thrombin  
dti's  
the desirudin story  
development programs  
bibliography  
Thrombin

"There exists a compelling connection between thrombin, coagulation, inflammation, and the immune response."

Thrombin is a multi-faceted protein with a wide range of functions. Although long recognized for the central part it plays in hemostasis and thrombosis, its role is not limited to the procoagulant process.1

Extensive research into the role of thrombin in coagulation led to identifying the interconnection and interdependence of coagulation and inflammation. This discipline, known as "integrative molecular physiology," has revealed that the generation of thrombin is a key event with many ramifications2:
  • Thrombin catalyzes the conversion of fibrinogen to fibrin, the key component of blood clots3
  • Thrombin is the most potent physiological activator of platelets2,4
  • Thrombin increases vascular permeability and promotes adhesion of molecules to the vascular endothelium accelerating the development of atherosclerosis2
  • Thrombin stimulates the growth of smooth muscle cells and promotes vasoconstriction3
  • Thrombin stimulates angiogenesis and has been shown to be involved in cancer metastasis3
Given the critical role thrombin plays in coagulation, inflammation, and the immune response, treatment strategies that directly target this key mediator have extraordinary therapeutic potential. Advances in thrombin-specific inhibition are essential to improving disease management and outcomes. Canyon Pharmaceuticals has made major strides in this area, and is committed to improving patient care through advances in direct thrombin inhibition.

Multiple functions of thrombin as a biological mediator1



Adapted from Chest, 2003

References:
1. Mann, KG. Thrombin. Can't live with it; probably die from it. Chest. September 2003; 124(suppl):1-3.
2. Tracy RP. Thrombin, inflammation, and cardiovascular disease: an epidemiologic perspective. Chest. September 2003; 124(suppl):49-57.
3. Coughlin SR. Thrombin signaling and protease-activate receptors. Nature. September 2000; 407: 258-264.
4. Frenkel EP, Shen YM, Haley BB. The direct thrombin inhibitors: their role and use for rational anticoagulation. Hematol Oncol Clin N Am. 2005;19:119-145.
Direct Thrombin Inhibitors (DTIs)

"As their connection to improved outcomes becomes better understood, DTIs represent a much anticipated advance over heparin-based anticoagulation."
Dr. Seng Chin Mah,
President and CEO, Canyon Pharmaceuticals Group

Anticoagulation is routinely used within the hospital setting to prevent thrombosis. Heparin-based anticoagulation has been the standard of care for more than 5 decades despite serious limitations in efficacy and continued concerns about safety.

Direct thrombin inhibitors, or DTIs, represent a major advance over heparin-based anticoagulation. Heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparin, and fondaparinux are incapable of directly inhibiting thrombin. Instead, these agents work by catalyzing the activity of antithrombin, a naturally occurring anticoagulant protein which circulates in blood. Thus, their ability to inhibit thrombin depends on the presence of this functioning cofactor. DTIs, on the other hand, bind directly to thrombin and require no cofactors which might influence their activity. Importantly, DTIs are capable of inhibiting thrombin whether it is circulating freely in the blood or is bound up in an existing clot. This direct inhibition of active thrombin provides a distinct advantage over heparin-based anticoagulation, which inhibits circulating thrombin only through activation of antithrombin and is ineffective at inhibiting clot-bound thrombin.1, 2

In addition, safety concerns of heparin-based anticoagulation are highlighted by a recent study of 2000 patients where over 1/3 had side-effects to heparins resulting in destruction of platelets. Platelets are cells in the body involved in blood clotting. A low platelet count, called thrombocytopenia, can result when platelets are activated by heparins or antibodies to heparins. Patients who developed thrombocytopenia while on heparin-based anticoagulation had significantly increased rates of in-hospital death and other adverse events. Unfortunately, thrombocytopenia is often under recognized or undetected until it’s too late. DTI’s are not known to cause thrombocytopenia and are useful in protecting patients from thrombosis when thrombocytopenia is caused by heparin. 3, 4

With the availability of improved clinical alternatives to heparin-based anticoagulants, DTIs such as desirudin and pegmusirudin demonstrate Canyon’s commitment to providing treatment solutions that advance today’s standard of care to dramatically improve patient outcomes.

