NEW YORK – Biogen and Ionis Pharmaceuticals on Thursday announced that they are discontinuing development of an investigational antisense oligonucleotide (ASO) for amyotrophic lateral sclerosis (ALS) on the heels of disappointing results from a randomized-controlled Phase I/II trial.
BIIB105/ION541, which the companies were codeveloping, was designed to lower expression of ATXN2, a protein whose function is largely unknown. However, Biogen and Ionis were betting on ATXN2's link to TDP-43, a protein that aggregates in motor neurons in many patients with ALS. In preclinical models, BIIB105 had shown signs it could prevent or reverse TDP-43 toxicity by targeting ATXN2.
But in an analysis of data from the Phase I/II ALSpire trial, investigators found that although the drug significantly reduced levels of ATXN2 in cerebrospinal fluid, it did not improve patients' clinical outcomes or reduce plasma neurofilament light chain (NfL). Biogen had used the NfL biomarker, which is related to neurodegeneration and axonal injury, as a surrogate endpoint in the trial that supported the accelerated approval of a different ALS treatment, Qalsody (tofersen), also developed by Ionis.
Additionally, in the ALSpire study of BIIB105/ION541, there was no evidence the treatment benefited any of the subgroups, including patients with certain mutations in the ATXN2 gene.
Separately on Thursday, Cambridge, Massachusetts-based Biogen announced that it would not exercise an option to license and lead development of BIIB121/ION582, yet another ASO it had been advancing with Ionis to treat Angelman syndrome. This genetic condition is caused by mutations in the UBE3A gene, and the ASO drug is designed to treat the condition by restoring expression of the protein that the UBE3A gene encodes, ubiquitin protein ligase E3A.
Carlsbad, California-based Ionis on the same day reported top-line results from the open-label Phase I/IIa HALOS trial, which showed signs that the drug improved cognition, communication, and motor function. Ionis said it plans to move the drug into a pivotal trial independently, without a partner.
Biogen and Ionis continue to collaborate on other investigational treatments for Alzheimer's disease, Parkinson's disease, spinal muscular atrophy, and multiple system atrophy.