CLINICAL RESEARCH

Pooled Analysis of Roxadustat for Anemia

in Patients With Kidney Failure Incident
to Dialysis
Robert Provenzano1, Steven Fishbane2, Lynda Szczech3, Robert Leong3, Khalil G. Saikali3,
Ming Zhong3, Tyson T. Lee3, Mark T. Houser4, Lars Frison5, John Houghton4,
Dustin J. Little4, Kin-Hung Peony Yu3 and Thomas B. Neff3,*

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1
School of Medicine, Wayne State University, Detroit, Michigan, USA; 2Department of Medicine, Donald and Barbara Zucker
School of Medicine at Hofstra/Northwell, Great Neck, New York, USA; 3FibroGen, Inc., San Francisco, California, USA;
4
AstraZeneca, Gaithersburg, Maryland, USA; and 5AstraZeneca, Mölndal, Sweden

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Introduction: Erythropoiesis-stimulating agents are associated with increased cardiovascular risk when
higher doses are used toward higher hematocrit targets. Patients new to dialysis are at higher risk for
morbidity and mortality. Systematic evaluation of this population was predefined in the roxadustat clinical
development program. Roxadustat is a hypoxia-inducible prolyl hydroxylase inhibitor.
Methods: Data were pooled from 3 phase 3, randomized, open-label, active-controlled trials. Eligible
adults had kidney failure and initiated dialysis for 2 weeks to # 4 months prior to randomization to
roxadustat or epoetin alfa. Efficacy was assessed as mean change in hemoglobin from baseline

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averaged over weeks 28 to 52, regardless of rescue therapy. Key cardiovascular safety endpoints were
major adverse cardiovascular events (MACE; all-cause mortality [ACM], myocardial infarction, and
stroke), and MACEþ (MACE plus unstable angina or congestive heart failure requiring hospitalization),
and ACM.
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Results: This study included 1530 patients with kidney failure incident to dialysis. Mean (SD) changes in
hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy, were 2.12 (1.45)
versus 1.91 (1.42) g/dl in the roxadustat and epoetin alfa groups (least-squares mean difference: 0.22; 95%
CI, 0.05 to 0.40; P ¼ 0.0130). Risks of MACE and MACEþ were lower in the roxadustat group (hazard ratio
[HR], 0.70; 95% CI, 0.51 to 0.96) than the epoetin alfa group (HR, 0.66; 95% CI, 0.50 to 0.89); the HR for ACM
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was 0.76 (95% CI, 0.52 to 1.11).
Conclusion: Roxadustat was at least as efficacious as epoetin alfa. Roxadustat had a lower risk of MACE/
MACEþ in patients new to dialysis.
Kidney Int Rep (2021) 6, 613–623; https://doi.org/10.1016/j.ekir.2020.12.018
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KEYWORDS: anemia; chronic kidney disease; dialysis; roxadustat

ª 2020 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

the first US Renal Data Systems Annual Data Report

See Commentary on Page 559
(ADR), Eggers documented that survival rates after the
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first year of dialysis ranged from 75.3% for white pa-

lobally, it is estimated that 2 million patients with
G chronic kidney disease (CKD) receive renal
replacement therapy every year; however, this may
tients to 82.9% for black patients.3 The 2007 Annual
Data Report noted that “first-year death rates among
incident hemodialysis patients had not changed in 11
represent only a fraction of the patients who need this
years, while steady improvements had been noted in
type of treatment.1 In 2016 in the United States,
subsequent years on dialysis.”4,5 The 2018 Annual Data
726,331 people had kidney failure treated by dialysis or
Report showed that the first-year survival rate for pa-
kidney transplantation, and 124,675 people received a
tients initiating dialysis was 78%.2 Arguably, patients
pre-emptive kidney transplant.2 Before publication of
soon after starting dialysis represent a vulnerable
population for whom treatment outcomes have not
Correspondence: K-H Peony Yu, FibroGen, Inc., 409 Illinois Street,
San Francisco, California 94158, USA. E-mail: pyu@fibrogen.com improved significantly in recent years.
*Deceased. Multiple studies have demonstrated increased car-
Received 12 November 2020; accepted 15 December 2020; pub- diovascular (CV) risks associated with the use of
lished online 24 December 2020 erythropoiesis-stimulating agents (ESAs) for treating

Kidney International Reports (2021) 6, 613–623 613

CLINICAL RESEARCH R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD

anemia in patients with CKD, including those on dial- the Declaration of Helsinki, the International Council
ysis.6–8 Research has shown that this increased risk is for Harmonisation Guidelines for Good Clinical Prac-
associated with higher doses of ESAs needed in at- tice, and all other applicable local health and regulatory
tempts to reach higher hematocrit targets.9,10 This requirements. All patients provided written informed
research supports an unmet need for safe and effective consent before enrollment.
treatment in patients with anemia of CKD, particularly
in populations in need of the highest ESA doses. The Participants
incident-dialysis population has the highest mortality Eligible patients (aged $18 years) had ID-DD CKD (on
rate and receives the highest doses of ESAs, which dialysis for 2 weeks to # 4 months prior to randomi-
further underscores the importance of considering their zation) and CKD-related anemia and were on hemodi-
outcomes.2 To date, no clinical trials have assessed the alysis or peritoneal dialysis. This included all of the
patients from the 063 study (n ¼ 1039) and a subset of

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effect of interventions for the treatment of anemia in
patients starting dialysis. patients from the 064 (n ¼ 71) and 002 (n ¼ 416)
In the past decade, research has established the role studies. Study-specific inclusion criteria are detailed in
of hypoxia-inducible factor (HIF), a transcription factor Supplementary Table S1. A key exclusion criterion was

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that is the body’s main oxygen tension sensor,11 in recent RBC transfusion.
orchestrating RBC production and hemoglobin
response. Roxadustat (FG-4592) is a potent and Interventions
reversible HIF prolyl hydroxylase inhibitor that tran- After screening, eligible patients were randomized (1:1)
siently induces HIF stabilization, mimicking the natural to oral roxadustat or parenteral epoetin alfa. Each
erythropoietic response associated with transient hyp- study’s drug dosing and titration procedures are pro-
oxia exposure, but occurring under normoxic condi- vided in the Supplementary Methods.

