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A Phase I, Single and Fractionated, Ascending-Dose Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of an Erythropoietin Mimetic Antibody Fusion Protein (CNTO 528) in Healthy Male Subjects

From Centocor Research and Development, Inc, Malvern, Pennsylvania (Dr Bouman-Thio, Dr Miller, Dr Getsy, Dr Bai, Dr Yohrling, Mr Frederick, Mr Marciniak, Ms Jiao, Dr Jang, Dr Davis) and Centre for Human Drug Research, Leiden, The Netherlands (Dr Franson, Dr Cohen, Dr Burggraaf).

The erythropoietin mimetic antibody fusion protein CNTO 528 was developed as a novel antibody fusion protein by constructing an active hematopoietic peptide onto an IgG1-based scaffold. This resulted in a molecule with a long circulating half-life and a prolonged effect of stimulating reticulocyte production and hemoglobin (Hgb) synthesis. To assess the safety, pharmacokinetics, and pharmacodynamics of CNTO 528, the authors gave 44 adult healthy male subjects single or fractionated doses of intravenous CNTO 528 or placebo. CNTO 528 was generally well tolerated. The maximum observed concentration (C_max) and the area under the concentration versus time curve (AUC) increased in an approximately dose-dependent manner between the 0.09-mg/kg and 0.9-mg/kg doses. The maximum effect on the reticulocyte response occurred approximately 8 to 9 days after administration. A median increase in Hgb (1 g/dL above baseline) was achieved 9 to 10 days after administration, with a maximum effect between 19 and 26 days. Two subjects in the 0.9-mg/kg dose group had elevated Hgb concentrations requiring phlebotomy. In this first-in-human study, CNTO 528 was well tolerated and effective in elevating and maintaining Hgb by at least 1 g/dL following a single intravenous administration, which suggests that an erythropoietin mimetic molecule, such as CNTO 528, may be an effective therapy for patients with anemia.

Key Words: erythropoietin • anemia • antibody

Address for reprints: Esther Bouman-Thio, MD, Centocor Research and Development, Inc, 200 Great Valley Parkway, Malvern, PA 19355; e-mail: ethio2{at}its.jnj.com.

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