Ulefnersen demonstrates efficacy against a rare genetic form of ALS following positive results from the Phase 3 FUSION clinical trial

Otsuka and Ionis Pharmaceuticals have announced positive Phase 3 results for Ulefnersen, demonstrating efficacy against the progression of amyotrophic lateral sclerosis (ALS) and further highlighting the potential of personalized therapies for the treatment of genetic forms of the disease.

Ulefnersen is an antisense oligonucleotide (ASO) targeting FUS, a gene in which variants cause approximately 4% of genetic ALS cases, corresponding to around 0.6% of all ALS patients. FUS-associated ALS is generally characterized by an early onset and rapid disease progression. The therapy works by reducing the expression of the mutant FUS protein, which is toxic to motor neurons. Its mechanism of action is based on the same principle as tofersen (Qalsody, Biogen), which targets mutant SOD1, accounting for approximately 2% of ALS cases.

The first results from the Phase 3 FUSION trial, announced by Ionis and Otsuka on September 22, 2026, showed a statistically significant improvement in both survival and functional disease progression in people with FUS-associated ALS. In addition, the trial’s secondary endpoints were also met, including a reduction in serum neurofilament levels, a biomarker of neuronal injury, as well as a delay in the need for permanent ventilation. Ionis and Otsuka also reported a favorable safety profile, with relatively mild adverse events.

This therapeutic approach is based on the hypothesis that FUS mutations cause a toxic gain of function in motor neurons. This hypothesis was demonstrated in 2016 by research of Professor Neil Shneider at Columbia University, in the United States,  and of Dr. Luc Dupuis, a founding member of the Institut Charcot, in collaboration with Erik Storkebaum and Clotilde Lagier-Tourenne. This finding was subsequently confirmed by other laboratories worldwide. In France, research conducted by Dr. Luc Dupuis has received extensive funding from ARSLA, which has been supporting patients and stimulating ALS research for more than 40 years.

In 2020, Professor Shneider developed jacifusen to treat Jaci Hermstad, who was suffering from a rapidly progressive form of FUS-associated ALS. Following encouraging results from this initial treatment and a subsequent investigator-initiated open-label study, the molecule, renamed ulefnersen during its clinical development was taken forward in 2021 by Ionis Pharmaceuticals – later joined by Otsuka – for evaluation in the Phase 1–3 FUSION clinical trial, the results of which have now been announced.

Following these positive results, Otsuka announced that discussions would be initiated with regulatory authorities to seek an accelerated marketing authorization.

« I am thrilled by the news that the FUSION trial met its primary clinical endpoint – an historic result that has significant impact beyond the relatively few ALS patients who will benefit directly from this antisense drug. This is what success looks like in ALS, and I am confident that other successes will follow for ALS and other neurodegenerative disorders. »

Pr. Neil Shneider

Claire Tow Professor of Motor Neuron Disorders (Neurology)

Director, The Eleanor and Lou Gehrig ALS Center

Department of Neurology and the Claire Tow Center for Motor Neuron Biology and Disease

Columbia University – Vagelos College of Physicians and Surgeons

Building on the FUS ALS program, Professor Neil Shneider established the Silence ALS initiative in 2022 in partnership with the n-Lorem Foundation to develop individualized ASOs for patients with ultra-rare genetic forms of ALS. The Institut Charcot, supported by ARSLA and the Institut Imagine, has initiated discussions with Professor Shneider with the aim of helping advance the development of these personalized therapies for rare genetic forms of ALS and facilitating access to these treatments for French patients.

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Sources

Otsuka, “Otsuka Announces Transformative Phase 3 FUSION Results for Ulefnersen, Bringing the FUS-ALS Community Closer to a Potential Targeted Treatment”, Otsuka US.

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Erratum in: Lancet. 2025 Aug 23;406(10505):810. doi: 10.1016/S0140-6736(25)01721-0. PMID: 40414239; PMCID: PMC12407188.