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tions. The intermittent dosing strategy of roxadustat
for the treatment of CKD-related anemia results in the
durable maintenance of a therapeutic effect over time,
Rescue therapy included RBC transfusion, ESAs, or
transfusion and ESAs. RBC transfusion was allowed for
all patients who needed rapid correction of anemia, or
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without a constant effect on the HIF system. for whom it was considered medically necessary. ESA
Individually, the pivotal, phase 3 studies of roxadu- use was allowed for patients who met all of the
stat in patients on dialysis were designed to evaluate its following criteria: (i) hemoglobin level had not
efficacy and general safety compared with an ESA. The responded sufficiently after $2 dose increases or if the
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single studies were not powered to assess the CV safety maximum dose limit had been reached; (ii) hemoglobin
of roxadustat. Therefore, data from the 3 pivotal phase 3 was <8.5 g/dl (064 and 002 only) and clinical judgment
studies of roxadustat in patients on dialysis were pooled did not suggest iron deficiency or bleeding as the
to assess the relative efficacy and CV safety of roxadustat reason for the lack of response or rapid decrease in
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versus epoetin alfa. Systematic evaluation of patients hemoglobin; and (iii) there was a need to reduce the
new to dialysis was predefined as part of the clinical risk of alloimmunization in transplant-eligible patients
development program for roxadustat. and/or reduce other transfusion-related risk. Each
study’s protocol for IV iron supplementation differed.
Study-specific details are included in the Supplemen-
METHODS tary Material.
Trial Designs
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Data were pooled from patients with CKD-related ane- Efficacy Outcomes
mia who enrolled in 1 of 3 pivotal, similarly designed The key US Food and Drug Administration efficacy
studies (Himalayas FGCL-4592-063 [NCT02052310], endpoint for the individual studies was mean change in
Sierras FGCL-4592-064 [NCT02273726], and Rockies hemoglobin from baseline averaged over weeks 28 to
D5740C00002 [NCT02174731]) who were new to dial- 52, regardless of rescue therapy. A key EU European
ysis (incident dialysis, defined as patients on dialysis Medicines Agency efficacy endpoint was the mean
for 2 weeks to # 4 months prior to randomization change in hemoglobin from baseline averaged over
[ID-DD]). All 3 trials were randomized, multicenter, weeks 28 to 36, without rescue therapy within 6 weeks
open-label, epoetin alfa‒controlled phase 3 studies of and during the 8-week evaluation period.
evaluating the efficacy of roxadustat to correct and/or Key secondary efficacy endpoints included: mean
maintain hemoglobin levels (Supplementary Table S1). hemoglobin change from baseline averaged over weeks
All study protocols were approved by relevant 18 to 24 in patients with high-sensitivity C-reactive
institutional review boards and/or ethics committees protein that was higher than the upper limit of normal,
and were conducted in accordance with the tenets of mean change from baseline in low-density lipoprotein
614 Kidney International Reports (2021) 6, 613–623
R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD CLINICAL RESEARCH

Study 063 (HIMALAYAS): Pa ents Randomized: 1043 Study 064 (SIERRAS): Pa ents Randomized: 741 Study 002 (ROCKIES): Pa ents Randomized: 2133

Roxadustat: 522 (ITT)* Epoe n alfa: 521 (ITT)* Roxadustat: 370 (ITT)* Epoe n alfa: 371 (ITT)* Roxadustat: 1068 Epoe n alfa: 1065

Discon nua ons 215 (41.2%) Discon nua ons 212 (40.7%) Discon nua ons 243 (65.7%) Discon nua ons 188 (50.7%) Discon nua ons 421 (39.4%) Discon nua ons 322 (30.2%)
Death or AE 93 (17.9%) Death or AE 76 (14.6%) Death or AE 97 (26.2%) Death or AE 71 (19.1%) Consent withdrawn 202 (18.9%) Consent withdrawn 152 (14.3%)
Consent withdrawn 37 (7.1%) Consent withdrawn 49 (9.4%) Consent withdrawn 41 (11.1%) Kidney transplant 39 (10.5%) Other 125 (11.7%) Other 142 (13.3%)
Other 32 (6.1%) Other 29 (5.6%) Kidney transplant 31 (8.4%) Other 30 (8.1%) Adverse event 54 (5.0%) Adverse event 22 (2.1%)
Kidney transplant 23 (4.4%) Kidney transplant 29 (5.6%) Physician decision 30 (8.1%) Consent withdrawn 29 (7.8%) Met criteria 32 (3.0%) Protocol devia on 3 (0.3%)
Physician decision 14 (2.7%) Study/site termina on 13 (2.5%) Other 28 (7.6%) Physician decision 15 (4.0%) Protocol devia on 6 (0.6%) Missing 2 (0.2%)
Lack of efficacy 6 (1.1%) Physician decision 7 (1.3%) Lost to follow-up 6 (1.6%) Lost to follow-up 3 (0.8%) Missing 2 (0.2%) Incorrect enrollment 1 (0.1%)
Study/site termina on 5 (1.0%) Protocol devia on 6 (1.2%) Lack of efficacy 6 (1.6%) Lack of efficacy 1 (0.3%)
Lost to follow-up 4 (0.8%) Lost to follow-up 2 (0.4%) Protocol devia on 4 (1.1%)
Protocol devia on 1 (0.2%) Lack of efficacy 1 (0.2%)

