Thromb Haemost 2011; 105(02): 302-312
DOI: 10.1160/TH10-05-0287
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue

Thijs van Iersel
1   QPS Netherlands B.V., Groningen, The Netherlands
,
Heimo Stroissnig
2   Celonic AG, Basel, Switzerland
,
Peter Giesen
3   Thrombinoscope B.V., Maastricht, The Netherlands
,
Johan Wemer
1   QPS Netherlands B.V., Groningen, The Netherlands
,
Karin Wilhelm-Ogunbiyi
4   PAION Deutschland GmbH, Aachen, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 12. Mai 2010

Accepted after major revision: 02. November 2010

Publikationsdatum:
25. November 2017 (online)

Summary

Solulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.

 
  • References

  • 1 Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257: 7944-7947.
  • 2 Van Walderveen MC, Berry LR, Atkinson HM. et al. Covalent antithrombin-heparin effect on thrombin-thrombomodulin and activated protein C reaction with factor V/Va. Thromb Haemost 2010; 103: 910-919.
  • 3 Toltl LJ, Swystun LL, Pepler L. et al. Protective effects of activated protein C in sepsis. Thromb Haemost 2008; 100: 582-592.
  • 4 Kearon C, Comp P, Douketis J. et al. Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2005; 3: 962-968.
  • 5 Saito H, Maruyama I, Shimazaki S. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5: 31-41.
  • 6 Leone G, Rossi E, Leone AM. et al. Novel antithrombotic agents: indirect synthetic inhibitors of factor Xa and direct thrombin inhibitors. Evidences from clinical studies. Curr Med Chem Cardiovas Hematol Agents 2004; 2: 311-326.
  • 7 Bramlage P, Pittrow D, Kirch W. Current concepts for the prevention of venous thromboembolism. Eur J Clin Invest 2005; 35: 4-11.
  • 8 Nowak G. Heparin-induced thrombocytopenia (HIT II) – a drug-associated autoimmune disease. Thromb Haemost 2009; 102: 887-891.
  • 9 Salem M, Elrefai S, Shrit MA. et al. Fondaparinux thromboprophylaxis-associated heparin-induced thrombocytopenia syndrome complicated by arterial thrombotic stroke. Thromb Haemost 2010; 104: 1071-1072.
  • 10 Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)- induced heparin-induced thrombocytopenia (HIT). Thromb Haemost 2008; 99: 779-781.
  • 11 Garcia Hejl C, Leclerc T. Incidence and features of heparin-induced thrombocytopenia (HIT) in burn patients. Thromb Haemost 2008; 99: 974-976.
  • 12 Chong BH, Isaacs A. Heparin-induces thrombocytopenia: what clinicians need to know. Thromb Haemost 2009; 101: 279-283.
  • 13 Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008; 28: 380-386.
  • 14 Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010; 115: 15-20.
  • 15 Turpie AG, Bauer KA, Davidson BL. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009; 101: 68-76.
  • 16 Diamantopoulos A, Lees M, Wells PS. et al. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost 2010; 30 (104) 760-770.
  • 17 Becker RC, Alexander JH, Newby K. et al. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010; 30 (104) 535-544.
  • 18 Weitz JI, Conolly SJ, Patel I. et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104: 633-641.
  • 19 Raskob G, Cohen AT, Eriksson BI. et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomized double-blind dose-response study. Thromb Haemost 2010; 104: 642-649.
  • 20 Ahrens I, Lip GY, Peter K. et al. New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 2010; 104: 49-60.
  • 21 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585.
  • 22 Olsson SB, Rasmussen LH. Safety and tolerability of an immediate-release formulation of the oral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Thromb Haemost 2010; 103: 604-612.
