Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study

 
Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study
CLINICAL RESEARCH             www.jasn.org

Roxadustat for Treating Anemia in Patients with CKD
Not on Dialysis: Results from a Randomized Phase 3
Study
Steven Fishbane,1 Mohamed A. El-Shahawy,2 Roberto Pecoits-Filho,3,4 Bui Pham Van,5
Mark T. Houser,6 Lars Frison,7 Dustin J. Little,6 Nicolas J. Guzman,6 and Pablo E. Pergola8
Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT
Background Current anemia therapies for patients with non–dialysis-dependent CKD may require injec-
tion and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimu-
lates erythropoiesis and improves iron homeostasis.
Methods In this double-blind phase 3 study, we randomized patients with non–dialysis-dependent CKD
stages 3–5 and hemoglobin ,10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses
were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean
change from baseline in hemoglobin averaged over weeks 28–52 versus placebo, irrespective of rescue
therapy use. We assessed patients for adverse events.
Results The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo.
Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline
was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33
to 0.47) with placebo, (P,0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive
protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat
versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P,0.001). Roxadustat reduced the risk of red blood
cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with
roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8%
versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).
Conclusions Roxadustat effectively increased hemoglobin in patients with non–dialysis-dependent CKD
and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of
placebo.
Clinical Trial registry name and registration number: Safety and Efficacy Study of Roxadustat to Treat
Anemia in Patients With CKD, Not on Dialysis, NCT02174627

JASN 32: ccc–ccc, 2021. doi: https://doi.org/10.1681/ASN.2020081150

Anemia is frequently experienced by patients with
non–dialysis-dependent CKD (NDD-CKD) and its
prevalence increases with advancing CKD stage.1–5               Received August 9, 2020. Accepted December 1, 2020.
Anemia of CKD is associated with reduced quality                Published online ahead of print. Publication date available at
of life and an increased risk of mortality and                  www.jasn.org.
hospitalization.6–11
                                                                Correspondence: Prof. Steven Fishbane, Department of Medi-
   The recommended therapies for anemia in pa-                  cine, Donald and Barbara Zucker School of Medicine at Hofstra/
tients with NDD-CKD include erythropoiesis-                     Northwell, 100 Community Drive, 2nd Floor, Great Neck, NY
                                                                11021. Email: sfishbane@northwell.edu
stimulating agents (ESAs), oral or intravenous
(iv) iron, and red blood cell (RBC) transfusion.12              Copyright © 2021 by the American Society of Nephrology

JASN 32: ccc–ccc, 2021                                                                                             ISSN : 1046-6673/3203-ccc   1
CLINICAL RESEARCH    www.jasn.org

However, these therapies may require injection and medi-
                                                                    Significance Statement
cal office visits, and may be associated with adverse
outcomes.12–15 RBC transfusion is associated with risks in-         Anemia is untreated in many patients with non–dialysis-dependent
cluding infection and allosensitization,15,16 and costs; thus, a    CKD. Barriers to the use of current anemia therapies among such
                                                                    patients include parenteral administration that may require a
treatment objective for anemia is to avoid RBC transfu-
                                                                    medical visit, a requirement for iron repletion, and potentially in-
sion.12,17,18 ESAs are an established therapy for anemia in pa-     creased risk of cardiovascular events. In a phase 3 placebo-
tients with NDD-CKD, and although effective at increasing           controlled international study, the authors compared roxadustat,
hemoglobin (Hb) and reducing the need for RBC transfusion,          an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with
safety concerns noted with ESAs have stimulated the develop-        placebo for the treatment of anemia of non–dialysis-dependent
                                                                    CKD. They report that roxadustat was statistically superior to pla-
ment of alternative treatments for anemia.19–21 According to
                                                                    cebo in increasing hemoglobin and reduced the need for red blood
US product labels and international clinical practice guide-        cell transfusion. The drug also was generally well tolerated and had
lines, ESAs can be considered in patients with Hb ,10 g/dl          an adverse event profile comparable to placebo. These findings
at risk of RBC transfusions.12,17,18 ESA US product labels state    indicate that roxadustat may be clinically useful for the oral man-
that dosing should be reduced or interrupted when Hb ex-            agement of anemia in patients with non–dialysis-dependent CKD.
ceeds 10 g/dl, and that supplemental iron should be admin-
istered among patients with ferritin ,100 mg/L or transferrin      METHODS
saturation (TSAT) ,20%.22,23 Oral iron, however, is associ-
ated with gastrointestinal side effects and barriers exist to      Trial Design and Oversight
administration of iv iron in NDD-CKD.13,24 These limitations       This phase 3, multicenter, randomized, double-blind,
of established therapies may contribute to estimates from in-      placebo-controlled study (NCT02174627) was performed in
ternational analyses that approximately 50%–90% of patients        385 centers across 25 countries worldwide. The study com-
with anemia of NDD-CKD are untreated.4,5,11,25–30 In partic-       prised a screening period of up to 6 weeks, a treatment period
ular, analyses estimate that ESA use among patients with           of variable duration up to 4 years, and an end of study (EOS)
anemia of NDD-CKD in the real world ranges from 11%                follow-up visit (Figure 1). Treatment end date was defined on
to 35%.11,28–30 Accordingly, research has focused on devel-        the basis of accrual of a predefined number of adjudicated
oping alternative therapies for patients with anemia of            cardiovascular events for a separate pooled analysis (to pro-
NDD-CKD on the basis of the physiologic pathways of                vide adequate power) of three phase 3, placebo-controlled
erythropoiesis.                                                    roxadustat studies in NDD-CKD conducted by different spon-
    Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) in-       sors (NCT02174627, NCT01887600, NCT01750190).
hibitors are a new class of drug for anemia of CKD following           The final study protocol and informed consent form, and
recent Nobel Prize–winning research delineating response           any amendments to them, were approved by an Independent
mechanisms to hypoxia.31 Roxadustat was the first-in-class          Ethics Committee or Institutional Review Board in each par-
HIF-PH inhibitor to be approved by a regulatory agency to          ticipating center. All patients provided written, informed con-
treat anemia in patients with dialysis-dependent CKD in Japan      sent. This study was performed in accordance with the ethical
and China and in patients with NDD-CKD in China. 32                principles of the Declaration of Helsinki and the International
Hypoxia-inducible factor (HIF) is a transcription factor that      Council for Harmonisation Good Clinical Practice (GCP).
regulates expression of genes stimulating erythropoiesis. In
normoxia, HIF-PH is active and promotes degradation of             Patients
HIF-a.33–35 Roxadustat reversibly stabilizes HIF-a, which          Eligible patients were aged $18 years; had eGFR ,60 ml/min
promotes a coordinated erythropoietic response by activat-         per 1.73 m2, corresponding to stages 3–5 CKD; were not on
ing a number of genes, including those encoding endoge-            dialysis; and had a mean of two values of Hb ,10 g/dl mea-
nous erythropoietin, enzymes of heme biosynthesis, and             sured at least 7 days apart during the screening period; and
proteins that promote bone marrow iron availability via            ferritin $50 mg/L and TSAT $15%. Full inclusion and exclu-
improved absorption and transport.35,36 HIF-PH inhibitors          sion criteria are provided in the Supplemental Material.
are taken orally and routinely self-administered. In phase 2
and smaller, single-nation phase 3 studies among patients          Treatment
with NDD-CKD and anemia, roxadustat increased and                  Eligible patients were randomly assigned in a 1:1 ratio to re-
maintained Hb levels, 37–39 with similar adverse events            ceive roxadustat or placebo in a double-blind manner, which
(AEs) compared with placebo.37,38 The roxadustat clinical          was performed centrally using an Interactive Web Response
development program comprises both placebo- and active-            System/Interactive Voice Response System. Randomization
controlled phase 3 clinical studies designed to assess the         codes were computer generated by AstraZeneca Research &
efficacy and safety of roxadustat in NDD-CKD. Here, we              Development using GRand and a block randomization sched-
report the results of OLYMPUS, a global phase 3 study of           ule comprising a block size of 4. Randomization was stratified
the efficacy and safety of roxadustat in 2781 patients with         by country to ensure a balanced global distribution. The in-
anemia of NDD-CKD.                                                 vestigator, study site staff, and patient were blinded to study

