Nephrol Dial Transplant (2021) 36: 1629–1639

doi: 10.1093/ndt/gfab057
Advance Access publication 25 February 2021

Roxadustat for the treatment of anemia in chronic kidney

ORIGINAL ARTICLE
disease patients not on dialysis: a Phase 3, randomized,
double-blind, placebo-controlled study (ALPS)

Evgeny Shutov1, Władysław Sułowicz2, Ciro Esposito3, Avtandil Tataradze4, Branislav Andric5,
Michael Reusch6, Udaya Valluri7 and Nada Dimkovic8
1
Botkin Clinical City Hospital, Russian Medical Academy of Continuous Professional Education, Moscow, Russia, 2Department of Nephrology,
Collegium Medicum, Jagiellonian University, Krakow, Poland, 3Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, Pavia, Italy,
4
L.Managadze National Center of Urology, Tbilisi, Georgia, 5Health Center Krusevac, Krusevac, Serbia, 6Astellas Pharma Europe B.V., Leiden,
The Netherlands, 7Astellas Pharma Global Development, Inc., Northbrook, IL, USA and 8Clinical Department for Renal Diseases, Zvezdara
University Medical Center, School of Medicine, University of Belgrade, Belgrade, Serbia

Correspondence to: Nada Dimkovic; E-mail: [email protected]

GRAPHICAL ABSTRACT

C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.

V
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 KEY LEARNING POINTS

What is already known about this subject?

• anemia is a common complication of chronic kidney disease (CKD); iron therapy (oral or intravenous) is the standard
first-line treatment for CKD anemia, while erythropoiesis-stimulating agents (ESAs) are available for the treatment of
CKD anemia that cannot be corrected by iron therapy alone;
• although iron therapy and ESAs are mainstays of the current CKD anemia treatment paradigm, studies have
highlighted shortcomings related to the convenience, adverse events and efficacy of these treatments, suggesting that
novel treatments should be explored in this patient population; and
• roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that has shown efficacy
and safety in Phases 2 and 3 trials in CKD patients with anemia who are nondialysis-dependent (NDD) and those
who are dialysis-dependent.
What this study adds?
• this study was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in mostly European patients
with anemia who have Stage 3, 4 or 5 CKD who were not on dialysis at the time of randomization;
• superiority of roxadustat versus placebo was demonstrated in terms of response rate to treatment during the first
24 weeks of treatment and hemoglobin (Hb) change from baseline to the average Hb of Weeks 28–52; sensitivity and
subgroup analyses confirmed these primary analyses in European patients; and
• the safety profile of roxadustat in this study was generally comparable to placebo, and markers of both lipid and iron
metabolism were improved in roxadustat-treated patients.
What impact this may have on practice or policy?
• roxadustat is an orally active HIF-PHI that has shown efficacy and safety in Phase 3 trials in several different cohorts
of CKD patients with anemia who are NDD; and
• roxadustat has also demonstrated improved iron availability and improved lipid metabolism in this pre-dialysis patient
population.

ABSTRACT P < 0.001). The incidences of treatment-emergent adverse

Background. Roxadustat is an orally active hypoxia-inducible events were comparable between groups (roxadustat: 87.7%,
factor prolyl hydroxylase inhibitor for the treatment of chronic placebo: 86.7%).
kidney disease (CKD) anemia. Conclusions. Roxadustat demonstrated superior efficacy versus
Methods. This Phase 3, multicenter, randomized, double-blind, placebo in terms of both Hb response rate and change in Hb
placebo-controlled study examined patients with Stages 3–5 from BL. The safety profiles of roxadustat and placebo were
CKD, not on dialysis (NCT01887600). Patients were random- comparable.
ized (2:1) to oral roxadustat or placebo three times weekly for
52–104 weeks. This study examined two primary efficacy end-
points: European Union (European Medicines Agency)— Keywords: anemia, chronic kidney disease, iron, non-dialysis,
hemoglobin (Hb) response, defined as Hb 11.0 g/dL that in- roxadustat
creased from baseline (BL) by 1.0 g/dL in patients with
Hb >8.0 g/dL or 2.0 g/dL in patients with BL Hb 8.0 g/dL,
without rescue therapy, during the first 24 weeks of treatment; INTRODUCTION
US Food and Drug Administration—change in Hb from BL to Anemia is a common complication observed in patients who
the average Hb level during Weeks 28–52, regardless of rescue have chronic kidney disease (CKD). While the pathogenesis of
therapy. Secondary efficacy endpoints and safety were examined. CKD is multifactorial, decreased synthesis of erythropoietin by
Results. A total of 594 patients were analyzed (roxadustat: 391; the kidneys due to impaired oxygen sensing [1, 2] and an al-
placebo: 203). Superiority of roxadustat versus placebo was tered iron metabolism are important etiologic factors [3].
demonstrated for both primary efficacy endpoints: Hb response Currently, iron therapy [oral or intravenous (IV)] is the stan-
[odds ratio ¼ 34.74, 95% confidence interval (CI) 20.48–58.93] dard first-line treatment for CKD anemia, while erythropoiesis-
and change in Hb from BL [roxadustat – placebo: þ1.692 (95% stimulating agents (ESAs) (IV and subcutaneous) are available
CI 1.52–1.86); both P < 0.001]. Superiority of roxadustat was for the treatment of CKD anemia that cannot be corrected by
demonstrated for low-density lipoprotein cholesterol change iron therapy alone [4]. Although iron therapy and ESAs are
from BL, and time to first use of rescue medication (both mainstays of the current CKD anemia treatment paradigm,

