Article Efficacy and Safety of Daprodustat Compared

CJASN ePress. Published on July 28, 2020 as doi: 10.2215/CJN.16011219 Article

Efﬁcacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia A Randomized, Double-Blind, Phase 3 Trial

1 2 3 3 4 5 Tadao Akizawa, Masaomi Nangaku, Taeko Yonekawa, Nobuhiko Okuda, Shinya Kawamatsu, Tomohiro Onoue, 1 3 6 7 Division of Yukihiro Endo, Katsutoshi Hara, and Alexander R. Cobitz Nephrology, Showa University School of Abstract Medicine, Tokyo, Japan Background and objectives Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that 2 fi Division of stimulates erythropoiesis and regulates genes related to iron metabolism. The ef cacy (noninferiority) and safety Nephrology and of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. Endocrinology, Graduate School of Design, setting, participants, & measurements This was a randomized, phase 3, double-blind, active-control study Medicine, The ’ University of Tokyo, in Japanese patients receiving hemodialysis with anemia of CKD. Participants treatment was switched from Tokyo, Japan – m 3 currenterythropoiesis-stimulating agents (ESAs) to daprodustat4 mg once dailyordarbepoetinalfa 10 60 gonce Medicines weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks Development, Japan for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin Development, during weeks 40–52 in the intent-to-treat population. GlaxoSmithKline, Tokyo, Japan 4Clinical Operations, Results Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; Japan Development, efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40–52 were maintained GlaxoSmithKline, within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for Tokyo, Japan 5Biomedical Data daprodustat,and10.8 g/dl [95% CI,10.7 to 11.0] for darbepoetin alfa). Daprodustatwas noninferiorto darbepoetin fi 2 Sciences, Japan alfa, as the lower bound of the con dence interval for the treatment difference (0.1 g/dl; 95% CI, 0.1 to 0.2 g/dl) Development, was greater than the noninferiority criterion of 21.0 g/dl. For most participants, hemoglobin was maintained GlaxoSmithKline, – – Tokyo, Japan within the target range (10.0 12.0 g/dl) during weeks 40 52 (88% daprodustat; 90% darbepoetin alfa). Geometric 6 mean hepcidin levels decreased more at week 52 with daprodustat (237%; 95% CI, 249 to 223) than with Clinical 2 2 2 Pharmacology, Japan darbepoetin alfa ( 20%; 95% CI, 36 to 1), and an increase in total iron-binding capacity was observed in the Development, daprodustat group. Frequency of adverse events were generally similar between daprodustat and GlaxoSmithKline, darbepoetin alfa. Tokyo, Japan 7Medicine Delivery, GlaxoSmithKline, Conclusions Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks – Collegeville, 40 52 in Japanese patients receiving hemodialysis switched from ESAs. Pennsylvania

Clinical Trial registry name and registration number 201754, Clinicaltrials.gov, NCT02969655. Correspondence: CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.16011219 Ms. Taeko Yonekawa, Medicines Development, Japan Development, Introduction used, or the inability to achieve target hemoglobin GlaxoSmithKline, 1-8- Anemia is a common complication of CKD, caused by levels. Hypoxia-inducible factor-prolyl hydroxylase 1 Akasaka, Minato-ku, multiple factors including erythropoietin deﬁciency Tokyo 107-0052, inhibitors (HIF-PHIs) are a class of therapeutic agents Japan. Email: taeko. and reduced iron availability (1,2). Erythropoiesis- being developed for the treatment of anemia of CKD [email protected] stimulating agents (ESAs) are used to treat anemia as (9). In phase 2 studies, the HIF-PHI daprodustat standard of care along with iron supplementation (0.5–25 mg once daily) achieved and maintained (intravenous [IV] or oral) (3,4). However, treatment target hemoglobin levels in patients receiving and with ESAs has been associated with higher risk of not receiving dialysis, with anemia of CKD (10–12). major cardiovascular events and exacerbation of A phase 3 trial in Chinese patients on dialysis reported hypertension when treating to higher hemoglobin that another HIF-PHI, roxadustat, administered targets than recommended (5–8). It remains unclear three times a week for 27 weeks was noninferior whether the risk is related to the hemoglobin levels to erythropoietin with regard to mean change in achieved, the rapid hemoglobin rise, the dose of ESA hemoglobin (13). www.cjasn.org Vol 15 August, 2020 Copyright © 2020 by the American Society of Nephrology 1 2 CJASN

In this phase 3 study, we tested the hypothesis that Study Treatments daprodustat is noninferior to darbepoetin alfa in main- Participants randomized to daprodustat received orally taining hemoglobin levels in Japanese patients on he- administered daprodustat once daily and IV darbepoetin modialysis with anemia of CKD currently being treated alfa matching placebo once weekly. On day 1, treatment with an ESA. The 1-year safety of daprodustat was with 4 mg daprodustat was started. From week 4 onward, also evaluated. the dose was adjusted every 4 weeks within the range of 1–24 mg according to a prespecified dose adjustment algorithm (Supplemental Table 1) to achieve and/or main- Materials and Methods tain hemoglobin within the target range (10.0–12.0 g/dl), Study Design using HemoCue hemoglobin values. This was a phase 3, double-blind, active-controlled, Participants randomized to darbepoetin alfa received parallel-group study to evaluate the efficacy (noninfer- oral daprodustat matching placebo once daily and IV iority) and safety of daprodustat compared with darbe- darbepoetin alfa once weekly. On day 1, darbepoetin alfa poetin alfa for 52 weeks in Japanese patients on treatment was started at a corresponding dose to the prior hemodialysis with anemia of CKD currently treated ESA. From week 2 onward, the dose was adjusted every with ESAs (Clinicaltrials.gov identifier NCT02969655, 2 weeks (on the basis of the Japanese label for darbepoetin registered November 21, 2016). The study was conduc- alfa) within the range of 10–60 mg, according to a prespe- ted between November 21, 2016 and July 2, 2018, with cified dose adjustment algorithm using HemoCue hemo- recruitment from the beginning of the study to May 30, globin values (Supplemental Table 2). 2017, at 50 centers in Japan, and included a 2- to 4-week Daprodustat could be administered without regard to screening period, a 52-week treatment phase, and a food or hemodialysis. Gemfibrozil and rifampin were 2-week follow-up period. The primary efficacy evalua- excluded medications from screening to 7 days after tionperiodwasweeks40–52. No interim analysis treatment completion. In both groups, IV iron or dose was planned. change for oral iron were not allowed from screening to The study was approved by the ethics committee at week 4. From week 4 onward, supplemental iron every participating institution and was conducted accord- therapy including IV and oral could be administered if ing to the recommendations of Good Clinical Practice and ferritin was #100 ng/ml and TSAT was #20%, accord- the Declaration of Helsinki. All participants provided ingtotheJapaneseSocietyforDialysisTherapyguide- written informed consent. lines for anemia in CKD (14).