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                          Hb
CLINICAL RESEARCH    www.jasn.org

$2.0 g/dl (if #8.0 g/dl at baseline); (2) mean change from         Material). Superiority of roxadustat compared with placebo
baseline in Hb averaged over weeks 28–52 among patients            was declared if the lower bound of the two-sided 95% confi-
with baseline high-sensitivity C-reactive protein (hsCRP; as-      dence interval (95% CI) of the difference between roxadustat
sessed among patients who consented to biobank samples)            and placebo exceeded 0 g/dl. Overall, 14.3% and 21.2% of
greater than the upper limit of normal (ULN; 5 mg/L); (3)          roxadustat and placebo datapoints, respectively, were imputed
proportion of total time of interpolated Hb values $10 g/dl        for the primary efficacy analysis of mean change from baseline
from weeks 28–52; (4) proportion of total time of interpolated     in Hb (ITT analysis set) and 200 datasets with simulated data
Hb values within 10–12 g/dl from weeks 28–52; (5) mean             were generated accordingly (Supplemental Material). Sub-
change from baseline in serum LDL cholesterol (LDL-C) to           group analyses were also performed using the ITT analysis
week 24; (6) need for first rescue therapy (composite) of any of    set (Supplemental Material).
iv iron, RBC transfusion, or ESA; (7) need for first RBC trans-         For the secondary efficacy end points, a fixed sequence
fusion as rescue therapy; (8) mean change from baseline in         approach adjusted for multiple testing; formal statistical hy-
SF-36 Vitality subscore averaged over weeks 12–28; (9) annual      pothesis testing was stopped once a test was accompanied by a
rate of change in eGFR starting from week 4, using all post-       P value $0.05. Secondary and key exploratory efficacy end
baseline eGFR values before initiation of dialysis/kidney trans-   points were analyzed using Cochran–Mantel–Haenszel tests,
plant; and (10) mean change from baseline in SF-36 Physical        Cox proportional hazard regression models, ANCOVA, and
Functioning subscore averaged over weeks 12–28.                    mixed-effect model repeated measures; full details of the sta-
    Key exploratory efficacy end points included: change in         tistical methods and analysis sets are listed in Supplemental
hepcidin (assessed from available biobank samples) from            Tables 1 and 2. Need for first rescue therapy end points are
baseline to week 24; change from baseline in serum iron pro-       presented as the number (%) of patients with the event and
files (iron, ferritin, total iron binding capacity [TIBC], and      event rates per 100 patient-years at risk (total number of years
TSAT) averaged over week 24 to end of treatment (EOT);             at risk).
and change from baseline in sitting systolic BP (SBP) and di-          Details of the assessment of treatment compliance are pro-
astolic BP (DBP). TSATwas calculated as: TSAT (%) 5 (serum         vided in the Supplemental Material.
iron level 3 100)/(TIBC).                                              AEs were analyzed using the ITT analysis set, with patients
    The primary safety objective was to contribute adjudicated     censored at their individual EOS visit regardless of study drug
cardiovascular safety data to a separate pooled safety analysis    discontinuation, at the date of withdrawal of consent or last
across the NDD-CKD studies in the roxadustat phase 3 pro-          study contact if the patient withdrew consent, or at the date
gram. Safety analyses included assessment of the incidence of      of death, whichever was earliest. Patients with more than one
AEs. AEs were coded using the Medical Dictionary for Regu-         event for the same AE category/preferred term were counted
latory Activities version 20.0. For patients who withdrew con-     once in that category/preferred term. The AE exposure-
sent, public record searches were used to confirm vital status      adjusted event rate (per 100 patient-years) was calculated as
(alive or dead), as appropriate, in accordance with local          follows:
regulations.                                                           [Number of patients with AEs/(the total number of
                                                                   days at risk for that AE across all patients in given
Statistical Analyses                                               group/365.25)] 3 100.
To contribute an adequate number of adjudicated cardiovas-             All data were analyzed using SAS software version 9.4 (SAS
cular safety events to the separate pooled analysis of phase       Institute, Cary, NC).
3 NDD-CKD studies (including approximately 4000 patients
overall), approximately 2600 patients were planned to be ran-
domized in OLYMPUS. The intent-to-treat (ITT) population           RESULTS
comprised all patients who were randomized to study treat-
ment throughout the duration of the study, irrespective of         Patients
their protocol adherence and continued participation in the        Overall, 5222 patients were screened. Of these, 2441 (46.7%)
study. The full analysis set (FAS) included patients from the      were not randomized, most commonly due to patients not
ITT analysis set who received study drug and had baseline Hb       meeting all inclusion/exclusion criteria (n52336 [95.7%];
and $1 postdose Hb assessments. The on-treatment (OT)              Figure 2). From June 26, 2014 to May 11, 2017, 2781 patients
128 analysis set comprised all patients who received $1            were randomized to roxadustat (n51393) or placebo
dose of randomized study treatment and was censored                (n51388). Twenty patients were excluded due to incorrect
28 days after last intake of study treatment.                      randomization (n54) or significant GCP violations (n516)
   The primary efficacy end point was analyzed in the ITT           in obtaining or recording the data that might affect the validity
analysis set using missing at random–based multiple imputa-        of the data; therefore, the ITT population comprised 1384 and
tion analysis of covariance (ANCOVA), containing terms for         1377 patients receiving roxadustat and placebo, respectively
treatment, baseline Hb measurement, baseline eGFR, geo-            (Figure 2). The FAS included 2728 patients (roxadustat
graphic region, and cardiovascular history (Supplemental           n51371; placebo n51357) and the OT128 population

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                                                             Patients screened (n=5222)             Not randomized (n=2441)
                                                                                                    Did not meet full eligibility criteria (n=2336)
                                                                                                    Death (n=16)
                               Randomized                   Patients randomized (n=2781)
                                                                                                    Patient decision (n=89)

                                                                      Allocation
                                            Allocated to roxadustat                 Allocated to placebo              Excluded from analysisa (n=11)
     Excluded from analysisa (n=9)                 (n=1393)                               (n=1388)                    Did not receive treatment (n=1)

                                             Received treatment                     Received treatment                 Withdrew from study (n=130)
                                                 (n=1384)                               (n=1376)                       Patient decision (n=128)
      Withdrew from study (n=84)                                                                                       Incorrect enrollment (n=1)
     Patient decision (n=84)                                                                                           Missing (n=1)

                                                                                                                      Discontinued treatment (n=801)
     Discontinued treatment (n=499)                                                                                   Patient decision (n=390)
                                                                      Follow-up
     Patient decision (n=250)                                                                                         Adverse event (n=52)
     Adverse event (n=79)                   Completed treatment                     Completed treatment               Protocol non-compliance (n=13)
     Protocol non-compliance (n=12)              (n=885)                                 (n=575)                      Study-specific discontinuation
     Study-specific discontinuation                                                                                   criteria (n=252)
     criteria (n=76)                                                                                                  Other (n=93)
     Other (n=82)                                                                                                     Missing (n=1)
                                               Completed study                       Completed study
                                                  (n=1300)                              (n=1247)

