FDA scientists weigh potential effect of Biogen ALS drug ahead of advisory meeting
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Although a pivotal trial failed to meet its primary and second endpoints, data indicates that Biogen's (NASDAQ:BIIB) amyotrophic lateral sclerosis (ALS) candidate tofersen may benefit those with the neurodegenerative disease, FDA scientists say.
The primary endpoint was clinical function with the ALS Functional Rating Scale-Revised (ALSFRS-R) total score.
In briefing documents posted Monday ahead of a Wednesday FDA advisory committee meeting, the scientists noted that while there was no significant difference between the treatment and placebo groups in the endpoints, biomarker assessments were more promising.
These biomarkers are SOD1 protein in cerebrospinal fluid ("CSF") concentrations and neurofilament light chain (NfL) in plasma. The latter is a marker of neuroaxonal damage and can predict disease progression.
Tofersen is aimed at patients with mutations in the superoxide dismutase 1 (SOD1) gene, which accounts for ~20% of familial cases and 2% of sporadic cases.
The drug is designed to bind and degrade SOD1 mRNA to reduce synthesis of SOD1 protein. None of the handful of approved ALS therapies target SOD1.
A reduction in CSF SOD 1 protein was observed at week 28 in the tofersen group compared to the placebo group, while a 55% reduction was seen in NfL plasma reduction at the same time.
"This is a situation where there is a negative clinical study that failed to show a statistically significant treatment effect in the prespecified primary analysis population," the FDA team wrote.
"The study, as designed, was markedly underpowered and thus limited in its ability to detect a difference if there was a drug effect; however, there are available data from that study that indicate target engagement of the therapy and a reduction in a biomarker that has been shown to be correlated with disease progression and prognosis in patients with ALS."
The scientists also noted that since the pivotal trial was conducted, there is a better understanding of the role NfL plays in ALS. Also, the decline in SOD1 protein is indicative of target engagement. 
"Post-hoc analysis suggest a correlation between the reduction in NfL in the treatment group with change from baseline in ALSFRS-R. Additional analyses by the Applicant, including a causal inference analysis, suggest that reduction in plasma NfL is associated with reduction in the decline of ALSFRS-R total score at Week 28."
Tofersen, which is being developed with Ionis Pharmaceuticals (NASDAQ:IONS), has an FDA action date of April 25.