Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD

Abstract

Background and objectives: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD.

Design, setting, participants, & measurements: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events.

Results: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported.

Conclusions: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Keywords: C-Reactive Protein; Erythropoiesis; Hemoglobins; Hepcidins; Humans; Iron; Renal Insufficiency, Chronic; anemia; chronic kidney disease; clinical trial.

Figure 1.

Patient disposition. AE, adverse event. *One patient died during the follow-up period. ^{^}Four of the 12 discontinuations of treatment occurred in cohorts A and B (16 weeks of treatment) after 1.1, 4.7, 13.3, and 13.4 weeks of dosing. The remaining eight discontinuations occurred in cohorts C–F (24 weeks of treatment) after 1 day (single dose) and 2.6, 3.4, 8.1, 8.9, 11.1, 18.1, and 21.7 weeks of dosing.

Figure 2.

Roxadustat effectively corrects and maintains Hb in NDD-CKD patients. (A) Time to hemoglobin response in the efficacy-evaluable population by dosing cohort. Patients who terminated treatment before the full treatment period (112 days for cohorts A and B and 168 days for cohorts C–F) and did not achieve hemoglobin response during their time on treatment were censored. Each circle in the plot represents one censored patient at the time when the patient was censored. Therefore, although cohorts B, D, and E reached 100% response in this analysis, only in cohort B did 100% of the evaluable patients meet the primary end point. The table below the figure denotes the number of efficacy-evaluable patients with valid hemoglobin data on the first day after each study week by cohort. (B) Hemoglobin over time in the efficacy-evaluable population by cohort (last observation carried forward). BIW, twice weekly; Hb, hemoglobin; QW, once weekly; TIW, thrice weekly.

Figure 3.

Platelet levels over time among patients in cohorts A, C, and D stratified on baseline platelet level (efficacy-evaluable population with last observation carried forward). BL, baseline. *P value <0.05 (ANOVA model comparing change from baseline with zero using the pooled variance from all groups).

Figure 4.

Change from baseline in total cholesterol over time (efficacy-evaluable population with last observation carried forward). Note that the vertical dashed lines show post-treatment levels. BIW, twice weekly; EOT, end of treatment; QW, once weekly; TC, total cholesterol; TIW, thrice weekly.