Eligibility Criteria Study End Points Patients aged $20 years who were on three times The primary end point was mean hemoglobin during weekly hemodialysis or hemodiafiltration for $12 weeks the primary efficacy evaluation period (weeks 40–52). before screening were included. Additional eligibility The principal secondary end point was the percentage of criteria included use of the same ESA (darbepoetin alfa participants with mean hemoglobin within target range 10–60 mg per week, epoetin [including biosimilars] during the primary efficacy evaluation period. Additional #9000 IU per week, or epoetin beta pegol #250 mgper secondary end points included change from baseline and 4 weeks) for $10 weeks before screening; hemoglobin mean hemoglobin at each assessment visit. Exploratory levels $9.5 g/dl and #12.5 g/dl, as determined by a end points included iron use during the treatment period hemoglobin analyzer (HemoCue) at the study site; and and change from baseline in iron parameters (ferritin, ferritin .100 ng/ml or transferrin saturation (TSAT) TSAT, hepcidin, total iron-binding capacity [TIBC], and .20% at screening. The completeinclusion,exclusion, serum iron). and study medication stopping criteria are listed in Safety assessments included adverse events (AEs), Supplemental Appendix 1. serious adverse events (SAEs), AEs of special interest, laboratory evaluations, and vital signs. AEs of special interest were defined apriorion the basis of nonclinical Randomization and Intervention studies of daprodustat, theoretical or potential risks related Patients who met all eligibility criteria at the start of to the mechanism of action of daprodustat, and the known treatment (day 1) were randomized at a 1:1 ratio to receive safety profile of ESAs. An internal Safety Review Team daprodustat or darbepoetin alfa. A biostatistician gener- conducted periodic case reviews in a blinded manner to ated the randomization codes using a company-validated evaluate which events constituted a potential “AE of special system. The system concealed the actual randomization interest.” Comprehensive ophthalmologic exams (best cor- codes until unblinding. A random permutation of treat- rected visual acuity, intraocular pressure, anterior segment ment assignments within blocks (block size was set to 4) examination, and funduscopic examination) were conduc- was used for the randomization sequence. The investi- ted in a blinded manner by a study-designated ophthal- gational products containers were also randomized mology specialist at baseline, week 12, and week 48 to independently of the treatment randomization by a support assessment of ocular AEs of special interest. third-party vendor with no clinical involvement in the study. At each dispensing visit, the investigators ac- cessed the Interactive Web Response System to obtain a Statistical Analyses particular container in a blinded manner and assigned Assuming a noninferiority margin of 21.0 g/dl, a true the patients to interventions. treatment difference of 0.0 g/dl, and an SD of 1.5 g/dl for CJASN 15: ccc–ccc, August, 2020 Efficacy of Daprodustat in Japanese Hemodialysis Patients, Akizawa et al. 3

the primary end point, noninferiority test has at least 99% groups and visits, and interaction terms between baseline power at a one-sided significance level of 2.5%, with a hemoglobin and visits. sample size of 100 participants per group. Assuming a The principal secondary end point was evaluated in the dropout rate of 25%, 135 participants per group were modified ITT population (all ITT participants with one or targeted to be randomized. This study was also designed to more hemoglobin measurement during the evaluation ensure long-term safety data from 100 patients on hemo- period). A logistic regression model, including treatment dialysis in the daprodustat group. group and baseline hemoglobin as covariates, was used The primary end point, noninferiority to darbepoetin to estimate the odds ratio (daprodustat/darbepoe- alfa, was evaluated in the intent-to-treat (ITT) population tin alfa). (all randomized participants with a baseline and one or Treatment difference in changes from baseline in iron more postbaseline hemoglobin assessment). Mixed model parameters were evaluated in the ITT population by the for repeated measures was used to estimate treatment same mixed model for repeated measures model used for difference in mean hemoglobin and 95% confidence inter- the primary end point. Other secondary end points and vals (95% CIs) during the primary efficacy evaluation exploratory end points were evaluated in the ITT popula- period. This model included treatment groups, baseline tion and are summarized descriptively. The safety pop- hemoglobin, visits, interaction terms between treatment ulation included all participants who received one or more

Enrollment

Assessed for eligibility (N = 332)

Excluded (N = 61) • Not meeting inclusion/exclusion criteria (n = 48) • Declined to participate (n = 10) • Physician decision (n = 3)

Randomized (N = 271)

Allocation Daprodustat (N = 136) Darbepoetin alfa (N = 135) • Received allocated intervention (n = 136) • Received allocated intervention (n = 135)

Follow-Up • Study Withdrawal (N = 21) Study Withdrawal (N = 15) Reason: Reason: • • Adverse event (n = 10) • Adverse event (n = 8)• • Met stopping criteria (n = 4) • Met stopping criteria (n = 2) - Hgb stopping criteria of <7.5 g/dL (n = 4) - Kidney transplant (n• = 1), Cancer event (n = 1) • Physician’s decision (n = 4) • Physician’s decision (n = 3) • Withdrawal by participant (n = 3) • Withdrawal by participant (n = 2)

Analysis • • Safety population (N = 136) • Safety population (N = 135) • ITT population (N = 133) • ITT population (N = 134)• - Excluded from analysis (n = 3), - Excluded from analysis• (n = 1), Reason: Did not have postbaseline Hgb Reason: Did not have postbaseline Hgb • Modified ITT population (N = 120) • Modified ITT population• (N = 125) - Excluded from analysis (n = 16), - Excluded from analysis (n = 10), Reason: Did not have Hgb at week 40 or later Reason: Did not have Hgb at week 40 or later

Figure 1. | Two hundred seventy-one participants were randomized (136 participants in the daprodustat group, 135 participants in the darbepoetin alfa group) in this study. Hgb, hemoglobin; ITT, intent-to-treat. 4 CJASN

dose of study treatment. Imputation for missing data were alfa group completed the study. The most common reasons not performed in any analyses. for study withdrawal in both treatment groups were AEs (ten daprodustat, eight darbepoetin alfa). All 271 participants were included in the safety population, 267 partici- Data Sharing pants (133 daprodustat, 134 darbepoetin alfa) were included Within 6 months of this publication, anonymized in the ITT population, and 245 participants (120 daprodu- individual participant data, the annotated case report stat, 125 darbepoetin alfa) were included in the modified form, protocol, reporting and analysis plan, data set ITT population. specifications, raw data set, analysis-ready data set, Participant characteristics were generally balanced and clinical study report will be available for research between treatment groups (Table 1). Overall, 66% of proposals approved by an independent review com- participants were men, and mean age was 64 years. mittee. Proposals should be submitted to www. Darbepoetin alfa was the most commonly used prior clinicalstudydatarequest.com. A data access agreement ESA for both treatment groups. Approximately two thirds will be required. of participants were undergoing hemodialysis and one third were undergoing hemodiafiltration, with an average time on dialysis of 8 years in both groups. Results Participant Disposition and Baseline Characteristics Of 332 participants screened, 271 participants were Hemoglobin Levels randomized (136 daprodustat, 135 darbepoetin alfa) The point estimates of mean hemoglobin in the ITT (Figure 1). A total of 115 participants (85%) in the population during the primary efficacy evaluation period daprodustat group and 120 (89%) in the darbepoetin were 10.9 g/dl (daprodustat) and 10.8 g/dl (darbepoetin

Table 1. Baseline characteristics of participants in a randomized, clinical trial evaluating the efﬁcacy (noninferiority) and safety of daprodustat compared with darbepoetin alfa in Japanese patients on hemodialysis (safety population)

