Gene-silencing drug works in rare ALS that strikes young people

A drug designed to switch off the faulty gene behind one of the most aggressive forms of motor neurone disease has succeeded in a phase 3 trial. Ionis Pharmaceuticals and Otsuka announced on 22 September 2026 that ulefnersen met its main goal in the FUSION trial in people with FUS-ALS, a rare genetic type of amyotrophic lateral sclerosis that often strikes teenagers and young adults.

The companies reported that ulefnersen improved a combined measure of survival and physical function compared with placebo (p=0.0005), and that key secondary measures also favoured the drug. Full numbers haven't been released yet. They'll be presented at a medical meeting and submitted to a journal, and the ALS Association has noted that the results are still to be peer reviewed.

If confirmed, ulefnersen would be the second gene-targeted medicine shown to work in a genetic form of ALS, after tofersen (Qalsody) for SOD1-ALS, and the first to show a benefit on a measure that includes survival in a phase 3 trial of this kind.

What FUS-ALS is

ALS, the most common form of motor neurone disease (MND), damages the nerve cells that control movement. As these motor neurones die, people progressively lose the ability to walk, use their hands, speak, swallow and breathe. Most people die within two to five years of diagnosis, usually from breathing failure. The diagram above shows the upper and lower motor neurones affected by the disease.

About one in ten cases runs in families, and a growing list of genes has been linked to the disease. FUS-ALS is caused by mutations in the FUS gene, which carries instructions for a protein involved in handling RNA inside cells. The faulty protein builds up in the wrong part of motor neurones and is toxic to them.

FUS-ALS accounts for only about 0.6% of all ALS cases, but it stands out for two reasons. It often begins young: FUS mutations are found in an estimated 43 to 52% of juvenile and paediatric ALS cases, with some patients diagnosed in their teens. And it can progress very quickly, with breathing failure and death sometimes within one to two years of the first symptoms. Diagnosis needs genetic testing, which isn't always offered.

There are no approved treatments that target the cause of FUS-ALS. Riluzole, the standard ALS drug, extends life by a few months on average.

How ulefnersen works

Ulefnersen is an antisense oligonucleotide, a short synthetic strand of genetic material. It's designed to bind to the FUS gene's RNA message before it's processed and lead to its breakdown, reducing how much FUS protein the cell makes. Because it lowers both the normal and faulty forms, the bet is that cells can cope with less FUS protein overall as long as the toxic version is reduced.

The drug can't cross from the bloodstream into the brain and spinal cord, so it's given by intrathecal injection, a lumbar puncture into the fluid around the spinal cord, similar to tofersen and to nusinersen (Spinraza) for spinal muscular atrophy.

Ulefnersen was discovered by Ionis and originally developed with Columbia University neurologist Neil Shneider under individual expanded access, beginning with Jaci Hermstad, a young woman from Iowa with FUS-ALS who was treated in 2019. Her story helped push the drug into a formal trial. The ALS Association reports that one person treated through the expanded access programme at Columbia regained the ability to walk and breathe without support. Single cases like this are striking, but they can't show how well a drug works across a group. In 2024, Otsuka licensed global rights to ulefnersen.

The FUSION trial

FUSION (NCT04768972) is a global, randomised, double-blind, placebo-controlled phase 1 to 3 trial. In Part 1, participants with FUS-ALS were randomly assigned to ulefnersen or placebo for 72 weeks. Afterwards, everyone could move to Part 2, an open-label period in which all receive ulefnersen. People whose disease worsened past a pre-specified threshold could move to the open-label drug early, which the trial calls rescue.

ClinicalTrials.gov lists 89 people enrolled in total, and the ALS Association reported that the main analysis included 73 participants. People aged 10 and over could take part.

The main goal used a joint rank analysis. This method ranks every participant against every other based first on whether and when they died or needed permanent ventilation, then on when they needed rescue treatment, and finally on how their ALS Functional Rating Scale Revised (ALSFRS-R) score changed up to day 505. The ALSFRS-R is a 48-point questionnaire covering speech, swallowing, handwriting, walking and breathing. Combining these outcomes into one ranking lets a small trial capture benefit across survival and function together, which matters in a rare disease where few patients are available.

The results

Ulefnersen beat placebo on the main joint rank goal, with a p value of 0.0005, a strong result for a trial of this size.

Two secondary goals were also statistically significant:

• Neurofilament light chain (NfL) in the blood. NfL is a protein released when nerve cells are damaged. A fall suggests less ongoing nerve damage.
• Time to the earliest of death, permanent ventilation, rescue or withdrawal because of disease progression. This is closer to a hard clinical outcome than the questionnaire scores.

The companies haven't yet reported the size of the differences, such as how many people died or needed ventilation in each group, how much NfL fell, or how ALSFRS-R scores changed. Other secondary measures, including breathing capacity, muscle strength and quality of life, are still to be reported.

Ulefnersen was described as having a favourable safety and tolerability profile, with most side effects mild or moderate. Repeated lumbar punctures commonly cause headache and back pain, and drugs of this type can occasionally cause inflammation around the spinal cord, so the detailed safety data will be read closely.

What it means for ALS research

ALS drug development has seen many failures. Tofersen showed that lowering a faulty protein could reduce NfL and, over time, slow decline in SOD1-ALS, but its main phase 3 measure at six months wasn't met and its US approval in 2023 was granted on the basis of the NfL reduction. FUSION appears to have gone further, showing a benefit on a main goal that includes survival.

That supports the wider idea that genetic forms of ALS can be treated by lowering the faulty protein, and that blood NfL can track whether such treatments are working. It may also encourage wider genetic testing for people with ALS, so that those with treatable mutations are identified early.

Limitations

• Topline only. No effect sizes have been published, and the full results haven't been peer reviewed.
• Small trial. About 73 people were in the main analysis, as is common in very rare diseases.
• Composite measure. The joint rank approach makes it hard to tell from the headline result which parts of the outcome drove the benefit.
• Applies to FUS-ALS only. The drug targets a single gene and isn't expected to help people with other forms of ALS.

What happens next

Ionis and Otsuka plan to discuss the results with the FDA and other regulators, looking for faster routes to approval. Ulefnersen has fast track and orphan drug status in the US and orphan designation from the European Medicines Agency. No timeline for applications has been given, and the drug isn't approved anywhere.

People with ALS, especially those diagnosed young or with a family history, can ask their neurologist about genetic testing. Those with a FUS mutation may be able to join ongoing studies or access programmes. In the UK, the MND Association can help families find information on trials and genetic counselling.

This article explains published research and isn't medical advice. Talk to your own doctor or specialist team before changing any treatment.