The Briefing Room

Stroke (the sudden onset of paralysis) is the third leading cause of death in Western industrialised countries, and the leading cause of disability. Fifty to 70 percent of stroke survi-vors regain functional independence, but 15 to 30 percent are permanently disabled. These disabilities include problems controlling movement, loss of sensations (touch, pain, and temperature), problems using or understanding language, problems with thinking and memory, and emotional disturbances.
The New Zealand company Neuren is developing drugs to help people who suffer brain damage from strokes, road accidents and heart attacks. All of these conditions cause nerves to die, and this underlies the long-term damage. One of the agents being developed to stop the nerve dying (to be neuroprotective) is glypromate. The news that glypromate is to be fast-tracked in its clinical testing has seen a surge in Neuren’s share values. However, the claims made by Neuren are being challenged on a web share chat room by a correspondent known only as ‘Labrat’. So, what is the likelihood of glypromate being a useful neuroprotective?
One of the reasons that stroke remains so devastating is that we have few treatments for it. Any successful treatment will have a huge market and will potentially be very lucrative for the company marketing it. Thus, it is not surprising that pharmaceutical companies, including Neuren, are attempting to develop treatments.
The most common type of stroke is due to a lack of blood supply (ischemia) to the brain and occurs when a blood vessel to the brain becomes blocked. Without the blood that carries oxygen and nutrients to the brain, the nerves in the brain progressively die.
Are there any warning signs that a stroke is imminent? Some people have a mini-stroke (transient ischemic attack, TIA) before they have a full blown stroke. With mini-stokes there are similar symptoms to strokes – weakness on one side of the body, and trouble in speaking, understanding, seeing, and walking. The only difference is that with a mini-stroke the symptoms resolve within an hour or so, whereas with a full blown stroke they don’t. Mini-strokes are due to a partial blockade of the blood vessels in the brain.
About one-third of people who have a mini-stroke will go on to have a full blown stroke within a year. These people may be the lucky ones as they have been warned to take steps to prevent a full-blown stroke. Such steps include taking aspirin to help prevent blood clots forming in narrowed blood vessels. Unfortunately, most people do not know that a stroke is imminent.
When treating stroke it is important to distinguish between ischemic stroke and the other kind of stroke, a hemorrhagic stroke. In hemorrhagic stroke there is a burst blood vessel and bleeding into the brain. In ischemic stroke, a new approach is to use an agent to unblock the blood vessel by dissolving blood clots, in the same way as coronary arteries are unblocked after a heart attack. Clot dissolving agents make a hemorrhagic stroke worse. So, when stroke is suspected a CT scan is used to distinguish between the ischemic and hemorrhagic types.
If it is an ischemic stroke, clot busting drugs can be given. If they are given within the first 3 hours of the onset of stroke, unblocking the blood vessel to re-supply the brain with oxygen and nutrients, leads to better outcomes (less disability). However, there is major drawback with these drugs – we don’t really know why, but if they are given any later than 3 hours, they make things worse. In New Zealand, clot busting drugs are only administered in specialist centres. Unfortunately, only a few people with strokes get to these centres within the 3 hours.
So what else can be done to stop the nerves from dying? Many pharmaceutical companies have tried and failed to develop neuroprotective agents. Dr Richard Green from AstraZeneca has been involved in the development of neuroprotective agents for many years. When Dr Green visited New Zealand, he discussed what was needed for a drug candidate to become a neuroprotective suitable for use in stroke. For instance, in testing, realistic animal models of stroke must be used, and the drugs must be administered after the stroke. Indeed, neuroprotective drugs that are helpful when administered long after the stroke would be particularly useful.
So, how does Neuren’s glypromate measure up? It was back in 1992 that Dr Peter Gluckman (Neuren’s Chief Scientific Officer) first proposed a protein in the body known as insulin-like growth factor was neuroprotective using an animal model of brain injury. Subsequently, Dr Gluckman’s group showed that the neuroprotective effect could be mimicked by a tiny fragment of the protein. That tiny fragment was initially developed as glycine-proline-glutamate (GPE), but is now known as glypromate.
When glypromate was injected directly into the brain, it was shown to be neuroprotective in an animal model of ischemic stroke. More importantly, it was effective when given 2 hours after the stroke. But it is difficult to imagine injecting drugs deeply into the brains of people without the needle causing serious damage!
