Discontinued therapy BIIB078 not effective in ALS, trial data show
Experimental treatment safe, well tolerated in Phase 1 study
The investigational therapy BIIB078 was generally well tolerated in a Phase 1 clinical trial, but did not show evidence of slowing disease progression in people with amyotrophic lateral sclerosis (ALS) caused by mutations in the C9orf72 gene, according to recently published data from the trial.
Because the trial failed to demonstrate evidence of BIIB078’s clinical benefit, the therapy’s development was discontinued in 2022. Still, researchers said the detailed study findings “will be informative in furthering our understanding of the complex [disease mechanisms] of C9orf72-associated ALS.”
The study, “Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study,” was published in The Lancet Neurology. It was funded by Biogen, which had been collaborating with Ionis Pharmaceuticals on BIIB78’s development.
Mutations in the C9orf72 gene are the most common genetic cause of ALS, estimated to underlie about 50% of familial ALS cases and up to 10% of sporadic cases.
ALS-causing mutations in C9orf72 are usually hexanucleotide repeat expansions, where a string of six nucleotides — the building blocks of DNA — are repeated excessively in the genetic code. This disrupts normal production of the C9orf72 protein, ultimately causing neurodegeneration.
Targeting abnormal protein production
BIIB078 was a type of therapy called an antisense oligonucleotide (ASO), and was designed to suppress the production of abnormal forms of the C9orf72 protein. ASOs are short strands of genetic material that bind to a gene’s messenger RNA — the template molecule used to produce a protein — and target it for degradation.
The Phase 1 trial (NCT03626012) tested the treatment’s safety and tolerability in 106 adults with C9orf72-associated ALS. Its goal was to “provide information regarding whether BIIB078 should move into later stages of drug development, and if so, at what dose,” according to the researchers.
Participants were randomly assigned to receive BIIB078 at a dose of 5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg — or a placebo — given via injection into the spinal canal. Participants received three loading doses, given two weeks apart, followed by once-monthly maintenance dosing for three to six months.
As previously reported, the therapy was generally well tolerated, with most adverse events being mild or moderate in severity. The most common ones in BIIB078-treated patients included falls, pain associated with the injections, headache, and post lumbar puncture syndrome, which happens when spinal fluid leaks into nearby tissues and causes a headache.
No serious adverse events or deaths were deemed related to the medication. Pharmacological experiments indicated that the therapy led to reductions in mutant versions of C9orf72.
However, across measures of overall disease severity, lung function, muscle strength, and tongue strength, there was no evidence that BIIB078 significantly slowed disease progression at any dose. The treatment also did not ease fatigue or improve life quality.
Patients treated at the 90 mg dose experienced numerically greater clinical worsening compared with the placebo group, although the study was not designed to look for statistical differences in these measures. These patients also showed greater increases in blood and spinal fluid levels of neurofilament light chain (NfL), a biomarker of nerve damage, compared to placebo.
According to the scientists, such elevations in NfL are “generally accepted as evidence that the drug was worsening axonal [nerve cell] injury and neurodegeneration.”
This finding, along with a failure to influence clinical outcomes, informed the decision to stop the treatment’s development.
The scientists noted that similar trends continued to be observed in the trial’s open-label extension study, which was ongoing but terminated when the decision to stop development was made.
Still, the study’s findings offer pathways for learning more about the mechanisms of C9orf72- associated ALS, the researchers said.
“Ongoing analysis of post-mortem tissue from trial participants could help to further our understanding of the underlying disease pathophysiology and effects of BIIB078,” they wrote.
The ongoing collaboration between Biogen and Ionis yielded Qalsody (tofersen), an ASO-based treatment that was approved in the U.S. last year for patients with mutations in the SOD1 gene.
More recently, the two companies stopped development of BIIB105, another experimental ASO treatment they were developing for ALS, after early-stage trial data failed to show a clinical benefit relative to a placebo.
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