IMI: Why was a project like Europain needed in the first place?
There are so many people suffering from pain – one out of every five Europeans needs treatment for pain, and between 7-8 per cent of all people in Europe suffer from neuropathic pain [where the nerve fibres themselves may be damaged, dysfunctional, or injured]. The availability of treatment is even lower in that latter group – normally you would say 30 per cent of people with chronic pain get an effective treatment, and in the neuropathic group the figure is even lower, so there is a high need for new treatments. However, it is difficult to make a new medicine; there are a lot of obstacles and unknowns.
IMI: What did Europain try to achieve? What was its main goal?
We wanted to overcome bottlenecks, places in the drug development process where we stumble and fall. We wanted to address all of them, so it was a very ambitious project.
IMI: To start with, your project achieved a lot to improve preclinical studies of pain. For example, you developed new animal models which could make future preclinical trials easier to conduct. Could you tell us a bit more about that?
When you perform preclinical studies with animals, one of the main problems is that the animals cannot tell scientists whether they’re in pain or not; whether their pain has decreased as a result of a treatment or not. We managed to do something that has been lacking: we provided ways of measuring pain by observing animal behaviour in a very structured and quantitative way. We developed and validated – ‘validated’ being a very strong word here – ways to measure spontaneous pain behaviour in rats. It sounds minor but it is actually quite major.
Traditionally you would squeeze the rats’ paw and see when the rat would retract the paw; or you would measure for how many seconds the rat would keep its tail in water of a certain temperature. Instead, we identified four or five behaviours which are all related to the rats’ normal behaviour. For example, in order to build a nest, rats dig a burrow. This burrowing is something they think is a lot of fun. When they’re in pain they burrow less, they don’t play the games the other guys play. When they get proper treatment for their pain they will again burrow more. We measured and validated such behaviours in a way that has never been done in animals: we did a multicentre, double-blind study. And that’s a great achievement.
IMI: You said ‘validate’ is a very strong word here. Could you explain why?
When you have scientists doing experiments in their labs, everyone has their own way of doing things. It becomes very individual-dependant and that’s not good because then you have results going all over the place. Our project partners agreed exactly on how to do the experiment and then the partners went home and they all did the same experiment. They all came up with the same results in different labs, both in industry and in academia. This is something which was made possible by the participation of the different partners in the consortium. These animal models were developed during a time period of 5 years – normally if you did that in the academic world, it would take at least 15 years. Doing this in a public-private consortium significantly reduced the time needed.
IMI: Your project also made significant advances in how to ‘translate’ the results of animal studies to human patients. What was the most significant achievement in this area?
There was one scientific result here which had a huge impact. Pain is usually measured by what the patient tells you, which can be subjective, and it’s one of the problems when measuring the effect of potential drugs in clinical studies. However, there is a technique, microneurography, which involves sticking a special fine needle into a nerve to measure pain. It sounds painful, but it’s actually not. The technique itself was not invented as part of Europain, but we were fortunate to have an SME as partner who could do this. This partner did exactly the same measurements in rats, in healthy volunteers and in patients. They could show that you get exactly the same pattern in animals and patients. That means that if you see that there is a potential drug which reduces a very specific pain pattern in rats, you can now more accurately predict that it will do the same thing in patients.
We submitted these results to the European Medicines Agency. They said that you cannot use this technique to replace pain assessment yet, but it can be used to demonstrate that a potential drug works. There is a fine difference, but it means that you can now use this technique in drug development and it’s absolutely valid, many companies are starting to use it. It helps them identify early on which drugs are likely to be effective.
IMI: In the development of new medicines, clinical studies are the most lengthy and expensive. Did your project achieve anything to make clinical studies more effective?
Indeed, we addressed that aspect too. For example, we did a number of brain imaging (magnetic resonance imaging - MRI) studies, and we could identify certain areas in the brain which are more active when a patient is in pain and become less active when the patient is given efficacious treatment. You can use this technique to show in a very controlled group of patients if a potential drug may work. This could significantly cut costs for the industry. For example, before you start a big clinical trial with hundreds of patients, which is very expensive, you could first do a smaller MRI study with only a fraction of the patients. That way you could be more confident that your bigger clinical study will have a high likelihood of succeeding.
