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Clinical Research
Open Access

Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients

Anatole Besarab, Elena Chernyavskaya, Igor Motylev, Evgeny Shutov, Lalathaksha M. Kumbar, Konstantin Gurevich, Daniel Tak Mao Chan, Robert Leong, Lona Poole, Ming Zhong, Khalil G. Saikali, Marietta Franco, Stefan Hemmerich, Kin-Hung Peony Yu and Thomas B. Neff
JASN April 2016, 27 (4) 1225-1233; DOI: https://doi.org/10.1681/ASN.2015030241
Anatole Besarab
FibroGen, Inc., San Francisco, California;
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Elena Chernyavskaya
Budgetary Healthcare Institution of Omsk Region, City Clinical Hospital #1, Omsk, Russia;
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Igor Motylev
City Hospital #33, Nizhny Novgorod, Russia;
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Evgeny Shutov
State Budgetary Healthcare Institution of Moscow, City Clinical Hospital, Moscow, Russia;
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Lalathaksha M. Kumbar
Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan;
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Konstantin Gurevich
Fresenius Medical Care, St. Petersburg, Russia; and
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Daniel Tak Mao Chan
Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
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Robert Leong
FibroGen, Inc., San Francisco, California;
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Lona Poole
FibroGen, Inc., San Francisco, California;
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Ming Zhong
FibroGen, Inc., San Francisco, California;
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Khalil G. Saikali
FibroGen, Inc., San Francisco, California;
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Marietta Franco
FibroGen, Inc., San Francisco, California;
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Stefan Hemmerich
FibroGen, Inc., San Francisco, California;
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Kin-Hung Peony Yu
FibroGen, Inc., San Francisco, California;
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Thomas B. Neff
FibroGen, Inc., San Francisco, California;
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  • Figure 1.
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    Figure 1.

    Patient disposition. Screened refers to the inclusion and exclusion criteria listed under "Selection of Study Population" in the Supplemental Material. FU, follow-up period. *The adverse events were dizziness in the no-iron cohorts and worsening gastritis in the IV iron cohort. ^Recovery of renal function. Most study patients (54 of 60 [90.0%]) were enrolled in Russia. The most common causes of renal failure (all patients combined) were unspecified GN (41.7%), pyelonephritis (21.7%), hypertensive nephropathy (18.3%), and diabetic nephropathy (15.0%).

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    Figure 2.

    Mean hemoglobin levels over time are similar through 7 weeks for all treatment groups and thereafter lower for the no-iron vs oral or IV iron groups. Data are for the EE population using last-observation-carried-forward imputation for missing data and are expressed as the mean±SEM Hb value at each time point. Week 0 (baseline) is the mean of three predosing Hb values. *P<0.05 in comparisons between no-iron cohort to the pooled iron cohorts based on the repeated-measures analysis of covariance model with baseline Hb and iron repletion status as covariates, using all observed data collected during treatment.

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    Figure 3.

    Cumulative Hb responses are similar among the cohorts. Data are for the EE population. Hb response was defined as the first Hb increase from baseline of ≥1.0 g/dl. Median time to first response was 3.0 weeks in all cohorts.

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    Figure 4.

    ΔHbmax during last 10 weeks of treatment (g/dl) is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. ΔHbmax versus log(baseline CRP): regression slope on log(CRP) = −0.31 (P=0.30). All patients with CRP greater than the upper limit of normal (ULN=5 g/ml) responded to treatment.

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    Figure 5.

    Weekly roxadustat dose during the last 2 weeks of the treatment period is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. Maintenance dose was defined as total dose during last 2 weeks of treatment. Maintenance dose versus log (baseline CRP): regression slope on log(baseline CRP) = −0.43 (P=0.38). ULN, upper limit of normal (5 ng/ml).

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    Table 1.

