Nephrol Dial Transplant (2015) 30: 1665–1673

doi: 10.1093/ndt/gfv302
Advance Access publication 3 August 2015

Original Article

Randomized placebo-controlled dose-ranging and
pharmacodynamics study of roxadustat (FG-4592) to treat
anemia in nondialysis-dependent chronic kidney disease
(NDD-CKD) patients

Anatole Besarab1, Robert Provenzano2, Joachim Hertel3, Raja Zabaneh4, Stephen J. Klaus1, Tyson Lee1,

Downloaded from by guest on January 4, 2017
Robert Leong1, Stefan Hemmerich1, Kin-Hung Peony Yu1 and Thomas B. Neff1
FibroGen, Inc., San Francisco, CA, USA, 2St Clair Specialty Physicians, Detroit, MI, USA, 3Kidney Care Associates, LLC, Augusta, GA,
USA and 4Northwest Louisiana Nephrology, Shreveport, LA, USA

Correspondence and offprint requests to: Anatole Besarab; E-mail:;

Conclusions. Roxadustat transiently and moderately increased
A B S T R AC T endogenous erythropoietin and reduced hepcidin. Adverse
events were similar in the roxadustat and placebo groups. Rox-
Background. Roxadustat (FG-4592) is an oral hypoxia-indu- adustat produced dose-dependent increases in blood Hb
cible factor prolyl hydroxylase inhibitor that stimulates erythro-
among anemic NDD-CKD patients in a placebo-controlled
poiesis. This Phase 2a study tested efficacy (Hb response) and trial.
safety of roxadustat in anemic nondialysis-dependent chronic Clinical Trials Registration. #NCT00761657.
kidney disease (NDD-CKD) subjects.
Methods. NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/ Keywords: anemia, chronic kidney disease, erythropoietin,
dL were sequentially enrolled into four dose cohorts and rando- hepcidin, HIF-PHI
mized to roxadustat or placebo two times weekly (BIW) or three
times weekly (TIW) for 4 weeks, in an approximate roxadustat:
placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb
change (ΔHb) from baseline (BL) and (ii) proportion of Hb re-
sponders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was INTRODUCTION
performed in a subset of subjects. Safety was evaluated by ad-
verse event frequency/severity. Anemia is a common complication of chronic kidney disease
Results. Of 116 subjects receiving treatment, 104 completed 4 (CKD) and is associated with significant morbidity and mortal-
weeks of dosing and 96 were evaluable for efficacy. BL charac- ity in dialysis-dependent (DD-) and nondialysis-dependent
teristics for roxadustat and placebo groups were comparable. In (NDD-) CKD populations [1, 2]. Erythropoietin (EPO) analogues
roxadustat-treated subjects, Hb levels increased from BL in a reduce the need for red blood cell (RBC) transfusion and have im-
dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. proved clinical outcomes and quality of life in dialysis [1, 3, 4] and
Maximum ΔHb within the first 6 weeks was significantly higher nondialysis [5, 6] settings. Anemia remains largely undertreated
in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb in NDD-CKD, in part from delayed referral to nephrologists
responder rates were dose dependent and ranged from 30% in and because EPO analogues require either intravenous (IV) or
the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and subcutaneous administration and are only available in nephrology
TIW groups versus 13% in placebo. settings [7, 8]. Further, 40–45% of patients in the USA initiate dia-
lysis without prior contact with a nephrologist, and as of 2011,
only 28% of newly initiated dialysis patients in the USA had re-
© The Author 2015. Published by Oxford University Press on behalf of ERA-
EDTA. This is an Open Access article distributed under the terms of the Creative
ceived one or more doses of EPO analogue prior to initiation of
Commons Attribution Non-Commercial License (
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and
reproduction in any medium, provided the original work is properly cited. For 1665
commercial re-use, please contact