A major breakthrough came in 2004, when Dr Gluckman’s group showed that glypromate was neuroprotective after administration into a vein in the neck of rats that had had an ischemic stroke. This suggests that glypromate can be administered intravenously to human stroke victims. Also, of interest was that glypromate was neuroprotective when administered 7 hours after the stroke in rats. This will give a greater opportunity to use the drug than the 3-hour limit with the clot busters.
After evidence of a benefit in an animal model of a medical condition, the next stage in drug development is clinical trial. Thus, having been shown to be neuroprotective in an animal stroke model, glypromate has gone into clinical trial. No results of clinical trials with glypromate have been made available to the general public or published in peer-review journals to date. Going into clinical trial is no guarantee that a drug will be successful – most drugs that make it to clinical trial do not become commonly used drugs in medical practice.
So why isn’t Labrat convinced? Apparently, glypromate acts as a NMDA site blocker, and Labrat thinks this is a problem. Indeed, synthetic NMDA site blockers have already been made and tested in stroke. One of the early difficulties in stroke is that the nerves release huge amounts of glutamate that act at this NMDA site to promote more nerve death. So, logically, anything that blocks the NMDA site should be neuroprotective. The main problem with many of the synthetic NMDA site blockers was that they caused too many side effects to be used in stroke victims. However, recently a weak synthetic NMDA site blocker (memantine) has been shown to slow the progression of Alzheimer’s disease, another indication for neuroprotective agents. So, it may be possible to use an NMDA site blocker after all in stroke, provided it is too weak to cause side effects. Perhaps it is time to give NMDA site blockers another chance.
Neuren have obviously highlighted their work and the best interpretation of it, but Labrat seems to have a problem with this spin. But surely, it is standard procedure for companies that list on the stock exchange to put the best spin on their products, and all pharmaceutical companies do this, so why not Neuren? As, Labrat points out, other people have done work with glypromate, which is not highlighted by Neuren. Thus, glypromate was first described as having effects on nerves in 1989 by a group from the well-respected Karolinska Institute in Sweden. Other groups have shown that glypromate is neuroprotective, and are (as is Neuren) trying to develop similar drugs as neuroprotective agents.
Labrat objects that Dr Gluckman has been telling the media since 1998 that Neuren ‘expect’ or ‘plan’ or ‘hope’ or ‘could’ start clinical trials ‘within months’ or ‘within 2 years’. I agree that this is a problem, but I don’t think the problem is with Gluckman/Neuren. Surely, it is up to the media, to pin him down.
The Business Herald has reported that ‘Glypromate helps stem the loss of brain function after coronary artery bypass grafting surgery’. Where is the evidence for this? If the Herald has been shown clinical evidence from the Phase II trial to support this, it may have been reasonable to have reported that ‘early evidence from a Phase II trial suggests that glypromate may be useful in reducing the loss of brain function after coronary artery bypass grafting surgery’.
Also from the Business Herald: ‘Neuren also says the drug can be used after strokes or other brain injuries – markets totalling a further US$4.5 billion’. This seems to be implying that glypromate has been shown to have major benefits in humans after strokes or brain injuries. If this was really true, the shareholder would all be guaranteed to be millionaires! Surely, it would have been more realistic to have reported that ‘Neuren is also developing glypromate for use after strokes or other brain injuries. Encouraging results have been obtained in animal studies, and they now hope to take the drug to clinical trial for this indication’.
Neuren is not the only company with promising leads for the treatment of stroke. Clinical trials of 12 different agents for the treatment of stroke have been reported in the peer-reviewed literature in the last year. However, in recent years, many of the major drug companies have abandoned their stroke programmes after the spectacular failure of the synthetic NMDA site antagonists.
The large pharmaceutical companies run several programmes for developing drugs for different indications simultaneously. With this approach, it is hoped that the millions lost by drugs that fail in clinical trials, can be countered by drugs that succeed. Small pharmaceutical companies are not able to spread the risk. Thus, they are likely to loose it all, or make millions.

In summary
• Stroke is a devastating condition, presently without good treatments
• Neuren’s glypromate (and related drugs) shows promise in early development for use in brain injury
• All investment in small pharmaceutical companies is speculative!

About the author
Sheila Doggrell is a biomedical researcher, lecturer and writer. She was working at the University of Auckland at the time the early development of glypromate was being undertaken. However, she has never had links to the research of Dr Gluckman or any of the companies he has/is involved with, and is not ‘Labrat’.