Figure 2. Patient disposition. aBecause of GCP violations. Study-specific discontinuation criteria included patients who required di-
alysis initiation and ESA rescue therapy. When possible, patients who discontinued treatment were followed for concomitant medi-
cations, AEs, vital status, and hospitalization.

included 2760 patients (roxadustat n51384; placebo                            0.29 to 0.45; nominal P,0.001). Withdrawal of consent was more
n51376). The predominant reason for exclusion from the                        common in placebo- than roxadustat-treated patients (n5128
FAS was the absence of postdose Hb data (n532).                               [9.3%] versus n584 [6.1%], respectively). Vital status at the end
    Baseline demographic and clinical characteristics were sim-               of the study was confirmed for 2756 of 2781 patients (99.1%),
ilar between the treatment groups (Table 1). Mean baseline Hb                 with ten (0.7%) roxadustat- and 15 (1.0%) placebo-treated
overall was 9.1 g/dl and mean eGFR was 19.7 and 20.0 ml/min                   patients having unknown vital status at the end of the study.
per 1.73 m2 in the roxadustat and placebo groups, respec-
tively. At baseline, approximately 58% of patients had ferritin               Dosing
.100 mg/L and TSAT .20% (Table 1). Iron supplements were                      Duration of exposure was longer with roxadustat than placebo
taken by 1777 of 2761 (64.4%) patients during the study, in-                  (mean [SD] 19.62 [10.39] versus 15.24 [10.48] months, re-
cluding oral bivalent (n51283 of 2761 [46.5%]) and oral tri-                  spectively; median [interquartile range] 20.80 [11.38–27.55]
valent (n5188 of 2761 [6.8%]) iron (Supplemental Table 3).                    versus 14.57 [5.52–23.51] months, respectively). The most
    Overall, 1300 patients discontinued study drug prema-                     common roxadustat doses were in the range of 40–100 mg
turely. Fewer patients in the roxadustat group (n5499 of                      orally three times weekly (Supplemental Table 4). Mean
1384 [36.1%]) discontinued study drug versus the placebo                      (SD) weekly dose, calculated as the total cumulative dose/ac-
group (n5801 of 1376 [58.2%]); the difference was observed                    tual treatment duration (in weeks), of roxadustat was 207.6
early and maintained throughout the study (Figure 3,                          (116.7) mg, with a median (interquartile range) of 182.3
Supplemental Figure 1). Post hoc analyses showed a 51% lower                  (124.1–267.3) mg. During treatment, 1204 (87.0%) patients
risk of study drug discontinuation with roxadustat versus pla-                in the roxadustat group compared with 577 (41.9%) patients
cebo (hazard ratio [HR] 0.49; 95% CI, 0.44 to 0.55; nominal                   in the placebo group had at least one dose reduction, whereas
P,0.001). In post hoc analyses, factors associated with study                 approximately 90% of all patients had at least one dose in-
drug discontinuation were baseline eGFR ,15 ml/min per                        crease (Supplemental Table 5). Compliance ($75%) to treat-
1.73 m2 and initiation of dialysis after randomization. Fewer                 ment was observed in 1330 (96.1%) patients with roxadustat
patients in the roxadustat arm discontinued study drug versus                 and 1330 (96.7%) patients with placebo.
placebo among those with baseline eGFR ,15 ml/min per
1.73 m 2 (n5250 of 591 [42.3%] versus n5421 of 597                            Primary Efficacy End Point
[70.5%]; HR 0.42; 95% CI, 0.36 to 0.49; nominal P,0.001)                      The adjusted least-squares mean (LSM) change from baseline
and those initiating dialysis while on study drug (n5174 of                   in Hb averaged over weeks 28–52 was significantly greater with
457 [38.1%] versus n5185 of 272 [68.0%]; HR 0.36; 95% CI,                     roxadustat versus placebo (11.75 g/dl [95% CI, 1.68 to 1.81]

JASN 32: ccc–ccc, 2021                                                                                           Roxadustat in Nondialysis CKD          5
CLINICAL RESEARCH    www.jasn.org

Table 1. Baseline demographic and clinical characteristics (ITT analysis set)
Characteristic                                                 Roxadustat (n51384)      Placebo (n51377)
Age, yr
  Mean (SD)                                                         60.9 (14.7)             62.4 (14.1)
Sex, n (%)
  Female                                                             820 (59.2)             774 (56.2)
Race, n (%)
  White                                                              623 (45.0)             611 (44.4)
  Black                                                               112 (8.1)              115 (8.4)
  Asian                                                              544 (39.3)             538 (39.1)
  Native Hawaiian or Pacific Islander                                     0                     2 (0.1)
  American Indian or Alaska Native                                    24 (1.7)                29 (2.1)
  Other                                                               81 (5.9)                82 (6.0)
Geographic region, n (%)
  USA                                                                343 (24.8)             340 (24.7)
  Canada                                                              26 (1.9)               24 (1.7)
  Latin America                                                      206 (14.9)             205 (14.9)
  Asia                                                               522 (37.7)             521 (37.8)
  Europe                                                             287 (20.7)             287 (20.8)
Weight, kg
  Mean (SD)                                                         69.9 (18.5)             70.6 (18.8)
BMI, kg/m2
  Mean (SD)                                                          26.7 (6.0)             26.9 (6.1)
Comorbidities, n (%)
  Hypertension                                                      1274 (92.1)             1280 (93.0)
  Type 2 diabetes mellitus                                           737 (53.3)              771 (56.0)
  Dyslipidemia                                                       683 (49.3)              691 (50.2)
  Coronary artery disease                                            160 (11.6)              178 (12.9)
  Cardiac failure congestive                                         151 (10.9)              155 (11.3)
Hb, g/dl
  Mean (SD)                                                          9.1 (0.7)               9.1 (0.7)
Hb, g/dl, n (%)
  #8                                                                  129 (9.3)              131 (9.5)
  .8 to #9                                                           386 (27.9)             402 (29.2)
  .9                                                                 869 (62.8)             844 (61.3)
eGFRa, ml/min per 1.73 m2
  Mean (SD)                                                         19.7 (11.7)             20.0 (11.7)
eGFR, ml/min per 1.73 m2, n (%)
  ,10                                                                291 (21.0)             283 (20.6)
  10 to ,15                                                          300 (21.7)             315 (22.9)
  15 to ,30                                                          534 (38.6)             520 (37.8)
  30 to ,45                                                          201 (14.5)             196 (14.2)
  45 to ,60                                                           55 (4.0)               59 (4.3)
  $60                                                                  3 (0.2)                4 (0.3)
LDL-C, mg/dl
  Mean (SD)                                                         94.4 (43.4)             92.4 (42.0)
Ferritin .100 mg/L and TSAT .20%, n (%)                             809 (58.5)              799 (58.0)
hsCRP, mg/dl
  Meanb (SD)                                                          0.7 (1.5)              0.7 (1.8)
hsCRP .ULNb, n (%)                                                   227 (16.4)             209 (15.2)
SBP, mmHg
  Mean (SD)                                                         134.4 (13.3)           135.5 (12.7)
DBP, mmHg
  Mean (SD)                                                          74.5 (9.1)             74.1 (9.3)
Most likely cause of CKD, n (%)c
  Diabetic nephropathy                                               614 (44.9)             602 (44.2)
  Ischemic/hypertensive nephropathy                                  207 (15.2)             192 (14.1)
  Chronic GN                                                         169 (12.4)             155 (11.4)

