CERA (Continuous Erythropoiesis Receptor Activator): Dose-response, pharmacokinetics and tolerability in phase I multiple ascending dose studies

Abstract

6692 Background: Preclinical trials have shown that the innovative erythropoietic agent CERA stimulates erythropoiesis more potently than epoetin (in terms of magnitude and duration of response) and has a prolonged serum half-life. Its use may thus allow less frequent dosing (every 3 or 4 weeks) and more flexible treatment of anemia associated with cancer or renal disease. In phase I single ascending dose studies, CERA administered intravenously (IV) or subcutaneously (SC) produced potent dose-dependent erythropoietic activity (Reigner et al. Proc Am Soc Clin Oncol 2003; 22: 732). To examine the pharmacodynamic effect and tolerability of CERA with multiple ascending doses, additional phase I studies were performed. Methods: In two open-label, parallel-group, placebo-controlled studies, healthy volunteers were randomized to receive CERA (0.4, 0.8, 1.6, or 3.2 μg/kg) by IV injection on three occasions at 3-weekly intervals (n=61), or by SC injection on four occasions at 2-weekly intervals (n=48). Results: A rapid and dose-dependent erythropoietic response to CERA was observed; peak effects in reticulocyte counts were seen 7 and 10 days after IV and SC administration, respectively, with cumulative hematocrit, hemoglobin, and RBC responses. Mean (± SEM) elimination half-life was 133 ± 9.83 h for IV and 137 ± 21.9 h for SC CERA. Repeated dosing had no apparent clinically relevant effect on pharmacokinetics. Volume of distribution was small with IV CERA (3.0–5.4 L) and clearance was low with both IV and SC CERA (IV 27.6–44.6 mL/h, SC 97–347 mL/h). Accumulation did not occur with 3-weekly IV dosing and was small with 2-weekly SC dosing. Adverse events were generally mild and there were no serious adverse events. No antibodies were detected by ELISA in any subject. Conclusions: CERA administered either IV or SC demonstrated potent, prolonged dose-dependent erythropoietic activity and was generally well tolerated in phase I multiple ascending dose studies. Phase II studies administering CERA at various dosing intervals to cancer patients are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration F. Hoffmann-La Roche