On the 8 September 2023, members of the Research Development team at the MND Association attended the 4th UCL Queen Square Motor Neuron Disease Centre International Symposium. Leading international researchers were invited to speak about key areas of MND research, with a focus on translational research. We listened to talks on early laboratory research and how this could translate into potential new therapies, what success looks like in MND clinical trials and the use of different clinical trial designs to speed up drug development.
What is translational research?
Translational research bridges the gap between lab-based research and clinical trials. It aims to take promising early research from the lab and develop this into potential new therapies that can be tested in clinical trials.
Clinical trials in the era of multiple potential treatments
More clinical trials than ever before are currently being undertaken to investigate potential treatments for MND. While having more clinical trials running provides more people living with MND with an opportunity to take part in research, it does bring some challenges.
Opening and running clinical trials is a costly and lengthy process. As healthcare systems differ around the world, this can lead to some countries not being able to run any or as many clinical trials as others.
One eye-opening talk from Caroline Ingre, Head of ALS from the Karolinska University Hospital, highlighted how Sweden has increased the number of clinical trials available over the last couple of years. A few years ago, there were very few clinical trials running in Sweden. Dr Ingre and colleagues worked with people living with MND to raise the profile of MND research, both with the general public and within the research community in her country. Sweden now has the most clinical trials running in the Nordics. The team is now looking to improve access to trials for people who live outside of Sweden in the Nordics.
Now that more clinical trials are running, many people living with MND have a choice over which clinical trial to take part in. Dr Ingre ended her talk with a question to the audience: “How do you help people living with MND who ask for your help in choosing which trial to take part in?”. This question provoked an interesting discussion between clinicians in the audience and highlighted the differences between common practice at centres across the globe. One clinician indicated how the act of a clinician making the choice for the person with MND might lead to bias in a clinical trial. Bias can have a negative impact on clinical trials and could result in the actual effect of the potential treatment not being observed correctly. The audience agreed the topic required additional discussion and that standardisation of this procedure may be useful for the whole MND community to help clinicians and people living with MND navigate clinical trials.
The impact of clinical trial design
While more potential treatments are being tested in trials than ever before, there are many more treatments which have shown potential benefit in early laboratory work. Trials are expensive and lengthy, and this can limit the number of treatments to be tested in humans. Platform trials are one way to overcome this issue. In platform trials, multiple treatments are tested at the same time. Participants are randomly assigned to either one of the treatments or the placebo (also known as a dummy drug). Platform trials provide the infrastructure needed to allow for more drugs to be added, but also to remove drugs if they are not showing any benefit.
During the UCL MND Symposium, we heard further details about two platform trials MND-SMART and MAGNET. Both trials are part-funded by the MND Association. Professor Suvankar Pal gave an overview of the MND-SMART trial, which is currently investigating three drugs that are used for other conditions but have shown promise in early laboratory work for MND. Excitingly, we heard how work is ongoing to add additional drugs to the trial in the future.
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Keeping MND-SMART moving
Platform trials are one of the latest advances in the design of clinical trials, aiming to accelerate drug development and provide more people living with MND an opportunity to take part in research. Many clinical trials have strict criteria which must be met in order to be accepted onto a trial. This results in many people living with MND being excluded from taking part. In principle, both the MND-SMART and MAGNET platform trials will give more people the chance to participate in clinical trials.
Inclusion and exclusion criteria, along with clinical trial design were hot topics of discussion during the Q&A sessions and breaks at the UCL MND Symposium. As already mentioned, it is important that potential treatments are tested across wide and diverse populations. However, as no two people experience MND in the same way and have different rates of progression, this can sometimes make it difficult to access the effect of a potential treatment. For example, some trials try to recruit people with an “average” progression rate. This is because for people with slow progression, any potential effects of the treatment might be small and difficult to observe, whereas for people with fast progression the treatment might not work quickly enough, making it any difficult for researchers to observe any effects.
The challenge therefore is in selecting who to recruit into clinical trials, to not only ensure the treatment is given the best chance of success, but also to observe the effect the treatment could have on anyone who is diagnosed with the disease.
The MAGNET trial is using a computer model to predict a person’s disease pattern, which aims to enable a greater number of people to participate in a clinical trial. It is hoped that models such as these continue to be developed and used widely, with the ultimate goal of providing everyone living with MND with the chance to participate in a clinical trial.
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Using biomarkers in MND clinical trials
The challenge doesn’t stop there. Over the past several decades, over 140 MND clinical trials have been undertaken, most of which showed little to no benefit for people living with MND. This often raises the question of whether the negative outcome of a clinical trial is down to the design of the trial rather than the treatment not being beneficial.
“Did the drug fail the trail or did the trial fail the drug?”
Research into how the design of clinical trials can be improved is ongoing. There is also work ongoing into what measurements can be used during a trial to determine if a treatment is beneficial or not. Biomarkers, unique measurable signals of MND in the body, are key to knowing if a treatment is beneficial. One potential biomarker is neurofilament light chain. Neurofilament light chain acts as a scaffold in the motor neurone so as the motor neurone is damaged, neurofilament light chain falls apart and can be measured in the blood or cerebrospinal fluid. Researchers suggest that a reduction in neurofilament light chain indicates a possible reduction in damage to the motor neurone and disease progression. The observed reduction in neurofilament light chain was instrumental in the approval of Tofersen, a genetic therapy for SOD1 MND, in the United States.
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What does the FDA approval of Tofersen mean for the UK MND community?
At the UCL MND Symposium, Tim Miller walked through the data from the Tofersen Phase 3 trial and open label extension (where everyone in the trial receives the treatment). These results provide increasing confidence that Tofersen is having a beneficial effect in people living with SOD1 MND. The results and analysis also highlight the importance of finding, developing and using biomarkers when measuring outcomes of clinical trials.
There are a variety of biomarkers for MND currently in development worldwide. Work in this area has led to a number of different biomarkers being used within trials to gain additional data and build evidence of their use. Dr Ingre highlighted this at the end of her talk, while in a discussion with the audience. She reiterated that standardisation of the biomarkers to be used in MND trials would be helpful when analysing clinical trial data and determining benefit. While researchers are making strides in the right direction, the identification of MND biomarkers is still in its infancy and there is much more work needed in this area.
The MND Association is currently funding 11 research projects which aim to identify and develop potential new biomarkers for MND. You can find out more about these projects on our website.
Over the past couple of years, the pace of MND research, especially in clinical trials, has increased dramatically. Researchers believe that with the continued momentum, funding and collaboration we are on the cusp of finding effective treatments of the disease. While this blog highlights some of the challenges, listening to researchers and clinicians openly discuss these challenges and indicating how they could be overcome provides hope for the future. Of course, clinical trials would not be possible without everyone who selflessly takes part and plays such a significant role in the fight against MND.
