (0.041) (0.164) (0.155) (0.078) (0.073) (0.063) (0.065) (2.298, (2.115, (0.185, (-0.239, (1.083, (1.008, (1.772, (1.546, 95% CI 2.461) 2.278) 0.829) 0.369) 1.387) 1.294) 2.020) 1.801) LSMean 0.18 (0.053) 0.44 (0.225) 0.08 (0.103) 0.22 (0.090) Difference (SE) 95% CI (0.079, 0.287) (0.001, 0.883) (-0.118, 0.286) (0.047, 0.399) Abbreviations: ANCOVA=analysis of covariance; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; Hb=hemoglobin; ID=incident dialysis; LSMean=least squares mean; Max=maximum; Min=minimum; Roxa=roxadustat; SD=standard deviation; SE=standard error. Note: Intent-to-treat analysis set.

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6. CLINICAL SAFETY

6.1. Overview of Safety Evaluation Plan The pooled safety analysis population consisted of all randomized patients who received at least one dose of study drug in 3 pooled NDD studies (Studies 001, 060, and 608), and 3 pooled DD studies (002, 063, and 064), consisting of 4,326 patients treated with roxadustat, 1,884 patients treated with placebo and 1940 patients treated with EPO. CV safety was examined using events that were adjudicated by an independent committee blinded to treatment assignment. In addition, supportive data from Study 610 (consisting of 323 patients treated with roxadustat and 293 patients treated with EPO) are presented due to that study's unique design as an active-controlled NDD trial which was not affected by bias due to different study drug discontinuation. Data from Study 613 (Study 613, consisting of 414 patients treated with roxadustat, 257 patients treated with EPO, and 163 patients treated with darbepoetin alfa) were excluded from the pooled DD CKD analyses because this study included 2 comparators (EPO and darbepoetin alfa), different from other 3 DD studies with a single active comparator (EPO).

6.2. Safety Data/Endpoints (NDD and DD) Safety data collection included AEs, SAEs, discontinuation of study medication due to AEs, and other standard safety measures (eg, laboratory values, vital signs, electrocardiogram, etc). All reported AEs for the pivotal studies were collected while patients remained on treatment up to 28 days, and those events occurring within this OT+28-day period were considered treatment-emergent. The approach to safety data collection following the OT+28- day period varied among the pivotal trials. In Study 608, patients that discontinued treatment prematurely were assessed every 6 months until the end of the study for vital status, SAEs, and CV and thromboembolic events, unless consent was withdrawn; Studies 063, 064, and 060 conducted telephone visits every 3–6 months to assess for CV events; and Studies 001 and 002 favored continued study visits with no change to safety data collection, but allowed for modified follow-up such as telephone visits, when necessary to avoid withdrawal of consent. The key CV safety endpoints were as follows: • MACE: consisting of adjudicated events of myocardial infarction, stroke, and ACM • MACE +: MACE plus additional adjudicated events of hospitalized unstable angina and hospitalized congestive heart failure • ACM: all-cause mortality

6.3. Clinical Safety–Overall Extent of Exposure (NDD and DD) A total of 9,600 patients with CKD anemia were exposed to the study drugs (roxadustat, placebo, EPO) in the Phase 3 studies as shown in Table 35.

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Table 37: Pooled NDD Studies: Primary Analysis of MACE, MACE+, and All- Cause Mortality MACE MACE+ ACM Roxadustat Placebo Roxadustat Placebo Roxadustat Placebo On-Study Analysis NDD Set (n=2386) (n=1884) (n=2386) (n=1884) (n=2386) (n=1884) Total PY 4509.6 3406.2 4368.9 3272.4 4797.7 3721.4 No. patients with 480 350 578 432 400 301 events IR/100 PY 10.6 10.3 13.2 13.2 8.3 8.1 HR (95% CI) 1.10 (0.96, 1.27) 1.07 (0.94, 1.21) 1.08 (0.93, 1.26) Abbreviations: ACM=all-cause mortality; CI=confidence interval; HR=hazard ratio; IR=incidence rate; on-study analysis=analysis evaluation period to include on-treatment and off-treatment long-term follow-up, until end of study; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure; PY=patient follow-up years. Note: Safety Population; On-study analysis, NDD Pool: Studies 001, 060,608. The Kaplan-Meier survival analysis plots for the endpoints of MACE show the probability of remaining event-free over time (Figure 39). Survival curves of the 2 treatment groups tracking closely together in all 3 endpoints are supportive of the comparable risks of MACE, MACE+ (Figure 61), and ACM (Figure 62) between roxadustat and placebo. Figure 61: Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of MACE+

Abbreviations: CI=confidence interval; MACE+=major adverse cardiovascular events (all-cause mortality, myocardial infarction, and stroke) plus hospitalization for unstable angina or congestive heart failure; NDD=non-dialysis-dependent. Note: Safety Population; On-study analysis, NDD Pool: Studies 001, 060,608, hazard ratio upper bound of 95% CI below reference margin of 1.3.

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Figure 62: Pooled NDD Studies: Kaplan-Meier Curves of Primary Analysis of ACM

Abbreviations: ACM=all-cause mortality; CI=confidence interval; NDD=non-dialysis-dependent Note: Safety Population; On-study analysis, NDD Pool: Studies 001, 060,608, hazard ratio upper bound of 95% CI below reference margin of 1.3. On-treatment Analysis of MACE in the NDD pool Figure 63 shows the Kaplan-Meier curve for MACE in the NDD pool in the OT+28 days analysis set. The curves track closely together until 9–12 months following randomization and then separate due to decreasing event rates in the placebo group, consistent with observed differences in rates of MACE being due to informative censoring in the placebo group. Figure 63: Pooled NDD Studies: MACE Results in the OT+28 Analysis Set

Abbreviations: CI=confidence interval; HR=hazard ratio; MACE=major adverse cardiovascular events (all-cause mortality, myocardial infarction, and stroke); OT+28=on-treatment plus 28 days.

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Study 001 Cardiovascular Safety Results Table 38: Study 001: Cardiovascular Safety Results Roxadustat Placebo N=1376 N=1384 Overall population n (%) n (%) HR (95% CI) MACE 332 (24.1) 287 (20.1) 1.13 (0.96, 1.32) MACE+ 394 (28.6) 352 (25.4) 1.10 (0.95, 1.27) ACM 284 (20.6) 245 (17.7) 1.15 (0.97, 1.37) Roxadustat Placebo N=1376 N=1384 NDD-NDD n (%) n (%) HR (95% CI) MACE 211 (15.3) 206 (14.9) 1.04 (0.86, 1.26) MACE+ 273 (19.8) 258 (18.6) 1.07 (0.90, 1.27) ACM 178 (12.9) 171 (12.4) 1.07 (0.87, 1.33) Roxadustat Placebo N=1093 N=1094 NDD eGFR ≥ 10 n (%) n (%) HR (95% CI) MACE 238 (21.8) 220 (20.1) 1.04 (0.87, 1.25) MACE+ 283 (25.9) 269 (24.6) 1.04 (0.88, 1.24) ACM 201 (18.4) 187 (17.1) 1.05 (0.86, 1.28) Abbreviations: ACM=all-cause mortality; CI=confidence interval; eGFR=estimated glomerular filtration rate; HR=hazard ratio; MACE=major adverse cardiovascular events (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure; NDD=non-dialysis-dependent. Note: Safety Population; On-study analysis.

6.4.1.1. Placebo Evaluation Period Adjusted Analysis Due to the differential discontinuation rates between the roxadustat and placebo groups in the pooled NDD population that result in informative censoring which biases event rate comparison in on-treatment analyses, a more appropriate comparison is to disregard the treatment-emergent window and allow comparisons to be based on equal follow-up time. One method, the placebo evaluation period adjusted method, adjusts the follow-up time in patients on placebo who were censored at OT+28 to be comparable to the expected time at risk accrued through OT+28 in patients on roxadustat with the same baseline characteristics that were associated with the risk of major clinical events. The observed OT+28 window of placebo patients is replaced by a randomly selected OT+28 window from a donor pool of roxadustat patients with similar baseline characteristics. This process is repeated 1000 times. The final estimate of HR and its 95% CI are obtained from the MI (MIANALYZE) procedure. Note that only the event evaluation periods of the placebo patients are adjusted. Additional events that occurred in the placebo patients that were originally not included may now be

Page 116 of 154 Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee included in the analysis only because of the lengthening of the evaluation period. There is no imputation on the occurrence of the events. Figure 64 shows results using the placebo evaluation period adjusted method for MACE, MACE+, and ACM. HR point estimates range from 0.90–0.99, with 95% CIs which cross 1.0 with upper bounds of 1.09–1.17. Figure 64: Pooled NDD Studies: Forest Plot of Analyses of MACE, MACE+, and ACM Using the Placebo Evaluation Period Adjusted Method

Abbreviations: ACM=all-cause mortality; CI=confidence interval; eGFR=estimated glomerular filtration rate; HR=hazard ratio; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure; NDD=non-dialysis-dependent. Note: HR is estimated using the Cox regression model by study in each sampling replicate. The Cox model includes cardiovascular/cerebrovascular/thromboembolic medical history (yes vs no), geographical region (Europe vs ex-Europe), baseline hemoglobin (< 8 g/dL vs ≥ 8 g/dL) and baseline eGFR (< 10 mL/min/1.73 m2 vs ≥ 10 mL/min/1.73 m2) as strata. The final HR and the 95% CI are estimated using MIANALYZE.