Characteristic Daprodustat, n5136 Darbepoetin Alfa, n5135

Sex, n (%) Male 91(67) 89(66) Age, yr, mean6SD 64610 64611 BMI, kg/m2,mean6SD 2263.8 2364.2 Prior ESA type, n (%) Epoetin 53(39) 58(43) Darbepoetin alfa 70 (51) 64 (47) Epoetin beta pegol 13 (10) 13 (10) Prior ESA dose, IU/wk, mean6SDa 450462318 450162474 ERI, IU/kg per wk per g/dl, n (%)b,c Tertile 1: ,4.79 41/133 (31) 48/134 (36) Tertile 2: $4.79 and ,8 45/133 (34) 44/134 (33) Tertile 3: $8.0 47/133 (35) 42/134 (31) Time on dialysis, yr, mean6SD 7.966.9 7.967.1 Mode of dialysis, n (%) Hemodialysis 86 (63) 88 (65) Hemodiaﬁltration 50 (37) 47 (35) Hgb, g/dl, mean6SDc 10.960.8 10.860.7 Iron parametersc Serum iron, mg/dl,mean(SD) 68(25) 65(23) TIBC, mg/dl, mean (SD) 254 (39) 249 (38) TSAT, %, mean (SD) 27.0 (10.1) 26.3 (8.9) Ferritin, mg/L, geometric mean (CV %) 86.5 (108.9) 96.6 (124.5) Hepcidin, ng/ml, geometric mean (CV %) 54.1 (107.9) 60.1 (105.0) Hypertension, n (%) 127 (93) 125 (93) Hyperlipidemia, n (%) 57 (42) 60 (44) Diabetes mellitus, n (%) 56(41) 52(39) Angina, n (%) 23(17) 39(29) Eye disorders, n (%) 52 (38) 42 (31) Diabetic retinopathy 39 (29) 39 (29) Macular edema 8 (6) 5 (4) Age-related macular degeneration 5 (4) 8 (6)

BMI, body mass index; ESA, erythropoiesis-stimulating agent; ERI, erythropoietin resistance index; Hgb, hemoglobin; TIBC, total iron- building capacity; TSAT, transferrin saturation; CV, coefﬁcient of variation; IV, intravenous; SC, subcutaneous; ITT, intent-to-treat. aStandardized to epoetin IV dose (IU/wk) as follows: epoetin SC dose (IU/wk) multiplied by 116/113; darbepoetin alfa dose (mg/wk) multiplied by 250; epoetin beta pegol dose (mg/wk) multiplied by 208. bERI (IU/kg per week per g/dl)5standardized prior ESA dose (IU/wk)/baseline weight (kg)/baseline Hgb (g/dl). cITT population. CJASN 15: ccc–ccc, August, 2020 Efﬁcacy of Daprodustat in Japanese Hemodialysis Patients, Akizawa et al. 5

Table 2. Summary of hemoglobin efﬁcacy data (intent-to-treat population)

Hemoglobin Daprodustat, n5133 Darbepoetin Alfa, n5134

Baseline Hgb, g/dl n 133 134 Mean (SD) 10.9 (0.8) 10.8 (0.7) Mean Hgb during wk 40–52, g/dl n 120 125 Mean (SD) 10.9 (0.7) 10.8 (0.6) Change from baseline (SD) 0.0 (1.0) 0.0 (0.8) Adjusted mean Hgb during wk 40–52, g/dl Adjusted mean (95% CI) 10.9 (10.8 to 11.0) 10.8 (10.7 to 11.0) Adjusted treatment difference (95% CI) for mean Hgb during wk 40–52 0.1 (20.1 to 0.2) No. (%) of participants with mean Hgb within target during wk 40–52a n 120 125 No. of participants (%) 105 (88) 113 (90)

Change from baseline in mean Hgb during weeks 40–52 was performed in a post hoc analysis. Adjusted values were estimated by a mixed model for repeated measures as specified in Statistical Analyses. ITT, intent-to-treat; Hgb, hemoglobin; 95% CI, 95% confidence interval. aModified ITT population.

alfa), with a between-group difference of 0.1 g/dl (95% CI, and the darbepoetin group having an unadjusted odds of 20.1 to 0.2 g/dl). The lower limit of 95% CI for the 9.42 (responder/non-responder; 113/12). The odds ratio treatment difference was greater than the prespecified point estimate (daprodustat/darbepoetin alfa) was 0.76 noninferiority margin of 21.0 g/dl, demonstrating non- (95% CI, 0.34 to 1.71), on the basis of a logistic regres- inferiority of daprodustat to darbepoetin alfa. Mean change sion analysis. from baseline to week 52 is shown in Table 2. The mean (95% CI) hemoglobin levels were maintained The percentage of participants with mean hemoglobin within the target range for both groups at all time points within the target range during the primary efficacy eval- during the treatment period (Figure 2). After switching to uation period was 88% (105 out of 120) in the daprodustat daprodustat, mean hemoglobin levels were lower rela- group and 90% (113 out of 125) in the darbepoetin alfa tive to baseline from week 4 to week 16; however, the group (modified ITT population). This translates to the mean changes from baseline were ,0.5 g/dl and the mean daprodustat group having unadjusted odds of being in the hemoglobin levels remained within target range. With target range equal to 7 (responder/non-responder; 105/15) subsequent dose adjustment, mean hemoglobin returned to

Mean ± 95% CI 13.0 Daprodustat (N = 133) 12.5 Darbepoetin alfa (N = 134)

12.0

11.5

11.0

10.5

Hemoglobin (g/dL) 10.0

9.5

9.0 Day 1 84 12 16 20 24 4440363228 48 52 Weeks Number of Participants at Visits Daprodustat 133127133 125 124 123 123 117120121122123 117 115 Darbepoetin alfa 134 132134 129 129 129 129 125125127127129 124 120

Figure 2. | The mean hemoglobin levels were maintained within the target range for the daprodustat and the darbepoetin alfa groups during the treatment period. Area between dashed lines indicates hemoglobin target range. Error bars represent 95% conﬁdence intervals. Data shown are nonadjusted values. 6 CJASN

baseline by week 20. The proportion of participants with a Iron Use rapid hemoglobin increase (.2g/dlforany4weeks) Fewer participants used IV iron in the daprodustat (Supplemental Table 3) and hemoglobin level .13 g/dl than in the darbepoetin alfa group (32% daprodustat, was similar in both groups (Supplemental Table 4). 43% darbepoetin alfa throughout the treatment period; 18% In a subgroup analysis according to erythropoietin daprodustat, 27% darbepoetin alfa during weeks 40–52). resistance index (ERI), daprodustat maintained mean The mean monthly dose of IV iron for all study participants hemoglobin within the target range during weeks 40–52 (ITT population) was 14 mg (daprodustat) versus 17 mg in all three subgroups. However, initially after switching (darbepoetin alfa) throughout the treatment period and to daprodustat, decreases in mean hemoglobin were 14 mg (daprodustat) versus 25 mg (darbepoetin alfa) observed in tertile 2 ($4.79 and ,8.0 IU/kg per week during weeks 40–52. The percentage of participants using per g/dl) and tertile 3 ($8.0 IU/kg per week per g/dl) ERI oral iron during the study was similar in both groups (32% subgroups, but not in tertile 1 ERI subgroup (,4.79 IU/kg daprodustat, 34% darbepoetin alfa). per week per g/dl). With subsequent dose adjustment, mean hemoglobin returned to baseline in the tertile 2 Iron Parameters and tertile 3 ERI subgroups. Correspondingly, median Baseline iron parameters are shown in Table 1. Mean daprodustat dose was increased to 6 mg (from 4 mg serum iron and TIBC (Figure 4, Table 3) increased with starting dose) by week 12 in those participants. Median daprodustat treatment and remained near baseline with (25th percentile, 75th percentile) daprodustat doses darbepoetin alfa throughout the treatment period. Mean during weeks 40–52 were 4.0 (2.7–6.0) mg, 6.0 (4.0–8.7) TSAT remained near baseline with daprodustat treatment mg, and 6.0 (4.0–8.0) mg for the tertile 1, 2, and 3 ERI (after a brief increase at week 4) and decreased slightly with subgroups, respectively (Figure 3). Mean hemoglobin darbepoetin alfa. levels generally remained constant in all three ERI Geometric mean ferritin decreased from baseline in both subgroups for the darbepoetin alfa group. In a post hoc treatment groups. Geometric mean hepcidin decreased in analysis, median (25th percentile, 75th percentile) dar- both groups, but decreased more in the daprodustat group bepoetin alfa doses during weeks 40–52 were 10.4 (percent change from baseline at week 52 was 237% for (4.2–15.0) mg, 15.0 (13.3–22.9) mg, and 25.8 (12.5–46.7) daprodustat and 220% for darbepoetin alfa; adjusted ratio, mg for the tertile 1, 2, and 3 subgroups, respectively, 0.74; 95% CI, 0.57 to 0.95). suggesting that a broader range of darbepoetin alfa dose Baseline mean transferrin levels (measured as a safety was used during the study. parameter) were 2.0 g/L in both treatment groups.

