Argatroban is a direct thrombin inhibitor that selectively binds to and inactivates thrombin in blood plasma. Unlike several other direct thrombin inhibitors in the market, Argatroban is a synthetic small molecule that may offer advantages in terms of efficacy and safety. In June of 2000, we received FDA approval of the drug for the prevention or treatment of thrombosis in heparin-induced thrombocytopenia (HIT), and the product was launched in November of 2000 by GSK.

Argatroban is also marketed by Mitsubishi-Tokyo Pharmaceuticals, Inc. in Japan, where it is approved as a treatment for ischemic stroke, peripheral arterial occlusion and hemodialysis in patients with anti-thrombin III deficiency, a clotting disorder that does not respond to heparin. Encysive in-licensed Argatroban from Mitsubishi in 1993. Both the Japanese experience with Argatroban as a treatment for stroke and our own preclinical tests provide strong support for investigating the use of Argatroban in ischemic stroke in the U.S.A. Phase 2 trial is currently in progress, with preliminary data expected in the second half of 2002.

Tissue plasminogen activator (tPA) is the only drug approved in the U.S. for use in ischemic stroke, but the drug must be used within three hours of onset. There is a clear need for additional therapies that can be used beyond the current three-hour treatment window. In addition to the stroke investigation that we initiated in March, 2001:

We believe Argatroban has the potential to become the direct thrombin inhibitor of choice in the hospital setting. If we are successful in obtaining a second approval for Argatroban in PCI or stroke, Argatroban has the potential to be a significant hospital drug, with annual sales in excess of $250 million.

In the clinical studies we have conducted in the U.S., a significant correlation has been found between the administered dose of Argatroban and the degree of anticoagulation achieved. This is potentially important as it suggests that the relationship between dose and effect is generally very predictable. As a result, Argatroban is "easy to monitor," in contrast to heparin therapy, which is typically more challenging to manage. Other potential advantages of Argatroban include a rapid onset of action, a relatively short half-life and no antibody response. As importantly, in clinical trials the incidence of major bleeding with Argatroban is similar to control levels. Intracranial bleeding was not observed in any of the 568 patients treated with Argatroban in the HIT trials.
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What is Thrombosis?
Thrombosis, the lodging of a blood clot so as to obstruct a blood vessel, is associated with a number of vascular diseases, with symptoms that depend on the location of the clot. An arterial thrombosis may lead to heart attack if lodged in a coronary artery, or stroke if lodged in an artery supplying oxygen to the brain. Venous thrombosis occurs principally in the arms or legs (deep vein thrombosis, or DVT), and may cause local inflammation, chronic pain and other complications. In some cases, a venous thrombus can cause lung injury (pulmonary embolism) by migrating from the veins to the lungs. Thrombosis can be treated surgically or through drug therapy using anticoagulant and/or thrombolytic drugs. Anticoagulant therapy aims to prevent thrombi from forming, and employs either antithrombotic or antiplatelet mechanisms. Antithrombotic drugs block the action of the blood protein thrombin, and may be used to treat both arterial and venous thrombosis. Antiplatelet drugs prevent platelets from aggregating and are only effective in treating arterial thrombosis.
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About Heparin and HIT
Heparin, first discovered over 80 years ago, is the most widely used injectable anticoagulant. In the U.S., approximately 12 million patients annually receive heparin to treat a variety of conditions that require inhibition of the body's natural clotting mechanism. Each year approximately 300,000 of these patients develop a profound immunological reaction to heparin that is known as heparin-induced thrombocytopenia, or HIT. The condition is characterized by a heightened risk of thrombosis, exposing the patient to the threat of major complications such as acute myocardial infarction, ischemic stroke, limb amputation or even death.