6.4.1.2. All-Cause Mortality in Pivotal Phase 3 NDD Studies: Cause of Death The rates of all-cause deaths were comparable in the roxadustat group and the placebo group. Adjudicated causes of death are presented in Table 39.

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Table 39: Pooled NDD Pooled: All-Cause Mortality NDD Roxadustat Placebo ITT (N=2386, PY=4797.7) (N=1884, PY=3721.4) n (%) IR/100 PY a n (%) IR/100 PY a Total Number of Deaths 400 (16.8) 8.3 301 (16.0) 8.1 Cardiovascular-related 143 (6.0) 3.0 102 (5.4) 2.7 Sudden cardiac death 66 (2.8) 1.4 42 (2.2) 1.1 Stroke 21 (0.9) 0.4 14 (0.7) 0.4 Acute myocardial infarction 20 (0.8) 0.4 23 (1.2) 0.6 Heart failure 19 (0.8) 0.4 15 (0.8) 0.4 Other CV causes 9 (0.4) 0.2 3 (0.2) 0.1 CV procedure 7 (0.3) 0.1 1 (0.1) 0.0 CV hemorrhage 1 (0.0) 0.0 4 (0.2) 0.1 Non-cardiovascular-related 185 (7.8) 3.9 116 (6.2) 3.1 Infection 87 (3.6) 1.8 39 (2.1) 1.0 Renal 54 (2.3) 1.1 37 (2.0) 1.0 Malignancy 11 (0.5) 0.2 8 (0.4) 0.2 Pancreatic 5 (0.2) 0.1 4 (0.2) 0.1 Hemorrhage 5 (0.2) 0.1 10 (0.5) 0.3 Hepatobiliary 4 (0.2) 0.1 3 (0.2) 0.1 Trauma 4 (0.2) 0.1 3 (0.2) 0.1 Non-CV procedure 4 (0.2) 0.1 4 (0.2) 0.1 Gastrointestinal 3 (0.1) 0.1 4 (0.2) 0.1 Inflammatory Immune/ Autoimmune 3 (0.1) 0.1 0 (0.0) 0 Neurological 3 (0.1) 0.1 2 (0.1) 0.1 Pulmonary 2 (0.1) 0 1 (0.1) 0 Suicide 0 (0.0) 0 1 (0.1) 0 Undetermined 72 (3.0) 1.5 83 (4.4) 2.2 Abbreviations: CV=cardiovascular; IR=incidence ratio; ITT=intent-to-treat analysis set; NDD=non-dialysis-dependent; PY=patient year. a IR/100 PY=100 x number of patients with events / PY. PY for each patient=(first event occurrence or censor date - first dose date + 1) / 365.25. Safety Population; On-Study evaluation period, NDD Pool: Studies 001, 060, 608.

6.4.2. Cardiovascular Safety in DD Population Table 40 shows retention and follow-up in the pooled NDD studies.

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Table 40: DD Studies: Retention and Follow-up (% Based on Patients Who Were Randomized and Received at Least One Dose of Study Drug) Study 002 Study 063 Study 064 Pooled DD Studies Roxa EPO Roxa EPO Roxa EPO Roxa EPO n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) (N=1048) (N=1053) (N=522) (N=517) (N=370) (N=370) (N=1940) (N=1940) Study completed on 696 (66.4) 796 (75.6) 307 (58.8) 308 (59.6) 127 (34.3) 183 (49.5) 1130 (58.2) 1287 (66.3) study drug Study completed follow-up in MACE 989 (94.4) 993 (94.3) 442 (84.7) 431 (83.4) 288 (77.8) 315 (85.1) 1719 (88.6) 1739 (89.6) (full data on MACE) Study completed follow-up in Vital status (ascertained at 1043 (99.5) 1047 (99.4) 437 (83.7) 428 (82.8) 282 (76.2) 310 (83.8) 1762 (90.8) 1785 (92.0) end of study ie, alive or dead) Abbreviations: DD=dialysis-dependent; EPO=epoetin alfa; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); Roxa=roxadustat. Table 41 shows the results of analyses of MACE, MACE+, and ACM with roxadustat treatment compared to placebo.

Table 41: Pooled DD Studies: Primary Analysis of MACE, MACE+, and All-Cause Mortality DD MACE MACE+ ACM OT+7 Roxadustat EPO Roxadustat EPO Roxadustat EPO (n=1940) (n=1940) (n=1940) (n=1940) (n=1940) (n=1940) Total PY 3315.3 3743.6 3315.3 3743.6 3315.3 3743.6 No. of patients with events 306 339 373 458 207 232 IR/100 PY 9.2 9.1 11.3 12.2 6.2 6.2 HR (95% CI) 1.02 (0.88, 1.20) 0.91 (0.80, 1.05) 1.02 (0.84, 1.23) Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; IR=incidence rate; HR=hazard ratio; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalization for unstable angina or congestive heart failure; OT+7=on-treatment plus 7 days; PY=patient years. Note: Safety Population, OT+7 analyses, DD Pool: Studies 002, 063, 064 The Kaplan-Meier survival analysis plots for the endpoints of MACE show the probability of remaining event-free over time (Figure 44). Survival curves of the 2 treatment groups tracking closely together in all 3 endpoints are supportive of the comparable risks of MACE, MACE+ (Figure 65) and ACM (Figure 66) between roxadustat and placebo.

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Figure 65: Pooled DD Studies: Kaplan-Meier Survival Curves of MACE+

Abbreviations: CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; FAIR=Follow-up adjusted incidence rate; MACE+=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke) plus hospitalizations for unstable angina or congestive heart failure; OT+7=on-treatment plus 7 days. Note: Safety Population, OT+7 analyses, DD Pool: Studies 002, 063, 064

Figure 66: Pooled DD Studies: Kaplan-Meier Curves of Primary Analysis of ACM

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; OT+7=on-treatment plus 7 days. Note: Safety Population, OT+7 analyses, DD Pool: Studies 002, 063, 064. In agreement with FDA, on-treatment plus 7 days (OT+7) was chosen as the primary analysis set for CV safety in the DD population. This analysis was chosen to allow for the capture of residual safety events, while minimizing confounding due to Hb fluctuation and/or ESA treatment following roxadustat discontinuation. OT+28 was agreed to as a supportive analysis, and the HR (95% CI) for MACE was 1.08 (0.94, 1.25) (Figure 67).

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Figure 67: Pooled DD Studies: Forest Plot of MACE, MACE+, and ACM (OT+28)

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalizations for unstable angina or congestive heart failure; OT+28=on-treatment plus 28 days. Roxa=roxadustat. Note: Safety Population, OT+28 Analysis, DD Pool: Studies 002, 063, 064. On-study results for the DD population are presented below (Figure 68). One concern with the use of on-study analyses in this patient population is that these analyses will reflect the period of Hb adjustment when roxadustat patients who discontinued study treatment had to be titrated to standard of care ESA treatment, or alternatively a period of no anemia treatment which would be expected to lead to a reduction in Hb. No such titration period was required for EPO-treated patients who discontinued study treatment as they would be expected to continue on ESA (Figure 70). Consequently, the ITT analysis of the DD population is biased away from the null and against roxadustat compared to ESA. Notably, on-study results in the ID subgroup revealed HR point estimates of 0.87–1.01 (Figure 69). Figure 68: Pooled DD Studies: Forest Plot of MACE, MACE+, and ACM (On-Study)

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; EPO=epoetin alfa; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalizations for unstable angina or congestive heart failure; Roxa=roxadustat. Note: Safety Population, On-Study Analysis, DD Pool: Studies 002, 063, 064.