Completed treatment: 307 (58.8%) Completed treatment: 309 (59.3%) Completed treatment: 127 (34.3%) Completed treatment: 183 (49.3%) Completed treatment: 696 (65.1%) Completed treatment: 796 (74.7%)

Completed EOS visit: 304 (58.2%) Completed EOS visit: 306 (58.7%) Completed EOS visit: 125 (33.8%) Completed EOS visit: 177 (47.7%) Completed study: 982 (91.9%) Completed study: 990 (93.0%)

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Par cipated in LTFU: 66 (12.6%) Par cipated in LTFU: 69 (13.2%) Par cipated in LTFU: 85 (23.0%) Par cipated in LTFU: 66 (17.8%)

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Figure 1. CONSORT flow diagram.

cholesterol averaged over weeks 12 to 28, mean adverse events, while minimizing confounding factors
monthly IV iron use during weeks 28 to 52, time to first likely to exist after study drug discontinuation due to
RBC transfusion during treatment, mean change in
mean arterial pressure averaged over weeks 8 to 12, and
time to first exacerbation of hypertension up to week
52 (increase from baseline $20 mm Hg for systolic
C institution of other therapies for treatment of anemia.

Adverse Events
Safety was monitored by assessment of treatment-
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blood pressure [SBP] and SBP $170 mm Hg, or increase emergent adverse events and treatment-emergent
from baseline $15 mm Hg for diastolic blood pressure serious adverse events during treatment and for 28
[DBP] and DBP $110.0 mm Hg). days after study drug discontinuation (OTþ28) in the
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safety population (all randomized patients who
CV Safety Endpoints received $1 dose of study drug).
All CV safety endpoints analyzed were positively
adjudicated by a central independent event review Statistical Analysis
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committee whose members were blinded to patients’ The overall clinical trial program of patients with
study-group assignment and hemoglobin level.12 The dialysis-dependent CKD was powered for non-
adjudication process is described in detail in the Sup- inferiority. Approximately 600 patients with OTþ7
plementary Material. MACE events, with a w90% power to demonstrate the
The primary CV safety endpoint was time to first upper limit of the two-sided 95% confidence interval
major adverse cardiovascular event (MACE), a com- (CI), would be required to exclude 1.3, if the true
posite measure of myocardial infarction, stroke, and all- hazard ratio (HR) was 1.0. This noninferiority margin
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cause mortality (ACM). Secondary CV safety endpoints was established based on the results of previous ESA
included time to first MACEþ (composite measure of clinical trials6–8 and US Food and Drug Administration
MACE plus unstable angina or congestive heart failure guidance on antidiabetic and oncologic drugs.13,14
[CHF] requiring hospitalization12) and time to ACM. The primary analysis of time to first MACE event
Supportive endpoints included time to MACE CV used a Cox regression model to obtain the HR of rox-
mortality and MACEþ CV mortality, time to CV mor- adustat versus epoetin alfa and the 95% CI. The Cox
tality, and time to each MACEþ component. CV model was stratified by history of cardiovascular, ce-
safety endpoints are defined in the Supplementary rebrovascular, or thromboembolic diseases (yes vs. no),
Material. geographic region (Europe vs. others), sex, body mass
The analysis period was the “on-treatment plus 7 index (<30 vs. $30 kg/m2), and race (black vs. other).
days” (OTþ7) time frame, which included events that In addition, analyses by study were pooled using meta-
occurred during the treatment period and within 7 analysis techniques. The proportional hazards
days of the last dose of study drug. Using this follow- assumption was checked graphically using a log-
up period allowed for the ascertainment of residual cumulative hazard plot against log-survival time.
Kidney International Reports (2021) 6, 613–623 615
CLINICAL RESEARCH R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD

Table 1. Baseline demographic and clinical characteristics (ITT) 760; epoetin alfa, n ¼ 770) (Figure 1). In the roxadustat
Roxadustat Epoetin alfa group, mean treatment exposure was 1.5 patient-
Characteristic (n [ 760) (n [ 770)
exposure years (PEY) per patient (up to 4.4 PEY), and
Age, mean (SD), year* 53.6 (14.8) 54.0 (14.6) total exposure was 1098.2 PEY. In the epoetin alfa
Male sex, n (%) 461 (60.7) 464 (60.3)
group, mean exposure was 1.6 PEY (up to 4.4 PEY), and
Race, n (%)
White 508 (66.8) 505 (65.6)
total exposure was 1189.5 PEY (Supplementary
Asian 116 (15.3) 127 (16.5) Table S2).
Black 67 (8.8) 67 (8.7) In general, baseline demographic and clinical char-
Other 69 (9.1) 71 (9.2) acteristics were comparable between the treatment
Region, n (%) groups (Table 1). Overall, the mean (SD) age was 53.8
United States 195 (25.7) 196 (25.5)
(14.7) years, and 39.5% were women. Sixty-six percent
Europe 362 (47.6) 374 (48.6)

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Other 203 (26.7) 200 (26.0)
of the patients were white, and nearly 50% were from
Weight, mean (SD), kg 74.3 (19.3) 75.0 (19.1) Europe. Mean (SD) baseline hemoglobin levels were
Hemoglobin, mean (SD), g/dl 8.8 (1.2) 8.9 (1.2) comparable in the roxadustat and epoetin alfa groups
Hemoglobin distribution, n (%) (8.8 [1.2] and 8.9 [1.2] g/dl, respectively). The majority

