Ionis and Otsuka report Phase 3 FUSION win for ulefnersen in FUS-ALS
核心洞察
The Phase 3 FUSION trial met its primary endpoint, with ulefnersen showing a statistically significant improvement in functional impairment and survival versus placebo in FUS-ALS (搜索) (p=0.0005).
Ulefnersen is the first treatment to target the underlying genetic cause of FUS-ALS (搜索) and the first to show potential to modify disease progression in a placebo-controlled study.
Secondary endpoints, including serum neurofilament light chain and time to death, permanent ventilation, rescue or withdrawal, also favored ulefnersen with a favorable safety profile.
Ionis Pharmaceuticals and Otsuka Pharmaceutical (搜索) Development & Commercialization reported positive topline results from the Phase 3 FUSION trial of ulefnersen in people living with amyotrophic lateral sclerosis (搜索) caused by mutations in the fused in sarcoma (FUS) gene, a subtype known as FUS-ALS (搜索). The study met its primary endpoint, with ulefnersen demonstrating a statistically significant improvement in functional impairment and survival compared with placebo (p=0.0005).
The primary endpoint used a prespecified joint rank analysis combining 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. According to the companies, FUSION is the first-ever placebo-controlled clinical study targeting the underlying genetic cause of FUS-ALS (搜索).
Ulefnersen, discovered and developed by Ionis, is described by the companies as the first treatment to target the underlying genetic cause of FUS-ALS (搜索) and to demonstrate the potential to modify disease progression.
Secondary endpoints and safety
The trial also showed statistically significant improvements favoring ulefnersen on key secondary endpoints, including change from baseline in serum neurofilament light chain (NfL) and time to the earliest of death, permanent ventilation, rescue, or withdrawal due to disease progression. Additional secondary endpoints specified in the trial design included respiratory function assessed by slow vital capacity, muscle strength assessed with handheld dynamometry, clinical function assessed by ALSFRS-R, quality of life assessed with the ALS Assessment Questionnaire (ALSAQ-5), and cerebrospinal fluid NfL and CSF FUS protein (搜索).
Ulefnersen demonstrated a favorable safety and tolerability profile, with most adverse events being mild or moderate in severity.
"These groundbreaking results offer hope for the FUS-ALS (搜索) 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 and chief development officer at Ionis. She said 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.
John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka, said the topline results mark a major milestone for people living with FUS-ALS (搜索), "re-shaping what is possible for a community that has long faced this devastating disease with limited treatment options." He added that as the first FUS-ALS clinical trial to meet its primary endpoint, FUSION provides evidence that a targeted genetic approach may help alter the course of disease.
Trial design
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 Part 1, participants were randomized to ulefnersen or placebo during a 72-week double-blind treatment period, after which they entered Part 2, an open-label extension in which all participants received ulefnersen. The primary analysis is based on the Part 1 cohort population only.
Ulefnersen is an investigational RNA-targeted medicine designed to bind FUS pre-messenger RNA and reduce production of FUS protein (搜索), including mutant forms that contribute to motor neuron degeneration in FUS-ALS (搜索). It is given by intrathecal injection to deliver the drug directly to the central nervous system.
Disease context and regulatory path
FUS-ALS (搜索) is a rare, genetically defined subtype of ALS caused by pathogenic variants in the FUS gene (搜索), representing an estimated 0.6% of all ALS cases. FUS mutations are more prevalent in juvenile and pediatric ALS, accounting for an estimated 43% to 52% of cases. These mutations lead to accumulation of toxic FUS protein (搜索) in motor neurons, driving neurodegeneration.
The disease occurs across a broad age range, including pediatric and juvenile patients, and is often rapidly progressive. In early-onset and juvenile cases, progression can lead to respiratory failure and death, often within 1 to 2 years of symptom onset. Diagnosis generally requires specialized clinical evaluation and confirmatory genetic testing. There are currently no approved therapies specifically targeting the underlying genetic cause of FUS-ALS (搜索).
Otsuka and Ionis plan to review the FUSION results with the U.S. Food and Drug Administration (搜索) and continue discussions with other health authorities globally to enable potential expedited regulatory submission pathways. Further prespecified and exploratory analyses will be conducted, and additional data from FUSION and the ongoing open-label extension will provide information on longer-term efficacy and safety. Detailed results will be presented at a future medical congress and submitted for publication in a peer-reviewed journal in the coming months.
Ulefnersen has been granted Fast Track designation for FUS-ALS (搜索) by the FDA and Orphan designation for ALS by the FDA, the European Medicines Agency (搜索) and Swissmedic (搜索). The product remains investigational and has not been approved by the FDA or any regulatory authority worldwide. In 2024, Otsuka Pharmaceutical (搜索) entered into an exclusive global licensing agreement with Ionis to further develop and commercialize ulefnersen.