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

Abstract

BackgroundFG-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).MethodsIn 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.ResultsIn 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.ConclusionsFG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

“…In Chen et al [27] study, no CV safety signals were noted, and no CV events were reported in this trial. Desidustat was well tolerated in the studied population.…”

“…In Besarab et al [26] study with twice or thrice (TIW) in a week treatment for 4 weeks, mean Hb increase of 0.8-2.2 g/dL from baseline was observed with 0.7-2.0 mg/kg dose. In Chen et al [27] study, mean Hb increase was 1.82 and 2.59 g/dL in the low (1.1-1.75 mg/kg) and high (1.50-2.25 mg/kg) dose cohorts, respectively, after 8 weeks of TIW treatment. In Holdstock et al [28] study after 4 weeks of every day dosing of HIF-PHI, mean Hb increase of 0.13, 0.49, and 1.05 g/dL from baseline with 0.5, 2, and 5 mg doses, respectively, was observed.…”

“…However, in the Holdstock et al [28] study, the concentration of hepcidin decreased only in the 5 mg arm of GSK1278863. In Chen et al [27] study, mean hepcidin decrease reported was -37.8 and -37.2 ng/mL in the low (1.1-1.75 mg/kg) and high (1.50-2.25 mg/kg) dose cohorts, respectively, after 8 weeks of TIW treatment. In this trial after 6 weeks of alternate day dosing, mean reduction in hepcidin compared to baseline was -59.7, -91.4, -59.2 ng/mL in Desidustat 100, 150, and 200 mg arms, respectively.…”

Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non‐elderly healthy adult male subjects

“…The ability of HIF‐PHIs to increase blood EPO to levels close to the normal physiologic range, but lower than those induced by treatment with intravenous erythropoiesis‐stimulating agents, may have the advantage of reduced adverse cardiovascular effects . In addition, roxadustat has been shown to improve iron availability by reducing hepcidin, and may reduce the need for intravenous iron . Roxadustat reaches maximum plasma concentration within 2 hours of oral administration and is eliminated by phase I oxidation (cytochrome P450 2C8) and phase II conjugation (glucuronidation via uridine diphosphate‐glucuronosyltransferase and glucosidation); the terminal elimination half‐life (t ½ ) is approximately 12 hours in healthy subjects .…”

Evaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects

“…anemia associated with CKD who are on [6][7][8] or not on dialysis, 9,10 and is currently being investigated globally in phase 3 clinical studies. Roxadustat is rapidly absorbed after oral administration, reaches maximum plasma concentration within 2 hours, and is highly bound to albumin; the terminal elimination half-life (t ½ ) is approximately 12 hours in healthy subjects after a single dose.…”