Targeted therapy shows phase 3 benefit in rare genetic form of ALS

Amyotrophic lateral sclerosis (ALS) caused by mutations in the FUS gene often develops at a younger age and progresses rapidly, with no approved treatment specifically targeting its genetic cause. Positive phase 3 trial results suggest that investigational ulefnersen could help change that outlook, potentially moving care toward treatment selected by a patient’s genetic diagnosis.

FUS mutations can cause a protein to accumulate abnormally in the nerve cells that control muscles. Ulefnersen reduces production of FUS protein, including its harmful mutant forms, and is delivered into the cerebrospinal fluid by intrathecal injection. If approved, it could provide a treatment directed at a driver of disease in this small subgroup, which accounts for an estimated 0.6% of ALS cases.

The randomized, double-blind FUSION trial compared ulefnersen with placebo over 72 weeks. According to topline results announced by Otsuka and Ionis, the study met its primary endpoint, a combined assessment of daily function, death or permanent ventilation, and time to rescue treatment. Rescue allowed participants whose disease met a prespecified progression threshold to enter the open-label treatment period early.

The finding supports the possibility that ulefnersen alters the disease course, but the combined endpoint does not establish that patients lived longer or regained function. The announcement did not provide the size of the treatment effect or separate results showing how much functional decline was slowed.

Secondary results favored ulefnersen for serum neurofilament light chain, a marker of nerve-cell injury, and for time to the earliest occurrence of death, permanent ventilation, rescue, or withdrawal because of disease progression. Together, these results strengthen the signal of benefit, although the magnitude of those effects was not reported.

The potential practice impact extends to the diagnostic workup. Existing consensus guidelines already recommend offering all patients with ALS genetic testing that includes FUS, alongside genetic counseling, even without a family history. A FUS-targeted treatment would make those results directly relevant to another treatment decision.

The companies reported that most adverse events were mild or moderate, but detailed safety findings were not released.

Full efficacy and safety results are planned for a medical congress and peer-reviewed publication, and discussions with regulators will explore potential expedited submission pathways.

Source: Otsuka Pharmaceutical Co., Ltd. (2026 Sep 22). Otsuka announces transformative phase 3 FUSION results for ulefnersen, bringing the FUS-ALS community closer to a potential targeted treatment