In the previous blogs we explored what a biomarker is and looked at the stages of drug development and clinical trials. In this blog we will combine these topics and focus on how biomarkers are used in clinical trials.
What are outcome measures in clinical trials and why do we need them?
Clinical trials test if a drug or treatment is safe and effective at reducing the disease but to know if a drug is safe and working you need to have something to monitor over time. These are called ‘outcome measures’ and can be something as simple as measuring side effects, symptoms or a change in heart rate, muscle strength or levels of a disease biomarker in the blood.
Most clinical trials use several outcome measures monitoring different processes in the body to allow for a better understanding of the effects a drug has on the whole body.
There will be a primary outcome measure that directly aligns to the aim of the trial. For example, if the aim is to find out whether a drug can reduce diabetes, the primary outcome measure would be to monitor blood sugar levels. Other primary measures can include monitoring survival rates or other ways of tracking the progression of the disease.
There are also usually several secondary measures that are the key indicators of whether the drug is effective at reducing certain symptoms, improving quality of life and showing the effects of the drug throughout the body. Within diabetes, a secondary measure could be body weight or heart health.
Outcome measures are used to ensure the drug is working as it is designed to in the body and can be used to indicate the right dose for the best effects. Monitoring several parts of the body that could be affected allows for a greater understanding of any side effects or alternative targets of the drug. Additionally, outcome measures may identify subgroups of people within the trial that have a better response to the drug allowing future trials to be more targeted which could lead to the drug being approved.
What outcome measures are used in clinical trials for MND?
For MND clinical trials, the most common primary outcome measure is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. This is not a biomarker as it is not something we can measure within the body, but it is a useful tool that is used by doctors to see how well someone with MND is functioning. It can be a good way of tracking the progression of the disease and how it affects someone’s day-to-day life. It is a questionnaire that covers different activities, including walking, speaking, breathing and swallowing food that is taken several times throughout the trial. If someone’s ALSFRS-R score drops, it shows that their condition is getting worse. The scale spans being healthy and mobile to being paralysed or using a ventilator. This scoring system has been around since before biomarkers were found and is still used to measure the severity of the disease in clinical trials.
Although the ALSFRS-R score is very good at showing changes in the disease progression, it is not as accurate as using biomarkers. The ALSFRS-R score uses physical symptoms as the key measure of severity however the disease will have already been affecting neurons for years prior to the diagnosis. Biomarkers such as neurofilament allows the disease to be monitored at a biological level so have the potential to detect neuron loss before people begin to show physical symptoms. Also, biomarkers are a more reliable measure of the disease as the ALSFRS-R score is subjective to the person filling out the questionnaire. For example, if someone struggled to feed themselves the morning they took the questionnaire, despite usually being able to feed themselves, they may answer that they can’t feed themselves. However, if this was monitored using biomarkers such as those measuring muscle strength it could show a steady decline in muscle strength that is an objective measure of muscle function. This makes the results more comparable and meaningful as they are more likely to represent the progress of the disease.
A more recent primary outcome measure within MND drug testing is monitoring the levels of the biomarker neurofilament light chain (NfL). This biomarker measures neuron damage and can indicate how fast neurons are dying. The more neurons that break down, the more NfL is released, which can be measured in the blood. This can give us a good picture of the speed of someone’s disease progression as more neurofilament indicates a faster progression whereas less indicates a slower disease progression.
Biomarkers like neurofilament can be useful in clinical trials to see if a drug is effective at reducing how fast the disease progresses. If the neurofilament levels are seen to drop as the drug trial continues, this is a good indication that the disease is slowing, and the drug is having an impact on the disease progression.
Why do we still use the ALSFRS-R scale when we have biomarkers?
NfL was only shown in recent years to be able to indicate changes in disease progression earlier than any of the other methods. The discovery of NfL has allowed for a more accurate measure of disease activity and effectiveness of drug treatments. Biomarkers are more accurate in showing when a drug is working as it is designed to in the body. However, with all measures there are limitations, for example, NfL can show the rate of disease progression at any one point but cannot tell us about someone’s symptoms or function. Combining the two approaches, using NfL for the rate of the disease progression, and the ALSFRS-R score to show the severity of symptoms, allows for a more complete understanding of the effects of drug treatments on MND.
