Update on Randomized Clinical Trials in of CKD KDIGO Chuan-Ming Hao Division of Nephrology, Huashan Hospital Fudan University DISCLOSURES

• Honoraria from FibroGen and AstraZeneca

KDIGO Content • HIF-PHD as a target for CKD anemia treatment • HIF-PHI : data from China phase 3 trials • HIF-PHI Roxadustat: data from global phase 3 trials KDIGO PHI KDIGO Erythropoiesis Angiogenesis Glycolysis … PHD as a Target to Stabilize HIF

KDIGO

Holt-Martyn JP, et al. Medchemcomm. 2019,10(4):500-504 PHI as New Treatment for CKD Anemia

Compound Company Development status Roxadustat FibroGen/Astra Zeneca Approved in China and Japan FG-4592 Akebia/Mitsubishi Tanabe Pharma AKB-6548 Expected to be approved in Japan in 2020 GSK/Kirin GSK-1278863 Expected to be approved in Japan in 2020 Bayer BAY 85-3934 Phase III Japan Tobacco Inc JTZ-951 KDIGO Phase III Cadila Healthcare Ltd ZYAN1 Phase III DDO-3055 Hengrui Medicine Phase I HEC53856 HEC Phase I HIF-117 3SBIO INC Phase I Content • HIF-PHD as a target for CKD anemia treatment • HIF-PHI Roxadustat: data from China phase 3 trials • HIF-PHI Roxadustat: data from global phase 3 trials KDIGO Roxadustat for NDD CKD : Study Design Phase 3, randomized, double-blind, placebo-controlled study

• Key inclusions: • Key exclusions: − CKD Stages 3-5 − Clinically significant infection − Age 18-75 years − Uncontrolled hypertension − Screening Hb 7.0-10.0 g/dL − Renal cell carcinoma − No ESA for at least 5 weeks − GI bleeding − IV iron during the screening and KDIGO/or unwilling to withhold IV iron

Non-dialysis Patients Study 808

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Roxadustat for NDD CKD : Study Design

Phase 3, randomized, double-blind, placebo-controlled study • Key inclusions: • Key exclusions: − CKD Stages 3-5 − Clinically significant infection − Age 18-75 years − Uncontrolled hypertension − Screening Hb 7.0-10.0 g/dL − Renal cell carcinoma − No ESA for at least 5 weeks − GI bleeding − IV iron during the screening and KDIGO/or unwilling to withhold IV iron Roxadustat Non-dialysis (N=101) Patients Placebo (N=51) Study 808

8-week primary endpoint

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Roxadustat for NDD CKD : Study Design

Phase 3, randomized, double-blind, placebo-controlled study • Key inclusions: • Key exclusions: − CKD Stages 3-5 − Clinically significant infection − Age 18-75 years − Uncontrolled hypertension − Screening Hb 7.0-10.0 g/dL − Renal cell carcinoma − No ESA for at least 5 weeks − GI bleeding − IV iron during the screening and KDIGO/or unwilling to withhold IV iron Roxadustat (N=101) Non-dialysis Patients Placebo (N=51) Roxadustat (n=43) Study 808

8-week primary endpoint 26-week

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Roxadustat for NDD CKD: Baseline Characteristics

Category Roxadustat (N=101) Placebo (N=51) Hb (g/L), Mean (SD) 88.7 (8.1) 89.3 (7.3) ≥80 g/L, n (%) 84 (83.2) 44 (86.3) <80 g/L, n (%) 17 (16.8) 7 (13.7) Years of CKD, Mean (SD) 5.3 (7.1) 4.2 (4.6) Most Common CKD Etiologies, n (%) Diabetic Nephropathy 17 (16.8) 13 (25.5) Glomerulonephritis Unspecified 40 (39.6) 20 (39.2) Hypertensive Nephropathy 15 (14.9) 7 (13.7) IgA Nephropathy 10 (9.9) 4 (7.8) Other 13 (12.9) 7 (13.7) eGFR (mL/min/1.73 m2), Mean (SD) 16.5 (8.0) 14.5 (7.6) <10, n (%) 18 (17.8) 19 (37.3) 10 - 20, n (%) 54 (53.5) 21 (41.2) ≥20, n (%) KDIGO29 (28.7) 11 (21.6) TSAT (%), Mean (SD) 20.6 (9.2) 23.0 (11.1) ≥20% 52 (51.5) 30 (58.8) <20% 49 (48.5) 21 (41.2) Ferritin (µg/L), Mean (SD) 191.4 (200.5) 266.2 (236.7) ≥200 35 (34.7) 23 (45.1) 100 - 200 24 (23.8) 14 (27.5) <100 42 (41.6) 14 (27.5) CRP, n (%) ≤ULN (4.9 mg/L) 89 (88.1) 46 (90.2) >ULN (4.9 mg/L) 12 (11.9) 5 (9.8) Roxadustat for NDD CKD: Primary Endpoint

