New brain-haemorrhage treatment tested on patients for the first time

Researchers from Rigshospitalet have launched first-in-human trials of a groundbreaking new treatment principle for brain haemorrhages. The professor behind the trials has been working on this breakthrough for 25 years, and he is now about to embark on the second treatment breakthrough in his career. ​​​

​Professor Lars Edvinsson (right) is behind the new treatment principle, and here Professor Kirsten Møller and Professor Tiit Mathiesen are helping him test the treatment on patients suffering from subarachnoid haemorrhage.

If an outpouching on one of the large blood vessels of the brain suddenly bursts, there are only a few hours to save the person's life. Physicians can provide life-saving treatment, provided the patient gets to hospital in time. However, the subsequent biochemical chain reaction in the blood vessels is uncontrollable. The blood vessels constrict around the damaged area, the metabolism is knocked off balance and the damage to the brain is constantly getting worse. These effects in the days after the acute operation are a major Achilles heel for neurosurgery. Even though many lives are saved in the first instance, patients do not necessarily regain mobility and a good life. 

But perhaps they soon will. Researchers at Rigshospitalet have launched a first-in-human trial, in which they are testing a treatment that has been clearly successful in rats, and which has the potential to help all patients suffering a brain haemorrhage. Professor in neuroanaesthesiology, Kirsten Møller, is among the researchers helping in the trial.

- Unfortunately, we're currently not able to do much for many patients who, despite successful treatment, suffer complications after a brain haemorrhage. The chain reaction has been set off, and patients are likely to become permanently dependent on assistance after being discharged from hospital. We very much hope that this new treatment principle will help these patients, said Kirsten Møller.

At first, the treatment principle will be tested on 30 patients with the type of haemorrhage that arises between the membranes of the brain. Rigshospitalet treats approx. 150 patients with subarachnoid haemorrhage every year.

Second career achievement

The project is a model example of translational research, in which researchers are trying to make improvements for patients by applying basic research. For a quarter of a century prior to this clinical trial, researchers have conducted laboratory experiments and rat experiments. The trial is headed by professor in cardiovascular diseases Lars Edvinsson from the Research Park at Rigshospitalet in Glostrup. Last year, he was awarded the world's largest brain research prize, The Brain Prize, by the Lundbeck Foundation for his discovery of the mechanism in migraine patients that made it possible to develop medicine specifically for migraine. ​This is a career achievement accomplished by only few researchers. Now, for the sake of patients, Lars Edvinsson hopes that a new achievement is on the way. 

In the past decades, he has been looking for an off-switch to stop the biochemical reaction in patients after a brain haemorrhage. He has found the switch in the last part of the chain, just before time runs out for the patient. We already knew that preventing the endothelin B receptor from becoming upregulated would protect the damaged tissue around the haemorrhage. 

- We discovered this by accident in the 1990s. A medical student researcher was studying blood cells in the brain of a dead rat and forgot to put the rat in the refrigerator overnight. The room temperature allowed the chain reaction in the vascular wall to continue instead of being stopped by the cold refrigerator. At that time, we discovered that the blood vessels had changed phenotype and function overnight. To me, this was an epiphany, Lars Edvinsson said.  

He explained that, until then, researchers had considered endothelin B as a ‘blood-vessel-dilating' receptor for the endothelial cells that line the inside of blood vessels. That night was the first time it became clear to Lars Edvinsson that the endothelin B receptor was instead attached to an upregulated smooth muscle cell in the vascular system of the brain, which caused the blood vessels to contract. 

In the following years, he studied this mechanism in patients with blood clots and brain haemorrhages with Niels Svendgaard, a former professor at Karolinska Institutet in Stockholm, Sweden, who interrupted his retirement to help in the trials. All rat experiments showed the same result, regardless of the type of brain haemorrhage they studied. 

In 2012, Lars Edvinsson had seen enough to move on to the next stage. Now, he had to find out whether the same process happened in humans.

- I went into a pathologist here at Rigshospitalet and harvested cells from the blood vessels of a patient who had died of a brain haemorrhage. Again, the result was the same: The endothelin B receptor had been upregulated. 

Cancer drug works

He then began to go through all the possible drug candidates and experimental drugs on the market. Which drug could stop endothelin B? The search took several years, and the breakthrough came with a so-called MEK1/2 inhibitor approved for various types of cancer treatment. 

Together with a group of investors, Lars Edvinsson set up the company Edvince, which has patented the special treatment principle of administering MEK1/2 inhibitors directly into the brain via a tube already inserted into the brain by neurosurgeons to prevent fluid build-up. 

- Imagine if a lot more patients could survive a brain haemorrhage and leave hospital with their mobility intact. As a physician, I’ve seen the hell patients have to go through after suffering a brain haemorrhage, so this would be huge, said Lars Edvinsson.  

The treatment principle has already been given orphan drug status by both the EU and the US. This means that if the drug works, the approval process will go faster. 

Most recently, Lars Edvinsson and Edvince were pledged a grant of EUR 2.5 million from the European Innovation Council. The Council received applications for funding from approx. 4,000 companies in the same round. The funding will be spent on the clinical trials. 

Project close to dying in Sweden

Six years. This is how long Lars Edvinsson has had to wait to start the clinical trials and test the treatment principle in humans. First, he went to Medicon Village in Lund in Sweden to conduct the trial in his home country, where he had found investors for a phase I and phase II trial. But the rules on consent in Sweden prevented him from conducting the trial. 

If treatment with the MEK1/2 inhibitor is to work, it must be given within eight hours after the patient has suffered a brain haemorrhage. Most patients are unconscious when they are brought in by ambulance – and neither they nor their relatives have time to give their consent to treatment or participation in a trial. In Sweden, the authorities require full consent. 

In Denmark, it is possible to conduct acute trials with a proxy consent, where a physician can consent on behalf of the patient in the acute phase. The relatives, and then the patient, can be asked later in the process. This approach is necessary in this type of trials. 

A rarity in neurosurgery

- In neurosurgery, researchers are only rarely allowed to be the first to test a treatment, because medical breakthroughs aren’t exactly commonplace in this field," explained neurosurgery professor Tiit Mathiesen, another researcher on the project. At Karolinska Institutet, he also conducted research in this area almost 20 years ago together with Niels Svendgaard, and now he has been given the opportunity to test this research in clinical practice.

To begin with, the first patient in the project will be given a third of the dose to ensure that he or she does not develop any adverse effects, and gradually the patient will be given a full dose before the researchers begin to test the treatment on several patients at a time. Tiit Mathiesen does not believe there is reason for concern about major adverse effects.

- We know the drug very well, and all reported adverse effects have arisen as a result of long-term treatment. In this trial, the patients will be given the treatment in much lower doses and only three times. So, we're very optimistic on behalf of patients. 

He explained that the drug may benefit patients in several ways. Partly by protecting against the biochemical chain reaction arising in blood vessels that contract around a haemorrhage, and partly through the broader anti-inflammatory effect of the drug. 

- Even if the drug doesn’t save more patients from dying, the patients that do survive may develop fewer disabilities, said Tiit Mathiesen. 


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