Neurofilament, a structural protein released into the blood and CSF by damaged or dead neurons, is increasing in popularity as a biomarker for the efficacy of a variety of drugs targeting neurodegenerative diseases. Neurofilament levels played a major role in the FDA’s recent approval of an ALS drug, tofersen, both cementing the biomarker’s role in future research and raising questions about what it can and can’t tell us.
What is Neurofilament (NfL)?
Neurodegenerative diseases are particularly challenging to study and treat due to our limited ability to access the brain. Often, by the time a disease is advanced enough that it is visible on a brain imaging scan, it is too late to intervene with any medication. As such, researchers are looking for biomarkers of brain health or disease status that can be measured outside of the brain, such as in blood or cerebrospinal fluid (CSF) samples.
About 10 years ago, scientists found a way to accurately measure levels of a neuronal protein, neurofilament (NfL), in blood. Neurofilament is a protein that is only expressed by neurons and helps make up part of their structure. When neurons are damaged or when they die, their neurofilament is released into the blood and CSF, providing a measurable indicator of neuron health.
Approval of Neurofilament as an ALS Treatment Biomarker
Since their discovery, neurofilament levels have been included as endpoints in over 100 clinical trials, but have just been acknowledged for the first time in April 2023 as a reason for a drug’s approval. Biogen and Ionis Pharmaceuticals received accelerated approval from the FDA for their drug Tofersen targeting a rare form of amyotrophic lateral sclerosis (ALS).
SOD1-associated ALS accounts for about 2% of all ALS cases and is caused by mutations in SOD1 that cause the proteins to form toxic clumps in the brain and spinal cord, killing motor neurons and causing severe, rapid disease. Tofersen is an antisense oligonucleotide drug that binds to SOD1 mRNA, ideally lowering the levels of the toxic mutated proteins and thus slowing disease progression.
Unusually, the drug’s approval is contingent on molecular markers of efficacy. After six months of treatment, ALS patients exhibited the same amount of physical decline as patients given a placebo. However, tofersen lowered levels of SOD1 in CSF and reduced levels of neurofilament in the blood, indicating it was performing its desired molecular function. The drug’s approval comes with the logic that six months may be too short to have seen a visible clinical benefit, and the FDA specifically granted accelerated approval based on the drug’s ability to lower neurofilament levels. A confirmatory trial for the drug is ongoing to hopefully translate these results into observable patient benefits.
The Future of Neurofilament
Although tofersen’s approval is an important recognition of neurofilament’s role in studying neurodegenerative disease, it’s not a complete validation of the biomarker. In spite of the popularity of NfL as a biomarker, very little is known about the exact relationship between lowering neurofilament levels and any protection from neurodegenerative disease progression.
It is important to note that as with all proteins at the center of ND disease research (like amyloid, for example), each individual protein is likely just one piece of the puzzle. ND diseases are incredibly complex and regulated by numerous interacting factors. Due to the regulatory precedent now set by the FDA, neurofilament will continue to be researched as an important factor in these complex diseases.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].