Laurie Barclay, MD, September 2005

Stroke, or cerebrovascular accident, refers to localized brain damage resulting from interruption of blood flow. The three main types of stroke are ischemic, in which a blood vessel is gradually occluded or stenosed by atherosclerotic build up; embolic, in which a blood vessel is suddenly blocked by a fragment of clot traveling from the heart or from a larger vessel; and hemorrhagic, in which a blood vessel ruptures and bleeds into the brain tissue, often in association with high blood pressure.

In the U.S., someone has a stroke every 45 seconds, and someone dies of stroke every three minutes, according to the American Stroke Association. The American Heart Association cites an incidence of 731,100 first or recurrent strokes in the U.S. in 1996, with over 4.4 million Americans estimated to be stroke survivors. Stroke is the third leading cause of death in the U.S., and is the leading cause of long-term disability. In 2004, direct and indirect costs of stroke in the U.S. were estimated to be $53.6 billion.

Risk factors for cerebrovascular disease include hypertension, cardiovascular disease, diabetes, smoking, family history of stroke, atherosclerosis, and cardiac arrhythmias.

As with heart attack, acute stroke is an emergency that must be diagnosed and treated promptly, because "time is tissue." Warning signs such as weakness, paralysis, or numbness of one side of the body or face or of one or more limbs; problems with speech, balance, vision, or swallowing; or loss of consciousness mandate immediate intervention.

Stroke prevention focuses on control of risk factors, and antiplatelet agents or anticoagulants in some patients. If patients are seen within three or possibly up to six hours of symptom onset, intravenous recombinant tissue plasminogen activator, (rt-PA) may limit stroke damage. Surgery and/or rehabilitation may be indicated in some patients, but estimates suggest that fewer than 10% of stroke patients are eligible for currently available therapies, and that fewer than 5% actually receive treatment.

CenterWatch has identified a pipeline of 23 drugs in various phases of development for stroke. These include anticoagulants, neuroprotective agents, and therapies designed to restore function in patients with fixed deficits.

Actelion Pharmaceuticals is in Phase III development of Clazosentan (AXV-343434), a competitive endothelin (ET-A) receptor antagonist. This drug is designed to prevent vasospasm, or contraction of blood vessels causing ischemia and neurological deficits 3-10 days after subarachnoid hemorrhage (SAH) caused by ruptured aneurysm.

Clazosentan has shown promising results in the prevention and treatment of vasospasm in preclinical models of SAH. In Phase I trials in healthy volunteers, clazosentan infusions were well tolerated, without affecting blood pressure or other vital signs. In patients with SAH, those given clazosentan had fewer cases of vasospasm, less severe vasospasm, and fewer new cerebral infarcts than did those given placebo.

A global Phase IIb/III development program began in late 2004 with the placebo-controlled, dose-finding CONSCIOUS-1 study in prevention of vasospasm following SAH. Trial results are anticipated by mid-2006.

Forest Laboratories is in Phase III testing of desmoteplase, an anticoagulant plasminogen activator derived from the saliva of the vampire bat Compared with TPA, desmoteplase is much more potent and has the potential to triple the current stroke treatment window without increasing the risk of additional brain damage. Animal studies suggest that desmoteplase breaks down fibrin underlying blood clots, but unlike rt-PA, without affecting two brain receptors that can promote brain damage. In Europe, Asia and Australia, desmoteplase is being tested up to nine hours after stroke onset in patients.

Neurobiological Technologies has completed Phase II testing of Viprinex (ancrod), a fibrinogen-depleting agent derived from the venom of the Malaysian pit viper. In U.S. and European trials enrolling more than 2,000 patients, Viprinex appeared potentially to have doubled the available treatment window after the onset of ischemic stroke symptoms. Phase III trials are planned for late 2005, pending FDA approval.

Disufenton (NXY-059, Cerovive), is in Phase III testing by AstraZeneca for acute ischemic stroke. This N-tert-butyl- alpha-phenyl-nitrone (PBN) derivative is given by intravenous infusion over 72 hours started within six hours of symptom onset. By trapping damaging free radicals, it may protect brain tissue. It is still unknown whether disufenton can be safely given without prior CT scanning. If so, it may be more widely applicable than TPA and may eventually be considered for use even by paramedics.

Another neuroprotectant thought to have multiple mechanisms of action is CerAxon (citicoline), in Phase III development by IVAX. It is thought to stabilize cell membranes long enough to reduce stroke-related brain cell injury.

In a trial enrolling nearly 400 patients in 33 US centers, CerAxon showed no statistically-significant difference from placebo in rates of full recovery and mortality or in neurological and cognitive function. However, CerAxon did appear to be more effective than placebo in a subset of patients with moderate to severe strokes.

Prasugrel (CS-747) is a platelet inhibitor in Phase III development by Eli Lilly/Sankyo. In three early-phase trials, this P2Y adenosine diphosphate (ADP) receptor antagonist resulted in significantly higher and more consistent inhibition of platelet aggregation than did placebo or clopidogrel (Plavix), the current standard of care. Currently, the drug is being tested primarily in acute coronary syndrome.