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Table 1. Continued

Characteristic                                                                                Roxadustat (n51384)                                      Placebo (n51377)
  Other primary or secondary GN                                                                       75 (5.5)                                                  82 (6.0)
  Cystic kidney disease                                                                               74 (5.4)                                                  62 (4.6)
  Chronic interstitial nephritis                                                                      36 (2.6)                                                  27 (2.0)
  Chronic pyelonephritis (infectious)                                                                 30 (2.2)                                                  44 (3.2)
  FSGS                                                                                                28 (2.0)                                                  17 (1.2)
  IgA nephropathy                                                                                     19 (1.4)                                                  23 (1.7)
  Obstructive nephropathy                                                                             17 (1.2)                                                  24 (1.8)
  Membranous nephropathy                                                                              13 (1.0)                                                  10 (0.7)
  Lupus nephritis                                                                                      7 (0.5)                                                   2 (0.1)
  Renal artery stenosis                                                                                2 (0.1)                                                 1 (,0.1)
  Minimal change                                                                                       2 (0.1)                                                   6 (0.4)
  Obstructive uropathy                                                                                1 (,0.1)                                                      0
  Not specified                                                                                        25 (1.8)                                                  15 (1.1)
  Unknown                                                                                             124 (9.1)                                               137 (10.1)
  Other                                                                                               92 (6.7)                                                 117 (8.6)
  Missing                                                                                                18                                                        16
BMI, body mass index.
a
  Calculated using the four-variable Modification of Diet in Renal Disease equation.
b
  hsCRP quantified from stored biomarker samples obtained at randomization (n5753 for roxadustat, n5717 for placebo); ULN is 5 mg/l (0.5 mg/dl).
c
  Percentages were on the basis of the number of patients with nonmissing data (n51366 for roxadustat, n51361 for placebo).

versus 10.40 g/dl [95% CI, 0.33 to 0.47], respectively; differ-                                 (8.5%) during the first 24 weeks of treatment (relative risk
ence 11.35 g/dl; 95% CI, 1.27 to 1.43; P,0.001) (Figure 4A).                                    9.12; 95% CI, 7.63 to 10.89; P,0.001) (Figure 4D). Among
An initial separation of Hb levels for roxadustat versus placebo                                411 patients with baseline hsCRP .ULN, the adjusted LSM
was observed after randomization and sustained until EOT                                        change from baseline in Hb averaged over weeks 28–52 was
(Figure 4C).                                                                                    significantly greater with roxadustat versus placebo (11.75 g/dl
                                                                                                [95% CI, 1.58 to 1.92] versus 10.62 g/dl [95% CI, 0.44 to 0.80],
Secondary Efficacy End Points                                                                    respectively; difference 11.13 g/dl; 95% CI, 0.91 to 1.35;
A significantly greater proportion of patients receiving roxa-                                   P,0.001) (Figure 4E). The proportions of total time of inter-
dustat (77.0%) achieved an Hb response versus placebo                                           polated Hb values $10 g/dl and 10–12 g/dl from weeks 28 to 52

                                                     100
                         Cumulative percentage (%)

                                                     80

                                                     60

                                                     40
                                                                                                                                                     Events/N    KM%
                                                                                                                            Placebo (eGFR
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        A                                                                                B                                    Iron replete            Non-iron replete
                                                         P
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were significantly greater with roxadustat versus placebo                  with roxadustat and increased with placebo (adjusted LSM
(P,0.001) (Table 2).                                                      [SD] change from baseline 235.94 [116.69] ng/ml versus
   Mean LDL-C levels at baseline were similar for roxadustat              19.42 [115.78] ng/ml, respectively) (Table 3). Adjusted LSM
(94.50 mg/dl) and placebo (92.52 mg/dl). The adjusted LSM                 changes in serum iron, ferritin, TIBC, and TSAT from baseline
change in LDL-C from baseline to week 24 was significantly                 averaged over week 24 to EOT were as follows: serum iron was
greater with roxadustat versus placebo (214.58 mg/dl versus               increased with roxadustat and reduced with placebo (16.63
20.70 mg/dl, respectively; difference 213.88 mg/dl; 95% CI,               versus 21.07 mg/dl, respectively; difference 7.70 mg/dl; 95%
216.37 to 211.39; P,0.001) (Table 2).                                     CI, 5.82 to 9.58) (Figure 7A, Table 3); serum ferritin was re-
   Fewer roxadustat- versus placebo-treated patients received             duced with roxadustat and increased with placebo (237.10
$1 rescue therapy for the overall composite, and for each indi-           versus 117.45 mg/l, respectively; difference 254.55 mg/l;
vidual component (RBC transfusion, iv iron, or ESA; Figure 5).            95% CI, 271.68 to 237.42) (Figure 7B, Table 3); serum
Event rates for use of first rescue therapy and first rescue RBC            TIBC was increased with roxadustat and reduced with placebo
transfusion were lower with roxadustat than placebo (Figure 5,            (130.79 versus 23.82 mg/dl, respectively; difference 34.61 mg/dl;
Table 2). Roxadustat achieved risk reductions versus placebo of           95% CI, 31.29 to 37.93) (Figure 7C, Table 3); and there was
74% for rescue therapy overall, 63% for RBC transfusion, 59%              no difference in change from baseline in TSAT (20.83%
for iv iron, and 87% for ESA (all P,0.001) (Figure 5).                    versus 20.26%, respectively; difference 20.57%; 95% CI, 21.31
   Adjusted LSM change from baseline in SF-36 Vitality                    to 0.18) (Figure 7D, Table 3). Iron profile parameters analyzed
subscore was 1.59 with roxadustat and 1.15 with placebo                   according to baseline quartile are shown in Supplemental
(difference 10.44; 95% CI, 20.11 to 0.99; P50.120) and                    Figure 2. The largest reductions in serum ferritin with roxadu-
in SF-36 Physical Functioning subscore was 0.14 with roxadu-              stat treatment were seen in those patients with the highest
stat and 20.39 with placebo (difference 10.52; 95% CI, 0.0 to             baseline values.
1.05; nominal P50.051; Supplemental Table 6).                                Adjusted LSM changes in SBP were similar with roxadustat and
   Annual rate of change in eGFR starting from week 4 was                 placebo (1.24 mmHg versus 2.06 mmHg, respectively; difference
23.70 ml/min per 1.73 m2 with roxadustat and 23.19 ml/min                 20.82 mmHg; 95% CI, 21.73 to 0.09). The adjusted LSM changes
per 1.73 m 2 with placebo (difference 20.51 ml/min per                    in DBP were 10.51 mmHg with roxadustat and 20.32 mmHg
1.73 m 2 ; 95% CI, 21.00 to 20.01; nominal P50.046;                       with placebo (difference 10.82 mmHg; 95% CI, 0.31 to 1.34).
Supplemental Table 6).
                                                                          Safety
Subgroup Analysis of the Primary Efficacy End Point                        Interpretation of AEs was on the basis of the ITT analysis set.
Results from the subgroup analyses were consistent with the               The proportions of patients with any AE were similar between
main analysis, including across baseline eGFR and Hb cate-                the roxadustat and placebo groups (89.8% versus 88.3%, re-
gories (Figure 6). Hb improvement with roxadustat versus                  spectively) (Table 4). The most commonly reported AEs by
placebo was similar among the 42% of patients with ferritin               preferred term were ESKD, urinary tract infection (UTI),
#100 mg/L and/or TSAT #20% (11.76 g/dl versus 10.43 g/dl,                 pneumonia, and hypertension (Table 5). Most AEs by pre-
respectively) compared with patients with values above                    ferred term had similar time at risk–adjusted event rates for
those thresholds (11.71 g/dl versus 10.39 g/dl, respectively)             both treatment groups; the only AE with an event rate differ-
(both P,0.001; Figure 4B).                                                ence of .2.0 events per 100 patient-years between roxadustat
                                                                          and placebo was UTI (6.8 versus 4.2 events per 100 patient-
Exploratory End Points                                                    years, respectively) (Table 5).
Mean (SD) baseline hepcidin was 163.16 (116.94) ng/ml for                    The frequency of serious AEs was similar for roxadustat
roxadustat and 155.45 (111.83) ng/ml for placebo (Table 3).               and placebo (57.4% versus 54.4%, respectively) (Table 4).
Compared with baseline, hepcidin at week 24 was reduced                   The most commonly reported serious AEs by preferred term