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<8.0 g/dl 180 (23.7) 179 (23.2) (79.2%) of patients were iron-replete, 41.6% had dia-
$8.0 g/dl 580 (76.3) 591 (76.8)
betes mellitus, and 43.2% had a history of CV disease.
Dialysis modality, n (%)
Hemodialysis 680 (89.5) 675 (87.7)
The majority of patients were on hemodialysis (88.6%)
Peritoneal dialysis 80 (10.5) 94 (12.2) compared with peritoneal dialysis (11.4%). Thirty-
Missing 0 1 (0.1) eight percent of patients had a high-sensitivity C-
Duration of dialysis, mean (SD), months 2.3 (0.9) 2.3 (0.9) reactive protein level greater than the upper limit of
Patients taking ESAs, n (%) 123 (16.2) 121 (15.7)
normal.
Hs-CRP distribution, n (%)
#ULN
>ULN
Missing
406 (53.4)
285 (37.5)
69 (9.1)
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401 (52.1)
301 (39.1)
68 (8.8)
Efficacy Endpoints
Patients with ID-DD CKD who received roxadustat
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LDL cholesterol, mean (SD), mg/dl 104.6 (39.1) 104.7 (38.1) showed larger increases in hemoglobin levels over
Iron repletion status, n (%) 52 weeks of treatment compared with patients who
Ferritin $100 ng/ml and TSAT $20% 603 (79.3) 608 (79.0)
received epoetin alfa (Figure 2). For the US efficacy
Ferritin <100 ng/ml or TSAT <20% 155 (20.4) 162 (21.0)
Missing 2 (0.3) 0
endpoint, the mean (SD) change in hemoglobin from
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Diabetes mellitus, n (%) 322 (42.4) 314 (40.8) baseline averaged over weeks 28 to 52, regardless
History of cardiac, cerebrovascular, or 328 (43.2) 333 (43.2) of rescue therapy, was significantly higher in the
thromboembolic disease, n (%) roxadustat versus epoetin alfa group in the indi-
ESA, erythropoietin-stimulating agent; Hs-CRP, high-sensitivity C-reactive protein ITT, vidual studies and also for the pooled analysis
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intent-to-treat population; LDL, low-density lipoprotein; TSAT, transferrin saturation;

ULN, upper limit of normal. (mean [SD]: 2.12 [1.45] g/dl vs. 1.91 [1.42] g/dl).
*Age was calculated in years from birthdate to date of informed consent or date of first The least-squares mean (LSM) treatment difference
dose.
was 0.22 (95% CI, 0.05 to 0.40; P ¼ 0.0130)
(Table 2). Thus, roxadustat was noninferior and
Supportive evidence was based on sensitivity and superior to epoetin alfa, as there were statistically
subgroup analyses, including MACE/MACEþ with CV significant larger increases in hemoglobin levels
mortality, and individual components. For the primary from baseline averaged over weeks 28 to 52,
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efficacy analysis, a multiple imputation analysis of regardless of rescue therapy. Subgroup analyses of
covariance model was used, including terms for treat- the US efficacy analysis were similar to the full
ment group, baseline hemoglobin, and stratification cohort (Supplementary Figure S1).
factors (except screening hemoglobin #8.0 vs. >8.0 g/ For the key EU efficacy endpoint, the mean (SD)
dl). A noninferiority margin for the estimated differ- change in hemoglobin from baseline averaged over
ence between treatment groups (roxadustat  epoetin weeks 28 to 36 censored for rescue therapy within 6
alfa) of 0.75 g/dl was predefined. Details regarding weeks of and during this evaluation period was
the statistical analyses are provided in the Supple- significantly higher in the roxadustat versus epoetin
mentary Material. alfa group in the individual studies and for the pooled
analysis (mean [SD]: 2.37 [1.57] vs. 2.12 [1.46]). The
RESULTS LSM was 0.28 (95% CI, 0.11 to 0.45; P ¼ 0.0013
Participants [nominal]) (Table 3). Thus, roxadustat was noninferior
Data from the intent-to-treat (ITT) population of 1530 to epoetin alfa and had a larger increase in hemoglobin
patients with ID-DD CKD were pooled (roxadustat, n ¼ levels.
616 Kidney International Reports (2021) 6, 613–623
R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD CLINICAL RESEARCH

Roxadustat Epoen alfa

11.4

11.2

Mean (SE) Hemoglobin (g/dL)

11.0

10.8

10.6

10.4

10.2

10.0

9.8

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9.6
0 4 8 12 16 20 28 36
Time (Weeks)
Figure 2. Hemoglobin levels by treatment arm (Full Analysis Set).

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Key Secondary Efficacy Endpoints The percentages of patients who received RBC
In patients with baseline high-sensitivity C-reactive transfusions during the study were 6.1% and 6.7% of
protein greater than the upper limit of normal, mean patients in the roxadustat and epoetin alfa groups. The
(SD) changes in hemoglobin from baseline averaged exposure-adjusted incidence rates were similar in the
over weeks 18 to 24 were 2.14 (1.34) in the roxadustat roxadustat and epoetin alfa groups (4.2 and 4.3 per 100
group and 2.11 (1.47) g/dl in the epoetin alfa group,
corresponding to an LSM difference of 0.27 (95%
CI, 0.04 to 0.58; P ¼ 0.09).
Mean (SD) changes from baseline in low-density li-
C PEY, respectively). The HR for time to first RBC
transfusion was 0.99 (95% CI, 0.66 to 1.47).
The mean (SD) change from baseline in mean
arterial pressure averaged over weeks 8 to 12 in the
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poprotein (LDL) cholesterol averaged over weeks 12 to roxadustat group and epoetin alfa group was 0.05
28 in the roxadustat group versus epoetin alfa group (9.00) and 1.03 (9.24) mm Hg, corresponding to a
were 22.57 (29.94) versus 4.79 (27.89) mg/dl. The LSM treatment difference of 0.35 (95% CI, 1.65
LSM treatment difference was 17.50 mg/dl (95%
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to 0.95).
CI, 22.22 to 12.78 mg/dl; P < 0.0001). The percentage of patients who experienced an
Mean (SD) monthly IV iron use over weeks 28 to 52 exacerbation of hypertension up to week 52 in the
in the roxadustat group and epoetin alfa group was roxadustat group and epoetin alfa group was 25.9%
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53.57 (143.10) mg versus 70.22 (173.33) mg per patient- (33.6 per 100 PEY) and 25.4% (32.0 per 100 PEY) (HR,
exposure months (P < 0.0001). 1.02; 95% CI, 0.84 to 1.25).

