Professor Andy Whiting and Dr Tony Lockett discuss how specific levels of a protein could be used to advance drug development in neurodegenerative diseases.
Neurofilament light (NfL) analysis is a potential biomarker for damage to both the central and peripheral nervous system. It has been used experimentally in international trials1, but researchers are hopeful that further use and evaluation in the UK will accelerate drug development for hard-to-treat neurodegenerative diseases.
The neurodegenerative landscape
The World Health Organization has estimated that neurological disorders affect up to 1 billion people across the world2. Interest in neurodegeneration amongst the public has increased in recent months due to several high-profile cases including rugby player Doddy Weir, who was diagnosed with motor neurone disease (MND) in 2016, and actor Bruce Willis, who was diagnosed with frontotemporal dementia (FTD) earlier this year. However, progress in the field has been painfully slow for decades – particularly in terms of disease modifying treatments – because of the complexity of these diseases, the expense involved in lengthy clinical trials and the uncertainty around efficacy.
To date, the clinical and research-based assessment of neurodegenerative diseases such as Alzheimer’s, Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS), has relied on clinical profiles, symptoms, scoring scales such as the ALS Functional rating scale (ALSFRS), and life expectancy. These parameters aim to measure the progression of disease over time by looking at the functional or observable change in a patient. They are quite coarse and time-consuming, often taking months, if not years, to show a clinically meaningful change.
It has been widely accepted3 that a measurement of biochemical change would be advantageous in terms of being able to assess patients’ progression of disease in a more sensitive manner – such biochemical changes are referred to as biomarkers. These biomarkers have considerable utility in chronic diseases such as neurodegeneration, as many neurodegenerative diseases are closely related. They can predict which drugs might clinically benefit patients in personalised medicine, thereby reducing the length and size of trials needed to screen for effective medication. Recently scientists and clinicians have proposed that neurofilament light chain (NfL), a protein found in cerebrospinal fluid (CSF) and blood, could act as a biomarker and be used to measure and track patient progression4.
The role of NfL
NfL is a protein found inside nerve cells that conduct impulses and messages to and from the brain (scientifically termed myelinated axons). NfL is important in maintaining the shape and integrity of a nerve cell, both in the central nervous system (CNS) and the peripheral nervous system, where the nerves connect from the CNS to other parts of the body. When nerve cells are damaged, they release NfL into the brain and surrounding fluid (CSF); as the neurodegenerative disease progresses in humans, the concentration levels of NfL in CSF (cNfL) and blood (bNfL) have been shown to rise. Where there are treatments available, for MS for example, NfL has proven to be a reliable indicator of treatment response5 and in ALS, NfL has been shown to be a prognostic marker, with high levels of NfL being linked to life expectancy6.
The first attempts to measure NfL were in the 1990s when enzyme linked assays (ELISA) were used to measure NfL in blood (bNfL) and CSF (cNfL). However, these assays were not sensitive enough and it was not until the development of more sensitive assays that low level quantification became possible, together with the measurement of NfL in the blood. The development of the sensitive assays allowed the evaluation of the correlation between clinical scores and bNfL and cNfL, with both cNfL and bNfL being found to correlate very closely (r = 0.88) using Simona7. The increased sensitivity of the assay also allowed for the separation of healthy NfL measurements and diseased patients, enabling the development of cut-offs and standardised assays. Correlations between cNfL and bNfL and disease progression have now been established for MS and Huntington’s Disease, representing an important step forward for the use of NfL as a useful analysis method.
The development of new and more sensitive assays for NfL measurements has led to the use of bNfL and cNfL in clinical trials. Since 2010, over 100 trials across the world have included NfL measurements as endpoints, and the number of trials is increasing – albeit not as rapidly as it could. Currently, 15 trials of the new potential therapies for ALS have included NfL as an endpoint8. It is also a valuable tool in preclinical evaluation, as damaged neurones from both cell culture and animal models of neurodegeneration, release NfL.
