Stroke and Neurovascular Protection

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Results from the SAINT I (Stroke Acute Ischemic NXY-059 Treatment) trial, published today in the New England Journal of Medicine, report the effect of AstraZeneca's investigational drug, NXY-059, intended for the treatment of acute ischemic stroke (AIS). The data showed a statistically significant reduction with NXY-059 versus placebo on the primary outcome of stroke-related disability, as assessed on the Modified Rankin Scale (mRS) (p=0.038 at 90 days). Additional analysis of the data showed a reduction in the disability of patients at both ends of the scale, with 4.4 percent more patients treated with NXY-059 becoming free of symptoms (mRS 0 vs. mRS > 0; p=0.003) and 3.7 percent more patients able to walk without help and being less dependent on others for bodily needs (mRS <3 vs. mRS >3; p=0.02), compared to placebo.1

SAINT I was a double blind, placebo-controlled phase III study, in which patients were randomized to receive NXY-059 or placebo within six hours of AIS. The study involved 1,722 patients in 158 centres from 24 countries. Clinical benefit was seen at the earliest time point assessed (7 days), and persisted through the end of the study (90 days). The treatment effects were not affected by the time to treatment, the severity of stroke, or use of thrombolysis.

Professor Kennedy Lees, Principal Investigator and Professor of Cerebrovascular Medicine at the University of Glasgow, UK, commented, “This is an exciting result. A treatment confirmed to reduce disability in such a wide range of stroke patients could have a profound effect on the number of families that are devastated by stroke. For a condition that carries a worse prognosis than most forms of cancer, the development of a completely new approach to treatment would be a fantastic achievement."

NXY-059 did not significantly improve neurologic function as measured on the National Institutes of Health stroke scale (NIHSS). Mortality was unaltered by treatment with NXY-059 compared with placebo. The most common adverse events for NXY-059 in the study were fever (19 vs. 19.2 percent for NXY-059 and placebo, respectively), constipation (9.8 vs. 11.7 percent), headache (9.6 vs. 9.7 percent), urinary tract infection (8.9 vs. 6.8 percent), stroke in evolution (6.5 versus 8.1 percent) and hypokalemia (6.4 vs. 4.4 percent).

The incidence of symptomatic intracranial hemorrhage (ICH) in patients treated with NXY-059 and alteplase, a tissue plasminogen activator (rt-PA), was lower than in patients treated with placebo and rt-PA (2.5 percent vs. 6.4 percent, p=0.036, post-hoc analysis).

Dr. Tomas Odergren, Global Product Director for NXY-059 at AstraZeneca added: “The results of SAINT I suggest that disruption of the ischemic cascade through neuroprotection, which is the proposed mechanism of action for NXY-059, could have clinical application for a broad range of patients suffering an acute ischemic stroke. The second phase III study, SAINT II, which will involve 3,200 patients at approximately 350 centres around the world, is well underway.”

NXY-059 is an investigational drug under development by AstraZeneca and licensed from Renovis, Inc. NXY-059 has a proposed mechanism of action of free radical trapping and is being studied as a neuroprotectant in clinical trials based on positive effects seen in experimental models of acute ischemic stroke.2,3

The SAINT trials for NXY-059 are being conducted worldwide in approximately 400 centres across 40 countries to evaluate the effect of the compound in acute ischemic stroke patients. These countries and regions include: Europe, Asia, Australia, New Zealand, South Africa, United States, Canada and Latin America. SAINT II is due to report in the first half of 2007.
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Subsequent to the outcomes of the CHANT and SAINT II trials, AstraZeneca plans to file regulatory submissions for NXY-059 in Europe and the U.S. in the first half of 2007.

-- NXY-059 was previously referred to as ‘Cerovive'. NXY-059 will be used from this point forward until a global trademark has been approved.

-- A preliminary analysis of SAINT I was first presented at the European Stroke Congress in May 2005.

-- The Modified Rankin Scale (mRS) is a commonly used global disability scale for assessing outcome following a stroke, and is a scale favored by regulatory authorities and clinicians. It is a simple measure of disability used in the rehabilitation phases of stroke. There are six outcome levels on the scale, progressing from no disability (mRS=0) to severe disability (mRS=5).4

-- Grade 0= No symptoms at all

-- Grade 1= No significant disability despite symptoms; able to carry out all usual duties and activities

-- Grade 2= Slight disability; unable to carry out all usual duties and activities

-- Grade 3= Moderate disability; requiring some help, but able to walk without assistance

-- Grade 4= Moderate severe disability; unable to walk without assistance, and unable to attend to own bodily needs without assistance

-- Grade 5= Severe disability; bedridden, incontinent, and requiring constant nursing care and attention

-- The National Institute of Health Stroke Scale (NIHSS) provides a quantitative assessment of the neurologic examination. This scale assesses neurologic impairment, providing a measure of stroke severity.
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-- CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) is a double-blind, randomized, placebo-controlled, parallel-group, multi-center, phase IIb study to assess the safety and tolerability of NXY-059 in adult patients with acute intracerebral hemorrhage.

This study is complete and is due to report in Q1 2006.

-- There are two major types of stroke: ischemic and hemorrhagic.

-- Ischemic stroke occurs when the blood supply to an area of the brain is interrupted in some manner, i.e. a blood clot blocks or plugs a blood vessel in the brain. The clot can be formed in a blood vessel supplying the brain when the wall of unhealthy arteries becomes clogged with a build-up of fatty deposits and cholesterol. Alternatively, the clot can be formed in another part of the body, usually the heart, and then travel up to the brain. Approximately 88% of strokes in the U.S. are ischemic strokes.5

-- Hemorrhagic stroke occurs when a blood vessel ruptures with consequent bleeding in or on the surface of the brain. Hemorrhagic strokes can be caused by a number of disorders that affect the blood vessels, including long-standing high blood pressure and cerebral aneurysms. An aneurysm is a weak or thin spot on a blood vessel wall.

Source: The New England Journal of Medicine