Table 2. Hemoglobin changes from baseline during weeks 28–52 regardless of rescue therapy (ITT)
Study 063 Study 064 Study 002 Pooled data
Roxadustat Epoetin alfa Roxadustat Epoetin alfa Roxadustat Epoetin alfa Roxadustat Epoetin alfa
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(n [ 522) (n [ 521) (n [ 36) (n [ 35) (n [ 202) (n [ 214) (n [ 760) (n [ 770)

Mean (SD) baseline hemoglobin*, g/dl 8.43 (1.04) 8.46 (0.96) 10.23 (0.80) 10.09 (0.91) 9.56 (1.16) 9.62 (1.24) 8.82 (1.22) 8.86 (1.19)
Mean (SD) weeks 28–52 hemoglobin†, 11.00 (0.82) 10.83 (0.88) 10.60 (0.79) 10.20 (0.78) 10.82 (0.90) 10.74 (1.01) 10.94 (0.84) 10.77 (0.92)
g/dl
Mean (SD) hemoglobin change from 2.57 (1.27) 2.36 (1.21) 0.37 (1.06) 0.10 (0.93) 1.25 (1.33) 1.12 (1.39) 2.12 (1.45) 1.91 (1.42)
baseline†, g/dl
MI-ANCOVA‡
LSM (SEM) 2.38 (0.04) 2.20 (0.04) 0.51 (0.16) 0.07 (0.16) 1.23 (0.08) 1.15 (0.073) 1.90 (0.06) 1.67 (0.07)
95% CI (2.30‒2.46) (2.12‒2.28) (0.19‒0.83) (0.24 to 0.37) (1.08‒1.39) (1.01‒1.29)) (1.77‒2.02) (1.55‒1.80)
LSM (SEM) difference 0.18 (0.05) 0.44 (0.23) 0.08 (0.10) 0.22 (0.09)
95% CI (0.08‒0.29) (0.00‒0.88) (0.12 to 0.29) (0.05‒0.40)
P value 0.0005 0.0493§ 0.4162§ 0.0130

CI, confidence interval; ITT, intent-to-treat population; LSM, least-squares mean; MI-ANCOVA, multiple imputation analysis of covariance.
*Baseline hemoglobin defined as the mean of up to 4 most recent laboratory values before the first dose of study drug.
†
Observed þ imputed.
‡
Treatment comparison using the multiple imputation strategy by combining the results of an ANCOVA model with baseline hemoglobin as covariate, and study; treatment; study 
treatment interaction; and history of cardiovascular, cerebrovascular, or thromboembolic disease (yes vs. no) as fixed effects.
§
Nominal.

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CLINICAL RESEARCH R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD

Table 3. Hemoglobin changes from baseline during weeks 28–36 censored for rescue therapy (PPS)
Study 063 Study 064 Study 002 Pooled data
Roxadustat Epoetin alfa Roxadustat Epoetin alfa Roxadustat Epoetin alfa Roxadustat Epoetin alfa
(n [ 490) (n [ 468) (n [ 31) (n [ 29) (n [ 152) (n [ 172) (n [ 673) (n [ 669)
Mean (SD) baseline hemoglobin*, 8.43 (1.04) 8.43 (0.96) 10.29 (0.80) 10.08 (0.92) 9.54 (1.17) 9.65 (1.25) 8.77 (1.20) 8.82 (1.20)
g/dl
Mean (SD) weeks 28–36 hemoglobin, g/dl 11.13 (1.06) 10.94 (1.02) 10.71 (0.76) 10.17 (0.96) 10.86 (1.10) 10.85 (1.16) 11.07 (1.05) 10.89 (1.06)
Mean (SD) hemoglobin change 2.70 (1.42) 2.50 (1.27) 0.48 (1.26) 0.08 (0.99) 1.31 (1.57) 1.15 (1.42) 2.37 (1.57) 2.12 (1.46)
from baseline, g/dl
MMRM
LSM (SEM) 2.59 (0.05) 2.39 (0.06) 0.42 (0.20) 0.02 (0.20) 1.23 (0.09) 1.18 (0.08) 2.17 (0.06) 1.89 (0.06)
95% CI (2.48–2.70) (2.28–2.50) (0.03–0.81) (0.41 to 0.36) (1.06–1.40) (1.02–1.34) (2.05–2.30) (1.77–2.02)
LSM (SEM) difference 0.20 (0.08)† 0.44 (0.28)‡ 0.05 (0.12)‡ 0.28 (0.09)‡

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95% CI (0.05–0.35) (0.10 to 0.99) (0.19 to 0.28) (0.11–0.45)
P value 0.0090 0.1123 0.6898§ 0.0013

CI, confidence interval; MMRM, mixed model of repeated measures; LSM, least-squares mean; PPS, per protocol set.
*Baseline hemoglobin defined as the mean of up to 4 most recent laboratory values before the first dose of study drug.
†
Treatment comparison made using an MMRM with baseline hemoglobin as a covariate, and treatment, visit, visit  treatment interaction, and randomization stratification factors,

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except mean qualifying screening hemoglobin (#8.0 vs. >8.0 g/dl), as fixed effects.
‡
Treatment comparison using the MMRM with baseline hemoglobin as covariate, and study; treatment; visit, visit  treatment interaction; study  treatment interaction; and history of
cardiovascular, cerebrovascular, or thromboembolic disease (yes vs. no) as fixed effects.
§
Nominal.

