PB1005 - Preclinical safety and toxicokinetics of VMX-C001 - an intravenous bypassing agent for factor Xa inhibitors

Background: VMX-C001, a modified form of human zymogen factor X, is being developed to stop or prevent bleeding in patients taking factor Xa inhibitors and is currently in human phase I studies.

Aims: To examine the safety pharmacology of VMX-C001 in rats and cynomolgus monkeys.

Methods: Subsequent to dose range finding studies, 2-week toxicity studies were performed at doses of 20, 50 and 100 IU/kg/day VMX-C001, followed by a two-week recovery period.

Results: In either species there were no unscheduled deaths, no clinical signs, no effects on body weight or food consumption nor on ECGs. There were also no hematology, coagulation (including TAT and d-dimer), clinical chemistry and urinalysis changes during the dosing and recovery periods. In rats, no positive ADAs were observed at the end of dosing. At the end of recovery, one female rat was positive for both anti-VMX-C001 and anti-factor X antibodies. One other female rat tested positive for anti-factor X antibodies. In monkeys, several animals tested positive for antibodies against factor X or VMX-C001. Only one animal screened positive against both factor X and VMX-C001. None of the animals developed a coagulation abnormality indicating the antibodies had no functional significance. Analysis of VMX-C001 levels in plasma revealed linear and dose proportional toxicokinetics without an effect of sex or period of administration. Accumulation of VMX-C001 was not observed after repeated dosing. The distribution volume was 80-100 ml/kg and was consistent with a single compartment model limited to the blood circulation. The half-life of VMX-C001 was 4-5 hours in rats and 6-8 hours in monkeys.

Conclusion(s): Administration of VMX-C001 for 2 weeks was clinically well tolerated in rats and cynomolgus monkeys at levels of 20, 50 and 100 IU/kg/. The No-Observed-Adverse-Effect Level (NOAEL) of VMX-C001was considered to be the highest dose administered in both species.