1630 E. Shutov et al.

studies have highlighted shortcomings related to the conve- no); and screening estimated glomerular filtration rate (eGFR)
nience (e.g. mode of administration), safety [e.g. increased risk (<30 mL/min/1.73 m2 versus 30 mL/min/1.73 m2).
of cardiovascular (CV) complications, mainly thromboembolic] This study consisted of three study periods (Figure 1),
and efficacy of these treatments in some patients with including screening (up to 6 weeks), a treatment period and
nondialysis-dependent (NDD) CKD, suggesting that novel a follow-up period. Within the treatment period, there was
treatments may benefit this patient population [5–8]. Hypoxia- a correction period, in which the study drug was initially
inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) rep- dosed for Hb correction until patients achieved a target Hb
resent a new strategy to increase hemoglobin (Hb) levels by ac- value of 11.0 g/dL and a Hb increase from baseline (BL)
tivating the body’s natural response to hypoxia independent of of 1.0 g/dL at two consecutive study visits separated by at
cellular oxygen levels [9–11]. least 5 days, and a subsequent maintenance period, where
Roxadustat is an orally administered HIF-PHI that has the aim was to treat to a Hb level of 11.0 g/dL by maintain-
shown efficacy and safety in Phases 2 and 3 trials in patients ing Hb levels between 10.0 and 12.0 g/dL. After the treat-
with CKD who are either dialysis-dependent (DD) [12–18] or ment period, patients proceeded to the 4-week follow-up
NDD [16, 19–23]. In recent Phase 3 studies performed in period. Patients who stopped treatment prior to Week 104
Japanese and Chinese patients with CKD, roxadustat was completed the end-of-treatment (EOT) visits (EOT visit
shown to be superior compared with placebo [21], and noninfe- and EOT þ 2-week visit) and the end-of-study (EOS) visit.
rior compared with traditional ESAs [12, 15], in correcting and Thereafter, these patients were followed for vital status and
maintaining Hb. Roxadustat has also been shown to increase se- serious treatment-emergent adverse events (TEAEs), as well
rum iron levels and iron absorption [12, 13, 15, 21, 23], increase as CV and thromboembolic TEAEs, until their projected
transferrin levels and total iron-binding capacity [12, 15, 21, date of completion, until the last patient randomized
23], decrease hepcidin [12, 15, 21, 23] and reduce low-density reached EOS or until consent was withdrawn.
lipoprotein (LDL) cholesterol [12, 15, 21]. Roxadustat was re- This study was conducted in accordance with the ethical
cently approved in China and Japan for the treatment of both principles of the declaration of Helsinki, Good Clinical Practice
DD- and NDD-CKD anemia. This global study, consisting (GCP), the International Council for Harmonization of
mostly of European patients, was conducted to evaluate the Technical Requirements for Pharmaceuticals for Human Use
efficacy and safety of roxadustat in the treatment of anemia in guidelines, and applicable laws and regulations. The protocol
individuals with NDD-CKD. was approved by each Institutional Review Board and all
subjects provided written informed consent. Details pertain-
ing to protocol revisions can be found in the Supplementary
MATERIALS AND METHODS Methods.
Study design
This was a Phase 3, multicenter, randomized, double-blind, Study population
placebo-controlled study in anemic patients with Stage 3, 4 or 5 In this study, patients were 18 years old, had been diag-
CKD who were not on dialysis at the time of randomization nosed with CKD Stage 3, 4 or 5 (eGFR <60 mL/min/1.73 m2)
(ALPS; ClinicalTrials.gov Identifier: NCT01887600). In this and were not receiving dialysis. The mean of each patient’s
study, anemia was defined as mean Hb 10.0 g/dL per repeated three most recent Hb values during the screening period had
screening measurements. Patients were randomized (2:1) to to be 10.0 g/dL, with a difference of 1.0 g/dL between the
oral roxadustat or placebo three times weekly (TIW) for highest and the lowest values. Patients were excluded if they
52–104 weeks. Randomization was stratified by the following had received ESA treatment or more than one dose of IV
four factors: region (Western Europe versus rest of the world); iron within 12 weeks prior to randomization, red blood cell
screening Hb values (8.0 g/dL versus >8.0 g/dL); history of (RBC) transfusion within 8 weeks prior to randomization,
CV, cerebrovascular or thromboembolic diseases (yes versus had chronic inflammatory disease that could impact

Screening Treatment period – correction and maintenance periods* Follow-up

6 weeks 52–104 weeks** 4 weeks

Primary treatment period Extended treatment period

Weeks 1–52 Weeks 53–104

Oral tablet; three times weekly during

Roxadustat
correction period and maintenance period
R Follow-up
2:1 visits
Oral tablet; three times weekly during
Placebo
correction period and maintenance period

FIGURE 1: Study design. R, randomized. *Once Hb correction was reached, the patient entered the maintenance period; correction period var-
ied from patient to patient. **The treatment period, a minimum of 52 weeks, provides sufficient data on the long-term treatment of patients
with anemia of CKD using roxadustat.