Because of these prompted the US Food and Drug Administration (FDA) to differences between PK/PD cohorts and treatment cohorts. serious adverse cardiovascular (CV) reactions and not eligible for efficacy evaluation. sive rate of rise in Hb levels. iron transport and Subjects and treatment heme synthesis [22].oxfordjournals. San Francisco.0 or 0. the focus was evaluation of dose–response of rox. Because of robust approved by all appropriate institutional review boards. dose cohorts: 1. These findings 11. in two European settings. In controlled trials. For the ment period. sites only (see also legend to Figure 1). 20].5. Untreated or delayed treat. is a first in class. mula [23] of 15−59 mL/min/1. involves more frequent phlebotomies. BL Hb was defined as the mean of the three most recent Hb measure- M AT E R I A L S A N D M E T H O D S ments prior to the first dose of study drug.5. 18 into the PK/PD co- newly initiated on dialysis [7] may have contributed to the hort (11 to roxadustat. In contrast. while a small subset of these patients at se- transfusion [16] and mortality rates [17. so subjects enrolled subsequent to ment of CKD-associated anemia with Hb <10 g/dL is asso. 6 to placebo and 1 untreated) and 17 into doubling of the blood transfusion rate in such patients [15]. . there were a total of 99 treat- These consequences of untreated anemia and the limitations ment subjects randomized to one of four dose cohorts (1. placebo BIW or placebo TIW. and a 2:2:1:1 ratio at PK sites. ORIGINAL ARTICLE erythropoietic mechanisms [21]. A com- This was a multicenter. Thus. An additional 82 treatment subjects were enrolled (64 to roxa- plant because of allosensitization from transfusion [19. 3.0. Selective stabilization of HIF with small. BIW versus TIW or to placebo) as detailed in cessible treatments for CKD anemia based on alternative Supplementary Information and Supplementary Figure 1. 2017 transfusion rate reduces a CKD patient’s suitability for trans.5 and 4. some entry criteria and analyses differed from those at treat- tion and limit target Hb levels.7 mg/kg. and Roxadustat. also known as FG-4592. With respect to erythropoiesis. 1. Subjects with severe hypertension [diastolic blood pressure (BP) > 109 mmHg or Study design systolic BP > 170 mmHg at screening] were excluded.5% [10] and and endogenous EPO (eEPO) levels in blood over time. maining 82 subjects were randomized 10:10:3:3 at treatment at the latter. PHI). planned higher conducted in accordance with the Declaration of Helsinki dose cohorts (2.0 g/dL to be included in efficacy analyses. If the and evaluation of frequency of administration] of roxadustat subject was on oral iron at BL during enrollment. HIF stabilization upon PK data from this trial will be presented together with those hypoxia or by HIF-PHIs induces activation of a group of of subsequent Phase 2 studies in a different manuscript. Downloaded from http://ndt. 18]. was Hb responses in the 2. Besarab et al. which 41% [11] received EPO analogues prior to dialysis. Inc. remain on a stable dose of oral iron throughout the study. The Eligible subjects were sequentially enrolled to one of four trial was registered at Clinicaltrials. respectively. proteins promoting iron absorption. issue multiple warnings in 2007 to reduce EPO analogue utiliza. weekly. first 35 subjects were randomized in a 7:7:2:2 ratio at treatment Initially. A higher RBC lected study sites could also participate in the PK/PD substudy. including those for EPO.0 mg/kg dose cohorts. effective and ac. TIW)] and up to a 12-week follow-up period. defined by an estimated glomerular filtration rate using to anemia treatment. Herein. with sequential dose escalation dices is provided in the Supplementary Information. The resulting downward trend in Hb in US CKD patients After 35 patients had been enrolled. De- sisted of a 28-day screening period.0 mg/kg) were not evaluated. potent all subjects from the PK and treatment cohorts are included hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF. FDA guidance for NDD-CKD patients has study was interrupted and then resumed under an amended emphasized ‘use the lowest dose of erythropoietin analogue to protocol with removal of PK-only cohorts that were initially avoid transfusions’ and to limit initiation of EPO analogues to planned to be tested (2. the Since June 2011. BIW) or 26 (three times investigator’s discretion. Thus. ‘early response’ target genes. subjects in the stroke occurred when EPO analogues were administered target.5 and 3. the treatment cohort (13 on roxadustat and 4 to placebo). this protocol amendment were all ‘treatment subjects’ (screen- ciated with a higher likelihood of hospitalization. The re- (mostly nephrology clinics but some from the PK/PD sites).gov (NCT00761657). a 4-week treatment period cisions relating to need for oral iron were otherwise left to the [Day 1 to Day 29 (two times weekly. they had to in subjects with anemia and Stage 3 or 4 CKD. dialysis [9]. of EPO analogues call for exploration of safer. 1. 2. there were pharmacokinetic/pharmacodynamic sites.73 m2 and not receiving dialysis. to roxadustat BIW. 26. randomized study [single-blind prehensive list of eligibility criteria including those for iron in- (subjects). further lowering targets in 2011 ment sites (see Supplementary Information).7 mg/kg. 13]. During the 4-week treat- adustat in raising Hb in anemic NDD-CKD patients. 3.0 mg/kg) to avoid exces- those patients with Hb <10 g/dL. oral roxadustat or placebo was administered as PK/PD cohort. Subjects were enrolled at 27 treatment and 2 PK sites. Similarly. treatment cohorts had to be anemic with baseline (BL) Hb ≤ ing hemoglobin (Hb) levels >13 g/dL [12.. placebo-controlled. subjects in the PK/ The safety of using EPO analogues to treat CKD-associated PD cohort were permitted to have an entry Hb up to 13 g/dL to anemia has been questioned. EPO re- ceptor. in the safety analyses. roxadu- (PK/PD) cohorts (at Phase 1 units) and treatment cohorts stat TIW. RBC ing Hb ≤ 11 g/dL). greater risks avoid declines in Hb from repeated blood sampling and were for by guest on January 4. [14]. 2. dustat and 18 to placebo). the major goal was to measure roxadustat levels capsules (FibroGen. The study con. we report the first Phase 2 clinical the modification of diet in renal disease (eGFR-MDRD) for- trial of roxadustat in anemic NDD-CKD patients. Treatment subjects are included in the efficacy analyses.5. CA) according to 1666 A. The and subjects provided written informed consent.0 and then 0. Eligible subjects were 18−80 years old with Stage 3 or 4 molecule HIF-PHIs may be an innovative therapeutic approach CKD.

