Otsuka Pharmaceutical's ulefnersen met the primary endpoint of its Phase III FUSION trial in FUS-ALS, delivering the first statistically significant result from a placebo-controlled study targeting the underlying genetic cause of this rare, often rapidly fatal disease. Otsuka and Ionis Pharmaceuticals (Nasdaq: IONS) announced they plan to discuss the data with the US FDA and other global health authorities to pursue potential expedited regulatory submission pathways.
The trial enrolled 89 patients with amyotrophic lateral sclerosis (ALS) caused by pathogenic variants in the fused in sarcoma (FUS) gene, a subtype representing an estimated 0.6% of all ALS cases but accounting for 43–52% of juvenile and pediatric ALS cases. The primary analysis population comprised 73 patients. FUS-ALS is characterized by earlier onset and rapid progression; in young patients, respiratory failure and death can occur within one to two years of symptom onset. No approved therapy currently targets its underlying genetic cause.
Ulefnersen is an antisense oligonucleotide (ASO) that targets FUS pre-messenger RNA to reduce production of the mutant FUS protein that accumulates in motor neurons and drives neurodegeneration. It is administered by intrathecal injection, delivering the drug directly to the central nervous system. The drug holds FDA Fast Track designation for FUS-ALS and Orphan designation from the FDA, the European Medicines Agency (EMA), and Swissmedic.
The FUSION study was a global, multicenter, randomized, double-blind, placebo-controlled Phase I–III trial. In Part 1, participants received ulefnersen or placebo over a 72-week double-blind period before entering an open-label extension in which all participants received ulefnersen. The primary endpoint combined assessments of functional impairment and survival using a joint rank analysis of time to death or permanent ventilation, time to rescue, and change in the ALS Functional Rating Scale Revised (ALSFRS-R) score from baseline to Day 505. Ulefnersen demonstrated a statistically significant improvement over placebo on this composite endpoint (p=0.0005). Secondary endpoints also favored ulefnersen, including statistically significant improvements in serum neurofilament light chain (NfL) from baseline and in time to the earliest of death, permanent ventilation, rescue, or withdrawal due to disease progression. Most adverse events were mild or moderate in severity.
Quantitative effect sizes, hazard ratios, and confidence intervals were not disclosed in the topline announcement. Detailed results are expected at a future medical congress and in a peer-reviewed publication.