Daprodustat (mg/day) Darbepoetin Alfa (µg/week) (post hoc analysis) 24 60 20 50 16 40 12 30 8 20 4 10 0 0 Day 1 4 8 12 16 20 24 28 32 36 40 44 48 Day 1 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Weeks ERI <4.79 IU/kg/week/g/dL ERI <4.79 IU/kg/week/g/dL ERI 4.79 and <8.0 IU/kg/week/g/dL ERI 4.79 and <8.0 IU/kg/week/g/dL ERI 8.0 IU/kg/week/g/dL ERI 8.0 IU/kg/week/g/dL

Median Dose (P25, P75) During W40-52 Daprodustat (mg/day) Darbepoetin alfa (µg/week)

ERI (<4.79) 4.0 (2.7, 6.0) 10.4 (4.2, 15)

ERI (4.79 and <8.0) 6.0 (4.0, 8.7) 15.0 (13.3, 22.9)

ERI (8.0) 6.0 (4.0, 8.0) 25.8 (12.5, 46.7)

Figure 3. | Daprodustat dose was increased by week 12 in the tertile 2 and 3 ERI subgroups. Daprodustat median dose during weeks 40–52 were 4.0 mg, 6.0 mg, and 6.0 mg for the tertile 1, 2, and 3 ERI subgroups, respectively. Error bars represent 25th percentile, 75th percentile for median dose. Median dose by ERI subgroup of darbepoetin alfa was a post hoc analysis. ERI, erythropoietin resistance index; W, week. CJASN 15: ccc–ccc, August, 2020 Efﬁcacy of Daprodustat in Japanese Hemodialysis Patients, Akizawa et al. 7

Serum Iron ABTIBC TSAT Mean (95% CI) Mean (95% CI) C Mean (95% CI) 90 320

31 85 310

80 300 29

75 290 27 70 280 µg/dl g/dl % 65 270 25

60 260 23 55 250

50 240 21

Week 4 Week 4 Week 4 Baseline Week 16Week 28Week 40Week 52 Baseline Week 16Week 28Week 40Week 52 Baseline Week 16Week 28Week 40Week 52

DEFerritin Hepcidin Geometric Mean (95% CI) Geometric Mean (95% CI) 120 70

110 65

60 100 55 90 50 80

ng/mL 45 g/L 70 40 60 35

50 30

40 25

Week 4 Week 4 Baseline Week 16Week 28Week 40Week 52 Baseline Week 16Week 28Week 40Week 52

Daprodustat Darbepoetin alfa

Figure 4. | Iron parameters over time. In the daprodustat group, serum iron and TIBC increased, ferritin and hepcidin decreased, and TSAT remained near baseline. Error bars represent 95% CIs. 95% CI, 95% conﬁdence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation.

Transferrin levels increased in the daprodustat group Of the AEs occurring in $5% of participants in any group (mean change from baseline at week 52: 0.3 g/L (Table 4), contusion and diarrhea were more frequent ($5% [SD 0.5 g/L] for daprodustat and 0.0 g/L [SD 0.3 g/L] difference) in the daprodustat group, whereas nasophar- for darbepoetin alfa), which was aligned with changes yngitis and extremity pain was more frequent ($5% in TIBC. difference) in the darbepoetin alfa group. Hyperkalemia was reported in 3% of participants in the daprodustat group versus 1% in the darbepoetin alfa group. SAEs Safety and AEs occurred in 15% (daprodustat) and 27% (darbepoetin alfa) Most participants in both treatment groups experienced of participants. SAEs reported in two or more partici- one or more AEs (93% daprodustat, 97% darbepoetin alfa). pants ($1%) in any treatment group were shunt stenosis 8 CJASN

Table 3. Iron parameters at end of treatment (intent-to-treat population)

Iron Parameter Daprodustat, n5133 Darbepoetin Alfa, n5134

n 115 120 TSAT at wk 52, %a Mean (SD) 27.0 (12.3) 24.6 (9.1) Change from baseline (SD) 0.3 (13.2) 22.1 (11.4) Adjusted treatment difference (95% CI) 2.8 (0.1 to 5.4) TIBC at wk 52, mg/dl Mean (SD) 303 (64) 257 (44) Change from baseline (SD) 49 (56) 6 (34) Treatment difference (95% CI) 41 (30 to 53) Serum iron at wk 52, mg/dl Mean (SD) 78 (29) 63 (24) Change from baseline (SD) 11 (34) 24(28) Treatment difference (95% CI) 16 (10 to 22) Ferritin, mg/Lb Geometric mean (CV %) 66.7 (143.5) 74.9 (127.8) Percent change from baseline (CV %) 222 (132.2) 220 (124.1) Adjusted ratio for percent change from baseline (95% CI) 0.95 (0.75 to 1.19) Hepcidin, ng/mlb Geometric mean (CV %) 37.9 (103.8) 51.5 (111.5) Percent change from baseline (CV %) 237 (116.1) 220 (133.6) Adjusted ratio for percent change from baseline (95% CI) 0.74 (0.57 to 0.95)

TSAT, transferrin saturation; 95% CI, 95% conﬁdence interval; TIBC, total iron-binding capacity; CV %, coefﬁcient of variation. aThe distribution in TSAT had been assumed to be skewed but was found not to be skewed after the data review; therefore, the analysis of TSAT on the basis of a nonlog transformation was done as a post hoc analysis. bThe distributions were assumed to be skewed and required a log transformation for the analysis. The distribution in ferritin had been assumed not to be skewed but was found to be skewed after the data review; therefore, the analysis of ferritin on the basis of a log transformation was done as a post hoc analysis.

(3% daprodustat, 4% darbepoetin alfa), shunt occlusion reported (13). Noninferiority of daprodustat to darbe- (,1% daprodustat, 2% darbepoetin alfa), shunt mal- poetin alfa was demonstrated, with a high proportion function (0% daprodustat, 1% darbepoetin alfa), pneu- of participants achieving and maintaining hemoglobin monia (,1% daprodustat, 1% darbepoetin alfa), sepsis levels within the target range. The daprodustat starting (0% daprodustat, 1% darbepoetin alfa), and cardiac dose (4 mg) and subsequent potential for monthly failure congestive (0% daprodustat, 1% darbepoetin titration according to the predefined algorithm (with alfa). No deaths were reported in the daprodustat group. doses ranging from 0 to 24 mg) provided an appropri- One fatal event (sepsis) was reported during the follow- ate balance between achieving target hemoglobin up period in the darbepoetin alfa group. AEs of special levels without rapid rises (.2.0 g/dl over 4 weeks) interest were generally reported in a similar proportion in hemoglobin or exceeding hemoglobin levels of participants in both groups for all categories .13.0 g/dl. (Supplemental Table 5). Differences in hemoglobin variability in the two There was little or no change from baseline in postdialysis treatment groups in this study could potentially be systolic and diastolic BP in both treatment groups becausealmosthalf(64outof135)ofthedarbepoetin during the treatment period. The percentage of partic- alfa group were on the same drug and dosage before ipants who had any change in antihypertensive med- study commencement. Furthermore, the difference in ications because of increased BP was 38% (daprodustat) the time interval for dose adjustment (once every and 49% (darbepoetin alfa) (Supplemental Table 6). No 4 weeks for daprodustat versus once every 2 weeks clinically relevant change from baseline was seen in for darbepoetin alfa) may have contributed to hemo- potassium in either group (Supplemental Table 7). The globin variability. proportion of participants with low, within range, or Interestingly, hemoglobin response varied between high postbaseline potassium was similar in the dapro- participants, as evidenced by the observation that some dustat and the darbepoetin alfa groups (Supplemental participants could maintain hemoglobin levels with Table 8). 4 mg of daprodustat even in the tertile 3 ($8.0 IU/kg per week per g/dl) ERI subgroup. Our results suggest Discussion that monitoring hemoglobin response upon treatment This was the first phase 3 study to evaluate the initiation with daprodustat is highly recommended. In efficacy and safety of daprodustat compared with an addition, the use of lower daprodustat doses may ESA over 1 year of treatment, although a phase 3 trial of reflectresolutionofESAresistanceasESAhypores- patients treated with roxadustat for 27 weeks has been ponsiveness can resolve over time. CJASN 15: ccc–ccc, August, 2020 Efficacy of Daprodustat in Japanese Hemodialysis Patients, Akizawa et al. 9