References:
1. Weitz JI. A novel approach to thrombin inhibition. Thromb Res. 2003 Jul 15;109 Suppl 1:S17-22.
2. Linkins LA, Weitz JI. Pharmacology and clinical potential of direct thrombin inhibitors. Curr Pharm Des. 2005;11(30):3877-84.
3. Oliveira GB;Crespo EM;Becker RC;et al. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy Arch Intern Med 2008;168:94-102.
4. Crespo EM;Oliveira GB;Honeycutt EF;Becker RC. Evaluation and management of thrombocytopenia and suspected heparin-induced thrombocytopenia in hospitalized patients: The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry. Am Heart J 2009;157:651-657.
Desirudin

"Connecting a clear vision with the relentless pursuit
of advancing treatment standards is what desirudin is all about."
Dawn Bell,
Senior Vice President & General Manager, US, Canyon Pharmaceuticals

Desirudin is a parenteral direct thrombin inhibitor with a unique and compelling commercial history. First licensed by Ciba-Geigy in the early 1980s, desirudin changed hands many times over the next 2 decades as a result of corporate mergers and acquisitions. Desirudin was then subject to a divestment decree issued by the Federal Trade Commission and European Council, which prevented the newly emerged corporate entity from commercializing the drug. Only because of the unwavering commitment of Canyon Pharmaceuticals to acquire the product and to advance the current standard of care, today desirudin has appropriate backing and is positioned to provide substantial value within the hospital setting and to be an important player in the anticoagulation space.

The clinical value of desirudin will not only be realized by the commitment and experience of the Canyon management team, but by the extremely robust and impressive clinical development history of the compound. Desirudin has been studied in 18,000 patients across 36 Phase I and II and Phase III clinical studies. Over 40 publications currently exist on desirudin, and clinical trials are currently underway to further establish the utility of desirudin in the hospital setting.

Desirudin is now well supported by a clear vision for advancing treatments for thrombin inhibition in acute-care patients, as well as patients requiring longer-term therapy.

Please see Full Prescribing Information

For US
  • US Prescribing Information

    For EU
  • English Prescribing Information
  • French Prescribing Information
  • German Prescribing Information
    • Development Programs

    Canyon Pharmaceuticals believes that desirudin will answer an important unmet need for Venous Thromboembolic Events (VTE) prophylaxis within the acute care setting. Canyon has also undertaken a robust development program for desirudin with clinical trials to support the expansion of its indication

    Canyon is also developing Pegmusirudin, a pegalated direct thrombin inhibitor with properties that may be attractive in patients who require longer term anticoagulation, such as patients with cancer at risk of thrombosis.


    SC: subcutaneous, IV: intravenous

    This above information about various clinical trials may contain uses for desirudin that have not been approved by the Food & Drug Administration (FDA) or European regulatory agencies. This site is not intended to promote such uses, but is offered to provide additional information about ongoing and completed studies for desirudin as well as trials for new products in the Canyon Pharmaceuticals pipeline. The safety and efficacy of desirudin for any unapproved uses discussed in these clinical trials have not been established. Please refer to the product's complete Prescribing Information below for Iprivask or for Revasc for information regarding approved indications, safety, efficacy and proper dosing.

    *In the United States, Iprivask (desirudin) is indicated for the prophylaxis of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing elective hip-replacement surgery; in Europe, Revasc (desirudin) is indicated for the prevention of deep vein thrombosis in patients undergoing elective hip or knee replacement.