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Figure 69: Pooled ID Studies: Forest Plot of MACE, MACE+, and ACM (On-Study Analysis)

Abbreviations: ACM=all-cause mortality; CI=confidence interval; ID=incidence dialysis; EPO=epoetin alfa; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalizations for unstable angina or congestive heart failure; Roxa=roxadustat. Note: Safety Population, On-study Analysis.

Figure 70: ESA Treatment Before, During, and After Treatment Discontinuation in the Roxadustat DD Program

Abbreviations: DD=dialysis-dependent; EOS=end of study; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin.

6.4.2.1. All-Cause Mortality in Pivotal Phase 3 DD Studies: Cause of Death The rates of all-cause deaths were comparable in the roxadustat group and the placebo group. Adjudicated causes of death are presented in Table 42.

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Table 42: Pooled DD Studies: All-Cause Mortality Roxadustat Epoetin Alfa DD (N=1940, PEY=3315.3) (N=1940, PEY=3743.6) OT+7 n (%) Incidence/100 PY n (%) Incidence/100 PY Total Number of Deaths 207 (10.7) 6.2 232 (12.0) 6.2 Cardiovascular-related 122 (6.3) 3.7 136 (7.0) 3.6 Sudden cardiac death 69 (3.6) 2.1 78 (4.0) 2.1 Acute myocardial infarction 20 (1.0) 0.6 11 (0.6) 0.3 Heart failure 16 (0.8) 0.5 14 (0.7) 0.4 Stroke 7 (0.4) 0.2 19 (1.0) 0.5 Other CV causes 5 (0.3) 0.2 6 (0.3) 0.2 CV procedure 4 (0.2) 0.1 4 (0.2) 0.1 CV hemorrhage 1 (0.1) 0.0 4 (0.2) 0.1 Non-cardiovascular-related 67 (3.5) 2.0 72 (3.7) 1.9 Infection 32 (1.6) 1 32 (1.6) 0.9 Renal 9 (0.5) 0.3 5 (0.3) 0.1 Gastrointestinal 4 (0.2) 0.1 7 (0.4) 0.2 Hemorrhage 4 (0.2) 0.1 4 (0.2) 0.1 Malignancy 4 (0.2) 0.1 6 (0.3) 0.2 Trauma 3 (0.2) 0.1 3 (0.2) 0.1 Hepatobiliary 2 (0.1) 0.1 1 (0.1) 0 Pancreatic 2 (0.1) 0.1 2 (0.1) 0.1 Neurological 2 (0.1) 0.1 1 (0.1) 0 Non-CV procedure 2 (0.1) 0.1 6 (0.3) 0.2 Inflammatory Immune/Autoimmune 1 (0.1) 0 2 (0.1) 0.1 Other 1 (0.1) 0 1 (0.1) 0 Pulmonary 1 (0.1) 0 0 (0.0) 0 Suicide 0 (0.0) 0 1 (0.1) 0 Drug reaction or overdose 0 (0.0) 0 1 (0.1) 0 Undetermined 18 (0.9) 0.5 24 (1.2) 0.6 Abbreviations: DD=dialysis-dependent; PEY=patient exposure year; OT+7=on-treatment plus 7 days. Note: Safety Population, OT+7 analyses, DD pool: Studies 002, 063, 064.

6.5. General Safety Assessment of Roxadustat in NDD Population

6.5.1. Exposure in Pivotal NDD Studies

The large safety population of the NDD pool (n=4,270) from 3 pivotal Phase 3 studies includes 2,386 patients treated with roxadustat and 1,884 patients on placebo. No patients were on dialysis at the time of randomization, but ~ 35% of patients were initiated on dialysis during the study period. As shown in Table 43, mean duration of exposure and PY were greater in the roxadustat treatment group than in the placebo group due to the earlier and greater rates of study drug discontinuations in the placebo group resulting in a more pronounced difference in overall exposure to study treatment between the treatment groups. Page 123 of 154

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Patient disposition and baseline demographics and other characteristics, including CV history, were generally similar for the treatment groups in the NDD pool. Table 43: Pooled NDD Studies: Overall Drug Exposure (Safety Population) Roxadustat Placebo (N=2386) (N=1884) Patient Exposure (Week): Mean (SD) 84.6 (48.79) 64.3 (44.82) Median (Min-Max) 87.1 (0 –234.9) 57.1 (0 –208.1) Mean Exposure (Year) 1.6 1.2 Total PY 3870.7 2323.2 Abbreviations: NDD=non-dialysis-dependent; PY=patient year; SD=standard deviation. Note: Safety Population, NDD Pool: Studies 001, 060, 608.

6.5.2. Safety Data from Pivotal NDD Studies

To account for differences in study drug exposure per treatment group in the NDD population, exposure-adjusted incidence rates are presented in addition to incidence. However, this does not account for overrepresentation of higher-risk patients in the roxadustat group for on-treatment analyses. An overview of AEs in the pooled NDD studies is provided in Table 44. Most patients experienced at least 1 AE in both groups. Roxadustat-treated patients had slightly higher incidence rates of SAEs. Roxadustat-treated patients had higher incidence rate of fatal events during the treatment emergent period; however, ACM, which includes deaths both on treatment as well as during long-term follow-up period, was similar for both groups: 8.3 deaths per 100 PY for roxadustat and 8.1 deaths per 100 PY for placebo. The incidence rate for AEs that led to discontinuation was similar for roxadustat and placebo (3.9 vs 3.8 per 100 PY). Table 44: Pooled NDD Studies: Summary of Overall Treatment-Emergent Adverse Events in Roxadustat and Placebo Groups Roxadustat Placebo N=2386 N=1884 n (%) IR/100 PY n (%) IR/100 PY Any AEs 2132 (89.4) 222.6 1608 (85.4) 211.5 Any SAEs 1308 (54.8) 45.9 845 (44.9) 43.9 AEs leading to discontinuation 157 (6.6) 3.9 92 (4.9) 3.8 Any Fatal AEs 276 (11.6) 6.9 134 (7.1) 5.5 All-Cause Mortalitya 400 (16.8) 8.3 301 (16.0) 8.1 Abbreviations: AE=adverse event; IR=incidence rate; ITT=intent=to=treat; N=number of patients within treatment group; n=number of patients with the specified event; NDD=non-dialysis-dependent; OT+28=on-treatment plus 28 days; PY=patient year; SAE=serious adverse event. a All-cause deaths occurred during both on-treatment and long-term follow-up period (ITT analysis). Each death was adjudicated by a central adjudication committee that was blinded to treatment assignment. Note: Safety Population, OT+28 analyses, NDD pool: Studies 001, 060, 608. Page 124 of 154

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6.5.2.1. Common Treatment-Emergent Adverse Events

Treatment-emergent AEs reported in ≥ 5% of patients in either group are presented in Table 45. The most commonly reported AEs in both roxadustat and placebo-treated patients were ESRD, hypertension, and peripheral edema. Other common events were mostly gastrointestinal events (ie, diarrhea, nausea, constipation, and vomiting), infections (urinary tract infection, upper respiratory infections, and pneumonia) and laboratory abnormalities (hyperkalemia and hypoglycemia). AEs with an incidence rate of > 1.0 patients per 100 PY in roxadustat versus placebo patients included hypertension, peripheral edema, hyperkalemia, diarrhea, urinary tract infection, nausea, constipation, and insomnia.

