Background

BIIB105 is an antisense oligonucleotide (ASO). It binds the mRNA for ataxin-2 and mediates its degradation, which results in lower ataxin-2 protein levels. BIIB105 was being developed to treat amyotrophic lateral sclerosis. 

The rationale for targeting ataxin-2 in ALS is twofold. First, polyglutamine expansions in the ataxin-2 gene increase carriers' risk for ALS. Second, work in yeast and fly models found that ataxin-2 promotes aggregation and toxicity of the TDP-43 protein (Elden et al., 2010). TDP-43 pathology is seen in almost all cases of ALS and is considered a common endpoint in both genetic and sporadic forms of the disease. Thus, decreasing ataxin-2 expression with an ASO could potentially benefit most people with ALS.

In contrast, other ASOs in development for ALS target inherited mutations in SOD1 (tofersen), C9ORF72 (BIIB078), or FUS (ION363) and, as such, are applicable only to the minority of patients with those genetic causes.

In preclinical work, an ataxin-2 ASO made at Ionis extended survival and improved motor function in a mouse model of TDP-43 proteinopathy (Becker et al., 2017). The ASO also delayed onset of symptoms and improved motor function in a mouse model of spinal cerebellar ataxia caused by polyglutamine expansion of the ataxin-2 gene (Scoles et al., 2017; Scoles and Pulst, 2018).

Findings

In September 2020, Biogen began a Phase 1 study to evaluate the safety and tolerability of BIIB105. Seventy people with ALS, with or without polyglutamine expansions in ataxin-2, were randomized to receive one of four doses or placebo by intrathecal injection. The multiple dosing schedule called for three loading injections one day apart, and two maintenance injections on later days over six months. The primary outcome was adverse events, with pharmacokinetics as a secondary outcome. In 2022, the companies upgraded the trial, now called ALSpire, to Phase 1/2, increased enrollment to 99, and added efficacy endpoints as well as a long-term extension. Participants in the two-year, open-label phase were to receive two or three loading doses plus 25 maintenance doses. Secondary outcomes were updated to include changes in the plasma biomarker neurofilament light chain, as well as clinical progression measured by the revised ALS Functional Rating Scale, muscle strength, time to needing permanent breathing assistance, and time to death. The study, ongoing at 13 sites in the U.S., Canada, Italy, and the Netherlands, was set to run through July 2026.

On May 16 2024, Biogen and Ionis announced they would discontinue development of BIIB105, based on negative topline results from this study (press release). While BIIB105 significantly reduced CSF ataxin-2 protein levels compare to placebo, it did not affect plasma neurofilament light chain, or clinical measures of function, breathing, and strength. Biomarker and efficacy data were similar after more than 40 weeks of follow-up in the open-label extension. The most common adverse events were pain due to the injections, headache, and falls.

For details, see clinicaltrials.gov.