Why the ALS Drug BIIB078 Failed Despite Target Engagement

A recent study conducted by Emory University’s ALS Center and the Center for Neurodegenerative Disease at the Goizueta Brain Health Institute sheds light on why the experimental ALS medication BIIB078 did not deliver expected clinical benefits, despite successfully reaching its target within the central nervous system (CNS). The research, published in the journal Cell, focused on a genetic form of amyotrophic lateral sclerosis (ALS) linked to the C9orf72 gene, which is the most common inherited cause of the disease.

BIIB078 is an antisense oligonucleotide (ASO), a synthetic genetic material designed to hinder the production of toxic RNA and proteins associated with ALS. The clinical trial was halted in 2021 after patients showed no significant clinical improvement. Although cerebrospinal fluid (CSF) biomarkers indicated that the drug engaged its target, it remained unclear whether the drug penetrated CNS tissues effectively and impacted the disease process.

Researchers analyzed CSF samples collected during patients’ lifetimes along with postmortem brain and spinal cord tissues from eight individuals with C9orf72-linked ALS who received BIIB078, and 31 ALS patients who did not. They observed that, although BIIB078 dispersed throughout the CNS and reduced some toxic proteins, it did not alter the fundamental disease mechanisms, such as the accumulation of abnormal brain proteins driving ALS progression.

The study emphasizes that simply achieving the drug’s presence in the CNS is insufficient; effective treatment must influence disease pathways. Variability in individual responses to the therapy was also noted, underscoring the importance of personalized approaches in future therapeutic development.

This research highlights the need for improved biomarkers that can accurately reflect disease changes in real time, which is essential for evaluating the efficacy of experimental treatments. Co-senior author Jonathan Glass from Emory states that understanding the biological effects of ASO therapies is crucial as multiple similar therapies are in clinical trials or already in use. The findings serve as a critical step toward designing more effective gene-targeted treatments for neurodegenerative diseases.

In summary, while BIIB078 was capable of reaching parts of the CNS and reducing some toxic proteins, it did not modify key disease processes in ALS. These results suggest that future therapies should not only target drug delivery but also effectively interfere with the pathological mechanisms of ALS, highlighting the importance of developing better biomarkers for monitoring treatment effects.