Erythropoiesis Equivalence, Pharmacokinetics and Antibody Analysis Following Subcutaneous and Intravenous Hematide™ Administration in Cynomolgus Monkeys.

Abstract

Hematide™ is a synthetic PEGylated peptidic erythropoiesis stimulating agent (ESA) that is presently being developed for the correction of anemia in patients with chronic kidney disease and cancer. The objectives of this study were to evaluate the pharmacokinetics (PK), erythropoietic response, and the potential of Hematide to induce the formation of antibodies in monkeys following subcutaneous (SC) and intravenous (IV) administration. Hematide was administered Q2Wx3 at 10 mg/kg SC (n=5) and IV (n=5) beginning on Day 1 with repeat administration (Q2Wx3) beginning on Day 71. A third dose cycle began on Day 141 with animals (n=10) receiving 10 mg/kg SC. Blood was collected following the first dose for PK analysis and then repeatedly throughout the study for anti-Hematide antibody analysis, hematology, and serum chemistry analysis. To avoid the possible consequences of chronic polycythemia 30 to 40 mL of blood was collected approximately every two weeks. As expected, Hematide induced significant erythropoiesis with characteristic increases in reticulocytes, red blood cells, hematocrit and hemoglobin (Hgb) levels. At Day 14, reticulocytes were 9.1 ± 2.1 and 9.6 ± 0.8% following IV and SC administration respectively, compared to 1.0 ± 0.2 and 1.4 ± 0.5 % at pre-dose. Hgb levels at Day 14 were also similar between the IV and SC dosing groups with Hgb levels of 16.9 ± 0.6 and 17.8 ± 1.5 g/dL corresponding to increases of 2.5 and 3.2 g/dL. Hgb levels progressively increased to a plateau by study Day 48. No differences were noted between the IV and the SC dosed groups with Hgb levels of 20.9 ± 2.5 and 20.3 ± 2.1 g/dL respectively, corresponding to increases of 6.5 and 6.7 g/dL over pre-dose levels. Following IV administration, PK analyses revealed disappearance of Hematide from plasma in a bi-exponential fashion, with a rapid initial phase followed by a dominant, prolonged terminal phase. The plasma clearance estimate was small, with a mean value of 0.17 mL/h·kg and the volume of distribution at steady state (Vss) was also small, 25.9 mL/kg indicating that Hematide is confined to the plasma compartment. The terminal half-life of Hematide following IV administration was 114 h. Hematide was slowly absorbed following SC injection, with a delayed pseudo Cmax at 48 to 168h. Essentially, a sustained and plateau plasma concentration was observed throughout the entire PK sampling interval. A terminal elimination apparently was not reached even at 169 h post SC dose. The SC bioavailability, estimated by AUC240h after IV and SC routes, was 57.1%. No detectable levels of Hematide-specific antibodies were observed in any of the ten monkeys dosed IV and/or SC with Hematide Q2W, with intermittent rest periods, for a total of 9 doses. In conclusion, Hematide is a potent erythropoiesis stimulating agent which exhibits a low clearance and small volume of distribution in monkeys. Similar erythropoietic responses were produced following IV and SC administration. The absence of antibody development in the repeatedly dosed animals indicates that Hematide is non-immunogenic at the dosing regimen tested.