Roxadustat for CKD-related Anemia in Non-dialysis Patients

Abstract

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and improves iron metabolism. We assessed the efficacy and tolerability of roxadustat in patients with chronic kidney disease (CKD)-related anemia not on dialysis.

Methods: ANDES was a global Phase 3 randomized study in which adults with stage 3-5 CKD not on dialysis received roxadustat or placebo. Patients were initially dosed thrice weekly; dose was titrated to achieve a hemoglobin level ≥11.0 g/dl, followed by titration for maintenance. The primary endpoints were change in hemoglobin (weeks 28-52) and proportion of patients achieving a hemoglobin response (hemoglobin ≥11.0 g/dl and increase ≥1.0 g/dl [baseline >8.0 g/dl], or increase ≥2.0 g/dl [baseline ≤8.0 g/dl]) (week 24). Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were recorded.

Results: In roxadustat (n = 616) and placebo (n = 306) groups, hemoglobin mean (SD) change from baseline over weeks 28-52 was significantly larger for roxadustat (2.00 [0.95]) versus placebo (0.16 [0.90]), corresponding to least-squares mean difference of 1.85 g/dl (95% confidence interval [CI] 1.74-1.97; P < 0.0001). The proportion of patients achieving a response at week 24 was larger for roxadustat (86.0%; 95% CI 83.0%-88.7%) versus placebo (6.6%; 95% CI 4.1%-9.9%; P < 0.0001). The proportion of patients receiving rescue therapy at week 52 was smaller for roxadustat (8.9%) versus placebo (28.9%); hazard ratio, 0.19 (95% CI 0.14-0.28; P < .0001). The incidences of TEAEs and TESAEs were comparable.

Conclusion: This study showed that roxadustat corrected and maintained hemoglobin and was well tolerated in patients with CKD-related anemia not on dialysis (ClinicalTrials.gov NCT01750190).

Keywords: anemia; chronic kidney disease; rescue therapy; roxadustat.

Graphical abstract

Figure 1

Study design. BL, baseline; EOS, end of study; EOT, end of treatment; ET, early termination; ICF, informed consent form; TIW, thrice weekly.

Figure 2

CONSORT flow diagram. ∗Including ESA rescue. †Patients who discontinued from the study and participated in the LTFU were evaluated for cardiovascular events of interest, vital status, and hospitalizations after EOS until study closure. AE, adverse event; EOS, end of study; ESA, erythropoiesis-stimulating agent; LTFU, long-term follow-up.

Figure 3

Percentage of patients on treatment over time by baseline estimated glomerular filtration rate (eGFR) category (safety population [SAF]).

Figure 4

Hemoglobin levels over time (a) and percentage of patients with a hemoglobin response (b). ∗Defined as the mean of up to 4 last central laboratory values before the first dose of study treatment. †Multiple imputation strategy by combining the results of ANCOVA model with baseline Hb and baseline eGFR as covariates, and treatment and other randomization stratification factors, except baseline Hb (≤8 vs. >8 g/dl) and eGFR (<30 vs. ≥30 ml/min per 1.73 m²), as fixed effects. ‡Patient who achieved Hb response (central laboratory values: Hb ≥11.0 g/dl and an Hb increase from baseline by ≥1.0 g/dl in patients with baseline Hb >8 g/dl, or an increase in Hb ≥2.0 g/dl in patients with baseline Hb ≤8 g/dl) at 2 consecutive visits ≥5 days apart during the first 24 weeks of treatment without rescue therapy. Patients who dropped out or received rescue therapy before or on the date of the second consecutive Hb value were classified as nonresponders. §Based on the exact method of Clopper-Pearson. ||CMH method adjusting for all randomization stratification factors. Δ, change; ANCOVA, analysis of covariance; CMH, Cochran-Mantel-Haenszel; CI, confidence interval; eGFR, estimated glomerular filtration rate; FAS, full analysis set; Hb, hemoglobin; I, imputed; ITT, intent to treat; LS, least squares; O, observed; SE, standard error; W, weeks.

Figure 5

Low-density lipoprotein (LDL) cholesterol levels over time (full analysis set).

Figure 6

Time from baseline to first use of rescue therapy (a) and first blood/RBC transfusion (b). Time to first event was calculated as: (first event date or censoring date − first dose date + 1)/7. Patients were censored at last dose, week 52, last visit date, or death date, whichever occurred first, if rescue therapy after the first 52 weeks did not occur. Rescue therapy was defined as any use of RBC transfusion, ESA, or i.v. iron. Cox proportional hazards model adjusted for baseline Hb, eGFR, and other randomization stratification factors, except baseline Hb (≤8.0 vs. >8.0 g/dl) and eGFR (<30 vs. ≥30 ml/min per 1.73 m²). eGFR, estimated glomerular filtration rate; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; i.v., intravenous; RBC, red blood cell.

Figure 7

Levels of hepcidin (a), ferritin (b), iron (c), and TSAT (d) (full analysis set). SE, standard error; TSAT, transferrin saturation.