Update on Randomized Clinical Trials in Anemia 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 Roxadustat: 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 Vadadustat Akebia/Mitsubishi Tanabe Pharma AKB-6548 Expected to be approved in Japan in 2020 Daprodustat GSK/Kirin GSK-1278863 Expected to be approved in Japan in 2020 Molidustat Bayer BAY 85-3934 Phase III Enarodustat Japan Tobacco Inc JTZ-951 KDIGO Phase III Desidustat 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 • 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 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 Hemoglobin 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.