- Ulefnersen demonstrated a statistically significant improvement versus placebo on the primary endpoint assessing functional impairment and survival in people living with FUS-ALS, supporting the potential to modify disease progression
- Secondary endpoints findings provided additional support for the benefit of ulefnersen treatment in FUS-ALS
- Ulefnersen demonstrated a favorable safety and tolerability profile, with most adverse events being mild or moderate in severity
- Results will be discussed with the U.S. FDA and health authorities globally to enable potential expedited regulatory submission pathways for approval
PRINCETON, N.J. & TOKYO--(BUSINESS WIRE)--Otsuka Pharmaceutical Development & Commercialization, Inc., Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Ionis Pharmaceuticals, Inc. today announced positive topline results from the Phase 3 FUSION trial evaluating ulefnersen, an investigational RNA-targeted medicine, in people living with a genetic subtype of amyotrophic lateral sclerosis (ALS) known as FUS-ALS, caused by mutations in the fused in sarcoma (FUS) gene1. The study met its primary endpoint, with ulefnersen demonstrating a statistically significant improvement on the primary endpoint assessing functional impairment and survival using a joint rank analysis of time to death or permanent ventilation, time to rescue* and change in ALS Functional Rating Scale Revised (ALSFRS-R) score from baseline to Day 505 compared to placebo (p=0.0005), providing evidence from the first-ever placebo-controlled clinical study targeting the underlying genetic cause of FUS-ALS.
The FUSION study also demonstrated statistically significant improvements favoring ulefnersen on secondary endpoints, including change from baseline in serum neurofilament light chain (NfL), and time to earliest of death, permanent ventilation, rescue, or withdrawal due to disease progression, further supporting the potential for ulefnersen to modify disease progression in people living with FUS-ALS. Ulefnersen demonstrated a favorable safety and tolerability profile in people living with FUS-ALS, with most adverse events being mild or moderate in severity.
“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,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. “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.”
FUS-ALS is a rare form of ALS that is characterized by an earlier age of onset and is often rapidly progressive1. The disease progresses by eroding muscle function, impacting patients' independence as they lose their ability to move, speak, swallow, and breathe, ultimately leading to premature death2. There are currently no approved therapies specifically targeting the underlying genetic cause of FUS-ALS1, underscoring the significant unmet need for effective treatment options. Taken together, the FUSION findings provide the first evidence from a placebo-controlled clinical study targeting the underlying genetic cause of FUS-ALS, an important advancement for people living with FUS-ALS and families who have long faced this disease without a potential therapy designed specifically for them1.
“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,” said Holly Kordasiewicz, Ph.D., executive vice president, chief development officer, Ionis. “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.”
Further prespecified and exploratory analyses of the data will be conducted to determine the full potential of ulefnersen for the treatment of FUS-ALS. Otsuka and Ionis plan to review results of the FUSION trial with the U.S. Food and Drug Administration (FDA) and continue discussions with other health authorities globally to enable potential expedited regulatory submission pathways for ulefnersen. 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. 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.
Otsuka and Ionis would like to thank the patients, their carers and families, investigators and advocacy organizations whose participation and support made the FUSION study possible and who continue to advance research for people living with FUS-ALS.
About the FUSION Trial
FUSION (NCT04768972) is a global multicenter, randomized, double-blind, placebo-controlled Phase 1-3 trial evaluating the efficacy and safety of intrathecally administered ulefnersen in people living with FUS-ALS. In Part 1 of the study, participants were randomized to receive ulefnersen or placebo during a 72-week double-blind treatment period. Participants then entered Part 2, an open-label extension period in which all participants received ulefnersen. The primary endpoint assessed functional impairment and survival using a joint rank analysis of ALS Functional Rating Scale Revised (ALSFRS-R), time to rescue, and ventilation assistance-free survival. The secondary endpoints included serum neurofilament light chain (NfL), time to death, permanent ventilation, withdrawal due to disease progression, respiratory function assessed by slow vital capacity (SVC), muscle strength assessed with handheld dynamometry (HHD), clinical function assessed by ALSFRS-R, quality of life assessed with ALS Assessment Questionnaire (ALSAQ-5), cerebrospinal fluid (CSF) NfL and CSF FUS protein. The primary analysis is based on the Part 1 cohort population only.