org/ by guest on January 4. as median. transferrin tient screening and disposition are summarized in Figure 1. electrocardiograms. *The AEs in the roxadustat arm were acute prostatitis (in the 1. Weekly Hb was obtained. dosing was discontinued.0 mg/kg BIW group). Optional automated blood pressure monitor. IV iron. was estimated using the Kaplan–Meier method. statistical power. Dose modifications Statistical analysis Excessive erythropoiesis was defined as ≥2.3 or higher. One placebo patient was discontinued because of SAEs of acute pericarditis and renal failure. PD data for eEPO are presented 6-week study period (ΔHbmax).0 mg/kg TIW group) and elevated liver enzymes (in the 2. transferrin. the goal being exploration of trends in Hb at sessment during the treatment period.0 g/dL increase Sample size of this exploratory study was not determined by in Hb within any 2-week period or ΔHb ≥3.5 weeks [efficacy-evaluable (EE) population]. Efficacy analyses were conducted on those subjects of the latter. Levels of plasma with EPO analogues. cluded from analysis.0 g/dL at any as. the doses selected in order to determine dose levels for future study drug doses were lowered by 50%.1. Patient disposition ing (ABPM) was performed in some patients. Safety assessments were based on physical examinations. Of 293 subjects screened. Pa- utilization included serum iron. the 2-week period beyond the dosing period permit. two weeks beyond study drug. and the subject was who had an Hb ≤11 g/dL at BL and who received study treat- followed up. and statistical sig- response was also assessed by the mean ΔHb at the end of nificance was based on P ≤0. to capture those with parisons. Results are presented as mean ± SD (text or tables) delayed response and the mean maximum ΔHb during the and mean ± SEM in figures. clinical laboratory tests and the incidence and severity of adverse events (AEs) and assessed by each R E S U LT S study investigator from the onset of treatment through to the end of follow-up. androgens or RBC transfusions eEPO for up to 72 h following dosing on the first and last was prohibited during the treatment period and for the first days of treatment were measured in the 17 subjects enrolled 4 weeks postdrug treatment but allowed during the remainder at the PK/PD sites. In confirmed cases studies. ferritin and hepcidin. The proportion of roxadustat sub- Hb response was defined as a change from BL Hb (ΔHb) of jects who achieved Hb response was compared with those of ≥1 g/dL at any time from Day 1 of treatment through 2 weeks of placebo subjects using Fisher’s exact test. Downloaded from http://ndt. 2017 F I G U R E 1 : Patient disposition. Time to response follow-up. ΔHb was compared between roxadustat-treated and placebo subjects Assessments using analysis of variance. In cases of the former. ment for ≥2. 117 were randomized to receive Exploratory biologic correlates of erythropoiesis and iron roxadustat (n = 88) or placebo (n = 29) at 29 US study sites. The Roxadustat in NDD-CKD anemia 1667 . ORIGINAL ARTICLE dose group and frequency. Subjects with any missing values were ex- of the follow-up period. The magnitude of were performed using SAS v9. Oral iron was permitted at all times.05 unadjusted for multiple com- Week 6. All analyses ting assessment of ongoing erythropoiesis. Treatment saturation (TSAT).oxfordjournals.

6) 10.9 (0.5 mg/kg 2.7) 4 (44.2) 31.1) 0 1 (7.8) 30.3 (6.8) 9 (90.2) 0 1 (8.4) 9 (90.1) 6 (60. 2017 .4) 3 (2.4) 8 (72.7) 64 (55.8) Race.9 (10.8) 92.6 60.5) 3 (27.0) 13 (100) 8 (66.8) 8 (66.3) 2 (22.7) 9.1) 32.8 63.0 (9. mean (SD) 28.5 (13.7) 27 (23.3) 3 (25.0) 1 (9.2) 91.0 mg/kg 1.3) 31.5) 10 (83.1) 0 0 1 (8.5) 10.7) 7 (77.4 (12.1 (8.4 (10.6) Age in years Mean 68.2) 4 ( by guest on January 4.1 (15.1 (6.6 64.6 (14.1) 231 (143) 174 (181) 167 (178) 228 (184) 184 (101) 242 (218) 190 (89. hemoglobin.0) 7 (63.0) 49 (55.5) 67 (57. Hb.3) 6 (60.0) 28.6 (7.0) 3 (33.3) 24.7 (9.7) 91.5 64.0 (9.4) Other 0 0 0 2 (16. n (%) Male 16 (57.3 (0. ORIGINAL ARTICLE 1668 Table 1.7) 6 (50.5 (5.4) 199 (150) 206 (161) >100 ng/mL.2) 33.7) ≤100.2) Black 11 (39.9) 10. mean (SD) 31.6 (11.9) 34. n (%) 21 (75.2) 6 (50.7) 20 (22. transferrin saturation.0) 11 (100) 6 (54.5) 49 (42.1 (11.7) 77 (87.4 (9. Besarab et al.3 (1.8) 3 (25.0) 55 (62.5) >20%.6) 1 (10. ng/mL n (%) 7 (25.4) 32.9) 10. Downloaded from http://ndt.0) 4 (36.3) 89 (76.3 (0.1 (14.6) Hb (g/dL).5) 13 (11.3) 0 0 0 0 1 (8.0 (7.3) 5 (41.0) 9 (81.1) 90.7 (12.3) 2 (2.8) ≤20%.2) Ferritin (ng/mL).3 66.0 (11.5 (14.0 63.mean (SD) 10.6) 45 (38.3 (12.7 mg/kg 1.8 Range 56–79 57–73 47–75 52–80 54–79 52–77 49–72 53–82 49–76 47–82 47–82 eGFR (mL/min/1.1) 10. A.7) 27.0) 9 (69.7) 34 (38.0) 10 (90.2) 40.3) 11 (12.0 (15. TSAT.1 (0.3) 34.0) 33 (37.0) 0 5 (45.4 (1.3) 68 (77.3 (0.9 (8.0 65.0) 4 (30.3) 3 (30.0) 5 (55.5) 30.3) Cuff BP (mmHg).5) 103 (88.8 (6. mean (SD) 92.3) 4 (3.1) 3 (27.7) 33. n (%) 26 (92.3) 5 (55.7 (5.0) 0 4 (33.9) 10 (100) 12 (92.5) 93.7) 10.7) 9 (75.4 (8.4) 91.9) TSAT (%).0) 93.73 m2).6 (12.3 (0. n (%) White 15 (53.8 64.3 (7.4) 23.5) 2 (16.8) Asian 2 (7.oxfordjournals.5 67. n (%) 2 (7.8) 11 (100) 11 (91.1) 25.6 (0.2) 96.7) 4 (40.7 (15.7) 88.1 (1.3) 6 (60.0) 6 (46.2) Female 12 (42.0 mg/kg Pooled roxadustat Total (N = 116) (n = 88) BIW (n = 10) TIW (n = 13) BIW (n = 12) TIW (n = 9) BIW (n = 10) TIW (n = 11) BIW (n = 11) TIW (n = 12) Sex.9) 4 (40.9) 8 (72. Patient demographics and BL characteristics (safety population) Characteristics Placebo (n = 28) 0.7 (10. estimated glomerular filtration rated (MDRD formula).7) 4 (33.0) 10.0) 88.2) 1 (10) 2 (18.0) 7 (70.1) 0 0 0 0 3 (3.3) 6 (66.6) 4 (40.7) 3 (33.0) 7 (53.6 69.0) 28.2 (9.1) 38.9) 10. mean (SD) 228 (193) 164 (68.7) 1 (11.3 (0.6) 7 (70.3) 8 (66.5) 35.8) 10.4) 30.0) 3 (30.6) eGFR.