  • 23 Phillips KW, Ansell J. The clinical implications of new oral anticoagulants: will the potential advantages be achieved?. Thromb Haemost 2010; 103: 34-39.
  • 24 Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
  • 25 Warkentin TE. Fondaparinux versus direct thrombin inhibitor therapy for the management of heparin-induced thrombocytopenia (HIT) – Bridging the River Coumarin. Thromb Haemost 2008; 99: 2-3.
  • 26 Lobo B, Finch C, Howard A. et al. Fondaparinux for the treatment of patients with acute heparininduced thrombocytopenia. Thromb Haemost 2008; 99: 208-214.
  • 27 Nakashima M, Kanamaru M, Umemura K. et al. Pharmacokinetics and Safety of a Novel Reecombinant Soluble Human Thrombomodulin, ART-123, in Healthy Male Volunteers. J Clin Pharmacol 1998; a 38: 40-44.
  • 28 Nakashima M, Uematsu T, Umemura K. et al. A Novel Recombinant Soluble Human Thrombomodulin, ART-123, Activates the Protein C Pathway in Healthy Male Volunteers. J Clin Pharmacol 1998; b 38: 540-544.
  • 29 Trujillo-Santos J, Nieto JA, Tiberio G. et al. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 435-439.
  • 30 Shbaklo H, Holcroft CA, Kahn SR. Levels of inflammatory markers and the development of the post-thrombotic syndrome. Thromb Haemost 2009; 101: 505-512.
  • 31 Clarke JH, Light DR, Blasko E. et al. The short loop between epidermal growth factor-like domains 4 and 5 is critical for human thrombomodulin function. J Biol Chem 1993; 268: 6309-6315.
  • 32 Glaser CB, Morser J, Clarke JH. et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J Clin Invest 1992; 90: 2565-2573.
  • 33 Lin JH, Mc Lean K, Morser J. et al. Modulation of glycosaminoglycan addition in naturally expressed and recombinant human thrombomodulin. J Biol Chem 1994; 269: 25021-25030.
  • 34 Wang W, Nagashima M, Schneider M. et al. Elements of the primary structure of thrombomodulin required for efficient thrombin-activable fibrinolysis inhibitor activation. J Biol Chem 2000; 275: 22942-22947.
  • 35 Light DR, Glaser CB, Betts M. et al. The interaction of thrombomodulin with Ca2+ . Eur J Biochem 1999; 262: 522-533.
  • 36 Fuentes-Prior P, Iwanaga Y, Huber R. et al. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 2000; 404: 518-525.
  • 37 Weisel JW, Nagaswami C, Young TA. et al. The shape of thrombomodulin and interactions with thrombin as determined by electron microscopy. J Biol Chem 1996; 271: 31485-31490.
  • 38 Light DR, Andrews WH, Clark JH. et al. Patent: Protease-resistant thrombomodulin analogs. Patent US5863760 (2004). Available at http://www.wikipatents.com
  • 39 Slungaard A, Vercellotti GM, Tran T. et al. Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease. J Clin Invest 1993; 91: 1721-1730.
  • 40 Su EJ, Geyer M, Wahl M. et al. The novel anticoagulant Solulin promotes reper-fusion and reduces infarct volume in a thrombotic model of stroke. J Thromb Haemost. 2009 7: Abstract PP-MO-244.
  • 41 Solis MM, Cook C, Cook J. et al. Intravenous recombinant soluble human throbmbomoludin prevents venous thrombosis in a rat model. J Vasc Surg 1991; 14: 599-604.
  • 42 Solis MM, Vitti M, Cook J. et al. Recombinant soluble human thrombomodulin: A randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model. Thromb Res 1994; 73: 385-394.
  • 43 Strijbos MH, Rao C, Schmitz PIM. et al. Correlation between circulating endothelial cell counts and plasma thrombomodulin levels as markers for endothelial damage. Thromb Haemost 2008; 100: 642-647.
  • 44 Wuillemin WA, Gasser KM, Zeerleder SS. et al. Evaluation of a Platelet Function Analyser (PFA-100) in patients with a bleeding tendency. Swiss Med Wkly 2002; 132: 443-448.
