Ulefnersen meets phase 3 endpoint in genetically defined amyotrophic lateral sclerosis

The phase 3 FUSION trial has met its primary endpoint, with the RNA-targeted therapy ulefnersen demonstrating a significant benefit across a combined measure of function and survival in people with fused in sarcoma-associated amyotrophic lateral sclerosis.

Ulefnersen, an investigational antisense oligonucleotide designed to target the genetic cause of fused in sarcoma-associated amyotrophic lateral sclerosis (FUS-ALS), has met the primary endpoint of the phase 3 FUSION trial, according to topline results announced by Ionis Pharmaceuticals and Otsuka Pharmaceutical.¹

The randomized, placebo-controlled trial showed a statistically significant improvement with ulefnersen compared with placebo on a prespecified joint-rank endpoint incorporating time to death or permanent ventilation, time to rescue treatment, and change from Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score through Day 505 (p=0.0005).¹

The findings represent the first positive placebo-controlled trial of a treatment specifically targeting the underlying genetic cause of FUS-ALS.¹

What did the FUSION trial show?

FUSION (NCT04768972) is a global, multicenter, randomized, double-blind, placebo-controlled phase 1–3 study evaluating intrathecal ulefnersen in people with FUS-ALS.^1,2

During the 72-week double-blind period, participants received either ulefnersen or placebo before entering an open-label extension in which all participants receive active treatment. The primary analysis population included 73 participants.¹

In addition to meeting the primary endpoint, treatment resulted in statistically significant improvements in key secondary endpoints, including change from Baseline in serum neurofilament light chain (NfL) and time to death, permanent ventilation, rescue treatment, or withdrawal because of disease progression.¹

NfL is a marker of neuroaxonal injury that has increasingly been incorporated into studies of genetically targeted ALS therapies. However, the magnitude of the NfL reduction observed in FUSION has not yet been reported.

Other prespecified trial measures include respiratory function assessed using slow vital capacity, muscle strength, ALSFRS-R score, quality of life, cerebrospinal fluid (CSF) NfL, and CSF FUS protein.¹

Ionis and Otsuka reported that ulefnersen had a favorable safety and tolerability profile, with most adverse events described as mild or moderate. Detailed adverse-event rates have not yet been released.¹

Holly Kordasiewicz, PhD, Executive Vice President and Chief Development Officer at Ionis Pharmaceuticals, said the results support the potential for ulefnersen to modify disease progression and build on the development of genetically targeted treatments for rare forms of ALS.¹

Targeting FUS in amyotrophic lateral sclerosis

FUS-ALS is caused by pathogenic variants in the FUS gene, which encodes the RNA- and DNA-binding protein fused in sarcoma. Although FUS variants account for only approximately 0.3–0.9% of ALS overall, the disease is frequently associated with younger age at onset and can progress particularly rapidly.³

FUS variants are disproportionately represented among people who develop juvenile ALS. Certain variants, including p.Pro525Leu, are associated with an especially aggressive phenotype, and some people with early-onset disease develop respiratory failure within 1–2 years of symptom onset.^1,3

Disease-causing FUS variants can disrupt the normal localization of FUS protein and promote the accumulation of abnormal FUS in the cytoplasm of motor neurons, contributing to neurodegeneration.³

Ulefnersen is designed to bind FUS pre-messenger RNA and reduce production of both mutant and wild-type FUS protein. It is administered intrathecally to deliver the antisense oligonucleotide directly into the CSF.^1,4

Earlier data provided the first clinical signal

Evidence supporting FUS suppression as a therapeutic strategy preceded FUSION. In 2025, Prof. Shneider and colleagues reported findings from an investigator-initiated, multicenter expanded-access series involving 12 people with FUS-associated motor neuron disease who received ulefnersen, then referred to as jacifusen.⁴

Participants received serial intrathecal doses over treatment periods ranging from 2.8 to 33.9 months. CSF NfL concentrations decreased by up to 82.8% after 6 months of treatment, and analyses of postmortem central nervous system tissue showed reduced FUS protein levels and an apparent reduction in FUS pathology.⁴

Most participants continued to experience functional decline, although one showed objective functional improvement after approximately 10 months and another remained asymptomatic with improvement in electrophysiological abnormalities.⁴

Because that study was an uncontrolled expanded-access series involving only 12 participants, the investigators emphasized that efficacy could not be established from those findings alone.⁴ The randomized FUSION results therefore provide substantially stronger evidence for the therapeutic approach.

A growing role for genetically targeted therapy in amyotrophic lateral sclerosis

The results also add to growing evidence that genetically defined forms of ALS may be amenable to RNA-targeted treatment. Tofersen (Qalsody®; Biogen, Cambridge, MA, USA), an antisense oligonucleotide targeting superoxide dismutase 1 messenger RNA, received accelerated FDA approval in 2023 for adults with ALS associated with mutations in the SOD1 gene.⁵

Ulefnersen uses a conceptually similar precision-medicine strategy but targets FUS protein production. No treatment is currently approved specifically for the underlying cause of FUS-ALS.^1,3

John Kraus, MD, PhD, Executive Vice President and Chief Medical Officer at Otsuka, described the findings as a major milestone for people with FUS-ALS and said the company plans to work with regulatory authorities to advance development of the treatment.¹

What happens next?

Otsuka plans to discuss the FUSION results with the FDA and other regulatory authorities, including the possibility of expedited submission pathways.¹ Ulefnersen has already received FDA Fast Track designation for FUS-ALS and orphan drug designation for ALS from the FDA, European Medicines Agency, and Swissmedic.¹

A global early access program for eligible people with genetically confirmed FUS-ALS has also been initiated.⁶

Further prespecified and exploratory analyses of FUSION are ongoing. Ionis and Otsuka plan to present the complete results at a future medical congress and submit the findings for publication in a peer-reviewed journal.¹

The full dataset will be important for establishing the magnitude of the treatment effect on function and survival, the relationship between changes in NfL and clinical outcomes, and the longer-term safety and efficacy of FUS suppression.

References

1. Ionis Pharmaceuticals. Ionis announces positive topline results from Phase 3 FUSION study of ulefnersen marking significant milestone in advancing first potential disease modifying treatment for FUS-ALS [Press release]. September 22, 2026. Available at: https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-phase-3-fusion-study (accessed September 24, 2026).
2. ClinicalTrials.gov. A study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of ION363 in participants with FUS-ALS. ClinicalTrials.gov Identifier: NCT04768972. Available at: https://clinicaltrials.gov/study/NCT04768972 (accessed September 24, 2026).
3. Moens TG, Da Cruz S, Neumann M, et al. Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications. Lancet Neurol. 2025;24:166–78. doi:10.1016/S1474-4422(24)00517-9.
4. Shneider NA, Harms MB, Korobeynikov VA, et al. Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. Lancet. 2025;405:2075–86. doi:10.1016/S0140-6736(25)00513-6.
5. US Food and Drug Administration. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. April 25, 2023. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene (accessed September 24, 2026).
6. Otsuka Pharmaceutical Development & Commercialization. Otsuka establishes ulefnersen early access program for eligible people living with FUS-ALS [Press release]. September 22, 2026. Available at: https://www.otsuka-us.com/news/otsuka-establishes-ulefnersen-early-access-program-eap-eligible-people-living-fus-als (accessed September 24, 2026).