Primary endpoint: mean Hb change from baseline averaged over Weeks 7 to 9

FAS: Roxadustat Placebo Mean (SD) Hb Values (g/dL) (n=101) (n=51)

Baseline Hb 88.7 (8.1) 89.3 (7.3) Week 7-9 Hb KDIGO108.3 (13.9) 85.4 (9.8) Change from Baseline 19.0 (11.8) -3.9 (7.9) Treatment Difference LSMean (SE) [CI] 22.5 (1.88) [18.8, 26.2] p-value/Superiority Comparison <0.000000000000001

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Hb Levels throughout Entire Treatment Period

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Effect of Roxadustat on Iron Homeostasis:NDD (Study 808)

Iron（μmol/L) Transferrin (g/L) TIBC (μmol/L) TSAT (%) Ferritin (μg/L)

0 0.8 20 0 0 0.73 18.2 -0.1 0.7 -10 -1 15 -20 -0.2 0.6 -30 -21.9 -0.24 0.5 -2 -1.7 -0.3 10 -40 0.4 -3 -50 -0.4 -60 0.3 5 -4 -70 -0.5 0.2 KDIGO -80 -0.6 0.1 0 -5 -0.33 -90 -0.64 0 -5.2 -100 -93.3 -0.7 -0.01 -5 -6 -0.1

Roxadustat Placebo Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Effect of Roxadustat on Hepcidin:NDD (Study 808)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Roxadustat for Dialysis Dependent (DD) CKD Anemia : Study Design Phase 3, randomized, open-labeled, active-controlled study

Key Inclusion Criteria Key Exclusion Criteria • Ages 18-75 years • CHF (NYHA Class III or IV) • CKD with ESRD on either HD or PD for ≥16 • ACS, stroke, seizure, or a thromboembolic event 52 weeks weeks prior to Day 1 • Stable epoetin alfa for ≥6 weeks (average dose • Uncontrolled hypertension ≤15,000 IU/week) • Recent history of malignancy • Mean of 2 most recent Hb values during • transfusion within 12 weeks prior to Day 1 or screening obtained ≥6 weeks apart must have anticipated need for transfusion been 9.0-12.0 g/dL with a difference of KDIGO≤1.5 g/dL • IV iron during screening/or unwilling to withhold IV iron

Dialysis Patients Study 806 Roxadustat for Dialysis Dependent (DD) CKD Anemia : Study Design Phase 3, randomized, open-labeled, active-controlled study

Key Inclusion Criteria Key Exclusion Criteria • Ages 18-75 years • CHF (NYHA Class III or IV) • CKD with ESRD on either HD or PD for ≥16 • ACS, stroke, seizure, or a thromboembolic event 52 weeks weeks prior to Day 1 • Stable epoetin alfa for ≥6 weeks (average dose • Uncontrolled hypertension ≤15,000 IU/week) • Recent history of malignancy • Mean of 2 most recent Hb values during • Blood transfusion within 12 weeks prior to Day 1 or screening obtained ≥6 weeks apart must have anticipated need for transfusion been 9.0-12.0 g/dL with a difference of KDIGO≤1.5 g/dL • IV iron during screening/or unwilling to withhold IV iron

Roxadustat (N=204) Dialysis Patients

Study 806 Epoetin Alfa (N=100)

26-week primary endpoint Mean Levels over Time: DD (Study 806)

KDIGO

Chen N, Hao C, et al. N Engl J Med. DOI:10.1056/NEJMoa1813599. Chen N, Hao C, Liu B-C, et al. N Engl J Med. DOI:10.1056/NEJMoa1901713. Iron Profile after Roxadustat Treatment: DD (Study 806)

Iron Transferrin 2 0.5

1 0.4

0 0.3 P<0.01 -1 0.2

-2 0.1 P<0.01 -3 0

-4 -0.1

-5 -0.2 Roxadustat Epoetin Roxadustat Epoetin

TSAT 0 Ferritin KDIGO0 -2 -20 -4 -40 -60 -6 -80 P<0.01 -100 -8 -120 -10 -140 Roxadustat Epoetin Roxadustat Epoetin

Chen N, Hao C, et al. N Engl J Med. DOI:10.1056/NEJMoa1813599. Chen N, Hao C, Liu B-C, et al. N Engl J Med. DOI:10.1056/NEJMoa1901713. Effect of Roxadustat on Hb in DD Patients with High CRP Study 806

KDIGO

Chen N, Hao C, et al. N Engl J Med. DOI:10.1056/NEJMoa1813599. Chen N, Hao C, Liu B-C, et al. N Engl J Med. DOI:10.1056/NEJMoa1901713. Change of Hepcidin Levels from Baseline at Week 27 (Study 806)

Roxadustat ESA

KDIGO

Chen N, Hao C, Liu B-C, et al. N Engl J Med. DOI:10.1056/NEJMoa1901713. Roxadustat Reduces Blood Lipid Levels

KDIGO

N Engl J Med. 2019 Jul 24. doi: 10.1056/NEJMoa1901713. Effect of Roxadustat on Blood Pressure: DD