Table 4. Adverse events reported in ‡5% of participants in any group (safety population)

Adverse Event Daprodustat, n5136, n (%) Darbepoetin Alfa, n5135, n (%)

Nasopharyngitis 57 (42) 73 (54) Pharyngitis 10 (7) 6 (4) Gastroenteritis 7 (5) 2 (1) Shunt stenosis 19 (14) 20 (15) Contusion 17 (13) 11 (8) Skin abrasion 10 (7) 7 (5) Procedural hypotension 11 (8) 5 (4) Diarrhea 20 (15) 12 (9) Vomiting 15 (11) 11 (8) Nausea 9 (7) 12 (9) Constipation 8 (6) 6 (4) Abdominal discomfort 3 (2) 7 (5) Back pain 6 (4) 10 (7) Arthralgia 5 (4) 10 (7) Muscle spasms 7 (5) 4 (3) Pain in extremity 1 (,1) 10 (7) Headache 8 (6) 6 (4) Pyrexia 7 (5) 3 (2) Hypertension 5 (4) 8 (6)

Fewer participants in the daprodustat than the darbe- levels (10–12). In our study, 29% of participants had poetin alfa group used IV iron throughout the double-blind diabetic retinopathy and approximately 5% had mac- treatment period, despite achieving comparable hemoglo- ular edema at baseline in both groups. Considering that bin levels. the incidence of ocular AEs of special interest was The observed decrease in ferritin with daprodustat similar across treatment groups, daprodustat treatment treatment may be secondary to increased iron utiliza- did not appear to exacerbate these conditions. These tion and depletion of iron stores owing to erythropoi- findings, together with previous clinical data showing esis. The greater decrease in hepcidin, accompanied minimal VEGF elevation with daprodustat, suggest that by decreases in ferritin and less IV iron use, may be daprodustat treatment for 52 weeks does not induce indicative of better iron mobilization and utilization in and/or worsen ocular AEs. participants treated with daprodustat compared with As mentioned above, treatment of Chinese patients on darbepoetin alfa. Observed increases in TIBC were dialysis with roxadustat was evaluated in a phase 3 likely determined by transferrin, which is increased by study. Effects of daprodustat on hemoglobin levels and hypoxia-inducible factor (HIF) (15). HIF has been iron parameters in our study were similar to the results reported to upregulate divalent metal transporter 1 observed with roxadustat; however, our study suggests and duodenal cytochrome B to increase intestinal iron the possibility of controlling hemoglobin with less IV absorption (16). Increases in serum iron observed in the iron use in patients treated with daprodustat, as physi- daprodustat group may be a consequence of upregu- cians were allowed to select the route of iron adminis- lation of divalent metal transporter 1 and duodenal trationasopposedtoIVironbeinglimitedtorescueuse cytochrome B by HIF stabilization; however, further in the roxadustat study. Furthermore, our study pro- investigation is needed. vides 1-year safety data for daprodustat compared with Daprodustat was generally well tolerated, with an AE ESAs. AEs reported more frequently with roxadustat, profile comparable to the comparator darbepoetin alfa, such as hyperkalemia, were not reported as a common including a similar incidence of AEs of special interest. AE ($5%) in our study, although differences in study Vascular access complication occurred in a similar pro- design and treatment period should be noted. portion of participants in both groups. Contusion and Study limitations included insufficient study duration diarrhea were reported more often in the daprodustat (1 year) and sample size to conclusively evaluate group; however, all events reported in the daprodustat cardiovascular and cancer events. In addition, patients group were mild or moderate and did not lead to with active malignancies or ESA hyporesponsiveness discontinuation of study treatment (13). were excluded from the study. Two ongoing, large Ocular AEs of special interest (proliferative retinop- outcome studies (Anemia Studies in CKD: Erythropoi- athy, macular edema, and choroidal neovasculariza- esis via a Novel PHI Daprodustat-Dialysis [ASCEND-D] tion) were evaluated because of theoretical concerns and Anemia Studies in CKD: Erythropoiesis via a Novel relating to HIF stabilization resulting in increased PHI Daprodustat-Non-Dialysis [ASCEND-ND]) exam- vascular endothelial growth factor (VEGF) protein ining the effect of daprodustat on cardiovascular expression with potential secondary effects on retinal risk will help provide a definitive conclusion in neovascularization. Prior phase 2 studies with dapro- this regard. dustat have shown moderate increases in endogenous In conclusion, oral daprodustat is noninferior to darbe- erythropoietin with no change in circulating VEGF poetin alfa in the maintenance of hemoglobin concentration 10 CJASN

