Stroke and the pharmaceutical industry

Medicines at the research and clinical trial stage

In the field of anti-platelet medicines, Eisai is developing a compound called satigrel (E5510). Biochemical studies suggest that it probably has dual targets in the body, which explains its wide range of properties. A preliminary trial conducted in Japan compared this compound with aspirin for the prevention of TIAs. Satigrel proved to be 30-50 per cent more effective than aspirin, but whether the compound is to be developed further is not known.

In the area of blood clotting, a particularly novel approach is being taken by BASF Pharma. The story began in the 1960s, when a British expert in tropical medicine based in Kuala Lumpur noticed that untreated blood samples from people bitten by the Malayan pit viper did not clot for up to three weeks. He and his assistants isolated the fraction in the snake venom responsible, which became known as ‘Ancrod’. It proved to be a powerful enzyme that lowers the level of fibrinogen, improves the fluidity of blood, and reduces its tendency to form clots. It apparently also triggers the release of substances from the blood vessel wall that help already formed clots to dissolve.

To produce Ancrod, the snakes are bred and their venom ‘milked’ from the fangs every three weeks – each snake giving about 50 milligrams of raw venom, which is then purified. A large clinical trial of people with ischaemic stroke indicated that treatment with Ancrod within three hours of onset of stroke does indeed reduce the amount of circulating fibrinogen and the first evidence of efficacy has now been reported. A second large clinical study is now taking place.

In a related approach, British Biotech is developing BB-10153, a genetically engineered protein related to plasminogen. It can be activated to plasmin, the main clot-dissolving enzyme in the body, by the action of thrombin, which is only found at sites of new clot formation. British Biotech believes this will reduce the risk of unwanted bleeding, including brain haemorrhage. This hope was supported by experimental studies and the compound satisfactorily completed Phase I clinical trials.

Though results from trials with streptokinase have been disappointing, another microbial clot-dissolving agent under preliminary investigation is staphylokinase. A variant of urokinase, pro-urokinase, is also being assessed and will be watched with interest.

The field of neuroprotection (neuroprotective medicines) remains one of intensive research and clinical activity and despite some disappointments in the past few years, there is good reason to believe they will eventually find a valuable role in stroke treatment.

AstraZeneca has three compounds in clinical development, each with different mechanisms of action. The first, clomethiazole, enhances GABA receptor activity in the brain. In a phase III study of ischaemic stroke, it showed significant improvement in people who had a large stroke of this type. This group has a high mortality and a significant incidence of permanent disability. A further phase III study to confirm this has been started.

The second compound, NXY-059, is a free radical trapping agent; it is being developed under an agreement with Centaur Pharmaceuticals and is in phase II trials. Phase I data have shown it to be well tolerated at plasma concentrations above those demonstrated to be neuroprotective in animal stroke models.

The third compound, AR-R15896AR, is an NMDA-antagonist, a substance that blocks the stimulation of certain receptors in the brain. Powerful neuroprotective effects have been seen in animal models and results from the first phase II study in people with acute stroke have shown it to be well tolerated. A second phase II study is continuing, with a slightly different dosage regimen to optimise the number of people reaching and maintaining neuroprotective levels during treatment.

Glaxo Wellcome is also developing a novel compound that blocks the NMDA receptors. GV150526 acts on a slightly different part of the cell membrane channel associated with ion transport. In animal models, the compound has been shown to protect the brain against damage caused by ischaemia and is now in Phase III trials in the USA and Europe.

Another neuroprotective agent under development is Bayer’s X3702. This acts as a stimulant for a different class of brain receptors, which also give it some anti-anxiety and anti-depressant properties. However, it has been shown to inhibit excessive glutamate release in models of ischaemia and to reduce the size of brain damage lesions in stroke models by as much as 50 per cent. It is not yet clear whether the compound will enter human trials in stroke, but the combination of properties could be quite interesting.

Despite this range of new potential medicines, the last two years have had their disappointments as well, illustrating only too clearly what a difficult area stroke research actually is. For example, tirilazad mesylate was expected to protect nerve cell membranes and limit ischaemic and haemorrhagic damage, but has been discontinued by Pharmacia & Upjohn after disappointing trial results (though it is available for sub-arachnoid haemorrhage). Similarly, selfotel (Novartis) and aptiganel (Cambridge Neuroscience), both of which act at the NMDA receptor, have been discontinued, as they had side effects that limited the dose that could be given. Yet another promising lead, lubeluzole (Janssen-Cilag) has also been discontinued. This agent acted by mopping up damaging and very reactive molecules called nitric oxide radicals and had almost reached the stage of receiving its licence.