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Table 45: Pooled NDD Studies: Summary of Treatment-Emergent Adverse Events (Incidence ≥ 5%) by Preferred Terms in Roxadustat and Placebo Groups Roxadustat Placebo Preferred Term N=2386 N=1884 n (%) IR/100 PY n (%) IR/100 PY Any AE 2132 (89.4) 222.6 1608 (85.4) 211.5 End-stage renal disease 437 (19.8) 13.0 282 (15.0) 12.1 Hypertension 329 (13.8) 9.0 153 (8.1) 6.6 Oedema peripheral 279 (11.7) 7.6 143 (7.6) 6.1 Hyperkalemia 261 (10.9) 7.0 133 (7.1) 5.7 Diarrhea 248 (10.4) 6.6 129 (6.8) 5.5 Urinary tract infection 248 (10.4) 6.6 120 (6.4) 5.1 Nausea 243 (10.2) 6.5 119 (6.3) 5.1 Viral upper respiratory tract infection 228 (9.6) 6.2 137 (7.3) 6.0 Pneumonia 212 (8.9) 5.5 118 (6.3) 4.9 Constipation 209 (8.8) 5.5 102 (5.4) 4.3 Upper respiratory tract infection 187 (7.8) 5.0 110 (5.8) 4.7 Headache 178 (7.5) 4.7 103 (5.5) 4.4 Cough 170 (7.1) 4.5 90 (4.8) 3.8 Vomiting 148 (6.2) 3.8 76 (4.0) 3.2 Dizziness 146 (6.1) 3.8 110 (5.8) 4.7 Hypoglycemia 146 (6.1) 3.8 77 (4.1) 3.2 Back pain 138 (5.8) 3.6 71 (3.8) 3.0 Pruritus 138 (5.8) 3.6 86 (4.6) 3.6 Insomnia 131 (5.5) 3.4 44 (2.3) 1.8 Dyspnea 124 (5.2) 3.2 90 (4.8) 3.8 Arthralgia 121 (5.1) 3.1 73 (3.9) 3.1 Acute kidney injury 121 (5.1) 3.1 53 (2.8) 2.2 Anemia 51 (2.1) 1.3 101 (5.4) 4.2 Abbreviations: AE=adverse event; IR=incidence rate; N=number of patients within treatment group; n=number of patients with the specified event; NDD=non-dialysis-dependent; OT+28=on-treatment plus 28 days; PY=patient year. Note: AEs ≥ 5% in either group, Safety Population, OT+28 analyses, NDD Pool: Studies 001, 060, 608.

6.5.2.2. Treatment-Emergent Adverse Events Leading to Discontinuation

The summary of AEs that led to treatment discontinuation is presented in Table 46. The overall incidence of AEs leading to discontinuation was comparable and low in both treatment groups. No single event leading to study discontinuation in any treatment group was reported in > 1% of patients.

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Table 46: Pooled NDD Studies: Summary of Treatment-Emergent Adverse Events (≥ 0.3%) Leading to Discontinuation by Preferred Terms in Roxadustat and Placebo Groups Roxadustat Placebo N=2386 N=1884 Preferred Term n (%) IR/100 PY n (%) IR/100 PY AEs leading to discontinuation 157 (6.6) 3.9 92 (4.9) 3.8 End-stage renal disease 18 (0.8) 0.4 7 (0.4) 0.3 Acute kidney injury 11 (0.5) 0.3 1 (0.1) 0.0 Sepsis 6 (0.3) 0.1 1 (0.1) 0.0 Anemia 2 (0.1) 0 8 (0.4) 0.3 Fatigue 0 0 5 (0.3) 0.2 Abbreviations: AE=adverse event; IR=incidence rate; N=number of patients within treatment group; n=number of patients with the specified event; NDD=non-dialysis-dependent; PY=patient year. Note: AEs leading to discontinuation ≥ 0.3% in either group, Safety Population, OT+28 analyses, NDD Pool: Studies 001, 060, 608.

6.6. General Safety Assessment of Roxadustat in DD Population

6.6.1. Exposure in Pivotal DD Studies

The pooled pivotal Phase 3 studies in patients with DD CKD include 1940 roxadustat-treated patients and 1940 EPO-treated patients. The exposure to treatment was shorter for the roxadustat group compared to EPO- (Table 47). The ID-DD subpopulation included 760 roxadustat-treated patients and 766 EPO-treated patients. Table 47: Pooled DD Studies (ID-DD and SDD-DD Subpopulations): Overall Drug Exposure Pooled DD Pooled ID Pooled SDD Roxadustat Epoetin Alfa Roxadustat Epoetin Alfa Roxadustat Epoetin Alfa (N=1940) (N=1940) (N=760) (N=766) (N=1180) (N=1174) Patient Exposure (Week): Mean (SD) 89.2 (58.69) 100.7 (57.54) 75.4 (57.62) 81.0 (60.29) 98.0 (57.68) 113.5 (51.82) Median 87.9 107.5 54.6 59.9 106.9 135.6 (Min-Max) (0.1–227.9) (0.1–226.9) (0.4–227.9) (0.1–226.9) (0.1–195.7) (0.4–195.4) Mean Exposure 1.7 1.9 1.4 1.6 1.9 2.2 (Year) Abbreviations: DD=dialysis-dependent; ID=incident dialysis; Min=minimum; Max=maximum; SDD=stable dialysis- dependent; SD=standard deviation. Note: Safety Population, DD Pool: Studies 002, 063, 064.

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6.6.2. Safety Data from Pivotal DD Studies

An overview of AEs in the pooled DD studies is provided in Table 48. Similar to the NDD studies, most patients in the DD studies also experienced at least 1 AE. The percentage of patients experiencing at least one AE was similar in both groups. Roxadustat- and EPO- treated patients had similar rates of SAEs and fatal events. More patients in the roxadustat group experienced AEs leading to discontinuation. Table 48: Pooled DD Studies: Summary of Overall Treatment-Emergent Adverse Events in Roxadustat- and Epoetin Alfa Groups Roxadustat Epoetin Alfa

N=1940 N=1940 n (%) n (%) Any AEs 1680 (86.6) 1669 (86.0) Any SAEs 1080 (55.7) 1071 (55.2) AEs leading to discontinuation 218 (11.2) 159 (8.2) Any Fatal AEs 292 (15.1) 303 (15.6) All-cause mortalitya 207 (10.7) 232 (12.0) Abbreviations: AE=adverse event; DD=dialysis-dependent; N=number of patients within treatment group; n=number of patients with the specified event; OT+7=on-treatment plus 7 days; OT+28=on-treatment plus 28 days; SAE=serious adverse event. a Data shown from OT+7 analyses. Each death was adjudicated by a central adjudication committee that was blinded to treatment assignment. Note: Safety Population, OT+28 analyses, DD Pool: Studies 002, 063, 064.

6.6.2.1. Common Treatment-Emergent Adverse Events

The AE profile was generally similar for patients receiving roxadustat compared with those receiving the EPO. The summary of AEs with ≥ 5% incidence is tabulated in Table 49. The most common AEs in both treatment groups were hypertension and diarrhea (both > 10%). Among other common events were headache, complications associated with vascular access, gastrointestinal events and infections.

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Table 49: Pooled DD Studies: Summary of Treatment-Emergent Adverse Events (Incidence ≥ 5%) by Preferred Terms in Roxadustat and Epoetin Alfa Groups Roxadustat Epoetin Alfa Preferred Term N=1940 N=1940 n (%) n (%) Any AE 1680 (86.6) 1669 (86.0) Hypertension 253 (13.0) 229 (11.8) Diarrhea 243 (12.5) 215 (11.1) Headache 181 (9.3) 141 (7.3) Arteriovenous fistula thrombosis 174 (9.0) 145 (7.5) Pneumonia 175 (9.0) 193 (9.9) Hypotension 170 (8.8) 147 (7.6) Nausea 169 (8.7) 155 (8.0) Vomiting 154 (7.9) 129 (6.6) Arteriovenous fistula site complication 146 (7.5) 152 (7.8) Cough 139 (7.2) 152 (7.8) Hyperkalemia 138 (7.1) 138 (7.1) Upper respiratory tract infection 136 (7.0) 114 (5.9) Dyspnea 122 (6.3) 139 (7.2) Fluid overload 120 (6.2) 128 (6.6) Constipation 113 (5.8) 101 (5.2) Pain in extremity 112 (5.8) 117 (6.0) Muscle spasms 107 (5.5) 92 (4.7) Pyrexia 105 (5.4) 101 (5.2) Back pain 100 (5.2) 109 (5.6) Dizziness 98 (5.1) 85 (4.4) Urinary tract infection 97 (5.0) 102 (5.3) Bronchitis 94 (4.8) 120 (6.2) Viral upper respiratory tract infection 93 (4.8) 99 (5.1) Fall 88 (4.5) 101 (5.2) Atrial fibrillation 59 (3.0) 107 (5.5) Abbreviations: AE=adverse event; DD=dialysis-dependent; OT+28=on-treatment plus 28 days. Note: Incidence ≥ 5%, Safety Population, OT+28 analyses, DD Pool: Studies 002, 063, 064.

