Tecarfarin is an oral anticoagulant for the treatment of patients who are at risk for the formation of dangerous blood clots, such as those with atrial fibrillation or those at risk of venous thromboembolism. Tecarfarin is designed to have the same therapeutic benefits as the drug warfarin, which for over 50 years has been the treatment of choice as an oral anticoagulant. Despite its widespread use, warfarin has several significant limitations. It is metabolized by CYP450 and has many drug-drug interactions that often lead to serious side effects. Tecarfarin has been designed to be metabolized through the esterase pathway, eliminating metabolism through CYP450 and avoiding drug-drug interactions. Warfarin also has a very steep dose response curve which means that a small change in dose may lead to a substantial change in the anticoagulation status of the patient. These two factors can create significant challenges in maintaining therapeutic levels of warfarin and this can put patients at risk for either life-threatening clotting or bleeding, especially in patients with compromised CYP clearance. In preclinical testing and in clinical testing to date, it appears that tecarfarin may be inherently more stable than warfarin due to its predictable metabolism through the esterase pathway that has a much larger capacity than CYP450.^[1] The rate of anticoagulation for both warfarin and tecarfarin is measured by the standard assay known as International Normalized Ratio, or INR.

Tecarfarin is a selective inhibitor of the vitamin K epoxide reductase enzyme, or a VKOR inhibitor. The blood clotting process in the body is a complex and well-controlled cascade of events that involves multiple clotting factors. Four of these factors are known to be controlled by the VKOR enzyme. Tecarfarin, like warfarin, is a VKOR inhibitor and by inhibiting this enzyme acts as an anticoagulant.

Atrial Fibrillation, Valvular Heart Disease, and Deep Vein Thrombosis

There are three major indications where tecarfarin has the potential for use:

Atrial Fibrillation is the most common form of cardiac arrhythmia, with approximately 2.4 million people in the United States diagnosed with this condition in 2006. Approximately 1.5 million of these patients are chronic users of oral anticoagulants. Atrial fibrilation is caused when the atria quiver instead of beat, causing the heart to beat erratically. Because the pumping function of the upper chambers of the heart are not working properly in atrial fibrillation patients, blood is not completely emptied from the heart's chambers, causing it to pool and sometimes clot. In patients with atrial fibrillation, clotted blood can dislodge from the atria and flow to the brain, causing a stroke. It is estimated that atrial fibrillation is responsible for more than 75,000 strokes per year in the United States alone.

Valvular Heart Disease is any disease that involves one or more of the heart's four valves. For more advanced disease, the diseased valves may be replaced with either tissue or mechanical valves. It is estimated that 72,000 patients in the United States had either a tissue or mechanical valve replacement in 2005. Patients with mechanical heart valves are at great risk of clotting and must have their level of anticoagulation managed with particular diligence for the remainder of their lives. There are an estimated 340,000 patients with mechanical heart valves in the United States and an estimated 34,000 mechanical valve replacements in 2005. Chronic oral anticoagulant therapy is almost always prescribed for patients with mechanical valves and is frequently prescribed for patients after tissue valve replacement surgery to reduce the risk of thromboembolic complications caused by the presence of the valve.

Venous Thromboembolism is the formation of a blood clot, or thrombus, in the veins, that may travel to other parts of the body and block blood flow. This condition includes both deep vein thrombosis and pulmonary embolism. There were approximately 510,000 patients being treated for venous thromboembolism in the United States in 2005, with approximately 130,000 estimated to be receiving chronic treatment. Chronic oral anticoagulant therapy, frequently with warfarin, is prescribed to both prevent and treat the formation of blood clots that cause venous thromboembolism.

Tecarfarin Development Status

We have treated over 400 patients with tecarfarin measuring the drug’s ability to maintain those patients within the target therapeutic range of INR of 2 to 3 (2.5 to 3.5 for heart valve patients). Two of the clinical trials performed were Phase 2 studies and the third was the recently completed Phase 2/3 trial, EmbraceAC (CLN-505). The tecarfarin efficacy results in each were nearly identical, appearing to demonstrate tecarfarin’s ability to maintain patients’ INR within the target therapeutic range during a consistent percentage of the time treated: 71.5%; 73.9%; and 74% (EmbraceAC). We believe that a second Phase 3 clinical trial, to be conducted comparing tecarfarin to warfarin in a “real-world” setting in which all monitoring and dosing decisions will be made at the study sites, would demonstrate a similar tecarfarin result while warfarin would be expected to demonstrate time in therapeutic range of 56% to 66% which has long been seen with that drug. Subsequent additional analyses of the data generated in the EmbraceAC trial, looking at specific subpopulations in the study, support our belief that a real-world study would demonstrate the importance of warfarin’s dependence on CYP450 metabolism versus tecarfarin’s avoidance of that metabolic pathway in maintaining patients within the target therapeutic range of INR. In previous discussions, the United States Food and Drug Administration (FDA) indicated that the ability to maintain patients within the targeted INR will likely be an acceptable surrogate and primary endpoint for tecarfarin’s clinical development. Using INR maintenance as a surrogate and primary endpoint should reduce both the size of and time to complete our planned clinical trials for tecarfarin compared to clinical trials measuring survival rates or other outcomes. Based upon our earlier discussions with the FDA, we believe the completed EmbraceAC clinical trial may qualify as a registration study. We are continuing to actively seek a pharmaceutical company partner for the full development and eventual commercialization of tecarfarin, in the event we obtain requisite regulatory approval.

Clinical Trial Information

Would you like to learn about tecarfarin in clinical trials? Details on the current trials, and contact information for questions you may have, can be found at ClinicalTrials.gov. There are currently no clinical trials underway testing tecarfarin. Please continue to check back for details on future clinical trials.

The ClinicalTrials.gov website is maintained as a public service by the United States National Institutes of Health and contains information provided by us.

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Reference

1: Distinct from tecarfarin's inherent dose response curve, published reports indicate that the administration of low dose vitamin K with VKOR inhibitors, such as tecarfarin, may reduce INR variability.