    Baseline patient characteristics (safety population)

    CharacteristicHD, No Iron (n=24)HD, Oral Iron (n=12)HD, IV Iron (n=12)PD, Oral Iron (n=12)Total (n=60)
    Age (yr)49.6±17.746.8±14.653.1±12.651.4±12.450.1±15.0
    Men, n (%)15 (62.5)9 (75.0)5 (41.7)2 (16.7)31 (51.7)
    Race, n (%)
     White23 (95.8)11 (91.7)11 (91.7)10 (83.3)55 (91.7)
     Other1 (4.2)1 (8.3)1 (8.3)2 (16.7)5 (8.3)
    Weight (kg)73.2±15.677.4±13.679.9±22.859.9±12.172.7±17.4
    BMI (kg/m2)25.7±6.126.5±5.328.6±6.522.9±4.725.9±5.9
    eGFR at initiation of dialysis (ml/min per 1.73 m2)10.9±4.712.6±6.17.6±3.37.9±3.810.0±4.9
    Time since first dialysis (mo)2.2±0.92.1±1.12.1±0.92.2±1.02.2±0.9
    Hb (g/dl)8.0±1.28.5±0.98.3±0.98.8±0.78.3±1.0
    CRP (mg/L)3.9 (0.3–53.5)1.6 (0.5–23.7)3.1 (0.3–12.7)3.3 (0.3–28.2)3.6 (0.3–53.5)
    • Values are expressed as mean±SD, number (percentage), or median (range). The weight was the postdialysis weight for HD patients and the edema-free weight for PD patients. BMI, body mass index.

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    Table 2.

    Roxadustat dose levels

    Roxadustat Dose LevelsLow Weight (40–60 kg)Medium Weight (>60–90 kg)Heavy Weight (>90–140 kg)
    1 (initial dose)60 mg100 mg140 mg
    1.0–1.5 mg/kg1.1–1.7 mg/kg1.0–1.6 mg/kg
    2100 mg140 mg200 mg
    1.7–2.5 mg/kg1.6–2.3 mg/kg1.4–2.2 mg/kg
    3140 mg200 mg300 mg
    2.3–2.5a mg/kg2.2–2.5a mg/kg2.1–2.5a mg/kg
    • Dose adjustments for Hb response: if Hb was <11.0 g/dl and the rate of rise of Hb was <1.0 g/dl in the previous 4 weeks, the roxadustat dose was escalated up one dose level. The maximum allowed dose was 2.5 mg/kg. If Hb was >13.0 g/dl or rate of rise of Hb was ≥2.0 g/dl in the previous 4 weeks (excessive response), the roxadustat dose was reduced by one dose level, or by approximately 30% if the patient was at dose level 1.

    • ↵a Roxadustat dose subject to a maximum of 2.5 mg/kg thrice weekly.

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    Table 3.

    Hepcidin levels and changes from baseline

    VariableHD, No Iron (n=22)HD and PD, Oral Iron (n=21)HD, IV Iron (n=9)
    Baseline
     OV (ng/ml)84.1±13.7107.4±27.185.6±24.4
    4 wk
     OV (ng/ml)16.4±3.251.1±14.350.9±15.6
     Δ (ng/ml)−67.7±12.0−56.3±19.2−34.7±12.6
     P value*<0.00010.00820.0252
    12 wk (end of treatment)
     OV (ng/ml)20.7±6.959.2±14.273.0±25.9
     Δ (ng/ml)−63.4±13.3−48.2±18.2−12.6±31.6
     P value*<0.00010.0156NS
    End of study
     OV (ng/ml)46.0±6.6136.9±27.7183.4±45.2
     Δ (ng/ml)−38.2±13.729.6±21.797.8±26.5
     P value*0.0112NS0.0061
    • Observed values (OV) and changes from baseline (Δ) of plasma hepcidin levels (in ng/ml) are presented as mean±SEM for the EE population. Missing values were imputed using the last-observation-carried-forward method. P values are from paired t test comparing absolute change from baseline. NS, not significant.

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    Table 4.

