Ulefnersen Meets Primary End Point in Phase 3 FUSION Trial for FUS-ALS

Otsuka Pharmaceutical and Ionis Pharmaceuticals announced positive topline results from the phase 3 FUSION trial (NCT04768972) evaluating ulefnersen, an investigational antisense oligonucleotide (ASO), in patients with a rare genetic subtype of amyotrophic lateral sclerosis (ALS) driven by mutations in the fused in sarcoma (FUS) gene, known as FUS-ALS.¹

According to the companies, the trial met its primary end point, showing a statistically significant improvement on a composite measure of functional decline and survival, marking the first placebo-controlled clinical evidence for an agent designed to target the underlying genetic cause of the disease. Otsuka and Ionis noted plans to share full results with the FDA and other regulators and to present detailed findings at a future medical congress and in a peer-reviewed publication.

“Today’s Phase 3 FUSION topline results mark a major milestone for people living with FUS-ALS, re-shaping what is possible for a community that has long faced this devastating disease with limited treatment options,” John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka, said in a statement.¹ “As the first FUS-ALS clinical trial to meet its primary endpoint, FUSION provides compelling evidence that a targeted genetic approach may help alter the course of disease. We are committed to working closely with health authorities to advance ulefnersen with urgency and scientific rigor and remain committed to advancing meaningful treatments for patients with significant unmet needs across neurology and rare diseases, including ALS.”

FUSION is a global, multicenter, randomized, double-blind, placebo-controlled phase 1-3 trial that assigned participants to intrathecal ulefnersen or placebo during a 72-week double-blind period (Part 1), followed by an open-label extension in which all participants received active treatment (Part 2). The primary end point used a joint-rank analysis combining time to death or permanent ventilation, time to rescue, and change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score through day 505.

Overall, ulefnersen showed a statistically significant benefit on this composite measure compared with placebo (P = .0005), based on the Part 1 cohort. Secondary end points, including change in serum neurofilament light chain (NfL) and a composite time-to-event measure incorporating death, permanent ventilation, rescue, or withdrawal because of progression, also favored treatment. The companies described the safety profile as favorable, with most adverse events mild or moderate.

READ MORE: RIPK1 Inhibitor Fails to Slow Functional Decline in Phase 2 ALS Trial

FUS-ALS accounts for an estimated 0.6% of ALS cases overall but a disproportionate share of pediatric and juvenile-onset disease, with FUS variants implicated in an estimated 43% to 52% of cases in that population.² The disease typically presents with rapid progression, and early-onset cases can progress to respiratory failure and death in 1 to 2 years of symptom onset. No therapy targeting the underlying FUS mutation has previously been approved.

Ulefnersen, also known by its earlier name jacifusen, was designed to bind FUS pre-mRNA and reduce production of both wild-type and mutant FUS protein, limiting accumulation of toxic protein species in motor neurons. Clinical interest in the compound was shaped substantially by an investigator-initiated, open-label case series of 12 patients treated under expanded-access protocols, published in The Lancet, which reported reductions in CSF NfL of up to 83% and, in 2 participants, meaningful functional recovery.³

“These groundbreaking results offer hope for the FUS-ALS community and represent an exciting milestone in our efforts to transform the treatment of this rare, rapidly progressive and fatal form of genetic ALS,” Holly Kordasiewicz, PhD, executive vice president, chief development officer, Ionis, said in a statement.¹ “Ulefnersen is the first investigational medicine to demonstrate a statistically significant benefit in a Phase 3 trial using a prespecified joint-rank analysis that combines assessments of function and survival, supporting ulefnersen’s potential to meaningfully modify disease progression.

“These unprecedented findings demonstrate the power of our science and technology for neurological diseases and build on our experience in rare genetic forms of ALS. We believe ulefnersen has the potential to be a transformative medicine for people living with FUS-ALS and are deeply grateful to the clinical trial participants and their families, investigators and advocates whose participation made this advance possible,” Kordasiewicz added in a statement.¹

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REFERENCES
1. Otsuka Announces Transformative Phase 3 FUSION Results for Ulefnersen, Bringing the FUS-ALS Community Closer to a Potential Targeted Treatment. News release. Otsuka. September 22, 2026. Accessed September 22, 2026. https://www.otsuka-us.com/news/otsuka-announces-transformative-phase-3-fusion-results-ulefnersen-bringing-fus-als-community
2. Moens TG, Da Cruz S, Neumann M, Shelkovnikova TA, Shneider NA, Van Den Bosch L. Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications. Lancet Neurol. 2025;24(2):166-178. doi:10.1016/S1474-4422(24)00517-9
3. 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(10494):2075-2086. doi:10.1016/S0140-6736(25)00513-6