A recent study from Emory University has provided new insights into why a once-promising experimental drug for amyotrophic lateral sclerosis (ALS) did not deliver clinical benefits, despite successfully reaching its target in the central nervous system. The research was conducted by the Emory ALS Center and the Center for Neurodegenerative Disease at Emory’s Goizueta Brain Health Institute.
The drug, BIIB078, is an antisense oligonucleotide designed to block production of toxic RNA and proteins in patients with a genetic form of ALS linked to mutations in the C9orf72 gene. This mutation is recognized as the most common inherited cause of ALS. Although initial disease-specific biomarkers suggested that BIIB078 was acting on its intended target, a 2021 clinical trial was halted after patients failed to show improvement.
“Disease-specific biomarkers in the cerebrospinal fluid (CSF) suggested that the ASO was hitting its intended target, but it was not clear if it penetrated CNS tissue and affected the disease itself,” said Zachary McEachin, PhD, assistant professor of Human Genetics and lead and co-senior author. “Getting the drug to the CNS is only part of the challenge. We need better ways to know whether a treatment is truly changing the course of ALS. Our study addresses some of those questions and shows that CSF biomarkers do not always reflect changes in the CNS.”
Researchers analyzed both CSF samples collected during life and postmortem brain and spinal cord tissue from trial participants. The study involved eight individuals with C9orf72-linked ALS who received BIIB078 and 31 ALS patients who did not receive the drug.
Findings showed that while BIIB078 spread throughout the central nervous system and reduced some toxic proteins associated with ALS, it did not halt or reverse key disease processes such as abnormal protein buildup in brain tissue.
“This work is an important step forward to better understanding the biology of ASO therapies in people with neurological diseases,” said Jonathan Glass, MD, director of the Emory ALS Center and professor in the Department of Neurology at Emory University School of Medicine. “Several ASO therapies are either now in clinical use or in trial. We expect our new data will be influential in the development of new ASO-directed therapies.”
The investigators observed variability among patients’ biological responses to treatment, highlighting challenges for precision medicine approaches aimed at tailoring therapies to individual needs.
“This work utilized integrated proteomic approaches to rigorously evaluate molecular changes in both tissue and CSF following ASO therapy, providing new biomarkers of treatment and insights to better design and monitor future clinical trials,” said Nicholas Seyfried, PhD, professor of Biochemistry and co-senior author.
ALS remains a progressive condition affecting nerve cells responsible for muscle movement. Most patients live two to five years after diagnosis; effective treatments are limited. While most cases are sporadic rather than inherited, this study focused on genetic forms representing about 10% of all cases.
The researchers emphasized an urgent need for improved real-time biomarkers that can reliably indicate whether experimental treatments are having a meaningful impact on disease progression.