    Change in serum iron variables overall and by treatment group

    VariableHD, No Iron HD, Oral Iron (n=12)HD, IV Iron (n=10)PD, Oral Iron (n=10)Total (n=55)
    Serum iron
     Patients (n)2312101055
     Baseline (μM)9.7±0.612.8±1.810.3±1.09.5±0.810.4±0.5
     ΔEOT(μM)−2.1±0.91.2±2.51.4±1.60.4±1.6−0.3±0.8
     P value for EOT0.031NSNSNSNS
    Ferritin
     Patients (n)2312101055
     Baseline (ng/ml)156±13163±31182±27137±27159±11
     ΔEOT(ng/ml)−120±12−51±25−25±34−65±29−78±12
     P value for EOT<0.001NSNS0.054<0.001
    Transferrin
     Patients (n)2312101055
     Baseline (μM)26.9±0.926.6±0.926.7±1.326.6±2.426.7±0.6
     ΔEOT(μM)9.5±1.25.7±1.75.5±1.45.6±2.97.1±0.8
     P value for EOT<0.0010.0080.004NS0.085
    TIBC
     Patients (n)2312101055
     Baseline (μM)44.7±1.645.2±1.744.4±2.145.8±4.254.0±1.1
     ΔEOT(μM)17.4±2.010.1±3.39.7±2.49.1±4.812.9±1.5
     P value for EOT<0.0010.0110.003NS<0.001
    sTfR
     Patients (n)2310101053
     Baseline (ng/ml)3.1±0.33.4±0.43.7±0.73.2±0.43.3±0.2
     ΔEOT(ng/ml)4.3±0.91.8±1.02.5±0.62.6±0.83.2±0.5
     P value for EOT<0.001NS0.0040.011<0.001
    TSAT
     Patients (n)2310101053
     Baseline (%)18.8±0.819.0±1.018.1±1.519.3±1.818.8±0.6
     ΔEOT(%)−7.4±1.42.6±2.50.7±2.9−1.6±2.6−2.7±1.2
     P value for EOT<0.001NSNSNS0.026
    Iron-depletea
     Patients (n)2310101053
     Baseline (%)16±69.68±66.78±80.07±70.039±70.9
     EOT (%)23±10010±83.36±60.09±90.048±87.3
     P value for EOT0.016NSNSNSNS
    CHr
     Patients (n)2110101051
     Baseline (pg)31.0±0.331.6±0.531.5±0.530.5±0.431.1±0.2
     Δ4wk(pg) −1.3±0.4−0.5±0.5−0.4±0.5−0.7±0.6−0.8±0.2
     P value for 4 wk 0.005NSNSNS0.002
     ΔEOT(pg)−2.2±0.7−1.9±0.9−1.0±0.6−0.2±0.6−1.5±0.4
     P value for EOT0.003NSNSNS<0.001
    • Unless otherwise noted, data are expressed as mean±SEM for the EE population using the last-observation-carried-forward imputation method. Baseline for iron variables was defined as the mean available values obtained before the first dose. P values are from paired t test: comparison to baseline values, except for iron-deplete, for which P value is from McNemar test. ΔEOT, change from baseline at end of therapy; NS, not significant; EOT, values at end of treatment; TIBC, total iron-binding capacity; sTfR, soluble transferrin receptor; CHr, reticulocyte Hb content; Δ4wk, change from baseline after 4 weeks.

    • ↵a Iron-deplete: TSAT <20% or ferritin <100 ng/ml.

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Journal of the American Society of Nephrology: 27 (4)
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April 2016
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Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients
Anatole Besarab, Elena Chernyavskaya, Igor Motylev, Evgeny Shutov, Lalathaksha M. Kumbar, Konstantin Gurevich, Daniel Tak Mao Chan, Robert Leong, Lona Poole, Ming Zhong, Khalil G. Saikali, Marietta Franco, Stefan Hemmerich, Kin-Hung Peony Yu, Thomas B. Neff
JASN Apr 2016, 27 (4) 1225-1233; DOI: 10.1681/ASN.2015030241

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Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients
Anatole Besarab, Elena Chernyavskaya, Igor Motylev, Evgeny Shutov, Lalathaksha M. Kumbar, Konstantin Gurevich, Daniel Tak Mao Chan, Robert Leong, Lona Poole, Ming Zhong, Khalil G. Saikali, Marietta Franco, Stefan Hemmerich, Kin-Hung Peony Yu, Thomas B. Neff
JASN Apr 2016, 27 (4) 1225-1233; DOI: 10.1681/ASN.2015030241
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