in Japanese patients undergoing hemodialysis who are Supplemental Table 5. Adverse events of special interest switched from their current ESA treatment. Daprodustat (safety population). was generally well tolerated, with an AE profile compa- Supplemental Table 6. Systolic and diastolic BP at week 52 rable to darbepoetin alfa. (safety population). Supplemental Table 7. Change from baseline in potassium (mmol/L) (safety population). Acknowledgments Supplemental Table 8. Potassium results: postbaseline relative to The authors wish to thank the participants, the principal inves- baseline (safety population). tigators, and the clinical research coordinators for their participation Supplemental Table 9. Institutional review board. and support in this study. The authors are grateful for the editorial support (Sarah Hummasti: assembling tables and figures, collating References author comments, copyediting, fact checking, and referencing) and 1. Babitt JL, Lin HY: Mechanisms of anemia in CKD. JAmSoc graphic services that were provided by AOIC, LLC, and were Nephrol 23: 1631–1634, 2012 funded by GlaxoSmithKline. 2. Zumbrennen-Bullough K, Babitt JL: The iron cycle in chronic kidney disease (CKD): From genetics and experimental All listed authors meet the criteria for authorship set forth by the models to CKD patients. Nephrol Dial Transplant 29: 263–273, International Committee for Medical Journal Editors. Dr. Tadao 2014 Akizawa, Dr. Masaomi Nangaku, Ms. Taeko Yonekawa, Mr. Yukihiro 3. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Endo, Mr. Katsutoshi Hara, and Dr. Alexander R. Cobitz contrib- Work Group: KDIGO clinical practice guideline for anemia in uted to the concept and design of the study, Dr. Tadao Akizawa, chronic kidney disease. Kidney Int Suppl 2: 279–335, 2012 4. Fishbane S, Spinowitz B: Update on anemia in ESRD and earlier Dr. Masaomi Nangaku, Ms. Taeko Yonekawa, Mr. Nobuhiko stages of CKD: Core curriculum 2018. Am J Kidney Dis 71: Okuda, Mr. Shinya Kawamatsu, Mr. Tomohiro Onoue, Mr. Yukihiro 423–435, 2018 Endo, Mr. Katsutoshi Hara, and Dr. Alexander R. Cobitz contrib- 5. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, uted to the data analysis and interpretation. All authors provided Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, critical review and final approval of the publication and agree to Lewis EF, McGill JB, McMurray JJ, Parfrey P,Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators: A trial of take responsibility for its content. darbepoetin alfa in type 2 diabetes and chronic kidney disease. NEnglJMed361: 2019–2032, 2009 6. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Disclosures Reddan D; CHOIR Investigators: Correction of anemia with T. Akizawa is a consultant for Astellas Pharma, Bayer epoetin alfa in chronic kidney disease. N Engl J Med 355: Yakuhin, GlaxoSmithKline, Japan Tobacco, Kyowa Kirin, 2085–2098, 2006 Nipro Corporation, Otsuka Pharmaceuticals, Sanwa Chemical, 7. Solomon SD, Uno H, LewisEF,Eckardt KU, Lin J, Burdmann EA, de and Torii Pharmaceutical. Lecture fees were received from Zeeuw D, Ivanovich P,Levey AS, Parfrey P,Remuzzi G, Singh AK, Bayer Yakuhin, Chugai Pharmaceutical, Fuso Pharmaceutical Toto R, Huang F, Rossert J, McMurray JJ, Pfeffer MA; Trial to Reduce Cardiovascular Events with Aranesp Therapy Industries, Kissei Pharmaceutical, Kyowa Kirin, Ono Phar- (TREAT) Investigators: Erythropoietic response and outcomes in maceutical, and Torii Pharmaceutical. M. Nangaku has re- kidney disease andtype2 diabetes. NEngl JMed 363: 1146–1155, ceived grants and personal fees from Astellas Pharma, Chugai 2010 Pharmaceutical, Daiichi Sankyo, GlaxoSmithKline, Kyowa 8. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Kirin, Mitsubishi Tanabe Pharma, and Torii Pharmaceutical; Patel UD, Singh AK: Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney grants from Bayer Yakuhin, Ono Pharmaceutical, and Takeda Int 74: 791–798, 2008 Pharmaceutical Company; and personal fees from AstraZeneca 9. Gupta N, Wish JB: Hypoxia-inducible factor prolyl hydroxylase andJTPharmaceuticals.T.Yonekawa, S. Kawamatsu, T. Onoue, inhibitors: A potential new treatment for anemia in patients with and K. Hara are employees of GlaxoSmithKline. N. Okuda, CKD. Am J Kidney Dis 69: 815–826, 2017 Y. Endo, and A. Cobitz are employees of and hold equity in 10. Akizawa T, Tsubakihara Y, Nangaku M, Endo Y, Nakajima H, Kohno T, Imai Y, Kawase N, Hara K, Lepore J, Cobitz A: GlaxoSmithKline. Effects of daprodustat, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor on anemia management in Japanese hemodialysis subjects. Am J Nephrol 45: 127–135, Funding 2017 Funding for this study was provided by GlaxoSmithKline. 11. Holdstock L, Cizman B, Meadowcroft AM, Biswas N, Johnson BM, Jones D, KimSG, ZeigS, LeporeJJ,CobitzAR: Daprodustat for anemia: A 24-week, open-label, randomized controlled trial in Supplemental Material participants with chronic kidney disease. Clin Kidney J 12: This article contains the following supplemental material online 129–138, 2019 at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN. 12. Meadowcroft AM, Cizman B, Holdstock L, Biswas N, Johnson 16011219/-/DCSupplemental. BM, Jones D, Nossuli AK, Lepore JJ, Aarup M, Cobitz AR: Supplemental Appendix 1. Full inclusion and exclusion criteria. Daprodustat for anemia: A 24-week, open-label, randomized Supplemental Table 1. Dose adjustment algorithm (daprodustat). controlled trial in participants on hemodialysis. Clin Kidney J 12: 139–148, 2019 Supplemental Table 2. Dose adjustment algorithm (darbepoe- 13. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, tin alfa). Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Supplemental Table 3. Number (%) of participants with a he- Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP: Roxadustat moglobin increase of .2.0 g/dl over any 4 weeks (intent-to- treatment for anemia in patients undergoing long-term dialysis. treat population). N Engl J Med 381: 1011–1022, 2019 14. Yamamoto H, Nishi S, Tomo T, Masakane I, Saito K, Nangaku M, Supplemental Table 4. Number (%) of participants with a he- Hattori M,Suzuki T,Morita S, Ashida A,ItoY,KuraganoT,Komatsu moglobin level .13.0 g/dl and number of episodes (intent-to- Y, Sakai K, Tsubakihara Y, Tsuruya K, Hayashi T, Hirakata H, treat population). Honda H: 2015 Japanese society for dialysis therapy: Guidelines CJASN 15: ccc–ccc, August, 2020 Efficacy of Daprodustat in Japanese Hemodialysis Patients, Akizawa et al. 11

for renal anemia in chronic kidney disease. Renal Replacement absorption following iron deﬁciency. Cell Metab 9: 152–164, Therapy 3: 36, 2017 2009 15. Rolfs A, Kvietikova I, Gassmann M, Wenger RH: Oxygen- regulatedtransferrin expressionismediated byhypoxia-inducible Received: December 30, 2019 Accepted: June 2, 2020 factor-1. JBiolChem272: 20055–20062, 1997 16. Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ: Intestinal Published online ahead of print. Publication date available at hypoxia-inducible transcription factors are essential for iron www.cjasn.org. Supplemental Material Table of Contents Supplemental Item 1. Full Inclusion and Exclusion Criteria Supplemental Table 1. Dose Adjustment Algorithm (Daprodustat) Supplemental Table 2. Dose Adjustment Algorithm (Darbepoetin Alfa) Supplemental Table 3. Number (%) of Participants with a Hemoglobin Increase of ˃2.0 g/dL over Any 4 Weeks (ITT Population) Supplemental Table 4. Number (%) of Participants with a Hemoglobin Level ˃13.0 g/dL and Number of Episodes (ITT Population) Supplemental Table 5. Adverse Events of Special Interest (Safety Population) Supplemental Table 6. Systolic and Diastolic Blood Pressure at Week 52 (Safety Population) Supplemental Table 7. Change from Baseline in Potassium (mmol/L) (Safety Population) Supplemental Table 8. Potassium Results: Post-Baseline Relative to Baseline (Safety Population) Supplemental Table 9. Institutional Review Board

1 Supplemental Item 1. Full Inclusion and Exclusion Criteria

Inclusion Criteria: A participant was eligible for inclusion in this study only if all of the following criteria applied at screening and day 1 (unless otherwise specified):

• Age (at informed consent): ≥20 years of age

• On hemodialysis or hemodiafiltration given 3 times weekly for at least 12

weeks before screening

• Use of the same ESA for at least 10 weeks before screening

o ESA dose: Darbepoetin alfa 10 to 60 μg per week, epoetin (including biosimilars) ≤9000 IU per week, or epoetin beta pegol up

to 250 μg per 4 weeks. Note: ESA dose must have been greater

than the minimum ESA dose if hemoglobin >12.0 g/dL to 12.5 g/dL

(minimum ESA dose: epoetins [including biosimilars], 1500 U per

week; darbepoetin alfa, 10 μg per week; and epoetin beta pegol, 25

μg every 4 weeks)

• Hemoglobin: ≥9.5 g/dL and ≤12.5 g/dL, determined by a hemoglobin

analyzer (HemoCue) at the site

• Ferritin >100 ng/mL or TSAT >20% (screening verification only)