Roxadustat for the treatment of anemia in CKD patients not on dialysis 1631
erythropoiesis, or had received any prior treatment with rox- Additional secondary efficacy endpoints included change
adustat or an HIF-PHI. A full list of eligibility criteria, as well from BL in mean arterial pressure (MAP) to the average MAP
as information regarding compliance requirements, can be value of Weeks 20–28, occurrence and time to the first occur-
found in the Supplementary Methods. rence of hypertension [defined as either systolic blood pressure
(SBP) 170 mmHg and an increase from BL 20 mmHg, or as
Study drug administration diastolic blood pressure (DBP) 110 mmHg and an increase
Patients were randomized via interactive response technol- from BL of 15 mmHg], rate of progression of CKD measured
ogy to receive roxadustat or placebo. The initial double-blind by annualized eGFR slope over time in the entire study cohort,
study drug dose for both groups was based on the tiered, change in Hb level without rescue therapy over treatment peri-
weight-based dosing scheme (weight 45 to 70 kg ¼ 70 mg; ods, time to first Hb response, change from BL in cholesterol
weight >70 to 160 kg ¼ 100 mg). Study drug was dosed TIW levels and apolipoproteins, the occurrence and time to the first
during the correction period with doses administered at least hospitalization, change from BL in serum hepcidin, change
2 days apart, but no more than 4 days apart. Dose adjustments from BL in soluble transferrin receptor and change from BL in
were permitted from Week 4 onward; doses had to remain sta- health-related quality of life (HRQoL) measures. Information
ble for 4 weeks following any dose adjustment. All dose adjust- pertaining to the HRQoL measures can be found in the
ments were made to maintain study patients’ Hb level within Supplementary Methods. Data pertaining to measures of iron
the predefined target range. utilization, including ferritin, transferrin saturation (TSAT) and
serum iron, were also collected.
The safety of roxadustat was assessed by monitoring the oc-
Study outcomes and assessments
currence of TEAEs. Severity of TEAEs was graded according to
Efficacy assessments of treatment with study drug were National Cancer Institute—Common Terminology Criteria for
based on Hb as assessed by a central laboratory from IV blood Adverse Events (NCI-CTCAE) version 4.0. Additional safety
sampling. For the European Union [EU; European Medicines assessments included findings from laboratory tests, vital signs,
Agency (EMA)], the primary efficacy endpoint was Hb re- physical examinations and 12-lead electrocardiograms (ECGs).
sponse defined as Hb 11.0 g/dL and an Hb increase from BL The safety-emergent period was defined as the evaluation pe-
by 1.0 g/dL in any patient with BL Hb >8.0 g/dL, or an in- riod from the analysis date of first drug intake up to 28 days af-
crease from BL by 2.0 g/dL in any patient with BL Hb 8.0 g/ ter the Analysis Last Dose date. The schedule of assessments is
dL at two consecutive visits separated by at least 5 days during reported in Supplementary data, Table S2.
the first 24 weeks of treatment without rescue therapy (i.e. RBC
transfusion, ESA or IV iron) prior to Hb response. For the US
Food and Drug Administration (FDA), the primary efficacy Statistical methods
endpoint was the change in Hb from BL to the average Hb level All statistical comparisons were made using two-sided tests
during the evaluation period (defined as Weeks 28–52), regard- at the a ¼ 0.05 significance level, unless stated otherwise. Null
less of rescue therapy. In the event that rescue therapy was re- hypotheses for superiority testing were of no treatment differ-
quired, rescue therapy guidelines were standardized (see ence and corresponding alternative hypotheses were two-sided.
Supplementary Methods). Key secondary efficacy endpoints Null hypotheses for noninferiority testing were of the inferiority
(listed in Table 1) were analyzed using the full analysis set of roxadustat treatment and were one-sided at the a ¼ 0.025
(FAS) (Supplementary data, Table S1). significance level.

Table 1. Analysis of key secondary efficacy endpoints

Number Endpoint Primary analysis method

1 Hb change from BL to the average Hb in Weeks 28–36, Analysis method: MMRM
without having received rescue therapy within 6 weeks Categorical variables: region, history of CV, visits and visits by treatment
prior to and during this 8-week evaluation period Continuous covariates: BL Hb, BL eGFR and BL Hb by visit
2 Change from BL in LDL cholesterol to the average LDL Analysis method: MMRM
cholesterol of Weeks 12–28 Categorical variables: region, history of CV, visits and visits by treatment
Continuous covariates: BL LDL, BL Hb and BL eGFR
3 Occurrence and time to first use of rescue therapy (compos- Analysis method: Cox regression þ Kaplan–Meier
ite of RBC transfusions, IV iron supplementation and Categorical variables: stratified by region, history of CV and adjusted for
rescue ESA) BL Hb and BL eGFR as continuous covariates
4 Change from BL in SF-36 VT subscore to the average VT Analysis method: MMRM
subscore of Weeks 12–28 Categorical variables: region, history of CV, visits and visits by treatment
Continuous covariates: BL Hb, BL SF-36 VT subscore and BL eGFR
5 Change from BL in SF-36 PF subscore to the average PF Analysis method: MMRM
subscore of Weeks 12–28 Categorical variables: region, history of CV, visits and visits by treatment
Continuous covariates: BL Hb, BL SF-36 PF subscore and BL eGFR

MMRM, mixed model of repeated measures. Superiority was tested using a fixed sequence testing procedure.

