Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China

Abstract

Background: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD).

Methods: In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed.

Results: In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects.

Conclusions: FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

Keywords: FG-4592; anemia in chronic kidney disease; erythropoiesis; erythropoietin; hypoxia-inducible factor.

FIGURE 1

Patient disposition. (A) NDD study: ^athe two adverse events in the low dose FG-4592 arm were urinary tract infection and worsening chronic renal failure. The one placebo subject was discontinued for adverse event of worsening anemia (and received rescue therapy). (B) DD study: ^awithdrawn due to having had one dose of epoetin alfa (prohibited medication) administered in error, ^brash (hypersensitivity). The latter subject was efficacy evaluable. FU, follow-up.

FIGURE 2

Hb over time and Primary Efficacy Endpoints. NDD study: data are for the ITT population. ^aThe P-values for ΔHb_max are from the CFB lab values comparison of FG-4592 cohort to placebo group based on the ANCOVA model with baseline lab values as a covariate, and these were ≤0.0001 at all-time points after Week 2 for the high-dose cohort and after Week 6 for the low-dose cohort. In the low-dose cohort, the P-values for the difference between mean Hb CFB and placebo were 0.016 at Week 3, 0.003 at Week 4 and 0.0003 at Weeks 5 and 6 (these P-values are from mixed model for repeated measurements model with baseline as covariate, comparing FG-4592 CFB with placebo CFB). DD study: data are for the EE population using LOCF for missing data and are the mean (SE) Hb value at each time point. ^bDefined as a Hb level maintained at no less than 0.5 g/dL below mean baseline value during the last two weeks of the 6-week dosing period in the EE population. ^cCochran-Mantel-Haenszel test after adjusting for randomization stratification. Zero weeks (baseline) is the mean of three pre-dosing Hb values. ^dP = 0.005, ^eP = 0.0002, P-values are from the average CFB Hb comparison between FG-4592 Cohorts 1, 2 or 3 and epoetin alfa arm after 6 weeks of treatment, based on the ANCOVA model with baseline Hb and randomization stratification as covariates, and treatment groups as the classification variable.

FIGURE 3

Cumulative probability of Hb response and achievement of Hb target in NDD study (ITT population, Kaplan–Meier analysis). Response was defined as first instance of Hb rise from baseline ≥1.0 g/dL during the treatment period (full lines). Achievement was defined as first reaching of Hb level ≥11.0 g/dL during the treatment period (dashed lines). Empty circles represent censored subjects. P-values (log-rank test) for Hb response comparison against placebo were <0.0001 for both doses. P-value for comparison of high-dose with low-dose was 0.0665. P-values (log-rank test) for target achievement comparison against placebo were 0.0034 for the low FG-4592 dose and <0.0001 for the high dose. The P-value for comparison of high-dose to low-dose was 0.0259. EOT denotes protocol planned end of treatment with study drug.