Otsuka and Ionis' Ulefnersen Meets Primary Goal in Phase 3 FUS-ALS Trial

Otsuka Pharmaceutical and Ionis Pharmaceuticals said on September 22 that ulefnersen, an investigational antisense medicine, met the primary endpoint of the Phase 3 FUSION trial in people with FUS-ALS, a rare genetic form of amyotrophic lateral sclerosis, according to the companies' joint announcement.

The companies described FUSION as the first placebo-controlled clinical study of a drug targeting the underlying genetic cause of FUS-ALS. The results are company-reported topline data; detailed figures beyond the primary p-value were not released.

The FUSION results

FUSION (NCT04768972) is a global, randomized, double-blind, placebo-controlled Phase 1-3 trial. In Part 1, participants received ulefnersen or placebo by intrathecal injection, into the fluid around the spinal cord, for 72 weeks. They then moved into an open-label extension in which all participants received the drug. The primary analysis is based on the Part 1 cohort only.

The primary endpoint used a joint-rank analysis combining time to death or permanent ventilation, time to rescue, and change from baseline in the ALS Functional Rating Scale Revised (ALSFRS-R) score through day 505. Ulefnersen showed a statistically significant improvement compared with placebo on that measure (p=0.0005), the companies said. Under the protocol, participants who met a pre-specified criterion for disease progression could enter the open-label period early, which the companies count as rescue.

The drug also showed statistically significant improvements on secondary endpoints, including change in serum neurofilament light chain (NfL), a blood marker of nerve injury, and time to the earliest of death, permanent ventilation, rescue or withdrawal due to disease progression. Most adverse events were mild or moderate, according to the announcement.

"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," said John Kraus, Otsuka's chief medical officer.

The disease and the drug

FUS-ALS is caused by mutations in the fused in sarcoma (FUS) gene, which lead to a buildup of toxic FUS protein in motor neurons. It accounts for an estimated 0.6% of all ALS cases but an estimated 43% to 52% of juvenile and pediatric cases, the companies said. In early-onset cases, the disease can lead to respiratory failure and death within one to two years of symptom onset.

Ulefnersen binds FUS pre-messenger RNA to reduce production of FUS protein, including the mutant forms. Ionis discovered the drug, and Otsuka licensed exclusive global rights in 2024. It has FDA Fast Track designation for FUS-ALS.

NeurologyLive reported that interest in the compound was shaped by an investigator-initiated, open-label case series of 12 patients treated under expanded-access protocols and published in The Lancet, which reported reductions in cerebrospinal fluid NfL of up to 83%.

Next steps

Otsuka and Ionis plan to review the FUSION results with the FDA and other health authorities "to enable potential expedited regulatory submission pathways for ulefnersen," the companies said. Further prespecified and exploratory analyses are under way, and the open-label extension continues. Ulefnersen has not been approved by the FDA or any other regulator.