cardiovascular/cerebrovascular/thromboembolic history, and geographic region (USA versus ex-USA) as predictor variables. Observed
values up to the EOT visit if treatment was completed; the EOS visit if patient discontinued treatment; or date of withdrawal of consent, last
contact, or death if patient withdrew consent, was lost to follow-up, or died; and imputed values up to death of patient were used to derive the
mean from weeks 28 to 52. (B) ITT analysis set. Iron replete defined as ferritin .100 mg/l and TSAT .20%. (C) ITT analysis set. Week 0 on
the x axis refers to the baseline value. (D) FAS. Hb response was defined as Hb $11.0 g/dl and Hb increase from baseline by $1.0 g/dl
for patients with baseline Hb .8.0 g/dl, or Hb increase from baseline by $2.0 g/dl for those with baseline Hb #8.0 g/dl, at two con-
secutive visits (with available data) separated by at least 5 days during the first 24 weeks of treatment without having received rescue
therapy before Hb response. Statistical analysis was on the basis of the Cochran–Mantel–Haenszel test, adjusting for baseline Hb
(#8, .8 g/dl), baseline eGFR (#30, .30 ml/min per 1.73 m2), cardiovascular/cerebrovascular/thromboembolic history, and geographic
region (USA versus ex-USA). Patients who had discontinued study drug or taken rescue medication before response were considered
nonresponders. (E) ITT analysis set. hsCRP was quantified from available stored biomarker samples obtained at randomization. ULN is
5 mg/l (0.5 mg/dl). Data were analyzed analogously to the primary analysis.

JASN 32: ccc–ccc, 2021                                                                                     Roxadustat in Nondialysis CKD      9
CLINICAL RESEARCH                              www.jasn.org

                 A                                                                          Time-to-first rescue therapy

                                          0.6                                                       Roxadustat (n=1384)
                                                HR      0.26
                                                                                                    Placebo (n=1376)
                                                95% CI (0.23, 0.31)
                                                P
www.jasn.org        CLINICAL RESEARCH

Table 2. Secondary efficacy end points
                                                    Roxadustat (n51384)                              Placebo (n51377)
                                                                                                     Number (%)/Adjusted                Relative Risk/HR/
                                                     Number (%)/Adjusted LSM                                                                                          P
End Point                                                                                          LSM (95% CI)/Event Rate              Difference in LSM
                                           N      (95% CI)/Event Rate per 100 PY              n                                                                     Value
                                                                                                   per 100 PY (Total Number             Changes (95% CI)a
                                                    (Total Number of Yr at Risk)a
                                                                                                         of Yr at Risk)a
1. Proportion with Hb response           1371                  1055 (77.0)                 1357                112 (8.5)                9.12 (7.63 to 10.89)       ,0.001
   during the first 24 wk of
   treatment, %
2. Change from baseline in Hb             213             1.75 (1.58 to 1.92)               198          0.62 (0.44 to 0.80)             1.13 (0.91 to 1.35)       ,0.001
   averaged over wk 28–52 in
   patients with baseline hsCRP
   .ULN, g/l
3. Proportion of total time of           1220             0.82 (0.80 to 0.85)              1145          0.33 (0.31 to 0.35)             0.50 (0.47 to 0.52)       ,0.001
   interpolated Hb values $10
   g/dl over wk 28–52, %
4. Proportion of total time of           1220             0.70 (0.68 to 0.72)              1145          0.28 (0.26 to 0.30)             0.42 (0.40 to 0.45)       ,0.001
   interpolated Hb values
   10–12 g/dl over wk 28–52, %
5. Mean change in LDL-C from             1147         214.58 (–16.67 to –12.49)            1133        20.70 (–2.78 to 1.37)             213.88 (–16.37 to         ,0.001
   baseline to wk 24, mg/dl                                                                                                                    –11.39)
6. Event rate for first rescue             254               11.90 (2134.88)                 574            39.76 (1443.49)               0.26 (0.23 to 0.31)       ,0.001
   therapy (composite)
7. Event rate for first rescue RBC         176                7.98 (2206.74)                 320            19.61 (1631.69)               0.37 (0.30 to 0.44)       ,0.001
   transfusion
Hb response was defined as Hb $11.0 g/dl and Hb increase from baseline by $1.0 g/dl for patients with baseline Hb .8.0 g/dl, or Hb increase from baseline by
$2.0 g/dl for patients with baseline Hb #8.0 g/dl, at two consecutive visits (with available data) separated by at least 5 d during the first 24 wk of treatment without
having received rescue therapy (RBC transfusion, ESA, or iv iron) before Hb response. PY, patient yr at risk.
a
 No. of patients (%) and relative risk (95% CI) are presented for secondary end point 1; adjusted LSM change (95% CI) and difference in LSM changes (95% CI) are
presented for secondary end points 2, 3, 4, and 5; and event rate per 100 patient-yr at risk (total number of yr at risk) and HR (95% CI) are presented for secondary end
points 6 and 7.

were ESKD, pneumonia, and azotemia, although cardiovascu-                                initiation of dialysis was 10.3% with roxadustat and 6.8%
lar AEs were also observed in this category (Supplemental                                with placebo (Supplemental Table 9).
Table 7).
    In an overview of cardiovascular AEs, the proportion of
roxadustat- and placebo-treated patients with AEs was                                    DISCUSSION
22.8% versus 21.3%, respectively, and with serious AEs was
12.6% versus 11.4%, respectively, in the cardiac disorders sys-                          The clinical development program for roxadustat for patients
tem organ class (Table 4). The complete listing of serious AEs                           with anemia of NDD-CKD includes placebo-controlled trials
in the cardiac disorders system organ class is provided in                               and trials comparing roxadustat with ESA treatment. In this
Supplemental Table 8.                                                                    large, global, phase 3 study of patients with anemia of NDD-
    The likelihood of death was ascertained in two popula-                               CKD, roxadustat was superior to placebo in increasing Hb.
tions: one that included only patients remaining in the trial                            Compared with placebo, roxadustat reduced the need for
(excluding deaths after withdrawal of consent) and one that                              RBC transfusions, iv iron, and ESAs. RBC transfusions are
included public record searches to increase ascertainment of                             common in patients with NDD-CKD and anemia, have in-
as many deaths as possible during the study period, includ-                              creased in frequency after US label changes, and carry poten-
ing deaths that occurred after withdrawal of consent but                                 tial risks including infection and allosensitization.12,15,16,40
before EOS (Table 4). Mortality rates for the roxadustat                                 Roxadustat treatment led to a 63% relative risk reduction
and placebo groups with more complete ascertainment                                      compared with placebo, and an absolute risk reduction of
were 9.6 and 8.4 events per 100 patient-years, respectively                              11.63 transfusions per 100 patient-years. Similar Hb improve-
(Table 4).                                                                               ments with roxadustat were observed among all patient
    The overall mean (SD) change from baseline in serum po-                              subpopulations assessed including patients with elevated or
tassium was similar between the roxadustat and placebo                                   normal baseline hsCRP levels. Studies have demonstrated an
groups (10.05 [0.522] mmol/l versus 10.01 [0.541] mmol/                                  inverse association between the inflammatory marker hsCRP
l, respectively). The proportion of patients with postbaseline                           and ESA responsiveness.41,42 Similar Hb improvements were
serum potassium concentrations $6.5 mmol/l before                                        observed with roxadustat treatment regardless of baseline iron