    Please see Full Prescribing Information

    For US
  • US Prescribing Information

    For EU
  • English Prescribing Information
  • French Prescribing Information
  • German Prescribing Information
    • Desirudin Bibliography

    Canyon Clinical Trials
    This following information about various clinical trials may contain uses for desirudin that have not been approved by the FDA or European regulatory agencies.  This site is not intended to promote such uses, but is offered to provide additional information about ongoing and completed studies for desirudin.  The safety and efficacy of desirudin for uses discussed in these clinical trials have not been established.  Please refer to the product’s complete prescribing information for information regarding approved indications, safety, efficacy and proper dosing.
     

    PREVENT-HIT
    A Comparative Clinical and Pharmacoeconomic Study Comparing Argatroban® IV vs. Desirudin SC for Patients with Suspected Heparin-Induced Thrombocytopenia (HIT) with or without Thrombosis Syndrome (HIT/TS)
    http://www.clinicaltrials.gov/ct2/show/NCT00787332?term=Desirudin&rank=3

    DESIRABLE
    Multi-Center Desirudin Utilization Trial in Patients with or without Thrombosis Requiring an Alternative to Heparin-Based Anticoagulation
    http://www.clinicaltrials.gov/ct2/show/NCT00913133?term=Desirudin&rank=2

    Other Relevant Links

    The Heart.org
    The Heart.org is a source for cardiology news, commentary and continuing medical education sponsored by WebMD.
    http://www.theheart.org

    North American Thrombosis Forum
    The North American Thrombosis Forum (NATF) is a multi-disciplinary organization founded with the objective of improving patient care through the advancement of thrombosis education. 
    www.NATFonline.org

    Coalition to Prevent DVT
    The Coalition to Prevent DVT is a group of more than 50 organizations who have joined the Coalition in a united effort to raise awareness of DVT among consumers, healthcare professionals, policy-makers and public health leaders.
    www.PreventDVT.org

    European Thrombosis Research Organization
    The objectives of ETRO include the furtherance in European countries of fundamental scientific research on all aspects of thrombosis.
    http://www.etro.eu.org/
     

    Associated Literature

    Canyon Clinical Trials
    This following information about various clinical trials may contain uses for desirudin that have not been approved by the FDA or European regulatory agencies.  This site is not intended to promote such uses, but is offered to provide additional information about ongoing and completed studies for desirudin.  The safety and efficacy of desirudin for uses discussed in these clinical trials have not been established.  Please refer to the product’s complete prescribing information for information regarding approved indications, safety, efficacy and proper dosing.
     

    PREVENT-HIT
    A Comparative Clinical and Pharmacoeconomic Study Comparing Argatroban® IV vs. Desirudin SC for Patients with Suspected Heparin-Induced Thrombocytopenia (HIT) with or without Thrombosis Syndrome (HIT/TS)
    http://www.clinicaltrials.gov/ct2/show/NCT00787332?term=Desirudin&rank=3

    DESIRABLE
    Multi-Center Desirudin Utilization Trial in Patients with or without Thrombosis Requiring an Alternative to Heparin-Based Anticoagulation
    http://www.clinicaltrials.gov/ct2/show/NCT00913133?term=Desirudin&rank=2

    Other Relevant Links

    The Heart.org
    The Heart.org is a source for cardiology news, commentary and continuing medical education sponsored by WebMD.
    http://www.theheart.org

    North American Thrombosis Forum
    The North American Thrombosis Forum (NATF) is a multi-disciplinary organization founded with the objective of improving patient care through the advancement of thrombosis education. 
    www.NATFonline.org

    Coalition to Prevent DVT
    The Coalition to Prevent DVT is a group of more than 50 organizations who have joined the Coalition in a united effort to raise awareness of DVT among consumers, healthcare professionals, policy-makers and public health leaders.
    www.PreventDVT.org

    European Thrombosis Research Organization
    The objectives of ETRO include the furtherance in European countries of fundamental scientific research on all aspects of thrombosis.
    http://www.etro.eu.org/