A Phase I, Single and Fractionated, Ascending Dose Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of an Erythropoietic Mimetic Antibody Fusion Protein, CNTO528, in Healthy Male Subjects.

Objectives: To assess the safety, pharmacokinetics (PK), pharmacodynamics and immunogenicity of single and fractionated IV doses of an erythropoietic mimetic antibody fusion protein, CNTO 528, in healthy males.

Methods: In this randomized, single-blind, and placebo (PBO)-controlled study, 44 subjects were enrolled in 5 dose cohorts. In Stage 1, 35 subjects received a single IV administration of 0.03, 0.09, 0.3, 0.9 mg/kg CNTO 528 or PBO. In Stage 2, 9 subjects received fractionated IV administrations of CNTO 528 or PBO on Days 1, 3 and 5 (3 infusions of 0.09 mg/kg or PBO).

Results:

Pharmacodynamics: In subjects treated with IV CNTO 528, a dose dependent increase in reticulocyte counts was observed. The maximum effect occurred at day 8 and returned back to baseline between days 22 through 29. Hemoglobin (Hgb) concentration increased in a dose dependent manner with a maximum effect occurring at day 22. Mean Hgb concentration remained 0.4 g/dL above baseline values at the last measurement, approximately 2.5 months after a single dose administration. A dose dependent increase in RBC count was observed with all RBC indices (MCV, MCH, MCHC) within normal range, indicating an increase in normocytic, normochromic RBCs. In all CNTO 528 treated subjects, a dose-dependent increase in soluble transferrin receptor concentration was observed. A dose-dependent increase in endogenous EPO concentration was observed, followed by a dose dependent decrease in endogenous EPO concentration. This may be the result of a competitive receptor binding mechanism.

Pharmacokinetics: With 1 dose, the Cmax and AUC increased in an approximately dose proportional manner. The mean terminal half-life ranged between 6 – 7 days in the higher dose cohorts.

Safety: Treatment with CNTO 528 was generally well tolerated. There were no serious adverse events (AEs) and few CNTO 528-related AEs. Two subjects in the highest dose cohort met the protocol pre-specified interruption rule of Hgb ≥ g/dL and underwent phlebotomy. In these subjects, high Hgb concentrations were not associated with AEs or clinical symptoms. All AEs were determined by the investigator to be mild to moderate in intensity. The most common AE across all groups was headache, occurring in both CNTO 528- and PBO-treated subjects. There was no dose-related trend across groups, and most subjects who experienced headaches were in the lowest 2 dose groups. There was no indication that any patterns of AEs or significant safety laboratory, vital signs, or ECG abnormalities were associated with the administration of CNTO 528.

Immunogenicity: None of the 24 subjects who received single IV administration of CNTO 528 were positive for antibodies to CNTO 528.

Conclusions: Single and fractionated IV administrations of CNTO 528 were well tolerated and resulted in prolonged, dose-dependent erythropoietic responses with notably low inter-subject variability. PK of IV CNTO 528 was linear and approximately dose proportional. No immunogenicity was observed. This data provides the first proof of concept in humans for erythropoietic responses and up-regulation of endogenous EPO levels by an erythropoietic mimetic antibody fusion protein.