European Heart Journal Advance Access originally published online on January 31, 2005
European Heart Journal 2005 26(7):682-688; doi:10.1093/eurheartj/ehi094
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Potent inhibition of thrombin with a monoclonal antibody against tissue factor (Sunol-cH36): results of the PROXIMATE-TIMI 27 trial
1TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
2Scripps Research Institute, La Jolla, CA, USA
3Sunol Molecular Corp., Miramar, FL, USA
Received 23 May 2004; revised 25 October 2004; accepted 25 November 2004; online publish-ahead-of-print 31 January 2005.
* Corresponding author. Tel: +1 6172780145; fax: +1 6177347329. E-mail address: dmorrow{at}partners.org
Aims Exposure of tissue factor (TF) is a critical proximal step in the pathogenesis of acute coronary syndromes. Sunol-cH36, a chimaeric monoclonal antibody to TF, blocks binding of factor X to the TF:VIIa complex. This report describes the first completed trial of Sunol-cH36 in humans.
Methods and results We assessed the safety and pharmacokinetics of Sunol-cH36 in an open-label, dose-escalating trial among subjects with stable coronary artery disease. The safety analysis included all adverse events with a focus on overt or occult bleeding. Five doses of Sunol-cH36 (0.03, 0.06, 0.08, 0.1, 0.3 mg/kg) were administered as a single intravenous bolus to 26 subjects (three to eight subjects per dose tier). No major bleeding (
2 g/dL haemoglobin decline) occurred. Spontaneous minor bleeding was observed with a dose-related pattern. Notably, the majority of spontaneous bleeding episodes were clinically consistent with platelet-mediated bleeding (e.g. gum, tongue) without thrombocytopenia. The median terminal half-life was 72.2 (25th, 75th: 28.4, 72.5) h.
Conclusion Sunol-cH36 exhibited dose-dependent anticoagulant effects. We postulate that the mucosal bleeding observed with this potent inhibitor of thrombin generation may reflect antiplatelet effects resulting from networking between the coagulation cascade and platelet pathways that could prove clinically relevant with this novel class of anticoagulants.
Key Words: Clinical trials • Antithrombins • Coronary artery disease • Tissue factor
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