Ulefnersen met the Phase 3 FUSION primary endpoint in FUS-ALS, showing significant benefits versus placebo in function and survival.
Written By: Aasritha Thippavajjala, PharmD
Reviewed By: Pharmacally Editorial Team
Otsuka and Ionis reported statistically significant improvements with investigational ulefnersen versus placebo in people with FUS-associated amyotrophic lateral sclerosis (FUS-ALS), including the trial’s prespecified joint analysis of functional impairment and survival.
Phase 3 FUSION Trial Meets Primary Endpoint
The global Phase 1-3 FUSION trial (NCT04768972) met its primary endpoint, with intrathecal ulefnersen producing a statistically significant benefit over placebo in people with FUS-ALS. The primary endpoint used a prespecified joint-rank analysis combining ALS Functional Rating Scale-Revised (ALSFRS-R) change from baseline to Day 505, time to rescue, and ventilation assistance-free survival. The analysis produced a p-value of 0.0005.
The primary analysis population included 73 participants, while the overall study enrolled more than 80 people with FUS-ALS across 16 countries. Earlier enrollment reporting identified 25 clinical trial sites across those countries.
The topline result provides placebo-controlled clinical evidence for an RNA-targeted treatment directed at the genetic cause of FUS-ALS. Detailed numerical efficacy results have not yet been disclosed.
Secondary Endpoints Show Additional Benefits
Ulefnersen also produced statistically significant improvements on secondary endpoints, including change from baseline in serum neurofilament light chain (NfL) and time to the earliest occurrence of death, permanent ventilation, rescue, or withdrawal because of disease progression.
NfL is a biomarker of neuronal injury, while the composite clinical endpoint captures major disease milestones in ALS. The trial also evaluated respiratory function through slow vital capacity, muscle strength using handheld dynamometry, ALSFRS-R, quality of life, cerebrospinal fluid NfL and cerebrospinal fluid FUS protein.
Further prespecified and exploratory analyses are planned to characterize the treatment effect across these measures.
FUS-ALS Is a Rapidly Progressive Genetic ALS Subtype
FUS-ALS results from pathogenic variants in the FUS gene and represents an estimated 0.6% of ALS cases. The disease can occur in pediatric, juvenile and adult patients and is often rapidly progressive. FUS mutations are estimated to account for 43% to 52% of juvenile and pediatric ALS cases.
Mutant FUS protein can accumulate in motor neurons and contribute to neurodegeneration. In early-onset and juvenile disease, respiratory failure and death may occur within one to two years of symptom onset.
Ulefnersen is an RNA-targeted therapeutic that reduces production of FUS protein, including mutant forms implicated in FUS-ALS. The investigational therapy is administered by intrathecal injection to deliver treatment into the central nervous system.
Safety Profile Remains Favorable
Ulefnersen showed a favorable safety and tolerability profile in the FUSION study, with most reported adverse events described as mild or moderate. The September 22 topline announcement did not provide detailed event rates or a complete treatment-emergent adverse-event breakdown.
In Part 1, participants received ulefnersen or placebo during the double-blind treatment period before entering an open-label extension in which all participants receive ulefnersen. The primary analysis was based on the Part 1 population.
Regulatory Review and Early Access
Otsuka and Ionis plan to discuss the FUSION findings with the U.S. Food and Drug Administration and other global health authorities to evaluate potential expedited regulatory submission pathways for ulefnersen. Detailed FUSION results are expected to be presented at a future medical congress and submitted for publication in a peer-reviewed journal.
Otsuka also has established an Early Access Program (EAP) for eligible people with genetically confirmed FUS-ALS. The program provides a potential route to access ulefnersen before commercial regulatory approval, subject to eligibility requirements and applicable regulatory processes.
The EAP does not represent marketing authorization. Ulefnersen remains an investigational medicine and has not been approved by the FDA or any other regulatory authority.
Ulefnersen has received FDA Fast Track designation for FUS-ALS and orphan designations for ALS from the FDA, European Medicines Agency and Swissmedic.
The FUSION results therefore establish a clinical development milestone for ulefnersen while regulatory review, additional analyses and longer-term follow-up continue.
Reference
Otsuka Announces Transformative Phase 3 FUSION Results for Ulefnersen, Bringing the FUS-ALS Community Closer to a Potential Targeted Treatment, Otsuka Pharmaceuticals, 22 September 2026
FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants with Fused in Sarcoma Mutations (FUS-ALS), ClinicalTrials.gov ID NCT04768972
About the Writer
Aasritha Thippavajjala (Linkedin) is a pharm D student and aspiring medical writer with medical writing, clinical training experience and a strong interest in clinical research and patient safety She has hands-on exposure to clinical pharmacy activities including medication profile assessment, clinical case review, identification of potential drug-related problems, ADR awareness, patient counselling, and clinical documentation. She has also gained experience in medical literature review, evidence synthesis, and scientific communication through her published review article on digital twin-based patient simulation and her poster presentation at the 74th Indian Pharmaceutical Congress. Certified in ICH Good Clinical Practice (E6(R3)) and Scientific Writing in Health Research, she is passionate about applying her clinical knowledge and research skills to medical writing ,clinical research and contributing to accurate, evidence-based healthcare.