Primary Cardiovascular Safety Endpoint the most common MACE and MACEþ event (data not
During a mean of 1.4 years of treatment exposure in the shown).
roxadustat group and a mean of 1.6 years of treatment
exposure in the epoetin alfa group, the risk for MACE
was lower in the roxadustat versus epoetin alfa group
(HR, 0.70; 95% CI, 0.51 to 0.96; P ¼ 0.029) (Figures 3a
C Subgroup Analysis
Subgroup analyses of MACE showed clinically consis-
tent results (Supplementary Figure S2). Among US-based
A
and 4b). patients, the HR for the roxadustat group versus epoetin
alfa group was 0.38 (95% CI, 0.20 to 0.73).
Secondary Cardiovascular Safety Endpoints Adverse Events
The risk for MACEþ was lower in the roxadustat
R
Eighty percent of patients in the roxadustat (611 of
group versus epoetin alfa group (HR, 0.66; 95% CI, 760) and epoetin alfa (619 of 766) groups experienced at
0.50 to 0.89; P ¼ 0.005) (Figures 3a and 4b). The HR for least 1 treatment-emergent adverse event. These
ACM was 0.76 (95% CI, 0.52, 1.11; P ¼ 0.15) adverse events, occurring in $5% of patients in either
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(Figures 3a and 4c). treatment group, are summarized in Table 4.

Treatment-emergent serious adverse events, occurring
Supportive Cardiovascular Safety Endpoints in $1% of patients in either treatment group, are
The risk for MACE CV mortality was significantly indicated in Table 5.
lower in the roxadustat group versus epoetin alfa
group (HR, 0.63; 95% CI, 0.43 to 0.92; P ¼ 0.018). DISCUSSION
Likewise, the risk for MACEþ CV mortality was For patients with CKD, during their first year on dial-
R

significantly lower in the roxadustat group versus ysis—the incident period—the risk for morbidity and
epoetin alfa group (HR, 0.60; 95% CI, 0.43 to 0.83; P ¼ mortality is high.2 In a controlled clinical trial of pa-
0.002). The HR for CV mortality was 0.63 (95% CI, 0.37 tients with prevalent dialysis, the patient sampling
to 1.05; P ¼ 0.075) (Figure 3b). technique (i.e., recruitment) is one of convenience; pa-
Although analyses of the MACE and MACEþ com- tients were screened and invited to enroll based on
ponents were not powered for noninferiority, the re- factors allowing them to survive through their incident
sults for the individual components of MACE and period to be eligible for enrollment. This survival bias
MACEþ are generally consistent with those for the imposed in a prevalent cohort must be recognized,
composite measures. The risk of stroke was lower in the given that US-based patients have a 3-year survival rate
roxadustat versus epoetin alfa group (HR, 0.41; 95% of only 57%.15 The current pooled analysis includes
CI, 0.18 to 0.94; P ¼ 0.035) (Figure 3c). A decomposi- data from patients who were on dialysis for 2 weeks to
tion of MACE and MACEþ endpoints into the first #4 months and received only a limited amount of ESA
occurrence of its components shows broadly similar and who then underwent comparative evaluation of
rates between the treatment groups, with ACM being study treatments for a mean of 1.5 years, which
618 Kidney International Reports (2021) 6, 613–623
R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD CLINICAL RESEARCH

a Roxadustat Epoen Alfa HR‡ (95% CI)

(n=760) (n=766) (P-value§)
MACE events 74 97 0.70 (0.51, 0.96)
Incidence/100 PEY† 6.7 8.2 (.029)

MACE+ events 88 121 0.66 (0.50, 0.89)

Incidence/100 PEY† 8.0 10.2 (.005)
ACM events 52 70 0.76 (0.52, 1.11)
Incidence/100 PEY† 4.7 5.8 (.154)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

D
Roxadustat Epoen Alfa HR‡ (95% CI)
(n=760) (n=766) (P-value§)
MACE CVM events 49 72 0.63 (0.43, 0.92)
Incidence/100 PEY† 4.5 6.1 (.018)

TE
MACE+ CVM events 65 98 0.60 (0.43, 0.83)
Incidence/100 PEY† 5.9 8.2 (.002)
CVM events 25 43 0.63 (0.37, 1.05)
Incidence/100 PEY† 2.3 3.6 (.075)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

c
Paents with events, n
MI events
Incidence/100 PEY†
Roxadustat
(n=760)
21
1.9
Epoen Alfa
(n=766)
18
1.5
C HR‡ (95% CI)
(P-value§)

1.17 (0.59, 2.32)

