Biogen, Ionis Terminate BIIB105 Following Disappointing Phase 1/2 Results


BIIB105, an antisense oligonucleotide, failed to demonstrate impact on outcomes of function, breathing, and strength, in addition to no impact on neurofilament light.

Frank Bennett, PhD, executive vice president and chief scientific officer at Ionis

Frank Bennett, PhD

Ionis and Biogen have announced topline results from the phase 1/2 ALSpire trial (NCT04494256) showing that BIIB105, an investigational agent in development for amyotrophic lateral sclerosis (ALS), did not result in the desired reduction in neurofilament light (NfL) and impact on clinical outcomes. Despite reaching target engagement in reducing expression of ataxin-2 (ATXN2) protein, the companies have decided to terminate development of the therapy, which acts as an antisense oligonucleotide (ASO).1

The trial, a randomized, placebo-controlled, dose-escalating study, included 99 participants with ALS who were randomly assigned patients 3:1 or 2:1 to either BIIB105 or placebo for 3 to 6 months. During the 6-month period, treatment with the agent resulted in statistically significant reductions in expression of ATXN2 and in cerebrospinal fluid (CSF); however, it failed to impact outcomes of function, breathing, and strength. Results remained similar for those who entered the open-label extension, with no impact on NfL or clinical outcome measures over 40+ weeks of follow-up.

"While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process," Stephanie Fradette, PharmD, head of the Neuromuscular Development Unit at Biogen, said in a statement.1 "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."

Additional analyses from the study assessing the ASO’s impact on underlying disease process of ALS are expected at the upcoming European Network to Cure ALS (ENCALS) meeting in Stockholm, Sweden, in June. According to the announcement, there were no observed benefits with BIIB105 in any specific subgroups evaluated, including those with a Poly-CAG expression in the ATXN2 gene. In terms of safety, procedural pain, headache, and falls were the most commonly observed adverse events within the first 6 months of treatment. AEs leading to study discontinuation were higher in the BIIB105 group (8.3%) compared with placebo (3.6%).

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"We are very appreciative of the people with ALS and investigators who participated in this study and were critical to advancing our scientific understanding of ALS," Frank Bennett, PhD, executive vice president and chief scientific officer at Ionis, said in a statement.1 "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."

The rationale behind BIIB105 and targeting ataxin-2 in ALS is twofold. First, polyglutamine expansions in the ataxin-2 gene increase the risk for ALS in carriers. Second, research in yeast and fly models have shown that ataxin-2 promotes aggregation and toxicity of the TDP-43 protein. TDP-43 pathology is implicated in most cases of ALS and is considered a common end point in both genetic and sporadic forms of the disease.

Observing NfL as a biomarker of efficacy became prominent when the FDA approved Biogen’s tofersen (Qalsody) as the first treatment for patients with SOD1 mutation-mediated ALS, based on reductions in NfL. The approval, which occurred in April 2023, was the first to use NfL, a biomarker of axonal injury and neurodegeneration, as a surrogate biomarker to predict clinical benefit. Tofersen, an ASO, was approved based on data from multiple studies, most notably the phase 3 VALOR trial (NCT02623699).

Ulefnersen, another investigational ASO from Biogen and Ionis, is designed to reduce the production of the fused in sarcoma (FUS) protein to treat patients with ALS caused by mutations in the FUS gene. Formerly known as ION363, this therapy is currently being investigated in the phase 3 FUSION trial, a 61-week trial that uses change in the revised ALS Functional Rating Scale as the primary end point.

1. Ionis and Biogen Announce Topline Phase 1/2 Study Results of Investigational Drug in Amyotrophic Lateral Sclerosis. News release. Ionis Pharmaceuticals. May 16, 2024. Accessed May 17, 2024.
2. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed May 17, 2024.
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