Biogen, Ionis to stop development of BIIB105 as treatment for ALS

Lack of benefit found in Phase 1/2 trial leads to companies' decision

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Biogen and Ionis Pharmaceuticals have decided to terminate the development of BIIB105, their experimental treatment for amyotrophic lateral sclerosis (ALS), based on data from a Phase 1/2 clinical trial.

The therapy resulted in no significant clinical benefit compared with a placebo after six months, and data from the open-label extension part of the trial, which evaluated BIIB105 for about nine months, also showed no evidence of an impact on clinical outcome measures, according to a press release issued by the two companies.

Further, among trial participants, more adverse events were seen with the treatment for ALS than with the placebo, the release stated.

Analyses of trial data — to further understand underlying disease processes and the effects of BIIB105 in ALS — are ongoing and will be presented next month at the upcoming European Network to Cure ALS (ENCALS) meeting in Stockholm.

“We are deeply grateful for the contributions of the study participants and remain committed to developing treatments that can meaningfully change the disease trajectory for people living with ALS,” said Stephanie Fradette, head of Biogen’s neuromuscular development unit.

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ALSpire trial tested safety, tolerability of BIIB105

Several genetic mutations have been associated with an increased risk of developing ALS — including one alteration in the ATXN2 gene. Mutations in this gene involve an unusually higher repetition of a trio of nucleotides, or DNA building blocks, causing too many copies of an amino acid called glutamine to be inserted into the ataxin-2 protein.

Regardless of whether ATXN2 is mutated or not, studies have suggested that the ataxin-2 protein may be targeted to prevent the toxic accumulation of TDP-43 protein clumps — which is observed in nearly 97% of all ALS cases.

Preclinical data supports this, demonstrating that blocking ataxin-2 in a mouse model of TDP-43-related ALS led to slower disease progression and longer survival times.

BIIB105 is an antisense oligonucleotide, or ASO, designed to reduce the amount of ataxin-2 in cells by binding and promoting the degradation of its messenger RNA — the intermediate molecule derived from the gene that’s used to guide protein production.

The ALSpire Phase 1/2 clinical trial (NCT04494256) was launched in 2020 to investigate the safety and tolerability of BIIB105 in about 99 adults with ALS, with or without mutations in the ATXN2 gene.

In a first part, participants were randomly assigned to receive either BIIB105 or a placebo, administered directly into the spinal canal (intrathecal injection), for three to six months.

Then, those who completed the placebo-controlled period were eligible to enroll in the open-label extension, in which all would receive the treatment for ALS for as long as three years.

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Results from the first part showed the therapy significantly reduced ataxin-2 levels in the spinal fluid, indicating it was working as intended.

However, no reductions in neurofilament light chain (NfL) levels, a marker of nerve damage, were observed, and BIIB105 also had no impact on measures of disability, breathing, and muscle strength over this period.

The most common side effects reported in people who received BIIB105 in this part included pain associated with the injection, headache, and fall. But according to the release, side effects or “[adverse events] leading to study discontinuation” occurred more frequently in the BIIB105 group (8.3%) than among those treated with the placebo (3.6%).

“While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process,” Fradette said.

Treatment over more than 40 weeks in the open-label extension part of the study led to similar results, with patients experiencing sustained reductions in ataxin-2 levels, but no significant changes in NfL or clinical measures of efficacy.

BIIB105 did not slow the disease process.

The absence of benefit was observed in all analyzed patient groups, including those with mutations in the ATXN2 gene.

The ongoing collaboration between the two companies has resulted in other ASO candidates for ALS, including the now-approved treatment Qalsody (tofersen) for people with SOD1 mutations. However, in 2022, the companies also discontinued development of another treatment candidate called BIIB078 for C9orf72-associated ALS, after a Phase 1 trial found no significant clinical benefit compared with a placebo. BIIB078 had been shown to be generally safe and well tolerated in that trial.

Ionis also is working on a similar therapy called ulefnersen, previously known as ION363, for people with mutations in the FUS gene.

“Ionis continues to be committed to the ALS community and is advancing our Phase 3 ulefnersen program for people with the genetic form of the disease known as FUS-ALS,” said Frank Bennett, PhD, Ionis’ executive vice president and chief scientific officer.