Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb#10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean6SD baseline Hb was 8.361.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by $2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean6SEM maximal change in Hb from baseline (DHb max ), the primary endpoint, was 3.160.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, DHb max was similar and larger than in the no-iron group. Hb response (increase in Hb of $1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

Background We evaluated the efficacy and safety of roxadustat vs. epoetin alfa for the treatment of chronic kidney disease (CKD) related anemia in patients new to dialysis. Methods This was a phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were on hemodialysis/peritoneal dialysis for ≥2 weeks and ≤4 months before randomization and had mean hemoglobin ≤10.0 g/dL. Primary endpoints were mean hemoglobin (g/dL) change from baseline averaged over weeks 28–52 regardless of rescue therapy (non-inferiority criterion: lower limit of 95% CI for treatment difference > −0.75) and percentage of patients achieving a hemoglobin response between weeks 1–24 censored for rescue therapy (non-inferiority margin for between-group difference: −15%). Adverse events were monitored. Results The intention-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (SD) hemoglobin changes from baseline averaged over weeks 28–52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior (least-squares mean difference: 0.18 [95% CI: 0.08, 0.29]) to epoetin alfa. Percentages of patients with a hemoglobin response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior to epoetin alfa (treatment-group difference: 3.5% [95% CI: −0.7%, 7.7%]). Adverse event rates were comparable between treatment groups. Conclusions Roxadustat was efficacious for correcting and maintaining hemoglobin levels compared to epoetin alfa. Roxadustat had an acceptable safety profile.

Background Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for the treatment of chronic kidney disease (CKD) anemia. Methods This phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with stage 3-5 CKD not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (EMA) - hemoglobin (Hb) response, defined as Hb ≥ 11.0 g/dL that increased from baseline by ≥ 1.0 g/dL in patients with Hb > 8.0 g/dL or ≥ 2.0 g/dL in patients with baseline Hb ≤ 8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; United States (FDA) - change in Hb from baseline to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. Results A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response (odds ratio: 34.74 [95% CI: 20.48, 58.93]) and change in Hb from baseline (roxadustat - placebo: +1.692 [95% CI: 1.52, 1.86]; both P<0.001). Superiority of roxadustat was demonstrated for LDL cholesterol change from baseline, and time to first use of rescue medication (both P<0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). Conclusions Roxadustat demonstrated superior efficacy versus placebo both in terms of Hb response rate and change in Hb from baseline. The safety profiles of roxadustat and placebo were comparable.

Background/Aims: Poor glycemic control can lead to increased morbidity and mortality in peritoneal dialysis (PD) patients. Serum fructosamine may be a more reliable marker of glycemic control than HbA1c in dialysis patients. Methods: We evaluated the effects of a glucose-sparing PD regimen on serum fructosamine. In the multicenter, controlled IMPENDIA trial, eligible diabetic PD patients were randomized (1:1) to a 24-hour combination of a glucose sparing regimen (n = 89) or a glucose-based therapy (n = 91). Serum fructosamine and HbA1c were measured at baseline, 3 months and 6 months; fructosamine measurements were corrected for serum albumin (AlbF). Results: Serum fructosamine decreased from 297 to 253 µmol/l in the glucose-sparing group (95% confidence interval [CI] for the difference, −26 to −68, p < 0.001), and increased from 311 to 314 µmol/l in the glucose-only group (95% CI for the difference, −23 to +19, p = 0.87). The mean difference in change of fructosamine levels between groups at 6 months was 64 µmol/l (95% CI 29-99, p < 0.001). HbA1c decreased versus baseline in both groups (treatment difference 0.3%, p = 0.07). The correlation between AlbF and baseline fasting serum glucose was stronger than that seen between HbA1c and baseline fasting serum glucose (r = 0.47, p < 0.0001 and r = 0.31, p < 0.0001, respectively). Conclusion: A glucose-sparing regimen (P-E-N) improved glycemic control as measured by serum fructosamine. Further studies are needed to establish fructosamine targets that will reduce the morbidity risk related to hyperglycemia in PD patients.

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