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6.6.2.2. Treatment-Emergent Adverse Events Leading to Discontinuation

As shown in Table 50, the incidence of AEs leading to discontinuation of treatment was 11.2% in roxadustat group and 8.2% in the EPO group. Cardiac arrest was the only single event reported in ≥ 1% of patients leading to study discontinuation in both treatment groups. Table 50: Pooled DD Studies: Summary of Treatment-Emergent Adverse Events (≥ 0.3%) Leading to Discontinuation by Preferred Terms in Roxadustat- and Epoetin Alfa Groups Roxadustat Epoetin Alfa N=1940 N=1940 Preferred Term n (%) n (%) AEs leading to discontinuation 218 (11.2) 159 (8.2) Cardiac arrest 19 (1.0) 25 (1.3) Sepsis 11 (0.6) 4 (0.2) Septic shock 12 (0.6) 4 (0.2) Acute myocardial infarction 10 (0.5) 6 (0.3) Cardio-respiratory arrest 10 (0.5) 7 (0.4) Nausea 8 (0.4) 0 Death 6 (0.3) 12 (0.6) Hepatitis C 6 (0.3) 6 (0.3) Myocardial Infarction 5 (0.3) 3 (0.2) Multiple organ dysfunction 5 (0.3) 3 (0.2) syndrome Sudden death 5 (0.3) 3 (0.2) Hemorrhagic stroke 3 (0.2) 5 (0.3) Abbreviations: AE=adverse event; DD=dialysis-dependent; OT+28=on-treatment plus 28 days. Note: Safety Population, OT+28 analyses, DD Pool: Studies 002, 063, 064.

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7. DATA FROM SUPPORTIVE STUDY 610

7.1. General Safety Data from Supportive Study 610 The overall incidence of AEs observed in this study was comparable between treatment groups; 91.6% of patients in the roxadustat group and 92.5% of patients in the darbepoetin alfa group experienced AEs (Table 51). The incidence of SAEs was 64.7% in the roxadustat group versus 61.8% in the darbepoetin group; the incidence of AEs leading to death was 10.5% versus 11.6%, respectively. The percentage of patients with AEs leading to discontinuation was 7.7% in the roxadustat group compared to 3.8% in the darbepoetin group. Table 51: Study 610: Overview of Treatment-emergent Adverse Events and Death (Safety Analysis Set) Roxadustat Darbepoetin alfa N=323 N=293 Adverse Event 296 (91.6%) 271 (92.5%) Serious Adverse Event 209 (64.7%) 181 (61.8%) Adverse Event Leading to Death 34 (10.5%) 34 (11.6%) Adverse Event Leading to Withdrawal of Treatment 25 (7.7%) 11 (3.8%) The most common AEs were ESRD (33.4% in the roxadustat group vs 36.2% in the darbepoetin group), hypertension (29.7% vs 33.8%), decreased glomerular filtration rate (17.0% vs 16.7%), edema peripheral (15.2% vs 12.3%), and hyperkalemia (11.8% vs 14.3%) (Table 52).

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Table 52: Study 610: Treatment-Emergent Serious Adverse Events (Safety Analysis Set) Roxadustat Darbepoetin alfa N=323 N=293

Preferred Term n (%) n (%) End-stage renal disease 108 (33.4) 106 (36.2) Hypertension 96 (29.7) 99 (33.8) Glomerular filtration rate decreased 55 (17.0) 49 (16.7) Oedema peripheral 49 (15.2) 36 (12.3) Hyperkalemia 38 (11.8) 42 (14.3) Nausea 35 (10.8) 25 (8.5) Viral upper respiratory tract infection 29 (9.0) 25 (8.5) Diarrhea 28 (8.7) 30 (10.2) Hyperphosphatemia 28 (8.7) 15 (5.1) Pneumonia 25 (7.7) 22 (7.3) Muscle spasms 25 (7.7) 15 (5.1) Dyspnea 24 (7.4) 12 (4.1) Bronchitis 22 (6.8) 18 (6.1) Constipation 21 (6.5) 15 (5.1) Vomiting 21 (6.5) 19 (6.5) Urinary tract infection 21 (6.5) 27 (9.2) Iron deficiency 21 (6.5) 25 (8.5) Headache 21 (6.5) 12 (4.1) Back pain 20 (6.2) 17 (5.8) Pruritus 20 (6.2) 13 (4.4) Insomnia 19 (5.9) 8 (2.7) Anemia 14 (4.3) 19 (6.5) Atrial fibrillation 18 (5.6) 12 (4.1) Cardiac failure 18 (5.6) 18 (6.1) Arthralgia 18 (5.6) 14 (4.8) Dizziness 16 (5.0) 15 (5.1) Abbreviations: N=number of patients in treatment group; n=number of patients with specified adverse event. Note: incidence ≥ 5% in either group. The overall incidence of AEs leading to treatment discontinuation was higher in roxadustat- treated patients: 7.7% in the roxadustat group vs 3.8% in the darbepoetin group. ESRD was

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8. DATA FROM SUPPORTIVE STUDY 613

8.1. Efficacy Data from Supportive Study 613 A total of 838 patients were randomized into the study. All data from site 70051 (2 randomized patients) are excluded due to Good Clinical Practice violations. Therefore, a total of 836 patients were considered as ITT for statistical analysis, 415 to the roxadustat treatment group and 421 to the ESA group. Of these patients, a total of 834 patients (414 roxadustat, 420 ESA) who received at least one dose of study drug, were included in the Safety Population. A total of 833 patients (413 roxadustat, 420 ESA) received at least one dose of study drug and had baseline and at least one post-dose Hb assessment were included in the FAS population. Baseline demographics in the Safety Population were notable, as the majority of patients receiving hemodialysis (91.5% vs 96.4%, respectively), with a median time since first dialysis of 2.89 and 2.97 years, respectively. Duration of exposure was comparable between the roxadustat group and ESA group (median: 103.71 weeks in roxadustat vs, 103.14 in ESA). Total PEY was 637.2 for roxadustat vs 719.7 for ESA. In general, the efficacy data from Study 613 was consistent with other pivotal studies (Studies 063, 064 and 002). Primary Endpoint: Mean Change in Hb from Baseline to Mean Over Weeks 28 to 52 The LSMean of the treatment difference between roxadustat and ESA was 0.171 (95% CI: 0.082, 0.261). IV Iron Supplementation Mean monthly IV iron use was 12.0 mg in the roxadustat treatment group compared with 44.8 mg in the ESA group. The LSMean difference for roxadustat vs ESA was -31.9 mg (95% CI: -41.4, -22.4); this difference was statistically significant (p < 0.001), which was consistent with other individual studies. RBC Transfusion 9.4% roxadustat-treated patients vs 12.9% ESA-treated patients received RBC transfusion with a HR of 0.867 (95% CI: 0.573, 1.313) in FAS during the efficacy emergent period (up to OT+7), demonstrating the non-inferiority between roxadustat and ESA.

8.2. Cardiovascular Safety Data from Supportive Study 613 Study 613 was an open-label Phase 3 DD CKD study with an active comparator group that was unique in the use of 2 different ESAs, EPO or darbepoetin alfa, as active controls; therefore, the CV safety data from this study are not included in the pooled CV safety DD CKD analyses. Baseline demographics are shown in Table 54. Please see the Executive Summary (Section 1.1) for a review of the design and limitations of Study 613.