1632 E. Shutov et al.

 The EU (EMA) primary efficacy endpoint was a binary patients were excluded due to GCP violations. Therefore, a total
variable—Hb response (yes/no)—and was analyzed using the of 594 randomized patients were analyzed: 391 in the roxadu-
FAS. The proportion of responders in the primary efficacy stat treatment group and 203 in the placebo group.
variable was analyzed using a Cochran–Mantel–Haenszel A total of 334 (56.2%) patients received study treatment for
(CMH) test adjusting for covariates (region; history of CV, ce- 2 years: 245/391 (62.7%) in the roxadustat treatment group and
rebrovascular or thromboembolic diseases; BL Hb; and BL 89/203 (43.8%) in the placebo treatment group (Figure 2). At
eGFR), comparing roxadustat with placebo. The CMH ad- 2 years, the incidence of treatment discontinuations was lower
justed odds ratio (roxadustat versus placebo) and its 95% con- for patients in the roxadustat treatment group (146/391, 37.3%)
fidence interval (CI) were calculated. Superiority of roxadustat compared with the placebo treatment group (114/203, 56.2%),
versus placebo was declared if the lower bound of the two- with the most pronounced difference in patients with lower
sided 95% CI of the CMH odds ratio was higher than one eGFR at BL (Supplementary data, Figure S1). Patient demo-
(>1.00). In addition, a 95% CI for the proportion of each graphics and BL characteristics were similar between treatment
treatment group (roxadustat and placebo) based on the exact groups (Table 2; Supplementary data, Table S3). Details regard-
method of Clopper–Pearson was calculated. ing treatment exposure can be found in the Supplementary
The primary efficacy endpoint for the US FDA was Hb Results.
change from BL to the average Hb of Weeks 28–52 regardless of
rescue therapy and was analyzed using all randomized patients. Efficacy outcomes
The change from BL to the average Hb of Weeks 28–52 was an-
alyzed using analysis of covariance (model with multiple impu- Primary endpoints. Following analysis of the primary end-
tations, adjusting for covariates (categorical: region and history point for the EU (EMA), superiority of roxadustat versus pla-
of CV; continuous: BL Hb and BL eGFR), comparing roxadu- cebo was demonstrated in terms of response rate to treatment
stat with placebo. Difference of least square means (LSMs; roxa- during the first 24 weeks of treatment without patients having
dustat minus placebo) and its 95% CI were estimated for the received rescue therapy in the FAS, as the lower bound of the
change from BL to the average of Weeks 28–52. Superiority of two-sided 95% CI of the odds ratio was higher than one
roxadustat versus placebo was declared if the lower bound of (>1.00) (Table 3). In the FAS, 79.2% of patients in the roxadu-
the two-sided 95% CI of the difference between treatment arms stat treatment group were responders compared with 9.9% in
(roxadustat minus placebo) was higher than zero (>0.00). the placebo group [odds ratio ¼ 34.74 (95% CI 20.48–58.93)].
Key secondary endpoints were tested using a fixed sequence The odds ratio was statistically significant in favor of roxadustat
testing procedure in order to maintain the overall two-sided (P < 0.001) (Table 3). Sensitivity and subgroup analyses of the
type I error rate at 0.05; if the null hypothesis was rejected for a primary EU (EMA) efficacy analysis confirmed the primary
test, the claim of superiority was considered successful and the analysis (Supplementary data, Figures S2 and S3).
test progressed to the next comparison in the sequence Following analysis of the primary endpoint for the US FDA,
(Table 1). The additional secondary efficacy endpoints—change superiority of roxadustat versus placebo was demonstrated be-
from BL in MAP to the average MAP value of Weeks 20–28 cause the lower bound of the two-sided 95% CI of the difference
and time to the first occurrence of hypertension—were tested between treatment arms (roxadustat – placebo) was higher than
for noninferiority using the per-protocol set, and remaining zero (>0.00). BL Hb was comparable between the treatment
endpoints were tested for superiority using the FAS. The treat- groups (Table 4). The LSM change from BL was 1.992 (95% CI
ment effect results for inferential analyses were presented as 1.82–2.16) g/dL for patients in the roxadustat group and 0.300
roxadustat versus placebo. (95% CI 0.09–0.51) g/dL for patients in the placebo group. The
Demographic and other BL characteristics for each treat- LSM of the treatment difference for roxadustat versus placebo
ment group were summarized using descriptive statistics and was þ1.692 (95% CI 1.52–1.86); this difference was statistically
frequency tabulations; the number and percentage of patients significant (P < 0.001) (Table 4; Figure 3; Supplementary data,
with TEAEs, as well as the incidence rate (per 100 patient-years Figure S4). Sensitivity and subgroup analyses of the primary US
at risk) and event rate (per 100 patient-years) of TEAEs, were FDA efficacy analysis confirmed the primary analysis
summarized for each treatment group. These data are under- (Supplementary data, Figures S5 and S6).
powered to assess and compare safety outcomes across groups.
All data processing, summarization and analyses were per- Secondary endpoints. In the sequentially tested key second-
R
formed using SASV version 9.3. A detailed description of sam- ary endpoints, superiority of roxadustat versus placebo was
ple size calculations and analysis populations can be found in demonstrated for Hb change from BL to the average of Weeks
the Supplementary Methods. 28–36 (Supplementary data, Figure S7), LDL cholesterol change
from BL to the average of Weeks 12–28 (mean change in LDL
cholesterol from BL, average of Weeks 12–28: 0.602 mmol/L
RESULTS for roxadustat; 0.151 mmol/L for placebo) and time to first use
of rescue medication (Supplementary data, Tables S1, S4 and
Patient disposition and demographics
S5; Figure 4). Decreases in LDL cholesterol in the roxadustat
A total of 1051 patients signed the informed consent form group were statistically significant compared with the placebo
and were screened. Of these patients, 597 met inclusion criteria group. Slight decreases in high-density lipoprotein (HDL) cho-
and were randomized to receive treatment. Three randomized lesterol and, subsequently, in the LDL/HDL cholesterol ratio

Roxadustat for the treatment of anemia in CKD patients not on dialysis 1633
 Screened
(n=1051)

Screen failures
(n=454)

Randomized
(n=597)

Excluded due to
GCP violations
(n=3)

Roxadustat Placebo
(n=391) (100%) (n=203) (100%)

Discontinued treatment: (n=146) (37%) Discontinued treatment (n=114) (56%)

• Adverse events or death (n=60) (15%) • Adverse events or death (n=25) (12%)
• Withdrawal by patient (n=58) (15%) • Withdrawal by patient (n=52) (26%)
• Lack of efficacy (n=3) (0.8%) • Lack of efficacy (n=26) (13%)
• Other (n=25) (6%) • Other (n=11) (5%)

Completed 2 years’ treatment

Roxadustat Placebo
(n=245) (63%) (n=89) (44%)

FIGURE 2: Patient disposition.

