Background
Ulefnersen (also known as ION363 and previously known as Jacifusen) is an antisense oligonucleotide (ASO) compound owned by Ionis Pharmaceuticals, currently undergoing phase 1-3 clinical trial to assess safety and efficacy in FUS-ALS (Clinicaltrials.gov ID: NCT04768972). The drug previously called Jacifusen, was named after Jaci Hermstad, the first person to receive this treatment, administered under the FDA compassionate use program.
Ulefnersen is an ASO designed to target the Fused in Sarcoma (FUS) gene, which is found to be mutated in 0.3-0.9% of ALS/MND cases, often manifesting early onset and aggressive symptoms (Moens et al., 2025). Mutant FUS is thought to cause the disease through a toxic gain of function mechanism, meaning that the presence of the mutated gene and/or deriving protein harms the cells, causing the disease. Ulefnersen targets the FUS RNA transcript and prevents its translation to protein, determining a lower expression of the FUS protein (Korobeynikov et al., 2022).
Preclinical data from a FUS-ALS mouse model showed that treatment with ulefnersen led to reduced FUS protein levels and delayed motor neuron loss. Under a compassionate use/expanded access program, ulefnersen was administered to a 25-year-old woman with juvenile FUS-ALS (JH) 6 months after clinical onset. Upon treatment, her rate of functional decline score (ALSFRSR) slowed. Tragically, JH died nearly a year after initial treatment for worsening of ventilatory and bulbar dysfunction consistently with natural history of FUS-ALS. In post-mortem analysis, ulefnersen showed good distribution throughout the central nervous system (CNS) even at 2 months after the last treatment. Furthermore, in the same analysis, a reduction in FUS level was observed throughout the CNS (Korobeynikov et al., 2022).
Trial Design & Results
Based on the results from the expanded access program, the FDA allowed the initiation of a multi-centre, three-part study in up to 95 people living with FUS-ALS (Clinicaltrials.gov ID: NCT04768972).
In the first part of the trial, called FUSION, participants are randomised 2:1 (double blind) to receive Ulefnersen or placebo for 60 weeks. This will be followed by an open label extension, where all participants will be treated with Ulefnersen for 84 weeks. Participants may continue to receive Ulefnersen for up to three years or until Ulefnersen becomes commercially available in the participant’s country or until the Ulefnersen development program is discontinued.
The study started in 2021 with an estimated primary completion in 2026 and full study completion in 2028. The study is currently recruiting in 25 locations in 16 countries. Participants must be at least 10 years old, have signs and symptoms of ALS and a confirmed FUS variant. Ulefnersen will be administered by lumbar intrathecal injection (through spinal tap) every 12 weeks with an additional loading dose at 4 weeks after the first administration.
The primary outcome measure is a change from baseline in functional impairment from day 1 to day 505. Functional impairment will be measured by joint rank analysis of the combined assessment of ALSFRS-R total score, time of rescue* or discontinuation from part 1 and entering part 2 due to a deterioration in function, and ventilation assistance-free survival (VAFS). Secondary outcomes include a change in quality of life as assessed by ALSSQOL-R, slow vital capacity, handheld dynamometry, neurofilament light concentration in CSF, and FUS concentration in CSF.
Although the full trial results have not yet been published, a recent report highlighted promising outcomes in at least two of the 12 people treated with Ulefnersen. However, aside from these two cases, most participants continued to show functional decline (Shneider et al., 2025).
Summary
Ulefnersen is an ASO treatment for FUS-ALS. Several people have been treated with Ulefnersen under the FDA expanded access program, the phase 1-3 clinical FUSION trial is currently recruiting more individuals living with FUS-ALS internationally.
The Alliance will continue to update this document with new information as they become available.
International Alliance of ALS/MND Associations
September 2024
*Rescue takes place if there is a deterioration to an ALSFRS-R total score of < 20 points at Study Day 253, or later, that is confirmed after an interval of at least (https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-005522-28/NL)
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.
SOURCES
Moens et al., 2025 – https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00517-9/abstract
Clinicaltrials.gov ID: NCT04768972 – https://clinicaltrials.gov/study/NCT04768972?cond=ALS%20-%20Amyotrophic%20Lateral%20Sclerosis&term=ION363&rank=1
ALS news today: Eight FUS-linked ALS Patients to Get Experimental Jacifusen
Nature medicine paper: Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis | Nature Medicine
Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, Jafar-Nejad P, Shneider NA. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022 Jan;28(1):104-116. doi: 10.1038/s41591-021-01615-z. Epub 2022 Jan 24. PMID: 35075293; PMCID: PMC8799464.
Shneider et al., 2025 – https://pubmed.ncbi.nlm.nih.gov/40414239/