Barriers to widespread adoption
However, not everybody is as enthusiastic as we are. The UK’s regulator, the MHRA, has indicated support in its early-stage advice, but suggests more clinical data is also needed. In Europe, where the review of the drug Tofersen is still ongoing, the European Medicines Agency (EMA) has issued a Letter of Support for the use of NfL but has also asked for further qualification. Some clinicians are wary too, as NfL measurement is not commonly in clinical use because there are several assays available, but assay types and methods have not been standardised globally, which causes issues of comparison. Also, NfL measurements are impacted by how test samples are handled – especially blood samples. Fortunately, both these issues are being addressed by health professionals, disease charities and trial sponsors and are likely to reach consensus in due course, enabling globally sourced NfL data to be accurately correlated together with other standard biomarkers and disease measurements.
Regulators have been traditionally reluctant to accept NfL measurements as primary, pivotal, endpoints or as solid evidence of the benefit of new drugs because of the lack of precision between neurodegenerative disease states and the difficulties in establishing low limits of concentration in disease states. This is complicated by the fact that NfL measurements also have a strong correlation with age.
These factors have made regulators reluctant to rely on NfL in benefit-risk assessments of new therapies. It is apparent that NfL has no role in the diagnosis of disease (NfL levels over-lap considerably between disease states and within disease states). However, it is now widely accepted that changes in NfL within a patient (i.e, a change from baseline) is a prognostic and disease progression marker across a range of neurodegenerative diseases.
Recent progress
The acceptance of NfL measurements as a primary efficacy endpoint has changed recently with the approval of Tofersen, which was based on changes in bNfL. In a Phase III study of 108 patients with SOD1 mutation associated ALS, the primary endpoint of a change in functional scores was not achieved9. However, the treatment was successful in reducing the SOD1 associated gene product and NfL. The US Food and Drug Administration (FDA) panel reviewed this data and decided it was sufficiently convincing to grant approval for Tofersen.
This approval, in addition to the other developments, has changed the positioning of NfL from a useful secondary to a potential primary endpoint. The adoption of NfL as a primary or pivotal endpoint has the potential for a major impact on the development of ALS therapeutic agents as NfL has proven a useful link between the often-imperfect animal models and the human disease, improving the strength of evidence of these in models. The FDA hopes that accelerating approval for promising drugs based on NfL results will result in promising drugs getting to market, as ineffective ones are quickly identified and discarded.
The use of NfL measurements could also indicate if a therapy is disease modifying. By following the change of NfL over time, it should be possible to say if the rate of neurological damage is slowing and potentially, complete loss of all NfL from blood and CFS would be indicative of neuronal repair.
Impact on the investment landscape
In neurodegeneration, we are looking for the ‘needle in a haystack’ drug. Progress has been slow in recent decades because these diseases are complex and clinical trials are long and expensive, which is a barrier for many researchers and early-stage companies. The good news is that new techniques like NfL biomarker analysis mean it’s possible to determine whether a drug is having any effect very quickly, and importantly, long before functional changes can be observed.
This means those developing medicines can ‘fail fast’ – instead of costing millions of pounds to assess whether a drug has any potential, researchers will be able to rapidly and cost effectively see whether a drug is worth continuing with. If a genuinely novel drug does show an effect, then those patients are not simply dropped at six weeks but go on to a longer adaptive and extendable trial that paves the way for more extensive testing and eventually drug licencing.
Consequently, the use of NfL in the conduct of clinical trials could enable investors and governments to target funding more accurately at the drugs with the best chance of working at a much earlier stage. At the moment, investment in medicines is spread thinly, meaning many potentially effective drugs do not make it far enough to assess efficacy.
Ethical considerations
Besides the potential for accelerated drug development, there is an ethical issue with keeping patients on 24-week trials if we have the tools to help us understand whether a drug is effective or not after six weeks. Neurodegenerative diseases can be cruel, with some patients having very short life spans and experiencing significant discomfort. The NfL development is exciting because it means patients could be given the option to be taken off ineffective drugs and placed onto new trials, potentially accelerating progress in the field.