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Table 54: Study 613: Demographics and Baseline Characteristics Parameter Subgroup: Darbepoetin Subgroup: Epoetin Roxadustat Darbepoetin Roxadustat Epoetin Alfa Alfa (n=158) (n=163) (n=256) (n=257) Sex, male, n (%) 97 (61.4) 98 (60.1) 148 (57.8) 137 (53.3) Race, White, n (%) 153 (96.8) 156 (95.7) 252 (98.4) 251 (97.7) Age, years, mean (SD) 61.1 (14.3) 61.8 (12.6) 61.0 (13.6) 61.9 (14.0) Weight, kg, mean (SD) 76.27 (15.75) 76.70 (16.65) 76.30 (15.99) 75.84 (17.65) BMI, kg/m2, mean (SD) 26.70 (4.81) 26.81 (5.30) 26.97 (4.89) 27.05 (5.78) Hb, g/dL, mean (SD) 10.70 (0.60) 10.74 (0.64) 10.78 (0.63) 10.80 (0.61) LDL cholesterol, mmol/L, n (%) ≤ ULN 86 (54.4) 92 (56.4) 123 (48.0) 140 (54.5) > ULN 72 (45.6) 71 (43.6) 133 (52.0) 117 (45.5) Previous ESA dose/week, n (%) < 25 µg darbepoetin alfa or < 5000 IU 96 (60.8) 86 (52.8) 126 (49.2) 103 (40.1) epoetin 25 to < 40 µg darbepoetin or 5000 to 40 (25.3) 56 (34.4) 71 (27.7) 77 (30.0) < 8000 IU epoetin 40 to < 80 µg darbepoetin or 8000 to 20 (12.7) 21 (12.9) 57 (22.3) 72 (28.0) < 16000 IU epoetin ≥ 80 µg darbepoetin or ≥ 16000 IU 2 (1.3) 0 2 (0.8) 5 (1.9) epoetin Baseline dialysis type, n (%) Hemodialysis 134 (84.8) 150 (92.0) 245 (95.7) 255 (99.2) Peritoneal dialysis 24 (15.2) 13 (8.0) 11 (4.3) 2 (0.8) Baseline hsCRP, nmol/L, n (%) ≤ ULN 83 (52.5) 87 (53.4) 127 (49.6) 139 (54.1) > ULN 75 (47.5) 76 (46.6) 129 (50.4) 118 (45.9) Dialysis vintage, years Mean (SD) 3.89 (3.65) 4.76 (4.23) 4.63 (4.46) 3.67 (3.17) Median (min, max) 2.75 (0.38, 3.41 (0.33, 3.14 (0.35, 2.60 (0.34, 20.88) 20.86) 27.04) 17.36) Iron repletion at baseline, n (%) Ferritin ≥ 100 ng/mL and TSAT ≥ 20% 135 (85.4) 144 (88.3) 220 (86.3) 222 (86.4) Blood pressure, mmHg, mean (SD) Systolic 134.6 (16.9) 136.7 (19.3) 135.5 (18.0) 137.0 (18.7)

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Parameter Subgroup: Darbepoetin Subgroup: Epoetin Roxadustat Darbepoetin Roxadustat Epoetin Alfa Alfa Diastolic 75.5 (10.6) 74.6 (11.3) 75.1 (11.3) 74.1 (11.2) History of cardiovascular, 55 (34.8) 70 (42.9) 114 (44.5) 131 (51.0) cerebrovascular, or thromboembolic diseases, n (%) History of diabetes, n (%) 43 (27.2) 52 (31.9) 61 (23.8) 81 (31.5) Abbreviations: BMI=body mass index; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; hsCRP=high-sensitivity C-reactive protein; LDL=low-density lipoprotein; max=maximum; min=minimum; OT+28=on-treatment plus 28 days; SD=standard deviation; TSAT=transferrin saturation; ULN=upper limit of normal. Note: Safety Population; OT+28 analyses. Table 55 and Figure 71 show the CV safety data: MACE, MACE+, and ACM from Study 613 using the Cox proportional hazards model during OT+7 evaluation window. Table 55: Descriptive Statistics of MACE, MACE+, and ACM of Study 613 MACE MACE+ ACM OT+7 Roxadustat EPO / Darbe Roxadustat EPO / Darbe Roxadustat EPO / Darbe Study 613 (n=414) (n=420) (n=414) (n=420) (n=414) (n=420) Total PEY 637.2 719.7 637.2 719.7 637.2 719.7 # of patients with events 65 59 72 66 57 45 Incidence / 100 PEY 10.2 8.2 11.3 9.2 8.9 6.3 Abbreviations: ACM=all-cause mortality; Darbe=darbepoetin alfa; DD=dialysis-dependent; EPO=epoetin alfa; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalizations for unstable angina or congestive heart failure; OT+7=on-treatment plus 7 days; PEY=patient exposure years. Note: Study 0613: randomized patients who took any dose of study medication in the DD study 0613. Note: Active control is erythropoietin-stimulating agent: epoetin alfa or darbepoetin alfa.

Figure 71: Study 613: Forest Plot of MACE, MACE+, and ACM

Abbreviations: ACM=all-cause mortality; CI=confidence interval; DD=dialysis-dependent; ESA=erythropoiesis- stimulating agent; HR=hazard ratio; MACE=major adverse cardiovascular event (all-cause mortality, myocardial infarction, and stroke); MACE+=MACE, plus hospitalizations for unstable angina or congestive heart failure; OT+7=on- treatment plus 7 days. Note: Study 613: randomized patients who took any dose of study medication in the DD Study 613. Note: Active control is erythropoietin-stimulating agent: epoetin alfa or darbepoetin alfa. Note: OT+7.

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8.3. General Safety Data from Supportive Study 613 Study 613 general safety results were not pooled with the other Phase 3 pivotal dialysis studies as advised by FDA. The overall summary of AEs during the treatment period and within 28 days of the last dose of study medication are tabulated in Table 56. The overall incidence of AEs was similar between the treatment groups: 86.7% of patients in the roxadustat group and 86.0% in the ESA group. The percentage of patients with SAEs was 50.7% in the roxadustat group and 45.0% in the ESA group. The incidence of AEs leading to death was 16.2% in the roxadustat group compared to 13.1% in the ESA group. The percentage of patients with AEs leading to discontinuation of study medication was higher in the roxadustat group: 8.5% for roxadustat group vs 3.8% for ESA group. Table 56: Study 613: Overview of Adverse Events and Death Roxadustat ESA N=414 N=420 n (%) n (%) Any AE 359 (86.7) 361 (86.0) Serious AE 210 (50.7) 189 (45.0) AE leading to death 67 (16.2) 55 (13.1) AE leading to withdrawal of treatment 35 (8.5) 16 (3.8) Death during the safety emergent period (OT+28) 64 (15.5) 51 (12.1) Abbreviations: AE=adverse event; ESA=erythropoiesis-stimulating agent; N=number of patients in treatment group; n=number of patients with specified AE. The summary of AEs with ≥ 5% incidence during the treatment period and within 28 days of the last dose of study medication are tabulated in Table 57. The most common AEs were hypertension (17.9% in the roxadustat vs 18.8% in the ESA group), AVF thrombosis (12.1% vs 7.4%) [AVF site complication (5.6% vs 5.0%)], headache (8.7% vs 6.9%), diarrhea (8.5% vs 8.3%) and bronchitis (8.0% vs 6.9%).

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Table 57: Study 613: Roxadustat AEs (Incidence ≥ 5%) by Preferred Term Compared to Erythropoietin-Stimulating Agents Roxadustat ESA N=414 N=420 Preferred Term n (%) n (%) Any AEs 359 (86.7%) 361 (86.0%) Hypertension 74 (17.9%) 79 (18.8%) Arteriovenous fistula thrombosis 50 (12.1%) 31 (7.4%) Headache 36 (8.7%) 29 (6.9%) Diarrhea 35 (8.5%) 35 (8.3%) Bronchitis 33 (8.0%) 29 (6.9%) Hypotension 33 (8.0%) 27 (6.4%) Iron deficiency 30 (7.2%) 51 (12.1%) Nausea 29 (7.0%) 8 (1.9%) Viral upper respiratory tract infection 29 (7.0%) 39 (9.3%) Pneumonia 23 (5.6%) 27 (6.4%) Arteriovenous fistula site complication 23 (5.6%) 21 (5.0%) Hyperparathyroidism secondary 22 (5.3%) 16 (3.8%) Anemia 21 (5.1%) 16 (3.8%) Atrial fibrillation 20 (4.8%) 25 (6.0%) Muscle spasms 15 (3.6%) 33 (7.9%) Upper respiratory tract infection 14 (3.4%) 22 (5.2%) Fall 13 (3.1%) 21 (5.0%) Abbreviations: AE=adverse event; ESA=erythropoiesis-stimulating agent; N=number of patients in treatment group; n=number of patients with the specified event; OT+28=on-treatment plus 28 days. Note: Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary version 20.0. Note: Patients with more than one event in a category are counted only once for that category. Note: OT+28.

The overall incidence of AEs leading to treatment discontinuation was higher in the roxadustat-treated patients; 8.5% in the roxadustat vs 3.8% in the ESA group. Individual AE leading to treatment discontinuation preferred terms were uncommon, with only acute coronary syndrome (2 [0.5%] vs 0 patients), acute myocardial infarction (2 [0.5%] vs 1 [0.2%]), cardiac arrest (0 vs 3 [0.7%]), death (2 [0.5%] vs 1 [0.2%]), sudden death (3 [0.7%] vs 0), sepsis (2 [0.5%] vs 0) and anxiety (2 [0.5%] vs 0) occurring in more than 1 patient in either treatment group.