JASN 32: ccc–ccc, 2021                                                                                                         Roxadustat in Nondialysis CKD                11
CLINICAL RESEARCH             www.jasn.org

                                                                                                            Roxadustat    Placebo    LS mean treatment
                                                                                                                N            N       difference (95% Cl)
                               Age 9 g/dl                                                                  869          844        1.26 (1.16, 1.36)
              eGFR
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               A                                            90                 Roxadustat (n=1384)    Placebo (n=1377)

                                  Mean serum iron (μg/dl)
                                                            80
                                                            70
                                                            60
                                                            50
                                                            40
                                                            30
                                                            20
                                                            10
                                                             0
                                                                  0      8              16             24                 36                  52
                                                                                               Week
             Roxadustat n=                                       1384   1295           1246           1220               1147               1112
               Placebo n=                                        1377   1292           1200           1144               1072               1010

               B                                     300                       Roxadustat (n=1384)    Placebo (n=1377)
                   Mean serum ferritin (μg/l)

                                                     250

                                                     200

                                                     150

                                                     100

                                                            50

                                                             0
                                                                  0      8              16            24                  36                  52
                                                                                               Week
             Roxadustat n=                                       1384   1299           1252           1220               1151                1110
               Placebo n=                                        1377   1289           1202           1146               1073                1005

               C                                     300                       Roxadustat (n=1384)    Placebo (n=1377)

                                                     250
                   Mean TIBC (μg/dl)

                                                     200

                                                     150

                                                     100

                                                            50

                                                             0
                                                                  0      8              16            24                  36                  52
                                                                                               Week
             Roxadustat n=                                       1384   1289           1233           1218               1133                1112
               Placebo n=                                        1377   1283           1195           1138               1065                1007

               D                                            35                 Roxadustat (n=1384)    Placebo (n=1377)
                                                            30
                                  Mean TSAT (%)

                                                            25
                                                            20
                                                            15
                                                            10
                                                             5
                                                             0
                                                                  0      8              16            24                  36                  52
                                                                                               Week
             Roxadustat n=                                       1384   1283           1226           1215               1127                1108
               Placebo n=                                        1375   1279           1185           1125               1055                1003

Figure 7. Serum iron parameters by visit. (A) Iron; (B) ferritin; (C) TIBC; (D) TSAT (ITT analysis set). Error bars are 95% CIs. Baseline is
defined as the last measurement before randomization. 95% CI of the mean is on the basis of the normal distribution.

JASN 32: ccc–ccc, 2021                                                                                                         Roxadustat in Nondialysis CKD   13
CLINICAL RESEARCH              www.jasn.org

Table 4. AEs summary (ITT analysis set)a
                                                                               Roxadustat (n51384)                                 Placebo (n51377)
AE Category                                                             Patients with                Event Rate           Patients with                 Event Rate
                                                                                               %                                                 %
                                                                            Event                   (per 100 PY)b             Event                    (per 100 PY)b
Any AE                                                                       1243            89.8        182.9                 1216            88.3        171.9
Any serious AE (including events with an outcome of                           795            57.4         42.1                  749            54.4         40.0
  death)
Any AE with an outcome of death                                               262            18.9          9.3                  213            15.5          7.8
All-cause mortalityc                                                          284            20.5          9.6                  245            17.8          8.4
Any AE in the cardiac disorders SOCd                                          316            22.8         12.7                  293            21.3         12.0
Any serious AE in the cardiac disorders SOCd                                  174            12.6          6.5                  157            11.4          6.0
Patients with multiple events in the same category were counted only once in that category. Patients with events in more than one category were counted once in
each of those categories. PY, patient yr at risk; SOC, system organ class.
a
  Included AEs with an onset date on or after the date of randomization and up to and including the EOS visit; or date of last contact or withdrawal of consent, if
before the EOS visit.
b
  Calculated as [No. of patients with AEs divided by (the total number of days at risk for that AE across all patients in given group divided by 365.25)] 3 100.
c
  Includes deaths from public record searches.
d
  Analyses performed post hoc.

increased serum iron levels and serum TIBC. The observed                             OLYMPUS was neither individually powered to assess nor
reduction in serum ferritin with roxadustat has been report-                         prospectively planned as a standalone study to determine car-
ed previously,37–39,44 and in this study was most prominent                          diovascular safety and mortality risk with roxadustat. The
in patients with the highest baseline values. Overall, the                           findings will be further assessed in the fully powered analysis
reduction in hepcidin, increased serum iron, and, in partic-                         of the pooled population of the phase 3, placebo-controlled
ular, increased TIBC with roxadustat support improved                                roxadustat NDD-CKD studies.
absorption, mobilization, and utilization of iron for eryth-                            Some safety data were difficult to interpret in the setting
ropoiesis in roxadustat-treated patients, particularly in the                        of differential study drug discontinuation. For example, a
setting of the increase in Hb from baseline regardless of                            numerically greater number of patients with roxadustat
baseline iron repletion status and the observed decreased                            than placebo had $1 postbaseline serum potassium con-
need for iv iron.                                                                    centration of $6.5 mmol/l. Because patients who discon-
    Observational studies have shown that patients with ane-                         tinued study drug prematurely and remained in the study
mia of NDD-CKD frequently have a high incidence of adverse                           with modified follow-up often did not continue central lab-
clinical outcomes.9 In OLYMPUS, the safety profile of roxa-                           oratory testing, OT data were used to assess serum potas-
dustat was comparable to placebo, as was seen in previous                            sium outlier values. However, these data are confounded by
placebo-controlled roxadustat studies.37–39 More patients re-                        patients at higher risk for hyperkalemia being more likely to
ceiving roxadustat who had low eGFR or initiated dialysis,                           remain on roxadustat than placebo. Notably, placebo-
which are associated with higher risk of death and cardiovas-                        treated patients with baseline eGFR ,15 ml/min per
cular events,6–8 remained on roxadustat versus placebo. To                           1.73 m2, which is associated with an approximate twofold
minimize potential bias due to differential dropout, the ITT                         and fivefold increased risk of hyperkalemia versus eGFR
analysis set and time at risk–adjusted event rates were utilized.                    15–29 ml/min per 1.73 m2 and 30–59 ml/min per 1.73 m2,
Event rates of UTI and pneumonia appeared higher for rox-                            respectively,45 were approximately 2.5-times more likely to
adustat than placebo, although there is no clear biologic mech-                      prematurely discontinue study drug versus roxadustat-
anism for these observations.                                                        treated patients. Therefore, and given the overall severe
    Because cardiovascular risk is increased in this patient pop-                    CKD of the studied population, mean changes in serum
ulation, event rates for AEs and serious AEs in the cardiac                          potassium between treatments are meaningful to assess
disorders system organ class were assessed. Analysis of cardio-                      the potential effects of roxadustat. Overall, mean changes
vascular events is limited by the size of the study and will be                      in serum potassium from baseline between treatments did
analyzed using a pooled analysis of multiple roxadustat stud-                        not differ, suggesting that roxadustat does not affect serum
ies; however, rates were generally comparable for roxadustat                         potassium. Similarly, numeric decreases and increases of
and placebo, both overall and for individual cardiac serious                         ,1 mmHg for roxadustat versus placebo in SBP and DBP,
AEs. Importantly, OLYMPUS allowed for a prospective and                              respectively, suggest that roxadustat does not meaningfully
complete ascertainment of patient mortality using public                             affect BP values.
record searches, even after withdrawal of consent, and vital                            For clinical trials among patients with anemia of NDD-
status was confirmed in .99% of patients. These results                               CKD, such as the Trial to Reduce Cardiovascular Events with
showed that mortality rates between roxadustat and placebo                           AranespÒ Therapy (TREAT), the use of a placebo control has
were 9.6 and 8.4 events per 100 patient-years, respectively.                         been considered to provide greater evidentiary power than use