A novel approach to inhibiting platelet clumping is ReoPro (abciximab, c7E3), in Phase II testing by Centocor for reperfusion after acute ischemic stroke. This fragment (Fab) of a monoclonal antibody binds to the glycoprotein (IIb/IIIa) platelet receptor, thereby preventing platelet adhesion.

Medicure is in Phase III testing of MC-1, a vitamin B6 metabolite and purinergic receptor antagonist that may also protect damaged cells in the heart or brain. In Phase I clinical studies, MC-1 had a high degree of safety for human use.

Idraparinux (SanOrg 34006), in Phase III development by Sanofi-Synthelabo, is a new member of the synthetic oligosaccharide family of anticoagulant drugs. After successful dose-finding phase II trials, idraparinux is being evaluated in over 10,000 patients for the treatment and secondary prevention of venous thromboembolism (VTE), and for prevention of thromboembolic events caused by atrial fibrillation.

The mechanism of action of idraparinux is selective inhibition of coagulation Factor Xa. Its potency and long duration of action allow administration as a single weekly injection. Unlike oral anticoagulants such as warfarin, idraparinux does not appear to interact with foods or drugs.

Neurochem has completed Phase II testing of Cerebril, an oral sulfated glycosaminoglycan (GAG) mimetic. By inhibiting amyloid beta fibrillogenesis, this drug may be useful in patients with intracranial hemorrhage caused by cerebral amyloid angiopathy. No safety concerns have been identified thus far.

For acute stroke, D-Pharm is in Phase II development of DP-b99, a neuroprotectant prodrug of the known calcium chelator BAPTA. In two Phase I clinical trials enrolling 70 volunteers, DP-b99 was well tolerated both in single and multiple dosing, with the only major adverse effect reported being reversible irritation at the injection site. A pilot Phase II trial in 34 patients with acute ischemic stroke confirmed that the drug was generally safe, and showed a strong trend for improvement in neurological stroke outcome compared with placebo. At 20 medical centers in Europe and Israel, an ongoing Phase II trial of efficacy will enroll 150 patients with acute stroke.

KAI Pharmaceuticals is in Phase II testing of KAI-9803, an isozyme-selective, delta-protein kinase C inhibitor being tested primarily in acute myocardial infarction. Because it is designed to reduce ischemia and reperfusion injury, it may also be useful in acute stroke.

For the treatment of stroke, deep-vein thrombosis and other conditions associated with antibody-mediated thrombosis (antiphospholipid syndrome), La Jolla Pharmaceutical is in Phase II development of LJP-1082, which is designed to reduce the production of disease- causing antibodies without affecting the defensive capabilities of the immune system. The target of these antibodies causing excessive thrombosis is a small region on the beta 2-glycoprotein I blood protein, which is implicated in about 90% of patients with antibody-mediated thrombosis, in about 50% of all stroke victims under age 50, and in about 10% to 15% of the general stroke population.

In a Phase I/II clinical trial, LJP 1082 was well- tolerated at all five dose levels, with an elimination half-life of at least 12 hours following intravenous injection. After treatment with a single 50 mg or 200 mg dose, some patients had reduced antibodies to LJP 1082. All adverse events were mild to moderate, and similar to those in placebo-treated groups. In the 20 patients studied, there was an apparent dose-dependent response in antibody reduction.

An interesting approach potentially offering hope to stroke survivors with fixed neurological deficits is LBS- Neurons, or cultured human neuronal cells, in Phase II testing by Layton BioScience. These neurons are intended to be transplanted into a patient's brain to improve the function of neurons injured by stroke. The ability of LBS- Neurons to be frozen, transported to clinical centers for transplantation, thawed and implanted may improve the feasibility of this therapy.

The LBS-Neurons are derived from a cell line of human teratocarcinoma initially developed in the mid-1980s and further manipulated in tissue culture and in animal models to become fully differentiated, non-dividing neurons. Animal models suggest that grafted LBS-Neurons will either restore the function of impaired host neurons, or replace host neurons destroyed by stroke. In a clinical trial, a single surgery was used to implant two million neurons divided among three sites within and surrounding stroke- damaged tissue, where it is hoped they will integrate with existing tissue and restore brain function. Proglia (ONO-2506), in Phase II development by Ono Pharmaceutical/Merck, is a neuroprotectant and neurotropic agent. This drug modulates astrocyte function by regulating uptake capacity of glutamate transporters and expression of GABA receptors and various astrocytic factors. Although U.S. Phase II studies in acute ischemic stroke were discontinued in May 2005, they are ongoing in Japan.

Boston Life Sciences has filed an Investigational New Drug (IND) application for the nerve growth factor Axosine (inosine), intended to facilitate recovery of motor function after stroke. Animal models have been encouraging. A proposed Phase I, dose-escalation study may treat 27 patients with moderate to severe stroke patients with Axosine administered via an implantable subcutaneous pump and catheter system.

For optimal outcome following stroke, it is still vital to control risk factors and to seek immediate medical attention at the first sign of symptoms, because prevention is more successful than cure, and because "time is tissue" when it comes to preserving brain cells. However, it is encouraging that new drugs in the pipeline may extend the therapeutic window of opportunity after acute stroke, and that neurotrophic or neural transplant approaches even have the potential to reverse fixed deficits.