Diagnosing disease faster, accurately predicting disease progression, assessing the ability of a new drug to reach its target – I think we’d all agree that these three things are essential requirements for treating all diseases. But how can we achieve this? The answer may lie in biomarkers.
In his plenary talk at last year’s International Symposium on ALS/MND, Prof Robert Bowser – Chief Scientific Officer at the Barrow Neurological Institute in the USA – posed the question ‘How important are biomarkers in drug discovery?’ and, in short, his answer was VERY.
What are biomarkers?
The US Food and Drugs Administration (FDA) has defined a biomarker and several subtypes of biomarkers through the Biomarker EndpointS and other Tools (BEST) resource as the following:
Taken from ‘Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis’. Staats et al. (2022).
Dr Bowser also talked about ‘surrogate biomarkers’ – these are biomarkers that can substitute commonly used clinical outcome measures in clinical trials. Currently these are usually changes in ALSFRS-R scores, slow vital capacity (SVC), forced vital capacity (FVC) and muscle strength tests. In MND there are not yet any biomarkers that are surrogates for outcome measures in clinical trials.
Where do biomarkers come from?
There are several sources of biomarkers:
- Genetic – gene mutations that cause MND.
- Biofluids – cerebrospinal fluid (CSF), blood, urine and saliva.
- Tissues – muscle, skin and post-mortem tissue. TDP-43 was identified from examining post-mortem tissue of people with MND. These also help to demonstrate which cells within the central nervous system are expressing those biomarkers that you find in biofluids.
- Digital – in the last few years there has been an increase in the use of digital biomarkers for speech and movement.
- Imaging – the use of scans (PET, MRI, DTI) to compare differences in regions of the brain affected by MND in people at different stages of the disease and people without the disease.
Why do so many clinical trials for MND fail?
There are many challenges in the development of drugs for MND and many of these lead to the late-stage failure of clinical trials. This is due to the heterogeneity (or differences) of both the biological origins and clinical characteristics of the disease. Over 40 genes have been implicated in the development of the MND, multiple cell types contribute to the disease and many pathways within these cells are altered over the course of the disease. Variations of the disease mean that in some cases both the upper and lower motor neurons are affected and, in others, only upper or only lower motor neurons are involved – these all contribute to the heterogeneity of MND. It should be no surprise, then, that a single drug tested in a very heterogeneous disease population ultimately fails in large Phase 3 trials.
Can biomarkers solve at least part of this problem?
The first hurdle in drug development is identifying the right target. This needs to be one that is relevant to the disease and might be targeted by drugs. The next hurdle is finding the right drug and then, finding the people it might benefit the most. And this is where biomarkers might come into play.
- Utilising biomarkers in preclinical testing – where a target and potential new drug have been identified – is important as they can tell us if the drug is hitting its intended target or having an effect on the pathway of interest. In early drug development this is carried out in cell and animal models of MND. Pharmacodynamic biomarkers can demonstrate that both or either of these things are happening.
Clinical trial efficacy:
- Can the pharmacodynamic biomarker then be translated into the clinical trial setting to help show that the participants are having a response to that drug?
- Could biomarkers be used to select the patients most likely to benefit from the drug? With a genetic marker it may be possible to identify presymptomatic people or individuals right at the beginning of their disease course. The earlier in the disease process that you can initiate a treatment, the better the chance that the trial will be successful.
Optimising clinical trials:
- Can biomarkers be used to ‘power’ a clinical study. The power of a test is the probability that the test will find a statistically significant difference between two populations. In clinical trials this will be a difference between the drug arm of the trial and the placebo arm – i.e., if the primary outcome measure was a slowing of progression as measured by ALSFRS-R scores, it would be hoped that there was significantly slower progression seen in the drug arm compared to the placebo as this would indicate that the drug of interest was having an effect. Using biomarkers to stratify, or sub-group, a very heterogeneous group of participants, would be incredibly advantageous.
- Can biomarkers be used to help reduce time for decision making? If a biomarker indicates a drug isn’t having an effect on the intended target, the trial can be stopped.
- Can biomarkers be used instead of traditional outcome measures?
The impact of biomarkers on drug development and clinical trial design
In the last 5-10 years, biomarkers for MND have really helped increase and expand the MND drug pipeline; they have impacted clinical trial designs; they are being used to monitor treatment response and are beginning to aid regulatory decisions.
Dr Bowser believes that biomarkers can facilitate a more precision medicine approach to MND, defining who to treat in clinical trials and then optimising treatment decisions and monitoring effects using biomarkers over time.
Clinical features in biomarkers can be used to help diagnose patients very early on. Genetic biomarkers can help direct patients to gene therapy drug trials. Biomarkers found in biofluids or imaging might be used to identify patients for trials targeting a particular pathway. Combined with other information, we can make sure that the right patients are included in specific trials that define optimal drug treatment strategies (and this may be more than one drug) and then ultimately monitor the long-term treatment response with biomarkers.
Biomarkers have not only had a tremendous impact in MND drug development in recent years, they are likely to make ever-increasing impacts on the drug development process and clinical trials for MND drugs.