14          JASN                                                                                                                             JASN 32: ccc–ccc, 2021
www.jasn.org        CLINICAL RESEARCH

Table 5. Most common AEs ($5%) by preferred term (ITT analysis set)a
                                                               Roxadustat (n51384)                                             Placebo (n51377)
Preferred Term                                                                           Event Rate                                                   Event Rate
                                                Patients with Event           %                              Patients with Event            %
                                                                                        (per 100 PY)b                                                (per 100 PY)b
ESKD                                                     290                 21.0            11.7                      282                 20.5            11.8
UTI                                                      177                 12.8             6.8                      110                  8.0             4.2
Pneumonia                                                165                 11.9             6.2                      130                  9.4             4.9
Hypertension                                             159                 11.5             6.1                      125                  9.1             4.8
Edema peripheral                                         149                 10.8             5.7                      111                  8.1             4.3
Diarrhea                                                 144                 10.4             5.5                      119                  8.6             4.6
Nausea                                                   125                  9.0             4.8                      104                  7.6             4.1
Hyperkalemia                                             118                  8.5             4.4                       95                  6.9             3.6
Cough                                                    105                  7.6             3.9                       69                  5.0             2.6
Viral upper respiratory tract infection                  101                  7.3             3.8                      106                  7.7             4.1
Upper respiratory tract infection                        96                   6.9             3.6                       76                  5.5             2.9
Headache                                                 94                   6.8             3.5                       82                  6.0             3.1
Constipation                                             92                   6.6             3.4                       88                  6.4             3.4
Hypoglycemia                                             91                   6.6             3.4                       73                  5.3             2.8
Gastritis                                                81                   5.9             3.0                       72                  5.2             2.7
Azotemia                                                 80                   5.8             2.9                       73                  5.3             2.7
Dyspnea                                                  78                   5.6             2.9                       74                  5.4             2.8
Bronchitis                                               78                   5.6             2.9                       73                  5.3             2.8
Vomiting                                                 78                   5.6             2.9                       69                  5.0             2.6
Dizziness                                                77                   5.6             2.9                       87                  6.3             3.4
AKI                                                      75                   5.4             2.7                       47                  3.4             1.7
Asthenia                                                 74                   5.3             2.7                       75                  5.4             2.8
Arthralgia                                               73                   5.3             2.7                       54                  3.9             2.0
Back pain                                                72                   5.2             2.6                       57                  4.1             2.1
Pruritus                                                 68                   4.9             2.5                       80                  5.8             3.1
Edema                                                    66                   4.8             2.4                       69                  5.0             2.6
Percentages were on the basis of the No. of patients in the ITT analysis set in that treatment arm. PY, patient yr at risk.
a
 Included AEs with an onset date on or after the date of randomization and up to and including the EOS visit; or date of last contact or withdrawal of consent, if
before the EOS visit.
b
  Calculated as [No. of patients with AEs divided by (the total No. of days at risk for that AE across all patients in given group divided by 365.25)] 3 100.

of an active control and to allow valid assessment of safety and                     DOLOMITES, 616 patients with NDD-CKD stages 3–5 and
efficacy.17,46 For studying efficacy, the placebo control means                        anemia were randomized to receive roxadustat (n5323) or
that roxadustat was assessed against a comparator not expec-                         darbepoetin alfa (n5293). Among these patients, roxadustat
ted to increase Hb or prevent RBC transfusion. For studying                          was noninferior to darbepoetin alfa in the correction of Hb
safety, the use of placebo allows a rigorous assessment of non-                      levels (Hb response rates: roxadustat 89.5% versus darbepoe-
inferiority for cardiovascular safety via separate pooled anal-                      tin alfa 78.0%; difference: 11.5%; 95% CI, 5.7% to 17.4%)
yses of the phase 3 NDD-CKD studies, and comparison with a                           during the first 24 weeks of treatment and safety profiles
therapy without known AEs. Although ESA is also a valid                              were comparable.
comparator, interpretation of safety against an active compar-                           Another reason that placebo might be considered is that
ator with reported cardiovascular safety concerns when dosed                         several reports estimate that many patients with anemia of
to achieve normal or near normal Hb levels19–21 can be com-                          NDD-CKD in the real world are untreated4,5,11,25–30 and
plex. Boxed warnings in the US product labels of approved                            ESA use is relatively uncommon in treated patients.11,28–30
ESAs state that no trial has identified an Hb target level, ESA                       In particular, a US study from 2018 showed that approxi-
dose, or dosing strategy that does not increase the risks of                         mately 11%–13% of patients with anemia of NDD-CKD
death and other cardiovascular events.22,23 The lack of an ac-                       received an ESA; of these, ,5% received ESA treatment
tive comparator in OLYMPUS precludes direct comparison of                            consistently.28 This likely reflects problems with affordabil-
roxadustat with ESAs. However, the roxadustat clinical devel-                        ity, physical access to injectable therapy, and interpretation
opment program comprises several placebo- and active-                                of current guideline recommendations including the rec-
controlled phase 3 clinical studies, and the efficacy and safety                      ommendation that ESAs are used intermittently and to pre-
of roxadustat compared with ESA among patients with anemia                           vent RBC transfusions, given their risk of cardiovascular
of NDD-CKD have been evaluated in the completed phase 3,                             events.19–21 The high discontinuation rate and need for res-
active-controlled DOLOMITES study (NCT02021318). In                                  cue therapy in the placebo arm in OLYMPUS support

JASN 32: ccc–ccc, 2021                                                                                                   Roxadustat in Nondialysis CKD               15
CLINICAL RESEARCH       www.jasn.org