dose regimens.s. roxadustat TIW (4. End of treatment (EOT) for n.5 and 2.5 or subjects and 28 placebo subjects. oral iron was begun in ORIGINAL ARTICLE Hb response rates were 13% in the pooled placebo group.8 ± 114 ng/mL). At 2 mg/kg dose. Nonresponders were *P < 0. BL characteristics were representative of subjects with Stage Fewer observations (n = 1−3) were available for the other 3–4 CKD and generally comparable across treatment groups. to roxadustat and 6 randomized to placebo) were enrolled at Plasma eEPO levels over time on Day 1 and Day 29 are pre- PK/PD sites and comprised the PK/PD population.8 g/dL (Figure 2). Last-observation- used. eEPO began to rise ∼4 population consisted of 73 (83.0 mg/kg dose groups were both significantly decreased from BL (−150 ± 89. a difference between placebo and pooled roxadustat-treated Three subjects had a ΔHbmax > 3. Oral quency. carried-forward (LOCF) method was used to impute missing values. Daily iron dose pre.0 mg/kg per week) achieved a response Serum hepcidin levels decreased significantly during treat- ment with roxadustat (Figure 5).1 (0. the time course of eEPO rise and fall was essentially the same as on Patient characteristics Day 1. Mean (SD) BL Hb was 10. sented in Figure 4 for six subjects in the placebo group and five eight (88.2%) placebo subjects in the 1.1 (0. median of 113 IU/ (82. Hb response and other biologic activity Iron indices were evaluated in the EE subjects. With study medication For the EE population. respectively.5 or 2. L and returned to BL within 24−48 h.6%) roxadustat subjects and 26 (92.5 and 2. 2017 having been administered TIW during the first 4 weeks.1 (0.7 mg/kg BIW and TIW groups.5. *From an intergroup t-test compared with placebo.048. fraction receiving oral iron between placebo (39%) and roxadu- ΔHb at 6 weeks in the 1. TIW was Day 26.1%) placebo subjects. peaked at ∼10 h. For period.0%) roxadustat subjects and 23 h after dosing on Day 1. there was no significant difference in the Downloaded from http://ndt.0 mg/kg BIW and TIW groups.7) g/dL for roxadustat population). and −225 ± 192 ng/mL.01 intergroup two-sample t-tests comparing roxadustat change censored at Day 42. eEPO subjects completed the study through the end of the treatment levels postdose remained essentially unchanged from BL.1 (0.5–6. P = 0.6) g/dL for placebo subjects. defined as Hb increase by ≥1 g/dL (EE F I G U R E 3 : Mean change from BL in Hb (ΔHb) in TIW cohorts (EE population). On Day 29. F I G U R E 2 : Mean maximum change from BL in Hb (ΔHbmax) and % subjects achieved Hb response. with a maximal observed value of 705 IU/L. 80 and 91% in fell while total iron-binding capacity (TIBC) rose significantly.5 mg/kg BIW and TIW groups and 100% in both 2.1 g/dL (both at P < 0.and poststudy ranged was both significantly greater than that of the placebo group: from 39 to 300 mg/day with a median of 130 mg/day without +1. Time to response was estimated using the Kaplan–Meier meth. were iron-replete at BL. Reasons for drop out are itemized in Figure 1.6) g/dL for placebo subjects. od. which was then continued. estimable for groups with >50% response. Levels invariably returned to BL within 48 population of 116 subjects included 88 roxadustat-treated at a median of 14 days compared with 25 or 21 days in the 1. TSAT and 40% in the 1.oxfordjournals.0 mg/ consistent with increased iron utilization.0 mg/kg BIW group. Seventy.01) (Figure 3). No significant kg groups. Of the 116 subjects. groups. Roxadustat in NDD-CKD anemia 1669 . 30 two roxadustat subjects only. 45% were already on ΔHbmax during the 6-week study period ranged from oral iron prior to study (10–626 days).0 mg/kg changes occurred in the placebo group (Table 2). In placebo subjects. Subjects treated with 1. Peak eEPO increased with dose but not fre- except for some gender and race differences (Table 1).4% of subjects at least once during study. Pooled placebo data subjects and 10.0 mg/kg BIW groups (3–4 mg/kg per week). respectively.: not significant. 0. By 4 weeks. The EE subjects in the 1. 60 During 6 weeks of roxadustat-induced erythropoiesis.8 versus −0. respectively) compared with the placebo group (−17. with median peak eEPO levels reaching 121 IU/L.2 ± by guest on January 4. Of these. P = 0. most of whom Roxadustat increased Hb in a dose-dependent manner.0 g/dL. the median peak level was 397 IU/L iron was taken by 53.7) g/dL for roxadustat TIW subjects and 10.8 ± 0. mean (±SD) hep- cidin levels in the 1. the 1.0 mg/kg BIW group.0 mg/kg treatment groups stat (47%) groups. from BL with placebo change from BL. and 58% in the roxadustat 0.2 and +1. No IV iron was permitted on study. During the active study period.0013. Mean (SD) BL Hb was 10. 17 (11 randomized 2.9 to 2.