It is also difficult to administer heparin dosages: a small change in dosage levels can trigger meaningful changes in its anticoagulant activity, either making the drug ineffective in preventing thrombosis, or preventing normal clotting activity and increasing the risk of excessive bleeding

Like most surgical patients, Gustave Botta received heparin in conjunction with his heart surgery. About 3-5% of patients receiving heparin develop HIT, an immune-mediated response in which, instead of acting as a blood thinner, heparin causes the patient's blood to clot. Gustave's reaction occurred before the approval of Argatroban; fortunately, his doctor knew about the clinical trial and Gustave was enrolled in one of our Phase 3 studies. Today, despite the loss of a leg to HIT, Gustave is back riding his bike, playing golf and enjoying his family.
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Clinical trials in HIT
We developed Argatroban as a treatment for HIT as there were no approved drugs to treat this very serious and life-threatening condition. We conducted two Phase 3 trials to evaluate the safety and efficacy of Argatroban as an anticoagulant in patients with HIT and heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Data from the trials were analyzed using two statistical methods: time-to-event and categorical. A time-to-event analysis provides the incidence of clinical endpoints, or outcomes, over a period of time. A categorical analysis provides the incidence of clinical endpoints at a point in time.

Our first trial, ARG-911, was a multicenter Phase 3 study that compared 304 patients treated with Argatroban for up to 14 days with historical controls (i.e., data outlining the reaction of 193 patients previously treated with heparin). While most clinical trials compare the drug under evaluation with either a placebo or another active drug, due to the life-threatening effects of HIT and the lack of existing treatments at the time, the FDA requested the use of historical controls. These data were derived from the hospital records of patients who closely resembled the patient population that was treated with Argatroban.

In the ARG-911 time-to-event analysis (over 37 days), historical control patients with HIT had a 68% greater risk of experiencing death, amputation or new thrombosis, and historical control patients with HITTS exhibited a 75% greater risk of experiencing one of these events than the patients receiving Argatroban. Statistical significance was achieved in both the HIT and HITTS arms of this analysis. The ARG-911 categorical analysis (at 37 days) showed historical control patients with HIT had a 51% greater risk of experiencing death, amputation or new thrombosis, while those with HITTS exhibited a 30% greater risk.

A second study, ARG-915, involving 264 patients treated with Argatroban, also used the same group of historical control patients. The primary endpoints in this categorical analysis were the composite or overall endpoints of all-cause death, all-cause amputation or new thrombosis at 37 days. The secondary endpoints were the resolution of thrombocytopenia and achievement of adequate anticoagulation. We also conducted a time-to-event analysis (over 37 days) involving these same primary and secondary endpoints.

In both trials, Argatroban significantly improved clinical outcomes, provided rapid, adequate anticoagulation and, relative to controls, exerted a positive influence on restoring patients' platelet counts. Argatroban also proved to be safe and well-tolerated, and it did not increase a patient's risk of bleeding, a common side-effect of conventional anticoagulant therapy.
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Clinical Trial in Acute Ischemic Stroke
"Time of treatment is a major limiting factor in our ability to treat stroke patients. Based on both the Japanese experience and preclinical results in the U.S., our hope is that Argatroban will increase this window of opportunity for treatment beyond the current three-hour limitation associated with tPA."

Marian P. LaMonte, M.D., M.S.N.
Assistant Professor of Neurology and Surgery, University of Maryland School of Medicine; Director, The Maryland Brain Attack Program, University of Maryland Medical Center, and Primary Investigator for the ARGIS-I trial

According to the National Stroke Association, there are 160,000 deaths per year in the U.S. as a result of a stroke, making it the third leading cause of death. There are approximately 720,000 individual stroke patients per year, of which 600,000 are ischemic stroke patients. From 1986 to 1996 the death rate from stroke declined by 14.8%, but the number of stoke deaths rose by 6.9%. Over 60% of stroke fatalities are female. At this time, tPA is the only approved product for use in acute ischemic stroke patients. The drug must be used within three hours of the initial onset of symptoms, yet data from market research show that less than 10% of patients reach the hospital in time to be treated. Overall, only 5 to 10% receive tPA.

Our multi-center, placebo-controlled trial (ARGIS-I) began in March of 2001, and is the first study in the U.S. to evaluate use of a direct thrombin inhibitor for this indication. The study is expected to include 180 patients at over 25 major stroke centers in North America.
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Related external links
Study Raises Hopes for Preventing Blood Clots
by American College of Cardiology (ACC)

American Thrombosis Association

Brain Attack

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