We have also validated measuring techniques for different biological clues (biomarkers) in the body – proteins and lipids – which react or change as a result of pain. This means that we have made a huge step forward in measuring pain as part of clinical studies. This has helped industry quite a bit because with all these different techniques they can be sure that they are measuring the ability of a potential drug to reduce pain, reliably, over time.
IMI: The outcomes of your project may also help in developing more personalised medicine for chronic pain patients. Could you explain your contribution there?
We came up with a new way to classify patients with neuropathic pain, and the European Medicines Agency accepted our classification tool , which could lead to the development of more personalised medicines.
As part of this process, we collected a database of 2 300 patients with neuropathic pain and 1 000 healthy volunteers. After putting the database together, we did a very thorough examination of how these patients perceive warmth, cold, sharp objects, etc. Instead of sorting people by the type of the disease which is at the origin of their pain (e.g. diabetes or shingles), we classified patients according to how their sensory system/nervous system responded to different stimulation. This was a completely new approach.
As part of validating these groups of patients with different sensitivity, we tested the effect of a drug similar to a local anaesthetic. We compared the effect of that drug in two groups of patients: hypersensitive patients who, for example, find it painful to have a bed sheet on their feet during the night vs. patients who are more numb and don’t have such increased sensitivity. We demonstrated that patients who have this hypersensitivity respond much better to this type of treatment than patients who are numb.
We went to the European Medicines Agency to see if they would agree that this is a valid way of stratifying patients when selecting them for clinical studies. And indeed, they accepted our tool, including it in their European guidelines for drug development This is quite significant. When drug companies develop new drugs, they follow these guidelines in deciding how to perform their studies, and how to group the patients. By following our new stratification, companies could, for example, develop a drug which is more effective in patients with increased sensitivity – so in that sense it would be more personalised medicine.
IMI: Would you say that the project has transformed the field in general?
Yes I think it has. Overall I would say that Europe now has a stronger position when it comes to the understanding of nerve pain. Our project has also triggered more research activity – a number of new projects are now building on the Europain results.
For example the needle technology to measure activity in the nerve is now being developed into something that could be useful on a daily basis for any physician. It is being refined so it could be more like an electrocardiogram (ECG): putting sticky plates on a patient and then measuring the activity in the nerves.
I think we ended up being more successful than what we thought is possible at the beginning. That’s what happens when you have fun.
IMI: How long before patients start experiencing benefits as a result of this project?
The goal of Europain was to improve the drug development process, so there needs to be a drug that actually comes through. As you know, it takes time for a new drug to come to the market, but I do know that one is under way. It is not being done by one of the partners in our consortium, but they have benefited from work which was done in the project. If they are successful, which the results are speaking in favour of, it should be on the market in a couple of years. This would be a big achievement, considering that the last big drug concept for pain was launched in 1995.
The knowledge and learnings from the project are also contributing to the personalisation of chronic pain treatment. For example, in one study we discovered that patients with a certain genetic predisposition may be a greater risk of developing chronic pain after surgery. We also found that patients who undergo endoscopic (keyhole) surgery develop chronic pain after surgery to a lesser extent than patients who undergo open surgery. This information is already being used to determine the risk of pain complications in Denmark, where the study was conducted, but also in other countries. It helps doctors develop a more personalised follow up and treatment early on, putting intensified resources where they are most needed.
IMI: How did the SME partners in the project benefit?
We had only one SME as a partner, Neuroscience Technology. They were the ones who contributed with the model of measuring nerve activity through microneurography and they went from being a company in Barcelona only to also having a subsidiary in London. They hired people and their business has grown substantially.
IMI: How did the public-private nature of IMI contribute to this project? Would it have been possible to do without IMI?
No, it wouldn’t have been possible. This kind of sharing and collaboration usually doesn’t happen. Academics are competing with each other: you don’t share everything because somebody might steal your idea and be the first one to publish. Likewise, when you’re in industry you don’t talk about your product while it’s being developed.
Through openness and collaboration in this project, people actually understood that we’re not that different – we’re just measured by different things: by the number of drugs, or successful studies, or the number of publications, but otherwise we have the same problems, and we see things the same way. This was the first time in this field that this kind of sharing and collaboration took place – and it was very successful.