About FUS-ALS
FUS-ALS is a rare form of amyotrophic lateral sclerosis (ALS) that occurs across a broad age range, including pediatric and juvenile patients, and is often rapidly progressive1. It is a genetically defined subtype of ALS caused by pathogenic variants in the fused in sarcoma (FUS) gene, representing an estimated 0.6% of all ALS cases1. FUS mutations are more prevalent in juvenile and pediatric ALS, accounting for an estimated 43–52% of cases3. These mutations lead to the accumulation of toxic FUS protein in motor neurons, driving neurodegeneration2.
In early-onset and juvenile cases, disease progression can lead to respiratory failure and death, often within 1–2 years of symptom onset1. Diagnosis generally requires specialized clinical evaluation and confirmatory genetic testing4. There are currently no approved therapies specifically targeting the underlying genetic cause of FUS-ALS1, underscoring the critical unmet need for effective treatment options.
About Ulefnersen
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.
By targeting the underlying genetic cause of FUS-ALS, ulefnersen represents a potential FUS-targeted therapeutic approach for people living with the disease. Ulefnersen is administered via intrathecal injection, allowing direct delivery to the central nervous system.
Ulefnersen is currently in clinical development and is being evaluated in the global Phase 1–3 FUSION trial in people living with FUS-ALS. In 2024, Otsuka Pharmaceutical entered into an exclusive global licensing agreement with Ionis Pharmaceuticals to further develop and commercialize ulefnersen. Ulefnersen was discovered and developed by Ionis.
Ulefnersen is an investigational product and has not been approved by the FDA or any regulatory authority worldwide.
Ulefnersen has been granted Fast Track designation for FUS-ALS by the U.S. Food and Drug Administration (FDA) and Orphan designation for ALS by the U.S. FDA, the European Medicines Agency (EMA) and Swissmedic.
About Otsuka
Otsuka Pharmaceutical Co., Ltd. is a total healthcare company that focuses on each individual's potential to enhance their well-being. Our medical-related business provides treatments and diagnostics for both physical and mental health. Our nutraceutical business supports daily health maintenance and improvement. Otsuka's unique products and services are based on scientific evidence, under the guidance of our corporate philosophy: Otsuka-people creating new products for better health worldwide.
Otsuka America Pharmaceutical, Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc. are the US-based indirect subsidiaries of the global healthcare company Otsuka Pharmaceutical Co. Ltd. Otsuka’s US companies share a deep commitment to the development and commercialization of innovative products in the spaces of neuroscience, nephrology, and immunology. At our core is perseverance—a fierce determination to overcome any obstacle, regardless of setbacks, on behalf of patients, caregivers, and their loved ones. We will not be bound by doing what’s been done before. Learn more at www.otsuka-us.com.
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* Meeting a pre-specified criterion for disease progression allowed early entry to the open-label period.
References
- Moens T, Da Cruz S, Neumann M et al. Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications. The Lancet Neurology, 24, 166-178
- U.S. Department of Health and Human Services. (2025, April 1). Silencing a faulty gene may uncover clues to rare forms of ALS. National Institutes of Health. https://www.nih.gov/news-events/news-releases/silencing-faulty-gene-may-uncover-clues-rare-forms-als
- Martins, I. (2020, April 17). FUS mutations cause most cases of ALS in adolescents, literature review finds. ALS News Today. https://alsnewstoday.com/news/fus-mutations-cause-most-cases-of-als-in-adolescents-literature-review-finds/
- Roggenbuck J, et al; ALS Genetic Testing and Counseling Guidelines Expert Panel. Ann Clin Transl Neurol. 2023;10(11):2074-2091
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