**P = 0.4)* Ferritin (ng/mL) by guest on January 4.5 (150) 141. Two episodes of moderate AEs (SAEs) were reported by four (5%) roxadustat-treated exacerbation of hypertension were reported by one site investi- subjects and one (4%) placebo patient.0 (6. These events were deemed unrelated to study medica- graft infection 4 days after arteriovenous (AV) graft placement tion.6) 248.1 (17. Downloaded from http://ndt. Safety AEs were reported by 52 (59%) roxadustat-treated and 13 (46%) placebo subjects.9) 25. *P < 0.1) −8. pite a good Hb response for 6 weeks.2 (170.1 (7. **P = 0.7) +41.5) 287. fem.2) −37. P-values are from intergroup two-sample t-tests comparing roxadustat change from BL with placebo change from BL. No hypertension exacerbation or other AEs of special whose BL eGFR was 18.8 (9. Data are for the PK/PD population (subjects with complete dataset only). All AEs are reported in Supplementary Table 1.3 (21.8) Data are for the EE population.1 (9. received the lowest roxadustat dose 0. LOCF method was used to impute missing data.7 mg/kg oral neck fracture. the SAEs in roxadustat.5) 58.4 mL/min.8 (61.4) −9. elevated alanine aminotransferase (ALT).9 (6. BIW and TIW placebo groups and all roxadustat treatment F I G U R E 5 : Mean change from BL in serum hepcidin (EE popula- groups were combined. the patient Liver function was monitored.0) 193. and overall. 26 (TIW). gator as AEs in the same patient who had a prior history of treated subjects included vascular access complications.5)a −68. One patient with a history of presented with signs and symptoms compatible with ‘graft’ in.0 (23.048.3 g/dL.0013.0001.3) TIBC (μg/dL) 248.5 (51.3) TIBC (μg/dL) 246. Besarab et al. .4 (128.1) −7. aspartate amino- No CV SAEs and no death occurred during study.3 (52. EOT was Day 29 (BIW) or Day 26 (TIW). Serious lation.8 (45.oxfordjournals.8 (8.4) 20. ferritin and TSAT levels Mean (SD) levels BL EOT Change from BL ORIGINAL ARTICLE Roxadustat (n = 73) (n = 67) Serum iron (μg/dL) 69.6) Ferritin (ng/mL) 234. group. a left arm AV graft was no safety signal was detected from the ABPM (data not shown). TIBC. 2017 Table 2.3) −11. Change from BL in mean serum iron.6 (26. heavy alcohol intake had study treatment discontinued due to fection and was treated with clindamycin and vancomycin. Des.7) 64.3 (43. noncardiac chest pain and dyspnea. *P = 0.0 mg/kg dose a n = 66.8 (70. transferase (AST) and bilirubin levels following the first dose 1670 A. no such AEs were reported. The BIW and gained excessive fluid weight. F I G U R E 4 : Changes in median plasma EPO on first and final days of treatment. EOT was Day 29 (BIW) or Day tion). interest were reported in the higher dose groups. Data from BIW and TIW groups were pooled for each dose level.1) TSAT (%) 28. hypertension. Serum hepcidin was not measured in the roxadustat 1. Four days later.9 (198.1 (19.3) TSAT (%) 29.1 (19.036. Details are given in vascular access complication was reported in a patient with Table 3.3) −3. intergroup two-sample t-tests comparing roxadustat change from BL with placebo change from BL. thromboembolic and CV events in CKD (Table 3) and did not differ clinically differ between during roxadustat treatment are of special interest in this popu- groups. placed to prepare for future dialysis. the most common AEs were expected The incidences of seizure. Initial Hb was 9.3)** Placebo (n = 23) (n = 18) Serum iron (μg/dL) 71.5 (19.8 (40.