were also seen in roxadustat treated patients (Supplementary

data, Table S6 and Figures S8 and S9). In this study, rates of comparable between treatment groups. Patients in the roxadu-
statin use were comparable between treatment groups. stat treatment group had a total of 476.7 events/100 patient ex-
Furthermore, LDL and HDL assessments by patient sub- posure years (PEY) TEAEs compared with 514.7 events/100
group—with or without use of concomitant statin treatment at PEY events in the placebo group (Table 6). Common (5% in
BL—were consistent with the overall population (data not either treatment group) TEAEs in either treatment group in-
shown). These findings, paired with the fact that decreases in cluded end-stage renal disease, hypertension, peripheral edema
the LDL/HDL cholesterol ratio were slightly more pronounced and decreased GFR. Noteworthy differences between treatment
in roxadustat-treated patients, suggest roxadustat may have an groups include greater incidences and event rates in the roxa-
additional effect on statins. dustat treatment group for hypertension, nausea and diar-
No difference was observed between the roxadustat and rhea, and lower incidences and event rates in the roxadustat
placebo treatment groups in terms of change from BL in Short treatment group for anemia. Overall, 241 (61.6%) patients in
Form 36 (SF-36) vitality (VT) and physical functioning (PF) the roxadustat treatment group had a total of 515 (103.6/100
subscores at each timepoint assessed (Weeks 12–28) PEY) serious TEAEs compared with 115 (56.7%) patients
(Supplementary data, Table S1). who had a total of 250 (119.0/100 PEY) events in the placebo
There was no apparent difference between the roxadustat group (Supplementary data, Table S7). The time to occur-
and placebo treatment groups in terms of change from BL in rence of serious TEAEs, TEAEs leading to patient death and
MAP, cumulative incidence of first occurrence of hypertension, TEAEs leading to withdrawal was comparable in both treat-
decrease in eGFR with time or mean changes by visit in ferritin, ment groups.
TSAT or serum iron. Details regarding secondary endpoints There were no apparent differences between treatment
are presented in the Supplementary Results as well as groups in the occurrence of potentially clinically significant
Supplementary data, Figure S10 (ferritin) and Supplementary liver assessments, other laboratory assessments, vital signs or
data, Figure S11 (TSAT). 12-lead ECG assessments. Incidence rates of potentially
clinically significant SBP values (SBP 170 mmHg in combina-
tion with an increase of 20 mmHg) per 100 PEY were 12.7
Safety and 10.4 for roxadustat- and placebo-treated patients, respec-
An overview of TEAE incidence by category of TEAE is pre- tively. Time-course data for SBP and DBP are presented in
sented in Table 5. The overall incidence of TEAEs was Supplementary Figures S12 and S13, respectively. No difference

1634 E. Shutov et al.

Table 2. Demographics and BL characteristics (safety analysis set)

Parameter Category/statistic Roxadustat (n ¼ 391) Placebo (n ¼ 203)

Sex Male 169 (43.2 %) 99 (48.8 %)
Female 222 (56.8 %) 104 (51.2 %)
Age (years) Median (range) 62.0 (20–89) 63.0 (26–90)
Race White 335 (85.7 %) 182 (89.7 %)
Black or African American 10 (2.6 %) 3 (1.5 %)
Asian 9 (2.3 %) 0
Other 37 (9.5 %) 18 (8.9 %)
Region Western Europe 28 (7.2 %) 16 (7.9 %)
Rest of World (mostly Eastern 363 (92.8 %) 187 (92.1 %)
European)
Hb (g/dL) Mean (SD) 9.08 (0.76) 9.10 (0.72)
8.0 g/dL 32 (8.2 %) 20 (9.9 %)
>8.0 g/dL 359 (91.8 %) 183 (90.1 %)
LDL cholesterol (mmol/L) Mean (SD) 2.99 (1.29) 2.88 (1.14)
eGFR (mL/min/1.73 m2) Mean (SD) 16.5 (10.2) 17.2 (11.7)
Median 13.1 13.4
eGFR (mL/min/1.73 m2) categories <10 119 (30.4 %) 57 (28.1 %)
10 to <15 102 (26.1 %) 61 (30.0 %)
15 to <30 128 (32.7 %) 58 (28.6 %)
30 to <45 34 (8.7 %) 19 (9.4 %)
45 to <60 8 (2.0 %) 7 (3.4 %)
60 0 1 (0.5)c
CKD etiology Diabetic nephropathy 109 (27.9 %) 66 (32.5)
Hypertensive nephropathy 116 (29.7 %) 58 (28.6)
Glomerulonephritis, unspecified 52 (13.3 %) 23 (11.3)
Pyelonephritis 49 (12.5 %) 24 (11.8)
Polycystic kidney disease 36 (9.2 %) 21 (10.3)
Other 84 (21.5 %) 41 (20.2)
Weight, kg Mean (SD) 73.86 (16.49) 76.50 (16.51)
Iron repletion at BL Ferritin 100 ng/mL and TSAT 20% 204 (52.2 %) 109 (53.7 %)
hs-CRP, nmol/La Mean (SD)b 92.02 (228.72) 87.37 (149.36)
Medianb 29.15 29.25
ULN 245 (63.1 %) 135 (66.8 %)
>ULN 143 (36.9 %) 67 (33.2 %)
Missing 3 1
SBP, mmHg Mean (SD) 135 (13.62) 134 (12.30)
DBP, mmHg Mean (SD) 77 (8.83) 77 (8.68)
Cardiac and vascular disorders Angina pectoris 40 (10.2 %) 26 (12.8 %)
Cardiac failure, chronic 68 (17.4 %) 44 (21.7 %)
Hypertension 379 (96.9 %) 194 (95.6 %)
Diabetes mellitus Present 131 (33.5 %) 76 (37.4 %)
Statin use at BL Yes 119 (30.4 %) 61 (30.0 %)
hs-CRP, high-sensitivity C-reactive protein; ULN, upper limit of normal.
a
ULN ¼ 47.6 nmol/L.
b
Based on data from FAS.
c
Patient met study criteria at screening.

