In latest ALS setback, Biogen and Ionis axe BIIB105 programme
OligonucleotidePhase 1
In a disappointing but familiar outcome, another drug under development for amyotrophic lateral sclerosis (ALS) has been scrapped after a clinical study letdown. The latest casualty is Biogen and Ionis Pharmaceuticals' BIIB105, an antisense oligonucleotide designed to reduce expression of the ataxin-2 (ATXN2) protein thought to play a role in ALS pathogenesis.
The decision to abandon the programme was based on results from the Phase I/II ALSpire study in 99 adults with ALS. Over the six-month, placebo-controlled period, treatment with BIIB105 did not result in a reduction in plasma neurofilament light chain (NfL) levels, a biomarker of neurodegeneration and neuronal damage. Nor did it demonstrate any impact on clinical measures of function, breathing ability or muscle strength.
Longer-term data showed sustained ATXN2 reductions, but no changes in NfL or clinical outcomes over 40-plus weeks. No subgroup benefits were observed either, including in those with Poly-CAG expansion in the ATXN2 gene. "While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process," stated Stephanie Fradette, who heads neuromuscular development at Biogen.
Familiar story in ALS
The termination of BIIB105 represents another failure for Biogen and Ionis, and the ALS space as a whole. In 2022, the companies terminated the ALS candidate BIIB078, an antisense drug targeting C9orf72 mutations, after it missed key efficacy goals in a Phase I study. Biogen later also pulled the plug on BIIB100, an XPO1 inhibitor also known as KPT-350 that was being evaluated as part of a 2018 collaboration with Karyopharm Therapeutics worth up to $217 million.
However, Biogen scored a win last year with the FDA accelerated approval of Qalsody (tofersen) for the rare SOD1 genetic form of ALS. Despite this, the broader ALS patient population awaits a disease-modifying therapy. Earlier this year, Amylyx Pharmaceuticals followed through on its promise to pull the ALS drug Relyvrio (sodium phenylbutyrate/taurursodiol) from the market after it failed the confirmatory PHOENIX trial. For more, see – KOL Views Q&A: Leading neurologist outlines where ALS field goes next after Amylyx's Relyvrio failure.
Biogen passes on Angelman therapy
In a separate statement, Biogen said it also decided not to take up its option to license and spearhead development of BIIB121 (ION582), Ionis’ antisense oligonucleotide designed to restore expression of ubiquitin-protein in patients with Angelman syndrome. The move was made despite Ionis reporting Thursday that the therapy showed “encouraging and consistent benefits” in the Phase I/IIa HALOS study.
According to Ionis, the most robust improvements in the trial were observed in key areas of functioning including cognition, communication and motor function. Brett Monia, the company’s chief executive, said “we look forward…to advancing ION582 into a pivotal study,”
Analysts at Stifel Nicolaus expressed surprise at Biogen’s decision “given how sparse” its pipeline is “with credible/exciting opportunities.” However, they conceded that with a lack of data in Ionis’ announcement, there remain a lot of unknowns, surmising that BIIB121’s magnitude of benefit over natural history in the study likely “isn't massive.”
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