A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome

Peter E Morris, Jay S Steingrub, Bee Y Huang, Shamay Tang, Patrick M Liu, Peter R Rhode, Hing C Wong, Peter E Morris, Jay S Steingrub, Bee Y Huang, Shamay Tang, Patrick M Liu, Peter R Rhode, Hing C Wong

Abstract

Background: The tissue factor (TF)-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS.

Methods: This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO(2)/FiO(2) ≤ 300 mm). Eighteen patients (6 per cohort) were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters.

Results: Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population.

Conclusions: Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS.

Trial registration: ClinicalTrials.gov: NCT01438853.

Trial registration: ClinicalTrials.gov NCT00879606 NCT01438853.

References

    1. Welty-Wolf KE, Carraway MS, Ortel TL, Piantadosi CA. Coagulation and inflammation in acute lung injury. Thromb Haemost. 2002;88(1):17–25.
    1. Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P. Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases. Thromb Haemost. 2008;99(3):494–501.
    1. Chambers RC. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br J Pharmacol. 2008;153(Suppl 1):S367–S378.
    1. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med. 2003;31(4 Suppl):S213–S220.
    1. Martin DM, Boys CW, Ruf W. Tissue factor: molecular recognition and cofactor function. FASEB J. 1995;9(10):852–859.
    1. Camerer E, Kolsto AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res. 1996;81(1):1–41. doi: 10.1016/0049-3848(95)00209-X.
    1. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3(8):1800–1814. doi: 10.1111/j.1538-7836.2005.01377.x.
    1. Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA. 2001;98(14):7742–7747. doi: 10.1073/pnas.141126698.
    1. Bastarache JA, Wang L, Geiser T, Wang Z, Albertine KH, Matthay MA, Ware LB. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax. 2007;62(7):608–616. doi: 10.1136/thx.2006.063305.
    1. Bastarache JA, Fremont RD, Kropski JA, Bossert FR, Ware LB. Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol. 2009;297(6):L1035–L1041. doi: 10.1152/ajplung.00214.2009.
    1. Idell S, Koenig KB, Fair DS, Martin TR, McLarty J, Maunder RJ. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol. 1991;261(4 Pt 1):L240–L248.
    1. Jiao JA, Kelly AB, Marzec UM, Nieves E, Acevedo J, Burkhardt M, Edwards A, Zhu XY, Chavaillaz PA, Wong A, Wong JL, Egan JO, Taylor D, Rhode PR, Wong HC. Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor × binding site. Thromb Haemost. 2010;103(1):224–233.
    1. Welty-Wolf KE, Carraway MS, Ortel TL, Ghio AJ, Idell S, Egan J, Zhu X, Jiao JA, Wong HC, Piantadosi CA. Blockade of tissue factor-factor × binding attenuates sepsis-induced respiratory and renal failure. Am J Physiol Lung Cell Mol Physiol. 2006;290(1):L21–L31.
    1. Morrow DA, Murphy SA, McCabe CH, Mackman N, Wong HC, Antman EM. Potent inhibition of thrombin with a monoclonal antibody against tissue factor (Sunol-cH36): results of the PROXIMATE-TIMI 27 trial. Eur Heart J. 2005;26(7):682–688. doi: 10.1093/eurheartj/ehi094.
    1. Vincent JL, Artigas A, Petersen LC, Meyer C. A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome. Crit Care Med. 2009;37(6):1874–1880. doi: 10.1097/CCM.0b013e31819fff2c.
    1. Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Phillips C, Weinacker A, Thompson BT, Eisner MD, Matthay MA. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008;178(6):618–623. doi: 10.1164/rccm.200803-419OC.
    1. Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536–545.
    1. Mackman N. The many faces of tissue factor. J Thromb Haemost. 2009;7(Suppl 1):136–139.
    1. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–2668. doi: 10.1002/jps.20178.
    1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709. doi: 10.1056/NEJM200103083441001.
    1. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286(15):1869–1878.
    1. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettila V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AA. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238–247. doi: 10.1001/jama.290.2.238.
    1. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353(13):1332–1341. doi: 10.1056/NEJMoa050935.
    1. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–843. doi: 10.1016/S0140-6736(07)60411-5.
    1. White B, Schmidt M, Murphy C, Livingstone W, O'Toole D, Lawler M, O'Neill L, Kelleher D, Schwarz HP, Smith OP. Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol. 2000;110(1):130–134. doi: 10.1046/j.1365-2141.2000.02128.x.
    1. Hancock WW, Grey ST, Hau L, Akalin E, Orthner C, Sayegh MH, Salem HH. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation. 1995;60(12):1525–1532. doi: 10.1097/00007890-199560120-00026.
    1. Feistritzer C, Sturn DH, Kaneider NC, Djanani A, Wiedermann CJ. Endothelial protein C receptor-dependent inhibition of human eosinophil chemotaxis by protein C. J Allergy Clin Immunol. 2003;112(2):375–381. doi: 10.1067/mai.2003.1609.
    1. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296(5574):1880–1882. doi: 10.1126/science.1071699.
    1. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9(3):338–342. doi: 10.1038/nm826.
    1. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161–3172. doi: 10.1182/blood-2006-09-003004.
    1. Camerer E, Cornelissen I, Kataoka H, Duong DN, Zheng YW, Coughlin SR. Roles of protease-activated receptors in a mouse model of endotoxemia. Blood. 2006;107(10):3912–3921. doi: 10.1182/blood-2005-08-3130.
    1. Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol. 2008;153(S1):S263–S282.
    1. Su X, Camerer E, Hamilton JR, Coughlin SR, Matthay MA. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms. J Immunol. 2005;175(4):2598–2605.
    1. Scotton CJ, Krupiczojc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, Moffatt JD, Laurent GJ, Derian CK, Eickelberg O, Chambers RC. Increased local expression of coagulation factor × contributes to the fibrotic response in human and murine lung injury. J Clin Invest. 2009;119(9):2550–2563.
    1. Howell DC, Johns RH, Lasky JA, Shan B, Scotton CJ, Laurent GJ, Chambers RC. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol. 2005;166(5):1353–1365. doi: 10.1016/S0002-9440(10)62354-1.

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