Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study

Introduction

RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males.

Materials and methods

We conducted a two-stage, single-center, open-label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950 IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24 hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated.

Results

All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A_max was 0.16 (± 0.02) IU/mL and AUC_0-24 was 1.11 (± 0.24) IU*h/mL, At the highest dose anti-FXa activity A_max was 1.67 (± 0.15) IU/mL; AUC_0-24 was 21.48 (± 4.46) IU*h/mL and t½ was 8.05 h. Mean T_max (all doses) was 2.86 (± 0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A_max among doses (p = 0.594) and normalized AUC_0-24 (p = 0.092), correlations between A_max-dose (R² = 0.89, p < 0.001) and AUC_0-24-dose (R² = 0.86, p < 0.001)]. Anti-FIIa activity was below the detection limit (0.1 IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin.

Conclusions

In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity.