Efficacy and safety of recombinant erythropoiesis-stimulating protein versus recombinant erythropoietin for maintenance treatment of anemia in patients with chronic renal failure on stable hemodialysis: A phase III, multicenter, randomized, open-label, pa

Among patients with chronic kidney disease (CKD) on stable hemodialysis, the use of recombinant human erythropoietin (rhEPO) requires frequent dosing and higher doses for patients with hyporesponsiveness for the treatment of anemia has been linked to a possibly increased cardiovascular risk. Early-stage trials have suggested that recombinant erythropoiesis stimulating protein (rESP), a genetically engineered, hyperglycosylated rhEPO, given once weekly or every other week, is as effective as rhEPO in increasing hemoglobin(Hb) levels, with comparable safety profiles.

In this randomized, open-label, phase III trial, we randomly assigned (1:1) patients with chronic renal failure on hemodialysis who had been receiving stable doses of rhEPO for ≥ 12 weeks and had steady hemoglobin levels (100 to 120 g/L) to receive rESP (50 μg, administered intravenously every other week) and rhEPO (administered intravenously one to three times weekly). The primary efficacy end point was the mean change in the hemoglobin levels from baseline to the average concentration from weeks 25 through 32, with a prespecified noninferiority margin of −7.5 g/L. Secondary efficacy end points were the proportion of patients whose hemoglobin concentration stayed within the target range (100-120 g/L).

A total of 300 patients underwent randomization to receive rESP (147 patients) and rhEPO (153 patients). All these patients received at least one dose of the study drugs and were included in the FAS. The mean (±SD) baseline hemoglobin level was 110.45±5.36 g/L overall. During the trial, the mean hemoglobin  levels of the rESP group and the rhEPO group at each visit are shown in Figure 1. The adjusted mean hemoglobin levels were 108.73±0.78 g/L in the rESP group and 108.61±0.75 g/L in the rhEPO group, with a LSM difference of 0.12 between the two groups (95% CI -1.74 to 1.98; MMRM P = 0.901). The adjusted least square mean change in the hemoglobin level from baseline to weeks 25 through 32 was -1.46±1.00 g/L in the rESP group and −1.58±0.96 g/L in the rhEPO group (difference, 0.12 g/L; 95% CI -1.82 to 2.06), which met the prespecified noninferiority margin of −7.5 g/L. The non-inferiority of rESP to rhEPO was consistent across nearly all prespecified subgroups (Figure 2). Similar proportions of patients in the two groups maintained hemoglobin concentration within the target range from weeks 25 through 32 (rESP 64.6% [95/147] and rhEPO 60.1% [92/153], CMH χ2 test P = 0.413)(Table 1). Treatment-related AEs were infrequent in both groups, reported by 22.4% (33/147) of patients receiving rESP, as compared with and 17.0% (26/153) of those receiving rhEPO. Hypertension occurred in 4.1% (6/147) of patients receiving rESP and 5.2% (8/153) of those receiving rhEPO (Table 2). The results of anti-rESP antibodies in all subjects in the study were negative.

In this 36-week, phase III trial comparing maintenance therapy with rESP administered intravenously every other week with rhEPO administered intravenously one to three times weekly, rESP was noninferior to rhEPO for the treatment of anemia in  patients with chronic renal failure undergoing hemodialysis, with comparable safety profiles.