Dose-finding and long-term studies wih C. E. R. A. (Continuous Erythropoietin Receptor Activator) administered subcutaneously (SC) or intravenously (IV) in Japanese patients with chronic kidney disease (CKD) not on dialysis

Background: C. E. R. A. (Continuous Erythropoietin Receptor Activator) is an innovative erythropoiesis stimulating agent (ESA) with unique activity toward erythropoietin receptor, and results in showing significantly prolonged half-life. These studies were planned to evaluate the appropriate dose of C. E. R. A. administered either SC or IV once every 2 weeks (Q2W) to correct renal anemia in Japanese CKD patients not on dialysis. Methods: C. E. R. A. was administered SC (77 patients) or IV (57 patients) at three dose levels of 25, 50 or 75 μg Q2W to attain the Hb level of 12 g/dL (correction period) for patients with Hb levels of < 10 g/dL. Once this Hb level had been attained, C. E. R. A. was administered Q4W at the dose levels ranging from 15 to 300 μg (SC) or 25 to 300 μg (IV) to maintain Hb levels within 11-13g/dL (maintenance period). The total observation period in these studies was 48-50 weeks. Primary endpoint is the slope of the Hb level/time curve (g/dL/week). Secondary endpoints are the percentage of patients who achieved the target Hb level of 12 g/dL and the time taken to reach target level in correction period, and the percentage of patients to maintain the target Hb levels of 11-13 g/dL in maintenance period. Results: Mean (SD) slopes of the Hb/time curves with SC administration of Q2W C. E. R. A. at each of 25, 50 or 75 μg were 0.100 (0.108), 0.227 (0.137) or 0.303 (0.159) g/dL/week, and those with IV were 0.129 (0.118), 0.352 (0.219) or 0.412 (0.174) g/dL/week (IV), respectively, which were similar between SC and IV route at the same dose. At each dose of 25, 50 or 75 μg, the percentages of patients achieving the Hb level of 12 g/dL were 75.0, 92.0 or 84.6% (SC), 84.2, 95.0 or 100% (IV), respectively, and the time to achieve Hb target was 140, 112 or 84 days (SC) and 112, 70 or 55.5 days (IV), in which both endpoints found to be dose-related. The percentages of the patients maintained Hb target levels (11-13 g/dL) after 24 week and 48 weeks were 81.1% and 72.7% (SC) and 73.3% and 85.0% (IV), respectively. Conclusions: These studies have demonstrated that a dose of C. E. R. A. Q2W as low as 25 μg, provides a smooth and steady increase in Hb levels in Japanese patients with CKD not on dialysis, regardless of administration route. Furthermore, administration of C. E. R. A. Q4W successfully maintained target Hb levels in this patient population.