  • 45 Segers O, van Oerle R, ten Cate H. et al. Thrombin generation as an intermediate phenotype for venous thrombosis. A proof-of-concept study. Thromb Haemost 2010; 103: 114-122.
  • 46 Dempfle CE, Borggrefe M. Do we need thrombin generation assays for monitoring anticoagulation?. Thromb Haemost 2008; 100: 179-180.
  • 47 Ten Cate-Hoek AJ, Dielis AW, Spronk HM. et al. Thrombin generation in patients after acute deep-vein thrombosis. Thromb Haemost 2008; 100: 240-245.
  • 48 Gatt A, van Veen JJ, Woolley AM. et al. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost 2008; 100: 350-355.
  • 49 Schols SE, van der Meijden PE, van Oerle R. et al. Increased thrombin generation and fibrinogen level after therapeutic plasma transfusions: relation to bleeding. Thromb Haemost 2008; 99: 64-70.
  • 50 Orbe J, Zudaire M. Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test. Thromb Haemost 2008; 99: 64-70.
  • 51 Notø AT, Mathiesen EB, Østerud B. et al. Increased thrombin generation in persons with echogenic carotid plaques. Thromb Haemost 2008; 99: 602-608.
  • 52 Gatt A, van Veen JJ, Woolley AM. et al. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro . Thromb Haemost 2008; 100: 350-355.
  • 53 Spronk HM, Dielis AW, Panova-Noeva M. et al. Monitoring thrombin generation: Is addition of corn trypsin inhibitor needed?. Thromb Haemost 2009; 101: 1156-1162.
  • 54 Spronk HM, Dielis AW, De Smedt E. et al. Assessment of thrombin generation II: Validation of the Calibrated Automated Thrombogram in platelet-poor plasma in a clinical laboratory. Thromb Haemost 2008; 100: 362-364.
  • 55 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
  • 56 Duchemin JD, Pan-Petesch B, Arnaud B. et al. Influence of coagulation factors and tussue factor concentration on the thrombin generation test in plasma. Thromb Haemost 2008; 99: 767-773.
  • 57 Machlus KR, Colgy EA, WU JR. et al. Effects of tissue factor, thrombomodulin and elevated clotting factor levels on thrombin generation in the calibrated automated thrombogram. Thromb Haemost 2009; 102: 936-944.
  • 58 Parkinson JF, Nagashima M, Kuhn I. et al. Structure-function studies of the epidermal growth factor domains of human thrombomodulin. Biochem Biophys Res Commun 1992; 185: 567-576.
  • 59 Tsiang M, Lentz SR, Sadler JE. Functional domains of membrane-bound human thrombomodulin. EGF-like domains four to six and the serine/threonine-rich domain are required for cofactor activity. J Biol Chem 1992; 267: 6164-6170.
  • 60 Hall SW, Nagashima M, Zhao L. et al. Thrombin interacts with thrombomodulin, protein C, and thrombin-activatable fibrinolysis inhibitor via specific and distinct domains. J Biol Chem 1999; 274: 25510-25516.
  • 61 Fuentes-Prior P, Iwanaga Y, Huber R. et al. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 2000; 404: 518-525.
  • 62 Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1982; 257: 859-864.
  • 63 Suzuki K, Stenflo J, Dahlbäck B. et al. Inactivation of human coagulation factor V by activated protein C. J Biol Chem 1983; 258: 1914-1920.
  • 64 Fulcher CA, Gardiner JE, Griffin JH. et al. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984; 63: 486-489.
  • 65 Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269: 31869-31880.
  • 66 Abeyama K, Stern DM, Ito Y. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115: 1267-1274.
  • 67 Kokkola R, Li J, Sundberg E. et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum 2003; 48: 2052-2058.
  • 68 Yang H, Ochani M, Li J. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004; 101: 296-301.