Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients

Abstract

Background: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects.

Methods: NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity.

Results: Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo.

Conclusions: Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial.

Clinical trials registration: Clintrials.gov #NCT00761657.

Keywords: HIF-PHI; anemia; chronic kidney disease; erythropoietin; hepcidin.

FIGURE 1:

Patient disposition. *The AEs in the roxadustat arm were acute prostatitis (in the 1.0 mg/kg TIW group) and elevated liver enzymes (in the 2.0 mg/kg BIW group). One placebo patient was discontinued because of SAEs of acute pericarditis and renal failure.

FIGURE 2:

Mean maximum change from BL in Hb (ΔHb_max) and % subjects achieved Hb response, defined as Hb increase by ≥1 g/dL (EE population). Mean (SD) BL Hb was 10.1 (0.7) g/dL for roxadustat subjects and 10.1 (0.6) g/dL for placebo subjects. Pooled placebo data used. Time to response was estimated using the Kaplan–Meier method, estimable for groups with >50% response. Nonresponders were censored at Day 42. *From an intergroup t-test compared with placebo; n.s.: not significant.

FIGURE 3:

Mean change from BL in Hb (ΔHb) in TIW cohorts (EE population). Mean (SD) BL Hb was 10.1 (0.7) g/dL for roxadustat TIW subjects and 10.1 (0.6) g/dL for placebo subjects. Last-observation-carried-forward (LOCF) method was used to impute missing values. *P < 0.01 intergroup two-sample t-tests comparing roxadustat change from BL with placebo change from BL. End of treatment (EOT) for TIW was Day 26.

FIGURE 4:

Changes in median plasma EPO on first and final days of treatment. Data are for the PK/PD population (subjects with complete dataset only).

FIGURE 5:

Mean change from BL in serum hepcidin (EE population). Data from BIW and TIW groups were pooled for each dose level. Serum hepcidin was not measured in the roxadustat 1.0 mg/kg dose group. LOCF method was used to impute missing data. *P = 0.048, **P = 0.0013, intergroup two-sample t-tests comparing roxadustat change from BL with placebo change from BL. EOT was Day 29 (BIW) or Day 26 (TIW).