How have biomarkers been used in clinical trials for MND?
In recent years, following the development of biomarkers, they are beginning to become a standard practice as secondary outcome measures in clinical trials. One example is within the VALOR trial, which was a study of the drug Tofersen, a treatment for a specific genetic form of MND called SOD1-MND. This trial had several primary outcomes to test the safety of the drug in people and measured the ALSFRS-R score to see if the drug was able to reduce the severity of the disease. After 6 months of taking the drug, there was no significant change in the ALSFRS-R score resulting in the initial conclusions of the trial being that Tofersen did not result in improvements for people living with MND.
However, the trial also measured several secondary outcomes including neurofilament light chain (NfL) levels in the blood to see if the drug was able to reduce the rate of neurons dying. Throughout the trial, blood samples were taken from both people on the drug and placebo. They tested the concentration of NfL in each sample. The results from the trial showed a significant drop in NfL in people who had taken tofersen (green line) compared to those who didn’t (blue line). This shows the drug is effective at reducing the speed of the neurons dying.
At the end of a trial all participants were offered the opportunity to get the drug, this is called an open label extension (OLE). During the OLE section of the Tofersen trial, those who had not been given the drug initially then saw a large drop in NfL levels from previously high numbers (blue line decline). This shows the drug had begun to reduce the rate neurons were dying indicating the treatment was working. Although the ALSFRS-R score had not changed during the trial, it was the OLE and NfL data that helped Tofersen gain approval from the FDA. The VALOR trial shows how biomarkers, such as NfL, have been used to measure the effects of a drug and can have a huge impact on the success of a drug trial.
However, not all clinical trials are as positive as Tofersen, and some trials can end if the biomarkers show no change. The clinical trial of a drug called TUDCA was also measuring the ALSFRS-R score as a primary outcome measure and the levels of NfL as a secondary measure in all participants. The results however did not see the same drop in NfL as Tofersen and instead remained at a high level in both groups. This shows that the neurons were continuing to die despite taking the drug. As there was no difference in NfL levels between those taking the drug and those not, it suggests this specific drug was not working as expected and didn’t have an impact on reducing disease progression. In case the drug needed to be taken for a longer time before it showed an effect, the trial continued to an open label extension. Still, those taking the drug continued to show high levels of NfL in their blood, further suggesting that the drug was not reducing the rate of cell death or disease progression. As the trial failed to meet its primary and secondary outcome measures, the drug was removed from further testing for MND.
How else can biomarkers help in clinical trials?
Biomarkers might be able to help us answer questions on the optimal time to begin a treatment, and how long a study would need to run to see meaningful results.
Some trials such as Tofersen as explained above, showed some signs that people who were treated earlier in the disease had lower levels of Neurofilament in their blood and responded better to the treatment. This has led to the ATLAS trial which is looking at using biomarkers to detect MND earlier in people who have family members with SOD1-MND but do not show symptoms. The trial will monitor the NfL levels of the people at risk of developing MND and begin treatments with Tofersen if the NfL levels begin to rise to see if giving the treatments before physical symptoms could delay or prevent the onset of MND.
Additionally, running a clinical trial is expensive and takes a lot of time. To counter this, a drug screening platform, called EXPERTS-ALS has been developed to rapidly screen drugs that show promise for MND in the laboratory. It will test several drugs in people with MND and measure Neurofilament levels to see if the drug shows signs of reducing neuron damage. Drugs where NfL levels are found to drop for most people will be prioritised for further testing in a longer trial which will have a placebo group. This larger trial will help to determine if the drug could be a treatment for MND.
Biomarkers, whilst still relatively new, are very useful at monitoring the effects of drugs within clinical trials for MND. As we discover more biomarkers of the disease, it’s likely that their use in clinical trials will continue to grow and they hold huge potential for personalised approaches to treatment in the future. If we can use biomarkers to group people with MND by similar biological features of disease, we can make sure the right people are taking part in the right trials and hopefully find more effective treatments for everyone with MND.