A
Stroke events 11 20 0.41 (0.18, 0.94)
Incidence/100 PEY† 1.0 1.7 (.035)
Unstable angina (H) 6 6 0.90 (0.26, 3.11)
Incidence/100 PEY† 0.5 0.5 (.871)
R
CHF (H) 25 28 0.77 (0.42, 1.40)
Incidence/100 PEY† 2.3 2.4 (.388)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Figure 3. Forest plot of cardiovascular safety analyses in incident-dialysis patients on dialysis for 2 week to #4 months prior to randomization.
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(a) MACE using all-cause mortality. (b) MACE using cardiovascular mortality. (c) Individual events. *OT-7: events that occurred during the
treatment period and within 7 days of the last dose of study drug. †PEY for each patient ¼ (last dose date  first dose date þ 1) / 365.25.
Incidence rate (per 100 PEY) ¼ 100  number of subjects with events / PEY. ‡HR derived using a meta-analysis method combining individual
study log-HRs with weights inversely proportional to the variants of the study-specific log-HRs. §P value reported when the point estimate of HR
was <1.0. ACM, all-cause mortality; CHF, congestive heart failure; CI, confidence interval; CVM, cardiovascular mortality; HR, hazard ratio;
MACE, major adverse cardivascular event; MACEþ, MACE plus unstable angina and CHF requiring hospitalization; MI, myocardial infarction;
OTþ7, on treatment plus 7 days after last study drug; PEY, patient-exposure years.
R

mitigates this bias. Thus, our findings provide insight Overall, the efficacy analysis of data pooled from pa-
into not only the prevalent period (most frequently tients with ID-DD CKD shows that roxadustat resulted in
evaluated in clinical trials) but also the incident period, larger increases in hemoglobin when compared with
when patients are at highest risk for adverse events in epoetin alfa. For the key US efficacy endpoint, roxadustat
general, and CV events in particular. Importantly, the was noninferior and superior to epoetin alfa for increasing
incident period is generally when a vast majority hemoglobin from baseline averaged over weeks 28 to 52,
(w80%) of patients on dialysis initiate anemia therapy, regardless of rescue therapy, with a statistically signifi-
as <15% of US-based patients were treated with an ESA cant larger change from baseline. Pooled results from
in the 12 months before dialysis initiation.2 Inclusion of patient subgroups, based on major demographic and
patients during the incident period also encompassed a clinical characteristics, were consistent with the overall
broader patient population than did the conversion findings. For the key EU efficacy endpoint, roxadustat
studies with median dialysis vintage of 3 years by also was noninferior and superior to epoetin alfa and achieved
including those who were less likely to survive the a larger hemoglobin increase from baseline averaged over
initial years of dialysis treatment. weeks 28 to 36 censored for rescue therapy within 6
Kidney International Reports (2021) 6, 613–623 619
CLINICAL RESEARCH R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD

1.0 MACE
HR, 0.70 (95% CI: 0.51, 0.96)

0.9

0.8

0.7
Roxadustat

D
Epoe n alfa
0.6
0 3 6 9 12 18 24 30 36
760 678 599 499 394 312 229 141 90
766 701 611 519 411 329 254 175 114

TE
Time (weeks)
Probability of Pa ents Remaining Event Free

1.0 MACE+
HR, 0.66 (95% CI: 0.50, 0.89)

0.9

0.8
C
A
0.7
Roxadustat
Epoe n alfa
0.6
R
0 3 6 9 12 18 24 30 36
760 673 594 495 389 304 223 137 87
766 699 605 511 401 316 246 171 111
Time (weeks)
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1.0 ACM
HR, 0.76 (95% CI: 0.52, 1.11)

0.9
R

0.8

0.7
Roxadustat
Epoe n alfa
0.6
0 3 6 9 12 18 24 30 36
760 681 603 504 399 317 236 147 95
766 705 617 528 421 340 262 182 119
Time (weeks)
Figure 4. Kaplan-Meier curves for MACE, MACEþ, and ACM. ACM, all-cause mortality; CHF, congestive heart failure; CI, confidence interval;
CVM, cardiovascular mortality; HR, hazard ratio; MACE, major adverse cardivascular event; MACEþ, MACE plus unstable angina and CHF
requiring hospitalization; MI, myocardial infarction; OTþ7, on treatment plus 7 days after last study drug.

620 Kidney International Reports (2021) 6, 613–623

R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD CLINICAL RESEARCH

Table 4. TEAEs occurring in $5% of ID-DD patients in either begin dialysis. All patients on dialysis are “incident to
treatment group (OTþ28)* dialysis” at some point in time. Because different sub-
Roxadustat (N [ 760) Epoetin alfa (N [ 766) groups experience different mortality rates (e.g., age is
PEY [ 1098.2 PEY [ 1189.5 directly correlated with mortality, and people with dia-
incidence rate incidence rate
Preferred term† n (%) (per 100 PEY)‡ n (%) (per 100 PEY)‡
betes also experience greater risk), the snapshot of pa-
Hypertension 112 (14.7) 10.2 105 (13.7) 8.8
tients on dialysis—when categorized as such by
Diarrhea 87 (11.4) 7.9 51 (6.7) 4.3 vintage—changes with time. It can be argued that the
Arteriovenous fistula 73 (9.6) 6.6 55 (7.2) 4.6 results from a study of patients with a mean vintage of
thrombosis several years may not be generalizable to patients who
Headache 67 (8.8) 6.1 50 (6.5) 4.2
did not survive to that point at baseline. Furthermore,
Muscle spasms 66 (8.7) 6.0 46 (6.0) 3.9
Hypotension 65 (8.6) 5.9 46 (6.0) 3.9
because anemia therapy is typically initiated during the

D
Hyperphosphatemia 53 (7.0) 4.8 36 (4.7) 3.0 incident period in the majority of patients starting dial-
Nausea 52 (6.8) 4.7 35 (4.6) 2.9 ysis, and the use of anemia treatment is generally long
Pneumonia 51 (6.7) 4.6 55 (7.2) 4.6 term, this population provides information on the full
Arteriovenous fistula site 42 (5.5) 3.8 51 (6.7) 4.3
spectrum of patients’ dialysis experience. The evaluation

