There has been huge interest in recent years in developing novel anticoagulants and factor Xa has proved a particularly fertile area of research
There has been huge interest in recent years in developing novel anticoagulants. The coagulation cascade can be interrupted in numerous places, and factor Xa has proved a particularly fertile area of research. This is a serine protease that is an essential part of the conversion of prothrombin to thrombin. Numerous direct factor Xa inhibitors are under development, and Bayer’s rivaroxaban is already available in Europe.
Another drug in this class, otamixaban, is being developed by sanofi-aventis.1 In one double blind, double dummy, parallel group dose-ranging Phase II trial, 947 patients undergoing non-urgent percutaneous coronary intervention were randomly assigned to one of five different weight-adjusted otamixaban dose regimens or weight-adjusted unfractionated heparin before their surgery.2 The otamixaban doses included a bolus dose between 0.025 and 0.140mg/kg, plus a three-hour infusion of between 0.035 and 0.200mg/kg/h.
The primary end-points were a change in prothrombin fragments 1 and 2, and anti-factor Xa activity. The median change in F1+2 from baseline to end of infusion was greater with the highest otamixaban dose than with the heparin, and anti-factor Xa levels increased with dose. There was no significant difference in bleeding rates or the number of ischaemic events between the otamixaban and heparin groups.
In another double blind Phase II trial designed to determine the optimum dose range for a Phase III study, 3,241 patients with non-ST-elevation acute coronary syndromes were randomly given a bolus of 0.08mg/kg of otamixaban followed by an infusion of between 0.035 and 0.175mg/kg/h, or unfractionated heparin plus eptifibatide.3
Enrolment in the lowest dose group was halted early on the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revasculation or bail-out inhibitor use within seven days. The lowest dose gave a primary efficacy endpoint of 7.2%, compared with 4.6% with 0.070mg/kg/h, but 3.8% and 3.6% for 0.105 and 0.140 doses. It rose again to 4.3% with the highest dose, and was 6.2% in the heparin group. Safety profiles were similar. Phase III trials started in 2010, with primary completion projected for 2012.
1. K.R. Guertin and Y.M. Choi, Curr. Med. Chem. 2007, 14, 2471
2. M. Cohen et al. Circulation 2007, 115, 2642
3. M.S. Sabatine et al. Lancet 2009, 374, 787