was observed between treatment groups in the incidence rate of 104 weeks. In this study, superiority of roxadustat versus pla-
deaths/100 PEY [7.4 roxadustat versus 7.6 placebo, hazard ratio cebo was demonstrated for both primary efficacy endpoints: Hb
of 0.96 (95% CI 0.53–1.74); P ¼ 0.902] during the safety- response [odds ratio ¼ 34.74 (95% CI 20.48–58.93)] and change
emergent period. in Hb from BL [roxadustat – placebo: þ1.692 (95% CI 1.52–
1.86); both P < 0.001]. Superiority of roxadustat was also dem-
onstrated for LDL cholesterol change from BL, and time to first
DISCUSSION use of rescue medication (both P < 0.001). The incidences of
TEAEs were comparable between groups (roxadustat: 87.7%,
This study, conducted in a mostly European population, was a
placebo: 86.7%).
Phase 3 randomized, double-blind, placebo-controlled study
In this study, demographics and BL disease characteristics,
designed to evaluate the efficacy of roxadustat in the treatment
including disease and anemia treatment history, were compara-
of anemia in patients with NDD-CKD. Patients with Stage 3, 4
ble between treatment groups and consistent with the expected
or 5 CKD (with eGFR <60 mL/min/1.73 m2) not receiving dial-
study population [12, 13, 15, 21]. It is worth noting that, in this
ysis were randomized in a 2:1 ratio to receive roxadustat or pla-
study, more patients with advanced CKD were part of the study
cebo. Treatment was to continue for at least 52 weeks and up to

Roxadustat for the treatment of anemia in CKD patients not on dialysis 1635
Table 3. Hb response without rescue therapyg [EU (EMA) primary efficacy
endpoint; FAS]
12
Parameter/statistic Roxadustat Placebo
Roxadustat
(n ¼ 389) (n ¼ 203) Placebo

Number of patients who met Hb 308 (79.2) 20 (9.9)

response criteria at Week 24,a n (%)
95% CI (%) 74.8–83.1 6.1–14.8 11

Hemoglobin (g/dL)
Number of nonresponders per 81 (20.8) 183 (90.1)
definition,a n (%)
Patients failing to meet 77 (19.8) 177 (87.2)
criteria for Hb response,b n (%)
10
Patients under rescue therapy,c n (%) 4 (1.0) 6 (3.0)
Patients who discontinued 0 0
treatment prior to Hb responsed
Difference of proportions 69.3
(roxadustat – placebo),e % 9
BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 EOT EOS
95% CI of difference (%) 63.6–75.1 +2
Visit (weeks)
Odds ratio (roxadustat – 34.74
placebo)f FIGURE 3: Mean Hb over time regardless of rescue therapy use
95% CI 20.48–58.93 (all randomized patients).
P-value P < 0.001
a
Response is defined as Hb 11.0 g/dL and change 1.0 g/dL if BL Hb >8.0 g/dL; or
change 2.0 g/dL if BL Hb 8.0 g/dL at two consecutive visits (dates) (with available
data) separated by at least 5 days during the first 24 weeks of treatment without having
received rescue therapy (RBC transfusion, ESA or IV iron), or having discontinued prior
to Hb response. The proportions and 95% CI are unadjusted for covariates, and the ex- 3.5 135.45
act method of Clopper–Pearson is used for 95% CI. Roxadustat
b Placebo
Patient who did not meet the Hb criteria detailed above during the first 24 weeks.
c
Patient who met the Hb criteria detailed above but started rescue therapy between the
two consecutive visits.
d
Patient who met the Hb criteria detailed above but discontinued prior to the day of the
LDL cholesterol (mmol/L)

LDL cholesterol (mg/dL)

second consecutive visit. 3.0 116.1
e
95% CI of the difference in proportions is calculated using Wald’s method.
f
CMH test is adjusted by region, history of CV disease, BL Hb and BL eGFR.
g
Rescue therapy is defined as RBC transfusion, ESA or IV iron.
ULN
2.5 96.8

Table 4. Change from BL to the average Hb in Weeks 28–52 regardless of

rescue therapy use (US FDA primary efficacy endpoint; all randomized
patients) 77.4
2.0
BL 4 8 12 20 28 36 44 52 68 84 104 EOS
Parameter/statistic Roxadustat Placebo Visit (weeks)
(n ¼ 391) (n ¼ 203)
FIGURE 4: Mean (695% CI) plot of LDL cholesterol regardless of
BL Hb, mean (SD), g/dL 9.078 (0.761) 9.095 (0.721)
fasting status by time (FAS). ULN, upper limit of normal.
Hb change from BL to the
average Hb in Weeks
28–52 (g/dL)
Table 5. Overview of TEAEs and death (safety analysis set)
N 312 146
Mean 1.988 0.406 Type of Event Roxadustat Placebo
SD 0.953 0.979 (n ¼ 391), n (%) (n ¼ 203), n (%)
Min 1.19 2.09
Median 1.938 0.209 TEAE 343 (87.7) 176 (86.7)
Max 4.43 3.80 Serious TEAE 241 (61.6) 115 (56.7)
Analysis using analysis of TEAE leading to death 40 (10.2) 19 (9.4)
covariance with multiple TEAE leading to withdrawal 23 (5.9) 8 (3.9)
imputations for Hb change of treatment
from BL to Weeks 28–52 TEAE NCI-CTC Grade 3 185 (47.3) 88 (43.3)
LSM 1.992 0.300 or higher
95% CI 1.82–2.16 0.09–0.51 Death during the safety- 37 (9.5) 16 (7.9)
LSM difference 1.692 emergent period
(roxadustat—placebo) TEAEs were defined as adverse events that started during the safety emergent period, i.e.
95% CI 1.52, 1.86 those starting after first administration of the study drug, to up to 28 days after last study
P-value P < 0.001 drug intake.

The model includes treatment as fixed factor, region and history of CV disease as class
factors, and BL Hb and BL eGFR as continuous covariates.
cohort relative to other anemia management studies that have
BL Hb is defined as the mean of four latest central laboratory Hb values prior to or on examined ESAs in patients with NDD-CKD. For instance, in
the same date as first study drug intake (pre-dose). the PEARL (Safety & Efficacy of Peginesatide for the Treatment

1636 E. Shutov et al.

Table 6. Common (5% patients in any treatment group) TEAE (safety analysis set)

MedDRA version 20.0 preferred term Roxadustat (n ¼ 391; PEY ¼ 496.9) Placebo (n ¼ 203; PEY ¼ 210.0)

n (%) #E (event rate/100 PEY) n (%) #E (event rate/100 PEY)

Overall 373 (87.7) 2369 (476.7) 176 (86.7) 1081 (514.7)
End-stage renal disease 135 (34.5) 135 (27.2) 62 (30.5) 63 (30.0)
Hypertension 87 (22.3) 142 (28.6) 28 (13.8) 46 (21.9)
Edema peripheral 45 (11.5) 54 (10.9) 21 (10.3) 22 (10.5)
GFR decreased 43 (11.0) 48 (9.7) 23 (11.3) 28 (13.3)
Hyperkalemia 39 (10.0) 52 (10.5) 15 (7.4) 21 (10.0)
Viral upper respiratory tract infection 38 (9.7) 50 (10.1) 9 (4.4) 15 (7.1)
Nausea 37 (9.5) 47 (9.5) 6 (3.0) 6 (2.9)
Diarrhea 33 (8.4) 41 (8.3) 7 (3.4) 10 (4.8)
Pneumonia 28 (7.2) 35 (7.0) 14 (6.9) 17 (8.1)
Iron deficiencya 26 (6.6) 26 (5.2) 8 (3.9) 10 (4.8)
Anemia 24 (6.1) 27 (5.4) 37 (18.2) 54 (25.7)
Headache 21 (5.4) 22 (4.4) 11 (5.4) 12 (5.7)
Arteriovenous fistula thrombosis 20 (5.1) 27 (5.4) 2 (1.0) 3 (1.4)
Pruritus 20 (5.1) 22 (4.4) 2 (1.0) 2 (1.0)
Asthenia 19 (4.9) 23 (4.6) 12 (5.9) 15 (7.1)
Hyperuricemia 9 (2.3) 9 (1.8) 11 (5.4) 11 (5.2)
Event rate per 100 PEY is defined as (number of events) x 100 divided by PEY during safety-emergent period.
Sorting order: incidence by preferred term in the roxadustat treatment group.
#E, number of events; PEY, patient exposure years.
a
Based on ferritin and TSAT.

of Anemia in Participants With Chronic Renal Failure Not on CKD [26–28]. These effects may be mediated, at least in
Dialysis) [24] and TREAT (Trial to Reduce Cardiovascular part, by HIF-dependent effects on acetyl coenzyme A that
Events with Aranesp Therapy) [5] studies, BL eGFR was are required for the first step of cholesterol synthesis and
roughly 30 mL/min/1.73 m2 (or higher) whereas, in this study, on the degradation of 3-hydroxy-3-methylglutaryl coenzyme A
mean [standard deviation (SD)] eGFR was 16.5 (10.2) mL/min/ reductase, the rate-limiting enzyme in cholesterol synthesis
1.73 m2 and 17.2 (11.7) mL/min/1.73 m2 in the roxadustat and [29–31].
placebo groups, respectively. This difference is likely due to dif- In this study, mean iron repletion status at BL was compara-
ferences in inclusion criteria between studies, in particular the ble between treatment groups (roxadustat: 52.2%; placebo:
lower maximum Hb value qualifying for inclusion. 53.7%) but changes in markers of iron status were greater in
This study met its primary objective by demonstrating supe- roxadustat-treated patients relative to placebo-treated patients.
riority of roxadustat in efficacy versus placebo in terms of both Also, the proportion of responders in the roxadustat treatment
response rate and Hb change from BL at Weeks 28–52. These group was slightly higher in iron-replete patients (84.3%)
findings are supported by previous work performed in patients compared with noniron-replete patients (73.5%). Also, when
with NDD-CKD [16, 19–22]. Although the studies in this evaluating Hb change from BL to the average in Weeks 28–36,
program were conducted by different companies in different the Hb change in roxadustat-treated patients was comparable
geographic regions where treatment practices may differ, in both subgroups. However, the treatment difference in
efficacy results were consistent between trials, suggesting that placebo-treated patients in the noniron-replete subgroup was
roxadustat is effective in this population. smaller due to a larger Hb change observed for placebo.
Superiority of roxadustat versus placebo was also demon- Roxadustat-related decreases in hepcidin and increases in solu-
strated for LDL cholesterol change from BL to Weeks 12–28. ble transferrin receptor levels, as seen in this study and previous
This finding is similar to previous studies performed in patients studies [16–21], help provide insight into the effects of roxadu-
with NDD-CKD [16, 21, 22]. Moreover, in roxadustat-treated stat on iron metabolism. For instance, decreases in hepcidin, a
patients, decreases in LDL cholesterol (mean change in LDL negative regulator of iron absorption and mobilization that
cholesterol from BL, average of Weeks 12–28: 0.602 mmol/L) impedes erythropoiesis, may mediate the stability of iron stores,
were comparable to decreases seen with low-dose statins [25] thereby leading to improved iron bioavailability via enhanced
and decreases in LDL cholesterol exceeded those observed in intestinal iron absorption and iron mobilization from macro-
HDL cholesterol, leading to a favorable reduction in the phages of the reticuloendothelial system [13, 21, 32]. Likewise,
LDL/HDL cholesterol ratio. Likewise, cholesterol levels and increases in soluble transferrin receptor levels improve iron
apolipoproteins showed a decrease at each timepoint in the availability given its role as a carrier protein for transferrin that
roxadustat treatment group compared with a slight increase in is required for the import of iron into the cell, which results in
the placebo treatment group. It may be possible that a reduction improved iron transport to tissues and to developing erythro-
in LDL cholesterol, as well as improvements to other blood lip- cytes [18]. In this study, initial increases in soluble transferrin
ids, may provide clinical benefit considering that dyslipidemia receptor (a consequence of HIF stimulation) appears most
is an established risk factor for CV disease in patients with pronounced in the first 12 weeks of treatment before stabilizing

