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.

“We are profoundly grateful to the patients, carers, families, investigators and study teams whose commitment made this study possible,” Kunal Gandhi, MD, MPH, Vice President, Head of Global Clinical Development, at Otsuka, told NeurologyLive^®. “These findings represent a major advancement for people living with FUS-ALS, a rare and often rapidly progressive genetic form of ALS. There are currently no approved therapies specifically targeting the underlying genetic cause of FUS-ALS, underscoring the significant unmet need for effective treatment options. 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.”

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.

“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.”

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 is an investigational RNA-targeted medicine designed to bind FUS pre-messenger RNA (pre-mRNA) and reduce the production of FUS protein in people with FUS-ALS. Through reduction of FUS mRNA levels, ulefnersen is intended to decrease production of FUS protein, including the mutant forms that contribute to motor neuron degeneration in FUS-ALS,” Gandhi told NeurologyLive. “By targeting the underlying genetic cause of FUS-ALS, ulefnersen represents a potential FUS-targeted therapeutic approach.”

“Ulefnersen is administered via intrathecal injection, allowing direct delivery to the central nervous system. Ulefnersen is an investigational product and has not been approved by the U.S. FDA or any regulatory authority worldwide,” Gandhi added. 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

“Further prespecified and exploratory analyses of the data will be conducted to determine the full potential of ulefnersen for the treatment of FUS-ALS. We plan to review the results of the FUSION trial with the FDA and continue discussions with other health authorities globally to enable potential expedited regulatory submission pathways for ulefnersen,” Gandhi told NeurologyLive.

“Additional analyses from FUSION and the ongoing open-label extension will provide further information on the longer-term efficacy and safety of ulefnersen in people living with FUS-ALS,” Gandhi added. “Detailed results from the FUSION trial will be presented at a future medical congress and submitted for publication in a peer-reviewed journal in the coming months to advance understanding of ALS and inform future research by Otsuka and the broader scientific community.”

Click here for more of our neuromuscular disorder coverage.

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