ROXA EPOTIN

KDIGO

N Engl J Med. 2019 Jul 24. doi: 10.1056/NEJMoa1901713. Adverse Events:NDD (Study 808)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Serious Adverse Events: NDD

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Adverse Events:DD (Study 806)

KDIGO Serum Potassium Levels in Non-dialysis Patients (central laboratory measures)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Serum Potassium Levels in Non-dialysis Patients (central laboratory measures)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Serum Potassium Levels in Non-dialysis Patients (central laboratory measures)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Serum Potassium Levels in Dialysis Patients (central laboratory measures)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Serum Bicarbonate throughout Entire Treatment Period (central laboratory measures)

KDIGO

Chen N, Hao CM, et al. N Engl J Med. 2019 Jul 24. Content • HIF-PHD as a target for CKD anemia treatment • HIF-PHI Roxadustat: data from China phase 3 trials • HIF-PHI Roxadustat: data from global phase 3 trials KDIGO Roxadustat Global Phase 3 Studies Efficacy and Pooled Cardiovascular Safety Endpoints • Efficacy endpoints: • Primary efficacy endpoint in individual studies and pooled analyses • Pooled efficacy results: potential clinical benefits differentiated from current standard of care • Safety: • Cardiovascular (CV) safety endpoints in NDD pool and in DD pool • Other safety findings have beenKDIGO summarized in individual study presentations in other sessions Roxadustat NDD and DD Program Phase 3 CKD non-dialysis-dependent (NDD) Pool D5740C00001 FGCL-4592-060 1517-CL-0608 NDD Pooled OLYMPUS ANDES ALPS Number of patients: 4277 AstraZeneca FibroGen Astellas Roxa Placebo N=2761 N=922 N=594 N=2391 N=1886 Patient exposure years: 6194 1.62 1.23 R 1:1 R 2:1 R 2:1 Avg PEY Avg PEY Phase 3 CKD dialysis-dependent (DD) Pool D5740C00002 FGCL-4592-064 FGCL-4592-063 DD Pooled ROCKIES SIERRAS HIMALAYAS AstraZeneca FibroGen FibroGenKDIGORoxa EPO Global US only Global Number of patients: 3880 N=2106 N=741 N=1043 N=1943 N=1947 Patient exposure years: 7059 R 1:1 R 1:1 R 1:1 Correction & Correction 1.71 1.92 Maintenance maintenance DD Vintage<4mos Only Avg Avg Early & Stable DD Early & Stable DD (Early) PEY PEY

2019 ASN Late Break Clinical Trials NDD Efficacy: Met Primary Efficacy Endpoint

KDIGO

2019 ASN Late Break Clinical Trials DD: Roxadustat Efficacious

KDIGO

2019 ASN Late Break Clinical Trials Roxadustat is superior to placebo regardless of iron-repletion

KDIGO

*Iron Replete: TSAT ≥20% and ferritin ≥100 ng/mL Roxadustat Efficacious Regardless of Inflammation

KDIGO DD: Less Monthly IV Iron Use in Roxadustat Patients Than in Epoetin Alfa Patients

KDIGO

2019 ASN Late Break Clinical Trials Effect of Roxadustat on Decline of eGFR in NDD

KDIGO Cardiovascular Safety Endpoint Pooled Analyses Key safety endpoints: Time to first MACE ØMACE (Major Adverse Cardiovascular Events): ü all-cause mortality ü myocardial infarction ü Stroke Time to first MACE+ KDIGO ØMACE+: ü MACE ü unstable angina requiring hospitalization *CV events were centrally adjudicated by independent experts blinded to treatment assignment ü congestive heart failure requiring hospitalization Time to all-cause mortality 2019 ASN Late Break Clinical Trials NDD Pool: Cardiovascular Safety Endpoints

KDIGO

*”comparable” based on hazard ratio (HR) upper bound of 95% confidence interval (95%CI) below reference non-inferiority margin of 1.3 **ITT analysis = Intent to treat analysis evaluation period to include on-treatment and off-treatment long term follow-up, until end of study DD Pooled: Cardiovascular Safety Endpoints

KDIGO

*“risk not increased” based on hazard ratio (HR) upper bound of 95% confidence interval (95%CI) below reference non-inferiority margin of 1.3. †On-treatment analysis 2019 ASN Late Break Clinical Trials Incident Dialysis Pool: Cardiovascular Safety Endpoints

KDIGO

2019 ASN Late Break Clinical Trials KDIGO Summary

• HIF-PHI Roxadustat is effective in treating CKD anemia • Its effect is not dependent on iv iron or less iv iron is required compared to ESA • Roxadustat is effective in inflammatory status • Safety: non-inferior in MACE compared to placebo or ESA in NDD and DD; Superior in MACEKDIGO in incident dialysis patients Acknowledgement Investigators (alphabetical order)

KDIGO All staffs who worked for the trials All patients who participated the trials Sponsor: Fibrogen

Astra Zeneca