There remain barriers to the widespread adoption of NfL as a primary measure in the conduct of clinical trials and the registration of new products, but this contrasts with the approach being taken in the US and that of other biomarkers. In diabetes for example, the glycated-haemoglobin (HbA1C) is taken as pivotal evidence of effect and is used in drug registration, so there is still hope. Further evidence of the value of NfL will be gained from trials looking at the preventative effects of Tofersen in ALS. These trials are due to report in the next year or so.
What next?
The summary question is: what next? If NfL is accepted as a biomarker, it is anticipated that the availability of NfL in clinical trials will accelerate the trend towards novel, innovative trial designs, such as adaptive, extendable and basket designs. This type of trial has been shown to be very effective in reducing the time taken to test and develop drugs – The RECOVERY and ADAPTIV trials used in Covid are examples of the potential to accelerate drug development.
Ultimately, the acceptance of NfL assays as a measure of neurodegenerative disease has the potential to bring game changing, disease modifying, novel therapeutic advances to patients quicker, which is a cause for celebration amongst the whole pharmaceutical and biotech industries. We just need to accelerate the pace of adoption for this vital tool if we are to make more progress in the next decade than we did in the last.
DDW Volume 24 – Issue 4, Fall 2023
References
- Gaetani L, Blennow K, Calabresi P, et al Neurofilament light chain as a biomarker in neurological disorders Journal of Neurology, Neurosurgery & Psychiatry 2019;90:870-88.
- https://www.who.int/news/item/27-02-2007-neurological-disorders-affect-millions-globally-who-report
- Koníčková D, Menšíková K, Tučková L, Hényková E, Strnad M, Friedecký D, Stejskal D, Matěj R, Kaňovský P. Biomarkers of Neurodegenerative Diseases: Biology, Taxonomy, Clinical Relevance, and Current Research Status. Biomedicines. 2022 Jul 21;10(7):1760. doi: 10.3390/biomedicines10071760. PMID: 35885064; PMCID: PMC9313182.
- Mullard, A., NfL makes regulatory debut as neurodegenerative disease biomarker, Nature Reviews Drug Discovery 22, 431-434 (2023) doi: https://doi.org/10.1038/d41573-023-00083-z
- Barro, C., Chitnis, T. and Weiner, H.L. (2020), Blood neurofilament light: a critical review of its application to neurologic disease. Ann. Clin. Transl. Neurol., 7: 2508-2523. https://doi.org/10.1002/acn3.51234
- Ching-Hua Lu et al., Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis, Neurology Jun 2015, 84 (22) 2247-2257; DOI: 10.1212/WNL.0000000000001642
- Hendricks R, Baker D, Brumm J, Davancaze T, Harp C, Herman A, Büdingen HV, Townsend M, Fischer SK. Establishment of neurofilament light chain Simoa assay in cerebrospinal fluid and blood. Bioanalysis. 2019 Aug;11(15):1405-1418. doi: 10.4155/bio-2019-0163. Epub 2019 Aug 12. PMID: 31401845.
- Data available via: www.clinicaltrials.gov
- Mullard, A., NfL makes regulatory debut as neurodegenerative disease biomarker, Nature Reviews Drug Discovery 22, 431-434 (2023) doi: https://doi.org/10.1038/d41573-023-00083-z
About the authors:
Professor Andy Whiting is CEO and founder of Nevrargenics, a UK-based Durham University spinout company developing drugs for neurodegeneration. Nevrargenics’ IP is based upon 15 years of academic research at Durham University, where he was Professor of Organic Chemistry, examining retinoid signalling pathways and effects upon neuronal cell development.
Dr Tony Lockett MBBS MBA PhD GFMD is a Senior Lecturer in the Centre for Pharmaceutical Medicine Research at King’s College London and the Chair of the Faculty of Pharmaceutical Medicine Expert Group in Rare Diseases.