the data from the present clinical trial are the poietic induction of iron absorption genes in the small intestine first to demonstrate the ability of an orally available HIF-PHI to but also for the increase in serum iron. data on file).0 mg/kg administered orally BIW or TIW increased Hb Number of subjects with TEAEa. This patient rapidly gained 8. AST and bilirubin levels following the first dose of study drug. possibly via direct of Week 6. Peak eEPO levels were within the Dizziness 2 (2.2 ure and stroke) [4. logues [35–37]. n (%) concentrations in NDD-CKD subjects who received no IV iron supplementation. a Induction of erythropoiesis by HIF stabilization through roxa- MedDRA version 11 (Part 1) or 13.5 and 2. which is necessary for treat CKD-associated anemia in man. Supplemental IV iron dence of liver toxicity or sustained increases of liver enzymes or improves Hb response to recombinant EPO [34] and is fre- serum bilirubin were reported in this study.5) 0 as improved iron delivery to the erythron from hepcidin reduc- Peripheral edema 3 (3. rate of Hb rise and direct stimulation noted. 2017 lower extremity edema. Roxadustat stimulated erythropoiesis and treated subjects during the dosing period of 4 weeks. all but one increased Hb concentration with the use of oral rather than sup- with the 1.1%) roxadustat subjects received EPO analogues. During the tion. this was accompanied by worsening levels of recombinant variants of EPO to induce erythropoiesis Downloaded from http://ndt. increased intestinal iron absorption and increases in iron transport en- DISCUSSION zymes [40]. strate that HIF acts as an iron sensor [39] and that HIF stabil- ization is associated with hepcidin suppression. other completed Phase 2 in the 0. BP was 136/87 and 138/84 mmHg with weight below BL at 97. 26] whereas Insomnia 2 (2.5%) during 4 weeks of treatment. impact on iron metabolism.043. This will be explored and con- None of the above episodes was associated with hypertension. One patient with a history of heavy alcohol intake had study treatment discontinued with greater EPO analogue doses is controversial. a key regulator of iron absorption and remobiliza- secondary to worsening congestive heart failure). Diastolic pressure increased [28.oxfordjournals. Use of greater doses in CKD patients is associated with only with the first larger weight gain to 99 mmHg. hospitalization for congestive heart fail- of study (16 weeks).1%) roxadustat patient (0.1) 13 (46.7 efficient erythropoiesis [41].6) Concomitant changes in eEPO. underlying due to elevated ALT.5) 1 (3.6) Back pain 4 (4. Improvement in TIBC seizure or CV event. all of which normalized within a week. Hb responses were prompt. 33].5 kg of fluid with decreases of BP reduction to 138/89 mmHg after first episode and 137/87 mmHg after second episode. AEs reported in three or more subjects −2.7 mg/kg TIW dose group and were considered to be unrelated to the study drug. Headache 6 (6.1) 2 (7. anemia follow-up period of 12 weeks.6 and 5.0 g/dL. 11 (12. 29].3) 2 (7.1) the 48-h time-averaged concentration is comparable with that Urinary tract infection (UTI)b 1 (1. SAEs with roxadustat included a Grade 3 [National Cancer Institute’s Common Limitations of this first proof of concept study of roxadustat Terminology Criteria for Adverse Events (CTCAE). increases in eEPO to near physiologic levels and improved iron transport and potentially enables effective anemia therapy without the adverse effects associated with EPO analogues. in a coordinated manner. BL BP was for 24 weeks (FibroGen by guest on January 4. Roxadustat in NDD-CKD anemia 1671 . Although variable transient heart rate increases were comorbidities. transfusion of three units of RBC 2 days after first roxadustat can prevent the development of functional iron deficiency. P = 0.7 mg/kg BIW. Functional iron deficiency is a common cause of suboptimal of study drug.1) 2 (7. Hb responses to EPO analogue therapy.1 (Part 2) preferred term. Two AEs of moderate exacerbation of hypertension occurred in the same patient receiving roxadustat trials have demonstrated durability of Hb response 0. dose (for Hb 8. Roxadustat doses of 0. hip fracture. 30. hepcidin and iron indices Fatigue 4 (4. However. HIF stabilization by HIF-PHI ap- roxadustat-treated subjects and 1 (3.1) physiological range seen with acute bleeding [25.1) treated with EPO analogues [24]. All these occurred and modest sample size..8) 1 (3. Roxadustat was well tolerated. b Post hoc analysis roxadustat versus placebo using Fischer’s exact test showed a difference dustat. five (17.4) 0 tion and increased TIBC. no clinically significant changes or trends in vital signs or laboratory values were of nonerythroid tissue have all been proposed [29. shorter than Any TEAE 52 (59.1) 3 (10. 31]. 131/83 mmHg. In total. pears to support erythropoiesis when biomarkers of iron me- enced an Hb level >13 g/dL on at least one occasion by the end tabolism indicate relative iron deficiency. No evi. On both occasions. see legend to Supplementary Table 1] in CKD patients include short treatment duration of 4 weeks AV fistula site reaction. quently provided as a necessary adjuvant therapy to EPO ana- Excessive erythropoiesis occurred in eight (9. firmed in subsequent Phase 3 studies. Two of these had their last plemental IV iron.4 kg above his BL weight over periods Current EPO analogue therapies rely upon supraphysiologic of 12 and 8 days. respectively. which ORIGINAL ARTICLE then normalized within a week. respectively. As ferritin and TSAT tended to decrease dose held because of ΔHb ≥3. The basis for poorer CV outcomes kg. Results of numerous investigations demon- and eight (9. The overall Roxadustat (n = 88) Placebo (n = 28) median time to increase Hb ≥1 g/dL was 21 days. At 6 weeks (2 weeks postdosing) and end (myocardial infarction. worsening heart failure symptoms and increases in systolic pressure from BL of 131–184 and 173 mmHg. 30.3–98. all of which decreased to <12 g/dL within 4–8 weeks. 32. permitting the efflux of stored One (1.7 mg/kg TIW) received a iron from macrophages and influx of oral iron onto transferrin.6 and 5. iron status.0 mg/kg doses.5) 0 indicated coordinated erythropoiesis from both eEPO as well Hyperkalemia 4 (4.0 g/dL during treatment for an SAE of dyspnea Hepcidin.4) the range of 29–43 days reported in similar patient populations Diarrhea 8 (9. observed.6%) placebo subject experi. Recent studies in HIF-2α knockout mice have shown that intestinal HIF-2α is critical not only for the erythro- To our knowledge.9%) placebo subjects and hypoxia [38]. and suppression of hepcidin.1%) roxadustat. is characterized by transient for UTI only.3) 1 (3. Aggressive diuresis was needed to worsening hypertension and increased risk for CV events remove 8. noncardiac chest pain and dyspnea.7) of high-altitude acclimation [27]. BL weight at entry was 100 kg for this 165 cm tall individual.Table 3. is normally downregulated by erythropoiesis.6) Seasonal allergy 1 (1.