• Not pregnant, having no childbearing potential, and not breastfeeding

• Females of childbearing potential had to agree to comply with one of the

contraception methods from 28 days prior to the first dose of study drug

2 until the completion of the follow-up visit

• Written informed consent, including adherence to the requirements and

conditions specified in the consent form and the protocol, must have been

obtained from each participant as specified in the protocol, Section 10.2

Exclusion Criteria: A participant was not eligible for inclusion in this study if any of the following criteria applied at screening or day 1 unless otherwise specified:

CKD-related criteria

• Planned living-related kidney transplant during the study

Anemia-related criteria

• History of bone marrow hypoplasia or pure red cell aplasia

• Other causes of anemia including pernicious anemia, thalassemia, sickle

cell anemia, or myelodysplastic syndromes

• Evidence of actively bleeding gastric, duodenal, or esophageal ulcer or

clinically significant gastrointestinal bleeding within 10 weeks before

screening or during a period from screening to day 1

Cardiovascular disease-related criteria

• Myocardial infarction, acute coronary syndrome, stroke, or transient

ischemic attack: Diagnosed within 10 weeks before screening or during a

period from screening to day 1

• Chronic Class IV heart failure, as defined by the New York Heart

3 Association (NYHA) functional classification system

• Corrected QT (QTc) interval (screening verification only): QTc >500 msec;

or QTc >530 msec in patients with bundle branch block. QT interval

corrected using the Bazett formula (QTcB) was used, and ECG could be

mechanically or manually read

Other disease-related criteria

• Liver disease (if any of the following occurred):

o Alanine aminotransferase (ALT) >2×upper limit of normal (ULN) (screening verification only)

o Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN was acceptable if bilirubin was fractionated and direct bilirubin was <35%) (screening

verification only)

o Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy,

hypoalbuminemia, esophageal/gastric varices, persistent jaundice,

or cirrhosis)

Note: Stable liver disease (including asymptomatic gallstones, chronic

hepatitis B/C, or Gilbert’s syndrome) was acceptable if the patient

otherwise met entry criteria

• History of malignancy within 2 years before screening, currently receiving

treatment for cancer, or complex kidney cyst >3 cm (II F, III, or IV based on

the Bosniak classification)

Note: The only exception was localized squamous cell or basal cell

carcinoma of the skin that had been definitively treated ≥10 weeks before

screening

Concomitant medication and other study treatment-related criteria

• Planned use of IV iron during the screening phase or during a period from

day 1 to week 4. Note: Oral iron was acceptable. However, the same dose

regimen must have been used throughout the screening phase and from

day 1 to week 4. Antihyperphosphatemic agents containing iron (eg, ferric

citrate hydrate) were also acceptable only if used for at least 12 weeks

before screening. However, they must have been continued throughout

the screening phase and from day 1 to week 4

• History of severe allergic or anaphylactic reactions or hypersensitivity to

excipients in the investigational product (see the daprodustat investigator’s

brochure [IB] or the prescribing information for darbepoetin alfa)

• Use or planned use of any prescription or nonprescription drugs or dietary

supplements that was prohibited during the study period (prohibited

medications: strong inducers and inhibitors of cytochrome P450 [CYP]

2C8)

• Use of an investigational agent within 30 days or 5 half lives of the

investigational agent (whichever was longer)

• Any prior treatment with daprodustat for a treatment duration of >30 days

• Any other condition, clinical or laboratory abnormality, or examination

5 finding considered by the investigator (or sub-investigator) would put the

patient at unacceptable risk and could affect study compliance or prevent

understanding of the aims or investigational procedures or possible

consequences of the study

Withdrawal Criteria:

Participants were withdrawn from the study if their hemoglobin levels fell below

7.5 g/dL (based on the average of 2 HemoCue hemoglobin values of the same sample). Other withdrawal criteria included kidney transplant, pregnancy, new or recurrent cancer, liver chemistry abnormalities exceeding threshold criteria, and the need for chronic use of prohibited medication (ie, CYP2C8 inhibitors/inducers).

Supplemental Table 1. Dose Adjustment Algorithm (Daprodustat)

Hemoglobin Hemoglobin increase over (g/dL) 4 weeks (g/dL) Treatment Interrupt treatment (and administer placebo) until hemoglobin decreases to less than 12.0 g/dL, and resume treatment at the one lower dose level (If >13.0 NA interrupted [and placebo administered] at 1 mg, resume treatment at 1 mg after the one-step dose increase criterion is met) ≥12.0 and ≤13.0 NA One-step dose reduction

>2.0 One-step dose reduction ≥10.0 and <12.0 ≤2.0 Continue treatment at the current dose level

>2.0 One-step dose reduction

≥7.5 and <10.0 0.5‒2.0 Continue treatment at the current dose level

<0.5 One-step dose increase

a Discontinue treatment permanently and initiate <7.5 NA another appropriate treatment aIf an initial hemoglobin value was < 7.5 g/dL, measurement was repeated at the same study visit (using the same sample) to calculate the average. If the average met the hemoglobin stopping criteria, study treatment was required to be permanently discontinued.

Supplemental Table 2. Dose Adjustment Algorithm (Darbepoetin Alfa)

Hemoglobin (g/dL) Treatment Interrupt treatment (and administer placebo) until Hgb decreases to less than 12.0 g/dL, and resume treatment at the one lower dose level (If interrupted >13.0 [and placebo administered] at 10 μg, resume treatment at 10 μg after the one-step dose increase criterion is met) ≥12.0 and ≤13.0 One-step dose reduction

≥10.0 and <12.0 Continue treatment at the current dose levela

≥7.5 and <10.0 One-step dose increaseb c Discontinue treatment permanently and initiate <7.5 another appropriate treatment aIf hemoglobin >1 g/dL increase over 2 weeks, the dose was reduced to the one-step lower dose level. bIf hemoglobin >1 g/dL increase over 2 weeks, treatment was continued at the same dose level. If there was a safety concern, however, the dose reduction was allowed at the investigator's (or sub-investigator's) discretion to the one-step lower dose level. cIf an initial hemoglobin value was <7.5 g/dL, measurement was repeated at the same study visit (using the same sample) to calculate the average. If the average met the hemoglobin stopping criteria, study treatment was required to be permanently discontinued.

Supplemental Table 3. Number (%) of Participants with a Hemoglobin Increase of ˃2.0 g/dL over Any 4 Weeks (ITT Population)

Daprodustat Darbepoetin alfa (N = 133) (N = 134)

Number of participants, n (%) 1 (<1) 2 (1)

CI, confidence interval; ITT, intent-to-treat.

9 Supplemental Table 4. Number (%) of Participants with a Hemoglobin Level ˃13.0 g/dL and Number of Episodes (ITT Population)

Daprodustat Darbepoetin alfa (N = 133) (N = 134)

Number of participants, n (%) 7 (5) 8 (6)

Number of episodes 9 12

Includes hemoglobin values measured during both scheduled and unscheduled visits. ITT, intent-to-treat.