8.4. Safety Assessment of Specific Adverse Events from Supportive Study 613 Some imbalances in specific AEs were noted during the review of safety data from the NDD and DD pools (Section 1.6.3). Table 58 presents a summary of those AEs for Study 613. A

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9. SAFETY DATA FROM OTHER PHASE 3 CKD STUDIES A total of 16 Phase 3 studies have been completed. Three NDD (Studies 001, 060, 608) and 3 DD studies (Studies 002, 063, 064) have been pooled, respectively, and have been presented in this document. Safety data from 2 global studies (Studies 610 and 613) were considered supportive and have been presented in Section 7 and Section 8, respectively. This section provides a summary of safety data from the remaining 8 studies (3 NDD studies; 5 DD studies). These were local studies conducted in Japan and China to support regulatory approval in these 2 countries, respectively.

9.1. Japan Studies Six Phase 3 studies sponsored by Astellas Pharma were completed in Japan; 2 studies in NDD population (Studies 1517-CL-0310, 1517-CL-0314) and 4 studies in DD population (Studies 1517-CL-0302, 1517-CL-0307, 1517-CL-0308, 1517-CL-0312). A total of 1,028 patients have participated in these studies. The clinical study reports were submitted to the FDA.

9.1.1. Study 1517-CL-0310 (NDD) This was a Phase 3 randomized open-label, active-controlled study to evaluate the efficacy and safety of roxadustat in the treatment of anemia in patients with NDD CKD (N=332). The incidence of AEs was 78.6% (103/131 patients) in the roxadustat (comparative) group, 70.2% (92/131 patients) in the darbepoetin alfa (comparative) group, and 77.1% (54/70 patients) in the roxadustat (referential) group. AEs occurring in ≥ 5% of patients in any treatment group included nasopharyngitis, CKD, hyperkalemia, and hypertension. The incidence of all the events in the roxadustat (comparative) group was similar to or lower than that in the darbepoetin alfa (comparative) group. The incidence of SAEs was 17.6% in the roxadustat (comparative) group, 13.0% in the darbepoetin alfa (comparative) group, and 12.9% in the roxadustat (referential) group. In the roxadustat (comparative) group, no patients died during the study. Deaths were reported in 1 patient (due to gastrointestinal necrosis) in the darbepoetin alfa (comparative) group and 2 patients (due to PE and myocardial ischemia) in the roxadustat (referential) group. In conclusion, roxadustat was well-tolerated demonstrating an AE profile comparable to darbepoetin alfa.

9.1.2. Study 1517-CL-0314 (NDD) This was a Phase 3 randomized open-label, noncomparative study to evaluate the efficacy and safety of roxadustat in ESA-untreated patients with renal anemia (N=99). The incidence of AEs was 62.6% (62/99 patients) in total. The common (incidence ≥ 5%) AEs were nasopharyngitis (20.2%), hypertension (6.1%), and diarrhea and hyperkalemia (5.1% each). The incidence of serious AE was 11.1% (11/99 patients) in total. The incidence of AEs leading to withdrawal of treatment was 6.1% (6/99 patients) in total. The incidence of drug- related AEs leading to withdrawal of treatment was 2.0% (2/99 patients) in total. No deaths were observed. In conclusion, roxadustat was well-tolerated and was consistent with other completed studies.

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9.1.3. Study 1517-CL-0302 (DD) This was a Phase 3 randomized multicenter, open-label, non-comparative study of the treatment of anemia in patients with CKD (N=56). The overall incidence of AEs was 87.5% (49/56 patients). The incidence of AEs was similar between the roxadustat treatment groups based on dose. The most common (incidence ≥ 5%) AEs in all the treatment groups were nasopharyngitis, back pain, catheter site infection, diarrhea, vomiting, abdominal pain, conjunctivitis, constipation, nausea and pruritus. The incidence of these events except for back pain and conjunctivitis in the pooled ESA-treated group was higher than that in the pooled ESA-untreated group. All AEs in all the treatment groups were mild or moderate in severity. No severe AEs were reported in any treatment group and there were no deaths in this study. A SAE which occurred in 2 or more patients in total was peritonitis (3.6%, 2/56 patients). One patient taking pravastatin experienced serious AE of rhabdomyolysis which was assessed as possibly related to roxadustat. In addition, to the roxadustat and pravastatin, febuxostat was also considered a suspect medication. Overall, roxadustat was well-tolerated demonstrating an AE profile similar to the underlying population of patients with anemia and CKD.

9.1.4. Study 1517-CL-0307 (DD) This was a Phase 3 randomized multicenter, 2-arm parallel, double-blind, active comparator (darbepoetin alfa) conversion study of intermittent oral dosing of roxadustat in patients with DD CKD with anemia (N=303). The incidence of AEs was 86.0% (129/150 patients) in the roxadustat group and 82.9% (126/152 patients) in the darbepoetin alfa group. The most common (incidence ≥ 5% in any arm) AEs were nasopharyngitis, shunt stenosis, diarrhea, contusion and vomiting. Of these, the events occurring more frequently in the roxadustat group compared with the darbepoetin alfa group were nasopharyngitis and vomiting. The incidence of SAEs was 20.7% (31/150 patients) in the roxadustat group and 14.5% (22/152 patients) in the darbepoetin alfa group. SAEs observed in 2 or more patients in the roxadustat group were shunt stenosis (4.0%, 6/150 patients), shunt occlusion (2.0%, 3/150 patients), cellulitis and DVT (1.3%, 2/150 patients each). Two deaths (1.3%, 2/150) were reported in the roxadustat group. One in a 64-year-old male patient that was on dialysis for 41 years and had a medical history of acute pericarditis and chronic heart failure died from acute myocardial infarction; the second case in a 75-year-old male patient with a history of hypertension, angina pectoris, hyperkalemia, and dyslipidemia who died from cardio- pulmonary arrest due to congestive cardiac failure.

9.1.5. Study 1517-CL-0308 (DD) This was a Phase 3 multicenter, randomized, 2-arm, open-label study of intermittent oral dosing of roxadustat in erythropoiesis-stimulating agent-naive patients with DD CKD with anemia (N=75). The incidence of AEs was 86.5% (21/37 patients), 94.7% (36/38 patients), and 90.7% (68/75 patients) in the roxadustat 50 mg, 70 mg groups, and total, respectively. The most common (incidence ≥ 5%) AEs were nasopharyngitis (20.0%), dermatitis contact (13.3%), shunt occlusion (9.3%), constipation, shunt stenosis and hyperphosphatemia (6.7% each), and diarrhea, vomiting, eczema, contusion, back pain and insomnia (5.3% each). The incidence of SAEs was 29.3% (22/75 patients) in total. SAEs observed in more than 1 patient were shunt occlusion 6.7% (5/75 patients) and cardiac failure congestive 2.7% Page 141 of 154

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(2/75 patients). No deaths were observed. The 50 mg starting dose group tended to be associated in general with a numerically lower AE rate compared to the 70 mg starting dose group. In conclusion, roxadustat was well-tolerated demonstrating an AE profile similar to the underlying population of patients with anemia and CKD.

9.1.6. Study 1517-CL-0312 (DD) This was a long-term study of intermittent oral dosing of roxadustat in patients with DD CKD with anemia converted from ESA treatment (N=163). The overall incidence of AEs was 95.7% (156/163 patients) in total. The common (incidence ≥ 5%) AEs in total were nasopharyngitis (52.8%), diarrhea (11.0%), vomiting (10.4%), contusion (9.8%), shunt stenosis, back pain (7.4% each), constipation, shunt occlusion (6.1% each), dental caries, and headache (5.5% each). According to the analysis for onset of AEs by time interval, there was no increase in the incidence of AEs dependent on the roxadustat administration period. The incidence of SAEs was 28.2% (46/163 patients) in total. SAEs observed in 2 or more patients were shunt occlusion (5.5%, 9/163 patients), angina pectoris, pneumonia (1.8%, 3/163 patients each), myocardial ischemia, shunt stenosis, arteriogram coronary, skin ulcer, and peripheral arterial occlusive disease (1.2%, 2/163 patients each). The incidence of deaths was 1.2% (2/163 patients) in total, and no relationships with roxadustat were found. A 79- year-old male patient died of pancreatic carcinoma and 67-year-old male patient died of hemorrhagic shock which was attributed to bleeding from multiple gastric and duodenal ulcers. The cause of the ulcers was unknown; however, it was considered that sepsis had a major influence. In conclusion, roxadustat was well-tolerated demonstrating an AE profile similar to the underlying population of patients with anemia and CKD.