the need for effective anemia treatment in patients with               OLYMPUS had limitations. Study personnel at local study
NDD-CKD.                                                           sites could not be blinded to Hb values; therefore, Hb increases
    The OLYMPUS study has several strengths that further our       could have in some cases been considered by patients and
knowledge of roxadustat from the previous phase 3 NDD-             physicians to be suggestive of treatment allocation and poten-
CKD study conducted in China.38 The OLYMPUS study had              tially affected continuation in the study or reporting of AEs.
a longer follow-up period than that previously assessed and        No assessment of site personnel or patients was performed to
enrolled a larger and more diverse patient population, which is    examine perception of treatment allocation. Median expo-
important for the generalizability of the data. This large pa-     sures of 20.80 and 14.57 months in the roxadustat and placebo
tient population allowed for the analysis of patient subgroups,    groups, respectively, do not allow for the assessment of rox-
such as by baseline eGFR and Hb categories and iron repletion      adustat in this population over a time period longer than the
status, and additional secondary analyses than were possible       maximum treatment duration of 4 years.
in earlier studies. Another strength of OLYMPUS is that,               In conclusion, oral roxadustat was more effective than
compared with the Correction of Hemogloblin and Out-               placebo in correcting anemia, reduced the risk of RBC trans-
comes in Renal Insufficiency (CHOIR) and TREAT ESA                  fusions, and had comparable safety to placebo in this interna-
studies,20,21 OLYMPUS enrolled a broader, real-world pa-           tional, double-blind, phase 3 study. Roxadustat was effective
tient population. For instance, baseline Hb and eGFR were          in a broad range of patients with NDD-CKD, including pa-
lower in patients in OLYMPUS (mean: 9.1 g/dl and approx-           tients with inflammation, and patients with more advanced
imately 20 ml/min per 1.73 m 2 ) compared with CHOIR               CKD (lower baseline eGFR), more severe anemia (lower base-
(mean: 10.1 g/dl and 27 ml/min per 1.73 m2) and TREAT              line Hb levels), and lower iron stores (low baseline ferritin and
(median: 10.5 g/dl and 34 ml/min per 1.73 m2).20,21 Evi-           TSAT) than those included in historical NDD-CKD trials with
dence from the CKD Outcomes and Practice Patterns Study            ESAs. The findings support anemia treatment using roxadu-
suggests that up to 45% of patients with NDD-CKD and               stat, an oral medication that can be administered in the home
Hb ,10 g/dl have stage 5 CKD, confirming the clinical ap-           setting and without requirement for routine iv iron supple-
plicability of the OLYMPUS study.4                                 mentation, which may simplify anemia treatment for patients
    Although the inclusion of patients with severe disease was     with NDD-CKD.
an advantage of OLYMPUS, it also affected data interpreta-
tion. The rate of study drug discontinuation was relatively high
in both treatment arms but higher in the placebo group. AEs        DISCLOSURES
were an uncommon reason for study drug discontinuation in
both treatment groups. Post hoc analyses identified low eGFR           M.A. El-Shahawy reports ownership interest in Paramount Hope Dialysis
and initiation of dialysis after randomization as contributors     Center, East LA Dialysis Center; research funding from AstraZeneca, Pfizer,
to study drug discontinuation overall and to differences in        Bayer, UCB, and Sanofi; honoraria from AstraZeneca; being a scientific advi-
                                                                   sor or membership from AstraZeneca and Bayer; and speakers bureau from
study drug discontinuation by treatment group. Although            AstraZeneca. S. Fishbane reports receiving research support and consulting
the study allowed continuation of roxadustat after dialysis ini-   fees from AstraZeneca; consultancy agreements from Akebia, Cara Therapeu-
tiation, study drug discontinuations may have been driven by       tics, and FibroGen; research funding from Cara, Gilead, and Merck; and hon-
administrative challenges relating to standardized processes of    oraria from Akebia and AstraZeneca. L. Frison, N.J. Guzman, and D.J. Little
anemia treatment at dialysis centers, avoidance of the added       are employees of AstraZeneca. N.J. Guzman and D.J. Little also report owner-
                                                                   ship interest in AstraZeneca. M.T. Houser is employed by and has ownership
complexity of experimental drug administration, and patients       interest in AstraZeneca. R. Pecoits-Filho reports receiving consulting fees paid
who may require hospitalization and have other medical com-        to his employer from Akebia and AstraZeneca for participation in advisory
plexities making strict adherence to the protocol difficult.        boards and educational events, and research grants from Fresenius Medical
Similar to TREAT,21 patients in OLYMPUS who discontin-             Care. R. Pecoits-Filho also reports consultancy agreements with Rethrophin;
ued study drug (but did not withdraw from study) were              being a scientific advisor or member with the Kidney Disease: Improving
                                                                   Global Outcomes Executive Board, International Society of Nephrology Ex-
followed for as long as possible and remained in the ITT           ecutive Board, and Standardised Outcomes in Nephrology Executive Com-
analysis until study closure/withdrawal, using follow-up           mittee; serving on editorial boards for American Journal of Kidney Diseases,
options designed, in part, to minimize withdrawal of con-          Blood Purification, Nephrology, Peritoneal Dialysis International, Hemodialysis
sent. The rate of study withdrawal in OLYMPUS was low              International, and the Brazilian Journal of Nephrology; and serving on the
                                                                   speakers bureau with AstraZeneca and Novo Nordisk. P.E. Pergola reports
(7.8%) compared with the ESA studies CHOIR (38%) and
                                                                   receiving research support and consulting fees from AstraZeneca. P.E. Pergola
PEARL (approximately 24%), 20,47 and vital status at the           also reports consultancy agreements with Akebia Therapeutics, Ardelyx,
end of the study was confirmed in .99% of randomized                Bayer, Corvidia Therapeutics, Gilead Sciences, Reata Pharmaceuticals, and
patients. However, although the ITT population allowed for a       Tricida; reports ownership interest in Unicycive Therapeutics; and reports
more balanced evaluation of safety, this population could also     receiving research funding as principal investigator or subinvestigator on mul-
contain reporting bias for AEs due to the higher withdrawal of     tiple clinical trials (the contracts are with his practice, not individual); being a
                                                                   scientific advisor or member with Ardelyx and Unicycive; and serving on the
consent in placebo patients and possible under-reporting of        speakers bureau with AstraZeneca. B.P. Van reports receiving research support
some events (e.g., nonserious AEs) in patients with modified        and consulting fees from AstraZeneca. B.P. Van also reports honoraria from
post-treatment follow-up.                                          Astellas, AstraZeneca, Boehringer Ingelheim, DiethelmKellerSiberHegner,

16       JASN                                                                                                               JASN 32: ccc–ccc, 2021
www.jasn.org        CLINICAL RESEARCH

Kalbe International, Nanogen (Vietnam), Otsuka, Pfizer, Servier, and Tedis;            Treatment compliance.
being a scientific advisor or member with Nguyen Tri Phuong University                 Supplemental Table 1. Statistical analyses of secondary efficacy end points.
Hospital (Vietnam); and serving on the speakers bureau with Astellas, Astra-          Supplemental Table 2. Statistical analyses of exploratory efficacy end points.
Zeneca, Boehringer Ingelheim, DKSH, Kalbe International, Otsuka, Pfizer,               Supplemental Table 3. Key medications taken during study treatment.
Sanofi, Servier, and Tedis.                                                            Supplemental Table 4. Exposure by dose.
                                                                                      Supplemental Table 5. Proportions of patients with at least one dose re-
                                                                                   duction or increase during treatment.
                                                                                      Supplemental Table 6. Secondary efficacy end points.
FUNDING                                                                               Supplemental Table 7. Most common serious adverse events ($1%) by
                                                                                   system organ class and preferred term (ITT analysis set)a.
  This study was supported by AstraZeneca.                                            Supplemental Table 8. Serious adverse events within the cardiac disorders
                                                                                   system organ class, by preferred term (ITT analysis set)a.
                                                                                      Supplemental Table 9. Serum potassium treatment-emergent laboratory
                                                                                   values (OT128 analysis set).
ACKNOWLEDGMENTS                                                                       Supplemental Figure 1. Time to premature study drug discontinuation by
                                                                                   treatment arm and baseline eGFR (OT128 analysis set).
The authors thank Dr. Mary Beth DeYoung, Dr. James Sloand, and Dr. Lynda              Supplemental Figure 2. Serum iron parameters by visit, according to base-
Szczech for their review of the data and manuscript drafts. Medical writing        line quartile. (A) Iron; (B) ferritin; (C) TIBC; (D) TSAT (ITT analysis set).
support was provided by Mr. Shaun W. Foley and Dr. Maria Alfaradhi, and
editorial support was provided by Ms. Rachael Cazaly, all of Core Medica
(London, United Kingdom), supported by AstraZeneca according to Good
Publication Practice guidelines.                                                   REFERENCES
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JASN 32: ccc–ccc, 2021                                                                                                 Roxadustat in Nondialysis CKD           17
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