Trial of BIIB105 Enrolling Patients With or Without ATXN2 Mutations

ALS study of therapy targeting ataxin-2 protein to lower TDP-43 protein levels

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration alerting readers to an enrolling clinical trial.

A Phase 1/2 clinical trial is investigating the long-term safety and tolerability of BIIB105, Biogen‘s investigational treatment targeting the ataxin-2 protein, in people with amyotrophic lateral sclerosis (ALS).

Called ALSpire (NCT04494256), the trial is currently recruiting adults with ALS at 12 sites in the U.S., Canada, and Europe. Additional trial sites — two in the U.S. and one in Spain — are planned to open early next year.

The study’s design and goals were recently discussed by Jonathan Glass, MD, a professor at Emory University’s School of Medicine and director of the Emory ALS Center, one of the trial’s active sites, at the annual meeting of the Northeast Amyotrophic Lateral Sclerosis (NEALS) Consortium. His oral presentation was titled, “The ALS Spire Study: For People with ALS.”

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TDP-43 protein at toxic levels in majority of ALS patients

Toxic buildup of the TDP-43 protein in nerve cells is evident in about 95% of ALS patients, and it is thought to contribute to nerve cell dysfunction and death. Studies in yeast and flies suggest that targeting the ataxin-2 protein may be a promising way to prevent TDP-43 toxicity.

Mutations in ATXN2 — the gene responsible for making ataxin-2 — have also been identified as a genetic risk factor for ALS. Specifically, the mutations involve an unusually greater repetition of a trio of nucleotides, or DNA building blocks, than is usually seen in people. These repetitions cause too many copies of an amino acid called glutamine to be inserted into the ataxin-2 protein.

Notably, the presence of intermediate-length repetitions of this sequence, called polyglutamine (polyQ) repeat expansions, is linked to a higher risk of ALS, and studies also suggest that a higher number of repetitions may be associated with poorer survival.

Preclinical work in a mouse model of TDP-43-associated ALS also demonstrated that blocking the ataxin-2 protein can prolong the animals’ survival and slow disease progression.

BIIB105 is an antisense oligonucleotide that works to reduce the amount of ataxin-2 in cells. It does this by binding to ataxin-2’s mRNA — the intermediate molecule that’s produced from the gene and needed for protein production — causing its degradation and preventing ataxin-2 from being made.

Because ataxin-2 is involved in the abnormal buildup of TDP-43, BIIB105 is expected to prevent TDP-43 from forming abnormal protein clumps and causing nerve cell toxicity in ALS, slowing disease progression.

ALSpire, a two-part and dose-escalating study, is investigating BIIB105’s safety and tolerability in about 108 ALS patients with or without polyQ repeats in the ATXN2 gene.

In its first part, patients are randomly assigned to one of four doses of BIIB105 or a placebo, injected directly into the spinal canal (intrathecal injection).

Participants in the first three dosing groups (groups A, B, and C) were treated over the course of three months. These patients have completed treatment and entered into the trial’s second part — an open-label and long-term extension phase — where all are receiving BIIB105 at the third dose level, Glass said in his presentation.

ALSpire trial enrolling final patient group at sites globally

A fourth dosing group, called group D, now is recruiting up to 48 adults with ALS and 18 adults with polyQ ALS, who will be randomly assigned to BIIB105 or a placebo for six months. Group D patients who finish this first part also will enter the trial’s open-label phase and be treated at the highest dose.

According to Glass, eight ALS patients and three with polyQ ALS have been enrolled to date in this fourth dosing group. Eligible ALS patients are those without known SOD1 and FUS gene mutations, both linked to this disease, or a family history of SOD1/FUS ALS.

ALSpire’s collective goal is to determine the long-term safety and tolerability of BIIB105. Secondary endpoints include assessments of the treatment’s pharmacokinetics — its movement into, through, and out of the body — as well as biomarker levels and measures of disease progression.

Researchers also plan to assess the impact of an earlier start to treatment — those randomized to BIIB105 treatment in the trial’s first part — versus a delayed start, or patients initially on a placebo who start on active treatment three-to-six months later in the study’s second part.

ALSpire is due to conclude in July 2026.

Biogen is also developing tofersen as a potential treatment for ALS patients with SOD1 mutations. Clinical trial data presented at NEALS showed the therapy, given early, has the ability to slow disease progression.

An ongoing Phase 3 trial, called ATLAS (NCT04856982), is evaluating tofersen in people with SOD1 mutations who have not yet developed ALS symptoms. Also discussed in a presentation at NEALS, this study’s goal is to assess whether one year of tofersen treatment can delay the emergence of symptoms compared with a placebo.

ATLAS is recruiting up to 150 adults at sites globally and is expected to conclude in August 2027.