9.2. China Studies Two Phase 3 studies sponsored by FibroGen China were completed in China; one in NDD population (Study FGCL-4592-808) and one in DD population (Study FGCL-4592-806). A total of 456 patients have participated in these studies. The clinical study reports were submitted to the FDA.

9.2.1. Study FGCL-4592-808 (NDD) This Phase 3 randomized, multicenter, double-blind, placebo-controlled study of the treatment of anemia in patients with NDD CKD (N=152) had an 8-week double-blind treatment period with roxadustat or placebo, an 18-week open-label treatment period and an extension period for 26 additional weeks for the patients who were randomized to roxadustat. During the double-blind treatment period, 69 (68.3%) patients in the roxadustat arm and 38 (74.5%) patients in the placebo arm reported AEs. The most commonly reported AEs higher on the roxadustat treatment arm than placebo included hyperkalemia, metabolic acidosis, peripheral edema, and hypertension. There was no specific safety signal or clustering of SAEs detected in either arm, and no deaths were reported during this study period. During the 18-week open-label treatment period, a combined total of 112 (87.5%) patients reported AEs. The most commonly reported AEs were ESRD/CKD, hyperkalemia, hypertension, upper respiratory tract infection, and metabolic acidosis, events commonly

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Roxadustat FibroGen Cardiovascular and Renal Drugs Advisory Committee encountered in this patient population. A total of 33 patients (25.8%) reported at least one SAE during this period of the study. Two deaths (2.4%) were reported during this study period: a 69-year-old female developed a sudden loss of consciousness at home without complaints of discomfort prior to the event and died before reaching hospital and a 60-year-old female died from post-operative retroperitoneal hemorrhage secondary to a surgical complication. Both deaths were considered by the investigators as not related to study drug. In the 26-week extension period, 20 (87%) reported AEs. The most common AEs were hyperkalemia, metabolic acidosis, upper respiratory tract infection, hypertension, and iron deficiency. The AEs reported in the 52-week extension treatment period were similar to the initial treatment period. During the extension treatment period, 8 (34.8%) of patients reported treatment-emergent SAEs. No deaths occurred during the extension treatment period. Overall, roxadustat was evaluated to be safe and well-tolerated in this NDD patient population.

9.2.2. Study FGCL-4592-806 (DD) This Phase 3 randomized, multicenter, open-labeled, active-controlled study in patients with anemia associated with CKD who were on dialysis (N=304) had a 26-week treatment period and an extension period for up to 26 additional weeks for the patients who were randomized to roxadustat. During the initial treatment period, a total of 160 (78.4%) patients in the roxadustat arm reported AEs, while 64 (64.0%) in the EPO arm reported AEs. The most common AEs that were reported in greater proportion in the roxadustat arm over the EPO arm were events of upper respiratory tract infection, hyperkalemia, chest discomfort, vomiting, and asthenia. The roxadustat-treated patients reported a slightly higher proportion (15.7%, including 1.5% hospitalized for routine dialysis treatment) of SAEs compared to the EPO-treated patients (10.0%). However, there was no important safety signal detected in the roxadustat arm. Among 32 patients reported with SAEs in the roxadustat arm, 3 deaths occurred during the initial treatment period: a 65-year-old male died from an acute myocardial infarction, a 61-year-old male died from gastrointestinal hemorrhage and a 57-year-old female, died from cardiac failure. All 3 deaths were assessed by the investigators and by the Sponsor to be unrelated to study medication. In the extension treatment period, a total of 96 (86.5%) patients reported AEs, most of which were mild or moderate in severity. The most common AEs reported were upper respiratory tract infection (31.5%), hypertension (15.3%), and hyperkalemia (9.9%). Two deaths were reported: one 64-year-old male who died from gastrointestinal perforation prior to surgical intervention, and another 52-year-old female with a history of hypertension who died from cerebral hemorrhage. None of these 2 deaths were considered related to study drug. Seventeen (15.3%) patients reported SAEs, the most common being AVF site stenosis/thrombosis (5 patients) in hemodialysis patients. Two peritoneal dialysis patients reported peritonitis.

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Overall, roxadustat was considered to be safe and well-tolerated in this DD patient population.

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10. DISPOSITION TABLES A total of 4,270 eligible patients from the 3 pivotal Phase 3 studies were randomized to roxadustat (N=2,386) or placebo (N=1,884) and received at least 1 dose of study treatment. Substantially more patients in the placebo group discontinued study treatment prematurely compared to roxadustat. The main reasons for discontinuation were withdrawal by patient, AEs, and development of study specific discontinuation criteria related to requirement for rescue therapy (ie, RBC transfusion, ESA use, and IV iron supplementation) due to lack of efficacy of study drug (Table 59). These imbalances in disposition led to greater duration of treatment in the roxadustat group and retention of higher-risk patients (eg, those with low eGFR and those who required dialysis initiation) in the roxadustat group compared to the placebo group over time, leading to bias and confounding in on-treatment safety analyses.

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Table 59: Pooled NDD Studies: Reasons for Discontinuation NDD (Studies 608, 060, 001) Roxadustat Placebo ITT Population 2391 1886 Main Reasons for Discontinuation, n (%): Adverse Event 150 (6.3) 83 (4.4) Deathb 81 (3.4) 30 (1.6) Development of Study Specific Discontinuation Criteriaa 76 (3.2) 252 (13.4) Dialysis Initiation 23 (1.0) 11 (0.6) Kidney Transplant 24 (1.0) 9 (0.5) Lack of Efficacy 7 (0.3) 74 (3.9) Lost to Follow-up 33 (1.4) 8 (0.4) Non-compliance to Protocol 23 (1.0) 20 (1.1) Not Reported 2 (0.1) 3 (0.2) Physician Decision 49 (2.1) 67 (3.6) Pregnancy 1 (0.0) 0 Site Terminated by Sponsor 2 (0.1) 1 (0.1) Study Terminated by Sponsor 2 (0.1) 0 Patient Decision 250 (10.5) 390 (20.7) Patient Relocated/Moved (or Lost to Follow-up) 6 (0.3) 10 (0.5) Withdrawal by Parent/Guardian 1 (0.0) 1 (0.1) Withdrawal by Patient 143 (6.0) 143 (7.6) Other 28 (1.2) 13 (0.7) Abbreviations: ITT=intent-to treat; NDD=non-dialysis-dependent. a In Study 001, patients reported “study specific discontinuation criteria” were patients who were discontinued from study drug for initiating dialysis during the study, and for whom there was a need for rescue with erythropoietin analogue. b In Table 36 in Section 6.4.1 patients who died while on treatment were considered to have completed treatment and completed the study. A total of 1943 patients were randomized in the roxadustat group and 1947 in the EPO group for a total of 3,890 patients who were included in the ITT set. A total of 1940 patients in each group received at least 1 dose of study drug and were included in the Safety Analysis Set. The ID-DD subpopulation consisted of 1,530 patients, and the SDD subpopulation consisted of 2,360 patients. The main reasons for premature treatment discontinuation were withdrawal by patient, AEs, death, and kidney transplant (Table 60).

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Table 60: Pooled DD Studies: Patient Disposition DD Pool ID-DD Pool SDD Pool Roxa Epoetin Roxa Epoetin Roxa Epoetin ITT Population 1943 1947 760 770 1183 1177 Reasons for discontinuation, n (%) Withdrawal by patient 213 (11.0) 166 (8.5) 56 (7.3) 62 (8.1) 157 (13.4) 104 (8.9) Adverse event 110 (5.7) 54 (2.8) 35 (4.6) 25 (3.3) 75 (6.4) 29 (2.5) Deatha 141 (7.3) 129 (6.6) 69 (9.1) 61 (8.0) 72 (6.1) 68 (5.8) Kidney transplant 115 (5.9) 147 (7.6) 26 (3.4) 33 (4.3) 89 (7.5) 114 (9.7) Abbreviations: DD=dialysis-dependent; ID-DD=incident dialysis-dependent; ITT=intent-to-treat; SDD=stable dialysis- dependent; Roxa=roxadustat. a In Table 40 in Section 6.4.2 patients who died while on treatment were considered to have completed treatment and completed the study. Note: Intent-to-treat analysis set.

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11. DOSE MODIFICATION MODEL Figure 72: Roxadustat Starting Dose Modifications

Abbreviations: Dcal=depletion calibration; EC50=concentration that achieves 50% of the effect; EMAX=maximum effort; HB=hemoglobin; Kee=roxadustat elimination rate constant; Khb=rate constant for elimination of Hb; Kp=precursor production rate constant; Prec=Hb precursor; Roxa=roxadustat.

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