Roxadustat for the treatment of anemia in CKD patients not on dialysis 1637
at levels higher than seen with placebo, which did not show a analyses of CV-related events in roxadustat- and ESA-treated
change from BL. patients are the focus of a forthcoming manuscript.
Overall, the safety profile of roxadustat in this study was gen- In conclusion, this study met its primary objective by dem-
erally comparable to placebo. While there was a slightly greater onstrating superiority of roxadustat in efficacy versus placebo
incidence of potentially clinically significant SBP values in the in terms of both response rate and Hb change from BL at
roxadustat treatment group compared with the placebo group, Weeks 28–52 in mainly European patients. In the sequentially
there was no apparent difference in the incidence of potentially tested key secondary endpoints, superiority versus placebo was
clinically significant DBP values or 12-lead ECG values, and demonstrated for Hb change from BL at Weeks 28–36, LDL
there was no apparent difference in terms of MAP with time or cholesterol change, decreases in hepcidin, increases in soluble
effect on overall BP between treatment groups. Furthermore, a transferrin receptor levels and time to use of rescue medication.
confirmatory assessment of deaths revealed no difference be- The safety profile observed in this study is in line with the
tween groups. The incidence of arteriovenous fistula thrombo- expected event profile in NDD-CKD patients and was generally
sis was greater in the roxadustat treatment group; an comparable between roxadustat and placebo over 104 weeks.
explanation of this difference is outside the scope of this study
and could be related to the treatment but not necessarily, consid- SUPPLEMENTARY DATA
ering the many factors that contribute to this complication.
However, it is worth noting that the majority of arteriovenous Supplementary data are available at ndt online.
fistula thrombosis events in roxadustat-treated patients (67%;
18/27 events) occurred after the start of chronic dialysis. ACKNOWLEDGEMENTS
In this study, there were fewer treatment discontinuations in Roxadustat is being developed by FibroGen, AstraZeneca and
the roxadustat treatment group compared with the placebo Astellas. Medical writing/editorial support was provided by
group. As expected, the incidence of discontinuation due to Patrick Tucker, PhD, and Elizabeth Hermans, PhD (OPEN
‘lack of efficacy’ was very low in roxadustat (0.8%) compared Health Medical Communications, Chicago, IL, USA), and
with placebo (12.8%), and withdrawals due to TEAEs were low funded by the study sponsor. We would like to sincerely
overall: 5.9% with roxadustat versus 3.9% with placebo. Overall thank the investigators who participated in this trial, as well
treatment exposure and PEY were notably higher in the roxa- as the patients and their family members for their support.
dustat treatment group compared with placebo; this is likely
due to the planned 2:1 randomization of patients and the
FUNDING
greater proportion of patients in the placebo treatment group
discontinuing treatment prematurely. The majority of TEAEs This study was funded by Astellas Pharma, Inc.
in both treatment groups was nonserious, Grade 2 or 3 in sever-
ity, and considered unrelated to treatment by the investigator. AUTHORS’ CONTRIBUTIONS
The safety profile in both treatment groups was generally
consistent with that expected in this study population. M.R. was responsible for conception and study design. E.S.,
One possible limitation to this study may be the homogene- W.S., C.E., A.T., B.A., M.R. and N.D. were involved in acqui-
ity of the study population (>85% White in both treatment sition of data. M.R. and U.V. were involved in analysis and
groups), which may limit the generalizability of the current interpretation of the data. Drafting and critical revision of the
findings. However, it should be noted that participants in this article for important intellectual content done by E.S., W.S.,
study were from a wide range of different countries, mainly C.E., A.T., B.A., M.R., U.V. and N.D.
from Europe, which may help increase heterogeneity. This
study also observed unequal discontinuation rates between CONFLICT OF INTEREST STATEMENT
treatment groups, which may complicate the interpretation
U.V. is an employee of Astellas Pharma Global Development,
of adverse event data. This study was not powered to show sig-
Inc. M.R. is an employee of Astellas Pharma Europe B.V. All
nificant differences in secondary endpoints. Lastly, this analysis
other authors have nothing to disclose. The results presented
did not consider ophthalmological data, data related to the de-
in this paper have not been published previously in whole or
velopment or worsening of renal cysts, or data related to the de-
part, except in abstract format.
velopment or worsening of pulmonary hypertension. It should
be noted, however, that ophthalmological considerations have (See related article by Locatelli and Vecchio. A new paradigm
been evaluated in other studies [12] and will be further in treating patients with chronic kidney disease and anaemia
addressed, in detail, in a forthcoming dedicated analysis. after a journey lasting more than 35 years. Nephrol Dial
It is also worth noting that, because this study used a placebo Transplant 2021; 36: 1559–1563)
comparator, an evaluation of the CV safety of roxadustat versus
ESAs is not presented here; CV safety is a pertinent concern
DATA AVAILABILITY STATEMENT
based on previous data that suggest an increased risk of
CV events is associated with ESA use [5, 33]. A comparison of Researchers may request access to anonymized participant-
CV-related safety between roxadustat and ESAs is a subject out- level data, trial-level data and protocols from Astellas spon-
side of the scope of the current analysis. However, pooled sored clinical trials at www.clinicalstudydatarequest.com. For

1638 E. Shutov et al.

the Astellas criteria on data sharing see: https://clinicalstudy disease on hemodialysis: Results from two phase 3 studies. Ther Apher Dial
datarequest.com/Study-Sponsors/Study-Sponsors-Astellas. 2020; 24: 628–641
19. Akizawa T, Iwasaki M, Otsuka T et al. Roxadustat treatment of chronic kid-
aspx. ney disease-associated anemia in Japanese patients not on dialysis: a phase
2, randomized, double-blind, placebo-controlled trial. Adv Ther 2019; 36:
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Received: 31.8.2020; Editorial decision: 8.2.2021
ESA-naive and ESA-converted patients with anemia of chronic kidney

Roxadustat for the treatment of anemia in CKD patients not on dialysis 1639