TE
complication
Vomiting 39 (5.1) 3.6 21 (2.7) 1.8
of anemia therapy started in the incident period and
Hyperkalemia 32 (4.2) 2.9 40 (5.2) 3.4 continued into the prevalent dialysis period, as done in
ID-DD, incident-dialysis dependent; PEY, patient-exposure years; TEAE, treatment-
this pooled analysis, provides a clinically meaningful
emergent adverse event. comparison of roxadustat versus epoetin alfa.
*OTþ28: a TEAE occurred (or a pre-existing condition worsened) during the treatment
period and within 28 days of the last dose of study drug. Patients with >1 event in a Lower rates of MACE and MACEþ were observed with
category were counted once for that category. roxadustat in this clinical study setting where patients
†
Based on Medical Dictionary for Regulatory Activities, version 20.0.
‡
PEY for each patient ¼ (last dose  date first dose date þ 1) / 365.25. Incidence rate treated with roxadustat or epoetin alfa generally required
(per 100 PEY) ¼ 100  number of patients with events / PEY.

weeks of and during the 8-week treatment period. In C Table 5. TESAEs occurring in $1% of patients in either treatment
group (OTþ28)*
A
patients with baseline high-sensitivity C-reactive protein Roxadustat (n [ 760) Epoetin alfa (n [ 766)
greater than the upper limit of normal, hemoglobin PEY [ 1098.2 PEY [ 1189.5
changes from baseline averaged over weeks 18 to 24 were †
incidence rate incidence rate
Preferred term n (%) (per 100 PEY)‡ n (%) (per 100 PEY)‡
greater in the roxadustat group compared with the
R
Any TESAE 318 (41.8) 29.0 318 (41.5) 26.7
epoetin alfa group. Between weeks 12 and 28, LDL
Arteriovenous fistula 44 (5.8) 4.0 26 (3.4) 2.2
cholesterol levels were significantly reduced in the rox- thrombosis
adustat group compared with the epoetin alfa group. In Pneumonia 36 (4.7) 3.3 38 (5.0) 3.2
general, the pooled efficacy results are consistent with Peritonitis 20 (2.6) 1.8 16 (2.1) 1.3
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those from the individual studies. Sepsis 18 (2.4) 1.6 11 (1.4) 0.9
Fluid overload 16 (2.1) 1.5 13 (1.7) 1.1
In terms of CV safety, the risks for MACE and MACEþ
Hypertensive crisis 11 (1.4) 1.0 17 (2.2) 1.4
were significantly lower in the roxadustat group compared Device-related 10 (1.3) 0.9 6 (0.8) 0.5
with the epoetin alfa group. Several analyses focusing on infection
individual component events, and their various combina- Urinary tract infection 10 (1.3) 0.9 6 (0.8) 0.5
Acute myocardial 9 (1.2) 0.8 18 (2.3) 1.5
tions, were mostly consistent with the main results. infarction
Consistent with the general tolerability profile for rox-
R

Cardiac failure 9 (1.2) 0.8 10 (1.3) 0.8

adustat, most patients in the roxadustat and epoetin alfa congestive
groups had at least 1 treatment-emergent adverse event. Arteriovenous fistula 8 (1.1) 0.7 3 (0.4) 0.3
site complication
From an analytical perspective, the ID-DD popula- Coronary artery 8 (1.1) 0.7 4 (0.5) 0.3
tion is a subgroup of the overall DD population who disease
participated in the roxadustat phase 3 clinical trial. As Hypotension 8 (1.1) 0.7 7 (0.9) 0.6

such, this was a prespecified subgroup of interest, Death 6 (0.8) 0.5 10 (1.3) 0.8

resulting in proactive efforts to recruit the >1500 pa- Gangrene 6 (0.8) 0.5 8 (1.0) 0.7
Hyperkalemia 6 (0.8) 0.5 9 (1.2) 0.8
tients who had newly initiated dialysis. Nevertheless, it Cellulitis 5 (0.7) 0.5 8 (1.0) 0.7
is appropriate to acknowledge that, although the sam- Cardiac arrest 4 (0.5) 0.4 9 (1.2) 0.8
ple size is the largest of ID-DD patients studied to date, PEY, patient-exposure years; TESAE, treatment-emergent serious adverse event.
it is smaller than the overall population and subject to *OTþ28: a treatment-emergent adverse event occurred (or a pre-existing condition
worsened) during the treatment period and within 28 days of the last dose of study drug.
variability in the point estimate related to its size. Patients with >1 event in a category were counted once for that category.
†
From a clinical perspective, the ID-DD population Medical Dictionary for Regulatory Activities, version 20.0.
‡
PEY for each patient ¼ (last dose date  first dose date þ 1) / 365.25. Incidence rate
represents the “universe” of all dialysis patients who (per 100 PEY) ¼ 100  number of patients with events / PEY.

Kidney International Reports (2021) 6, 613–623 621

CLINICAL RESEARCH R Provenzano et al.: Roxadustat for Anemia in Patients With ID-DD

initiation of treatment and correction of anemia, followed Table S1. Summary of phase 3 clinical trials in patients
by maintenance treatment. MACEþ results are consistent with dialysis-dependent chronic kidney disease.
with those of the overall DD population, where a reduction Table S2. Patient numbers and exposure by study and
in MACEþ risk with roxadustat was also observed. overall.
Although these studies were not designed to identify the Figure S1. Subgroup analysis for the key US efficacy
mechanism(s) for these findings, one potential explanation endpoint (ITT).
may be the lower erythropoietin exposure with roxadustat Figure S2. Subgroup analysis of MACE (OTþ7)
versus treatment with erythropoietin analogs, and it may
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