Hypoxic regulation of erythropoiesis and iron metabolism. J Am Soc Nephrol 2006. 44: 866–876 Soc Nephrol 2007.B. Macdougall IC. Mohanram A. 324: 1339–1344 7. 2013 Annual Data Report: Atlas of End-Stage 33. Besarab Tang KL et al. Erythropoietin production in patients 1.B. 28: 1504–1515 16. In summary.oxford- ® 14. Cotes PM. C O N F L I C T O F I N T E R E S T S TAT E M E N T Semin Nephrol 2006. 361: 2019–2032 13. 19: 1599–1605 8. observational cohort study. Zhang Y. http://pi. Macdougall IC et al. Bosch JP. Stevens LA et al. Macdougall IC. 6: 2579–2586 1672 A. Levey AS. Clin J Am Soc Nephrol 2013. All authors ings in 2006. J Appl Physiol 1985.A.Y. Selvin E. Am A. 17: 1181–1191 2007. Goon Spinowitz BS. Gandra SR et al. Kato A. Fox KM. N Engl J Med 2006.B. prospective.N. T. was af. Am J Kidney Dis 2004. Baptista J et al. All authors reviewed the manuscript and signed blood cell transfusions does not decrease allosensitization rates in potential off on its accuracy. 5: 882–888 FibroGen Inc. 34. Effect of red cell transfusions on future kidney transplantation. kidney transplant candidates. PRE-dialysis survey on an- NDD-CKD patients increased Hb in the absence of IV iron aemia management. Renal Data System. Egrie JC.R. Cheung WK. 8: 610–618 Nephrol 2011.pdf (20 March 2015. The balance of benefits and risks with roxa.. Leukocyte reduction of red Downloaded from http://ndt. Obrador GT. plant 2009. Renal Disease in the United States. ASAIO J 1994. Regidor DL. Prevalence of chronic kidney disease in and its relation to plasma renin. 2017 the analyses.. 16: 267–271 18.. Results of a tiple subcutaneous doses to healthy subjects. Xia A et al. Trends in anemia treatment with erythropoi. The non-haematopoietic biological effects of erythropoietin. Arcasoy MO. 24: 578–588 12.-H. 25: 548–554 2008. Besarab A. contributed pa- ease in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol 2013. Erythropoietin response to blood loss in hemodialysis patients is blunted but preserved. Pharmacokinetics and pharma- 3. Bethesda. Provenzano R et al. MD: National Institutes of Br J Haematol 2008. Milledge JS. 355: 2085–2098 Supplementary data are available online at http://ndt. Nephrol Dial Transplant 2013. Tucker B et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. Macdougall IC. Correction of the anemia of end. date last accessed) ficiency anemia in CKD. Valderrabano F. N Engl J Med 2009. Novel erythropoiesis stimulating pro- dialysis chronic kidney disease (CKD) patients: a multicentre prospective tein for treatment of anemia in chronic renal insufficiency. Clin J Am Soc Nephrol vival in hemodialysis patients. National Institute of Diabetes and Digestive and Kidney Diseases. Clin J Am tality in hemodialysis patients. Locatelli F. At the time the study was performed. Yan G. Seliger S. Schmidt R. Pfeffer MA. Stefanik K et al. K. N Engl J Med 1987. Haase VH. closures. 30. Levin A. Olivares J.J. 18: 89–100 11. Macdougall IC. Epoetin requirements predict mor- for initiation of treatment of anemia of chronic kidney disease. JAMA 2007. Anaemia management in non. Secondary analysis of the CHOIR ciated with recombinant human erythropoietin therapy for predialysis trial epoetin-alpha dose and achieved hemoglobin outcomes. Chen CY et al. 40: REFERENCES M880–M885 26. Kausz AT. Fort J et al.B. 16: 645–651 etin usage and patient outcomes. Dembinski I et al. Pochinco D. 130: 461–470 filiated with the Henry Ford Health System and with Wayne 24.H. Health-related quality of life asso. controlled trials in multicentre. The associations between race and geo. 316: 73–78 64: 412–423 4. Eschbach JW.E. Besarab et al.). Epogen Package Insert. Timing of erythropoiesis- stimulating agent initiation and adverse outcomes in nondialysis AUTHORS’ CONTRIBUTIONS CKD: a propensity-matched observational study. patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. 2009. Mechanism of increased mortality risk with erythro- hemoglobin and administered erythropoiesis-stimulating agent and sur. Kidney Int 2004. with chronic renal failure. Erslev AJ. GillKS. Erythropoietin. Walker R et al. was the study sponsor that designed the study in 17. Locatelli F. Epoetin alfa once every 2 weeks is effective 31. Kidney Int chronic renal disease patients. Gallieni M et al. J Am Soc Nephrol 2004. 