rb-006 and Thrombosis

Heparin and protamine are standard for anticoagulation and reversal for cardiopulmonary bypass (CPB). The REGADO biosciences protocol 1 (REG1) anticoagulant system, consisting of the Factor IXa (FIXa)-inhibitor pegnivacogin and its reversal agent (anivamersen), has been studied in patients undergoing coronary catheterization and in CPB in sheep and pigs. Prior to first human use in CPB, we wanted to test the safety and efficacy of REG1 in a primate model.. Fourteen baboons undergoing 2 h of CPB followed by 1 h of reperfusion were studied. Three received heparin/protamine and 11 received 1 of 2 doses of pegnivacogin followed by anivamersen. Thrombin-generating capacity was tested in additional in vitro experiments.. Targeted drug levels and near-complete FIXa inhibition were achieved. Bypass was run uneventfully in all animals without any clotting in the circuit and bleeding was minimal in the two groups. However, in contrast to heparin-treated baboons, those receiving pegnivacogin/anivamersen displayed thrombi in the bypass cannulae upon cannulation and kidney cortical infarcts. Inter-species comparisons revealed that in the presence of high levels of FIXa inhibition, tissue factor-mediated thrombin generation in baboons was much higher than that in other species.. These data highlight the limitations of the baboon model for assessing factor-specific coagulation inhibitors during CPB. The justification for Phase 1 human studies using REG1 for CPB is unclear.

Topics: Animals; Anticoagulants; Aptamers, Nucleotide; Cardiopulmonary Bypass; Coagulants; Drug Therapy, Combination; Factor IXa; Female; Heparin; Intraoperative Complications; Oligonucleotides; Papio; Perioperative Care; Postoperative Complications; Postoperative Hemorrhage; Protamines; Thrombosis; Treatment Outcome

REG-1, under development by Regado Biosciences Inc, is an intravenously administered anticoagulant system comprising the Factor IXa-inhibiting aptamer RB-006 and its complementary active control oligonucleotide, RB-007, for the potential treatment of arterial thrombosis. The evolution of anticoagulant therapy for the prevention and acute treatment of thrombotic disorders has progressed at a relatively modest pace considering the scope of the problem and the current understanding of platelet biology, coagulation proteases and vascular science, and their role in protective hemostasis and pathological thrombosis. This drug profile highlights a novel field of anticoagulant therapy referred to as aptamers (derived from the Latin aptus - to fit) and, in particular, the aptamer/active control agent system REG-1, which demonstrated efficacy as an anticoagulant in preclinical studies. In phase I clinical trials in healthy volunteers and patients with stable coronary artery disease, RB-006 inhibited Factor IXa activity, an effect that was titratibly reversible by the application of RB-007. In a phase IIa trial, REG-1 was well tolerated in patients undergoing elective percutaneous coronary intervention, and the treatment was successful with no procedural complications. At the time of publication, an extensive phase IIb trial in patients with acute coronary syndrome undergoing cardiac catheterization was ongoing.

Topics: Animals; Anticoagulants; Aptamers, Nucleotide; Arteries; Clinical Trials as Topic; Coronary Artery Disease; Drug Combinations; Drug Evaluation, Preclinical; Factor IXa; Humans; Mice; Oligonucleotides; Swine; Thrombosis