Viprinex™

Viprinex™ (ancrod) Injection has been studied in more than 1900 patients in various clinical studies in the U.S. and Europe and is believed to have the potential to double the available treatment window following the onset of stroke symptoms. Currently, the only available therapy for stroke must be administered within the initial three hours, significantly limiting the number of patients that may be treated.

One of the primary goals for the treatment of acute ischemic stroke is improving blood flow through a blocked vessel so that the flow of oxygen and nutrient supply to brain tissue is not interrupted or compromised. Brain tissue starved of oxygen can cause loss of neurological function such as speech and mobility. Fibrinogen, a protein involved in blood clotting, has been known to contribute to high blood viscosity, which in turn may impede blood flow to critical regions of the brain. Thus, an agent that reduces fibrinogen levels may significantly impact stroke treatment.

Derived from the venom of the Malayan pit viper,
Viprinex™ is a thrombin-like
enzyme that is highly specific to fibrinogen.

When administered systemically, ancrod has been shown to rapidly deplete plasma fibrinogen (it is a defibrinogenating agent). The effects are anticoagulation, improved blood viscosity and a secondary fibrinolytic or clot lysing action. Combined, these effects constitute a perfusion strategy that appears to restore and enhance oxygen flow to the affected area of the brain.

Studies have shown that in patients receiving Viprinex™ within six hours of stroke onset, blood viscosity is progressively reduced by 20-30% from pretreatment levels, resulting in an improvement in blood flow and microcirculation. After stopping treatment with Viprinex™, viscosity levels have been shown to return to pretreatment levels very slowly, within about 10 days.

MEAN PLASMA FIBRINOGEN CONCENTRATIONS

1. Brief infusion can produce desired fibrinogen pattern extending for several days.

2. Time course of fibrinogen as seen here similar to that reported after IV infusion of 1-2 IU/kg over 4-6 hours in normal subjects patients.

3. Other studies showed dose-related decreases with different infusion regimens over 3hrs, 6hrs and 24hrs.

A randomized, double-blind, placebo-controlled U.S. Phase III clinical study was completed in 1998 to evaluate the safety and efficacy of Viprinex™ given within three hours after the onset of acute, ischemic stroke in 500 patients. In this study, Viprinex™ was shown to be effective in preserving neurological function in this patient population.

A separate randomized, double-blind, placebo-controlled Phase III study was completed in Europe in 2000, enrolling patients within six hours of onset of acute ischemic stroke. The trial was stopped after a planned interim analysis indicated lack of efficacy and increased incidence of intracranial hemorrhage. The higher dosing levels in the European trial and the use of protocol criteria that permitted entry of patients at higher risk of hemorrhage are thought to have contributed to the trial's failure.

A retrospective review of the relative strength of the positive U.S. findings versus the European findings has suggested the need for a revised Viprinex™ dosing strategy. This new dosing strategy is being used in the current Phase III program.

NTI is conducting two Phase III pivotal studies in acute ischemic stroke. The studies are being conducted in the U.S., Europe, South Africa, and Australia.

ABOUT STROKE

According to the American Stroke Association, every 45 seconds someone in the U.S. suffers a stroke and every three minutes someone dies of one. It is the nation's third leading cause of death after diseases of the heart and all forms of cancer and is the leading cause of serious, long-term disability.

A stroke occurs when a blood vessel that carries oxygen and nutrients to the brain is either blocked (ischemic) by a clot or ruptures (hemorrhagic). When the tissues are deprived of needed blood they begin to die, affecting various parts of the body and causing paralysis, speech, vision and other problems. It is estimated that less than ten percent of stroke patients are suitable for current therapies and less than five percent actually receive treatment. The estimated direct and indirect costs of stroke in the U.S. in 2004 are estimated to be $53.6 billion.