26: 313–318 ORIGINAL ARTICLE 22. Downing MR et al. Singh AK. Modification of Diet in Renal Disease Study Group. Ferumoxytol for treating iron de- http://www. Inrig JK et al. Hishida A. Szczech LA.amgen.L. Serum erythropoietin in humans at high altitude 2. All authors had full access to the study data and 19. Ma JZ et al.P. Kidney Int 2001. are employees of J Physiol Renal Physiol 2010. 66: tients to the study. Correction of anemia with epoetin alfa S U P P L E M E N TA R Y D ATA in chronic kidney disease. C. 35. glomerular filtration rate from serum creatinine: a new prediction equation. poietin treatment to higher hemoglobin targets. LafayetteRAetal. Burdmann EA. . Ross SP. Nephrol Dial Trans- both nondialysis and dialysis populations.L. 8: 852–860 21. Am J Kidney Dis 1995. N Engl J Med 1991. Wiecek A. Perez-Garcia R. S. 2: 1274–1282 5..B. 2: 215–221 32.S. Szczech L. 32: S133–S141 27. There are no other dis. Minutolo R. Thamer M. Am J Kidney Dis 1998. Zhang Z. R. Ren Fail 1994. study in renal clinics. S. Benz R. J Am Soc Nephrol 2008. FibroGen was responsible for data collection 1131–1138 and analysis. Barnhart HX. Guilfoyle MC et al. is a former employee of FibroGen. 28: 3035–3045 60: 741–747 9. Curr Opin Nephrol Hypertens 2007. Clin Pharmacol Ther 1998. Brown RE. 74: 791–798 6. Ma JZ. Martin-Malo A. A more accurate method to estimate FibroGen and hold stock and/or stock options in FibroGen. oral roxadustat administered BIW or TIW in 10. Ann Intern Med 1999. Kovesdy CP et al. MuntnerP. Collins AJ. Recent advances in erythropoietic agents in renal anemia. date last accessed) journals. Shahinfar S et al. 3: 337–347 25. Fishbane S. Baseline characteristics of an supplementation. Karpinski M. 299: F1–F13 23. Associations between changes in 29. Lewis JB et al. A. Redblood celltransfusion use inpatients with chronic kidney disease. 36. 15: 818–824 20. The treatment of anemia in chronic kidney disease: understand- consultation with the Principal Investigator (A. Dose-finding study of peginesa- graphic area and quality-of-care indicators in patients approaching tide for anemia correction in chronic kidney disease patients. Cheung AK. McCrea JB. Clin J Am Soc Ne- phrol 2010. corrects anemia in State University School of Medicine. and T. 59: 360–364 the United States. combined phase I and II clinical trial. Clin J Am Soc ESRD. Nephrol Dial Transplant by guest on January 4.K.oxfordjournals. Kelly K et al. Nephrol Dial Transplant 2003.htm (1 October 2014. incident haemodialysis population in Spain: results from ANSWER—a dustat is being evaluated in ongoing large. Revicki DA. Coresh J. Clin J Am Soc Nephrol 2008. codynamics of recombinant human erythropoietin after single and mul- stage renal disease with recombinant human erythropoietin. Horl WH. Walker R. epogen_pi_hcp_english. 15. Feeny DH et al. 141: 14–31 Health. Anemia and end-stage renal dis- except those of the sponsor but including A. Kopple JD. 298: 2038–2047 28. Kumagai H et al.

26: 323–342 19533–19540 39. Shah YM. 2017 ORIGINAL ARTICLE Roxadustat in NDD-CKD anemia 1673 . C. Woitas RP et al.7.A. Anderson ER. Locatelli F. 117: 1926–1932 Received for publication: 7. Accepted in revised form: 9. Intestinal hypoxia-inducible transcrip- rects anaemia and maintains haemoglobin in patients with chronic tion factors are essential for iron absorption following iron deficiency. Xue X. Cell kidney disease not on dialysis.oxfordjournals. Regulation of iron metabolism by hepcidin. Nemeth E. Annu Rev (HIF-2α) is critical for efficient erythropoiesis.E. once every 4 weeks cor. J Clin Invest 2007. Nephrol Dial Transplant by guest on January 4. Schuepbach RA et al. Intestinal hypoxia-inducible factor-2α 38.R.5.37. Roger SD. Ito S et al. Shah YM. 26: Metab 2009. J Biol Chem 2011.2015 Downloaded from http://ndt. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).2015. 9: 152–164 3980–3986 41. 286: Nutr 2006. Matsubara T. Peyssonnaux C. 40. Ganz T. Zinkernagel AS.