10 Supplemental Table 5 Adverse Events of Special Interest (Safety Population) Daprodustat Darbepoetin Alfa AE, n (%) (N = 136) (N = 135) Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis 9 (7) 10 (7) of vascular access Arteriosclerosis coronary artery 0 1 (<1) Cardiac failurea 1 (<1) 2 (1) Cerebral infarction 1 (<1) 1 (<1) Pulmonary edema 0 1 (<1) Retinal vein occlusion 2 (1) 1 (<1) Retinal artery occlusion 0 1 (<1) b Shunt events 4 (3) 4 (3) Venous occlusion 1 (<1) 0 Esophageal and gastric erosions 3 (2) 5 (4) Gastritis erosive 2 (1) 2 (1) Chronic gastritis 0 1 (<1) Duodenal perforation 1 (<1) 0 Gastric ulcer 0 1 (<1) Hemorrhagic erosive gastritis 0 1 (<1) Proliferative retinopathy, macular edema, 4 (3) 4 (3) choroidal neovascularization Macular edema 2 (1) 2 (1) Anterior chamber angle neovascularization 2 (1) 1 (<1) Retinal hemorrhage 0 1 (<1) Cardiomyopathy 0 1 (<1) Hypertensive cardiomyopathy 0 1 (<1)

Pulmonary artery hypertension 1 (<1) 0 Pulmonary hypertension 1 (<1) 0

Cancer-related mortality and tumor 0 1 (<1) progression and recurrence

11 Pancreatic carcinoma 0 1 (<1) Exacerbation of rheumatoid arthritis 0 1 (<1) Rheumatoid arthritis 0 1 (<1)

Thrombosis and/or tissue ischemia 0 0 secondary to excessive erythropoiesis aCardiac failure and cardiac failure congestive. bShunt malfunction, shunt occlusion, shunt stenosis, shunt thrombosis. AE, adverse event

Supplemental Table 6. Systolic and Diastolic Blood Pressure at Week 52 (Safety Population) Daprodustat (N = 136) Darbepoetin Alfa (N = 135) Post Dialysis Post Dialysis Systolic blood pressure (mmHg) Baseline, n 136 135 Mean ± SD 139 (23) 137 (23) Change from baseline 115 119 at week 52, n Mean ± SD -1 (24) 2 (27) Diastolic blood pressure (mmHg) Baseline, n 136 135 Mean ± SD 78 (14) 78 (13) Change from baseline 115 119 at week 52, n Mean ± SD -1 (13) 1 (15) HTN medications changed due to 51 (38) 66 (49) increased BP, n (%) BP, blood pressure; HTN, hypertension; SD, standard deviation.

13 Supplemental Table 7. Change from Baseline in Potassium (mmol/L) (Safety Population)

Daprodustat Darbepoetin alfa (N = 136) (N = 135) Baseline

n 136 135

Mean (SD) 5.0 (0.8) 5.0 (0.7)

Change from Baseline at Week 4

n 133 134

Mean (SD) 0.0 (0.5) 0.0 (0.5)

Change from Baseline at Week 16

n 123 129

Mean (SD) -0.1 (0.5) -0.1 (0.6)

Change from Baseline at Week 28

n 122 126

Mean (SD) -0.1 (0.6) -0.1 (0.6)

Change from Baseline at Week 40

n 120 125

Mean (SD) -0.1 (0.6) -0.1 (0.6)

Change from Baseline at Week 52

n 115 120

Mean (SD) -0.1 (0.6) -0.1 (0.6)

Note: Baseline value is derived from the latest pre-dose assessment. SD, Standard deviation.

14 Supplemental Table 8. Potassium Results: Post-Baseline Relative to Baseline (Safety Population)

Change Category (lower/upper boundary Daprodustat Darbepoetin of clinical concern) (N = 136) Alfa (N = 135) n 136 134

Low (>0.5 mmol/L below LLRR), n (%) 1 (<1) 0 Within range or no change, n (%) 120 (88) 109 (81) High (>1.0 mmol/L above ULRR), n (%) 15 (11) 25 (19)

Note: Participants are counted in the category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose lab value category was unchanged (eg, high to high), or whose value became within range, are recorded in the “To within range or no change” category. Participants are counted twice if they had values that changed “To low” and ”To high", so the percentages may not add to 100%. Participants with a missing baseline value are assumed to have a within range value. ULRR, Upper limit of normal range; LLRR, Lower limit reference range.

15 Supplemental Table 9. Institutional Review Board

Institutional Review Board List Institution Name Name of IEC/IRB Kasugai Municipal Hospital Kasugai Municipal Hospital, Institutional Review Board 1-1-1, Takaki-cho, Kasugai-city, Aichi, 486-8510, Japan Fukui-ken Saiseikai Hospital Fukui-ken Saiseikai Hospital, Institutional Review Board 7-1, Funabashi, Wadanaka-cho, Fukui-city Higashinaebo Hospital Higashinaebo Hospital, Institutional Review Board Japanese Red Cross Society Azumi Hospital Japanese Red Cross Society Azumi Hospital, Institutional Review Board 5685, Toyoshina, Azumino-city, Nagano-ken Kasaoka Daiichi Hospital Jinbo Orthopedic Clinic, Institutional Review Board Miyaji Clinic Hasegawa Hospital Kasugai Municipal Hospital Kasugai Municipal Hospital, Institutional Review Board 1-1-1, Takaki-cho, Kasugai-city, Aichi, 486-8510, Japan Kurobe City Hospital Kurobe City Hospital, Institutional Review Board 1108-1, Mikkaichi, Kurobe-city, Toyama, 938-8502, Japan Anjou Kyoritsu Clinic Nagoya Kyoritsu Hospital, Institutional Review Board Meiko Kyoritsu Clinic 1-172 Hokke, Nakagawa-ku, Nagoya-shi Kaikoukai Central Clinic Medical Corporation Kaikoukai Hekikai Kyoritsu Clinic Medical Corporation Jiyoukai Akagaki Clinic Nihonbashi Sakura Clinic, Institutional Review Board Kano Hospital Medical Corporation Houshikai 1-9-2 Nihonbashi Kayaba-cho, Fukuoka Wajiro Hospital Chuo-ku, Tokyo, 103-0025, Japan Takayama Hospital Meiyo Clinic Matsumoto City Hospital Kanno Dialysis & Vascular Access Clinic Kohitsujikai Group Naganuma Clinic Review Board of Human Rights and Ethics for Clinical Yokohama Jin Clinic Studies Ethics Review Committee Suda Clinic 13-2 Ichibancho, Chiyoda-ku, Tokyo Kamiiida Clinic Kyoto Okamoto Memorial Hospital Ora Hospital Kusunoki Hospital Isesaki Municipal Hospital Social medical corporation Seichokai Fuchu Hospital Nozaki Clinic Oda Clinic

16 Kuwajima Clinic Jusendo Clinic Tsuchiura Beryl Clinic Medical Corporation Hakuyukai Kikuchi Internal Sugiura Clinic, Institutional Review Board Medicine Clinic Rm301, 4-4-16, Honcho, Kawaguchi-shi, Saitama Kinashi Obayashi Hospital Tenjin Clinic Futakotamagawaeki mae Clinic St. Hill Hospital Kawadairanaika Medical Clinic Houshinkai Yokodai Central Clinic Houshinkai Yokohama Minami Clinic Tachibanadai Hospital Tokiwa Clinic Suzuki Clinic Sunagawa City Medical Center Sunagawa City Medical Center, Institutional Review Board 3-1-1, Nishi4-jo Kita, Sunagawa-city Hosaka Clinic Supporo Dermatology Clinic, Institutional Review Board Minami 3 Jo Nishi 2 Chome 1-1, Chuo-ku, Sapporo-shi Takikawa Municipal Hospital Takikawa Municipal Hospital, Institutional Review Board 2-2-34, Omachi, Takikawa-city Social Welfare Organization Saiseikai Imperial Tokai Memorial Hospital, Institutional Review Board Gift Foundation, Inc. Osaka prefecture branch of 681-47 Ohhora Hazama-cho, Kasugai-shi, Aichi-ken Saiseikai Tondabayashi Hospital Yamagata Tokushukai Hospital Tokushukai Group, Institutional Review Board Hanyu General Hospital 1-8-7, Koji-machi, Chiyoda-ku, Tokyo 102-0083, Japan