Targeted therapy may improve function, survival in FUS-ALS
Phase 3 FUSION trial met its main goal in a prespecified joint-rank analysis
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- FUS mutations are common in juvenile and pediatric ALS, which can progress rapidly and, in early-onset cases, lead to respiratory failure and death.
- Ulefnersen targets FUS messenger RNA to reduce FUS protein production and significantly improved a combined measure of function and survival versus placebo.
- Ulefnersen is given by intrathecal injection every 12 weeks; its developers are discussing potential expedited approval pathways with regulators.
Otsuka Pharmaceutical’s experimental therapy ulefnersen improved a combined measure of function and survival compared with a placebo in people with amyotrophic lateral sclerosis (ALS) caused by mutations in the FUS gene.
That’s according to top-line data from the first part of the ongoing, global Phase 3 FUSION clinical trial (NCT04768972), which enrolled 89 people with FUS-ALS. The trial met its main goal, according to results announced in a press release from Ionis Pharmaceuticals, the therapy’s original developer, and Otsuka, which licensed ulefnersen from Ionis in 2024 under an exclusive global licensing agreement to further develop and commercialize the therapy.
Phase 3 results support targeted approach for FUS-ALS
“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, PhD, Ionis’ executive vice president and chief development officer.
Otsuka plans to discuss the results with the U.S. Food and Drug Administration (FDA) and other regulatory authorities, including potential expedited pathways toward approval.
“We are committed to working closely with health authorities to advance ulefnersen with urgency and scientific rigor,” said John Kraus, MD, PhD, Otsuka’s executive vice president and chief medical officer.
Mutations in the FUS gene, which encodes a protein of the same name, are particularly common in juvenile and pediatric ALS, accounting for an estimated 43% to 52% of cases. FUS-ALS can be particularly aggressive, and in early-onset and juvenile cases, disease progression can lead to respiratory failure and death, often within one to two years of ALS symptom onset.
Disease-causing FUS mutations lead to the buildup of toxic FUS protein in motor neurons, the nerve cells that control movement, contributing to their progressive damage.
Ulefnersen is designed to reduce production of the FUS protein, including mutant forms, by targeting FUS gene messenger RNA, an intermediate molecule derived from DNA that guides protein production. By doing so, ulefnersen — which is administered directly into the spinal fluid via an intrathecal injection — may be able to slow disease progression.
The therapy was previously called jacifusen, named in honor of Jaci Hermstad, a young woman with FUS-ALS whose advocacy helped launch the research that led to its early development. Hermstad became the first person to receive the experimental therapy in 2019. She died from the disease in 2020.
Early funding, expanded access paved way for FUSION
When early clinical work ran short of resources, the ALS Association partnered with Project ALS to help fund it. Both organizations later supported an expanded access program (EAP), allowing people with FUS-ALS to receive the experimental therapy outside clinical trials. Early positive findings from that program helped pave the way for the FUSION study.
“Today’s results happened because of an amazing young woman named Jaci Hermstad, her family and a community that refused to accept that a rare form of ALS was too rare to treat,” Calaneet Balas, president and CEO of the ALS Association, said in an organization press release. “We are proud that ALS Association donors helped make the early work possible, and we will keep pushing for a fast, thorough regulatory review.”
In FUSION’s first part, participants were randomly assigned to receive either ulefnersen or a placebo by intrathecal injection every 12 weeks over a 60-week double-blind treatment period. An additional loading dose was given four weeks after the first injection. The primary outcome was assessed through Day 505, or about 72 weeks.
Participants could enter an open-label extension in which all received ulefnersen every 12 weeks for 84 weeks, or about 19 months. An additional loading dose was given four weeks after the first dose in this part. They could then enter a third part and continue receiving ulefnersen every 12 weeks for up to another three years.
The study’s main goal was to assess functional impairment and survival through Day 505, or about 72 weeks. This was measured using a combined assessment of:
- changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores
- time to rescue or discontinuation from part one and entry into part two due to worsening function
- survival without permanent ventilation
The ALSFRS-R measures the ability to perform everyday activities, with higher scores indicating better function.
Ulefnersen met primary endpoint in Phase 3 analysis
In the primary analysis population of 73 participants, ulefnersen significantly improved this combined measure compared with placebo, meeting the study’s main goal.
Benefits were also seen on key secondary outcomes. Ulefnersen significantly improved a measure of blood neurofilament light chain, a marker of nerve cell damage, and prolonged the time until death, permanent ventilation, rescue treatment, or study withdrawal due to disease progression.
The therapy had a favorable safety and tolerability profile, “with most adverse events (AE) being mild or moderate in severity,” the release stated.
The magnitude of the reported improvements has not yet been disclosed. The companies plan to share detailed trial results at a future medical meeting and submit them for publication in a peer-reviewed journal.
“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,” Kordasiewicz said, adding that the results support its “potential to meaningfully modify disease progression.”
Otsuka recently launched a global EAP to provide potential access to ulefnersen for eligible people with confirmed FUS-ALS who are unable to participate in an ongoing clinical trial and meet other program criteria.
“Our approach to early access for ulefnersen is guided by an assessment of the available clinical evidence and our commitment to patient safety,” Kraus said in a separate press release announcing the EAP initiation.
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