Australian therapy aiming to halt motor neurone disease advances to national Phase 2 trial

An Australian-developed therapy aimed at halting motor neurone disease and restoring lost function is advancing to a national Phase 2 clinical trial, in what researchers hope could be a significant step towards a treatment for a disease that currently has no cure.

The therapy, known as NUN-004, is the lead candidate of Queensland-based biotechnology company NuNerve. The 75-participant trial will run across six Australian clinical sites — on the Sunshine Coast, in Sydney, Newcastle, Brisbane and Perth — and follows encouraging early signs of disease stabilisation and functional improvement in a smaller Phase 1/1b study.

Participants in the new trial will be randomised two-to-one to receive either NUN-004 or a placebo for a 24-week double-blind study, followed by a 24-week open-label extension in which all participants receive the therapy. Researchers will assess changes in the ALS Functional Rating Scale-Revised, a standard measure of everyday function, alongside safety and tolerability, respiratory and neurophysiological measures, quality of life and biomarkers.

NUN-004 is a long-acting, protein-based therapy designed to inhibit EphA4, a receptor whose excessive signalling has been linked to motor neuron degeneration and to impaired recovery of nerve connections. The idea is not only to slow the disease, but to protect motor neurons and create the conditions for damaged neural connections to repair — going beyond current treatments, which largely focus on slowing functional decline.

Motor neurone disease, known as amyotrophic lateral sclerosis (ALS) in many countries, is a progressive neurodegenerative condition in which the motor neurons that carry signals from the brain to the muscles gradually die. People living with it lose the ability to move, speak, swallow and eventually breathe, usually within a few years of diagnosis. No approved treatment has been shown to halt or reverse its progression across the broad population of people living with the disease, a point NuNerve's chair, Emeritus Professor Perry Bartlett, underlined in announcing the trial.

The Phase 2 trial builds on a published Phase I/Ib study involving 20 healthy volunteers and eight people living with motor neurone disease. That study found NUN-004 was well tolerated, with stabilisation of the disease during treatment and participants reporting improvements in fine and gross motor tasks including grip, balance, walking and strength, as well as reduced fatigue. The results were published in a peer-reviewed journal, and the researchers say the new, larger trial is designed to find out whether that early signal is a real treatment effect.

The science behind NUN-004 has been more than 25 years in the making. It originates in research at the University of Queensland's Queensland Brain Institute by Emeritus Professors Perry Bartlett and Andrew Boyd, and NuNerve was established by the university's commercialisation company, UniQuest, and the Estate Peter Goodenough Unit Trust to advance it. The programme has received three consecutive grants from FightMND, the Australian charity that funds motor neurone disease research.

Professor Bartlett said the therapy was designed to go further than existing options. "No approved treatment has been shown to halt or reverse progression across the broad MND population," he said, adding that NUN-004 was "designed to go further to protect motor neurons and create the conditions for damaged neural connections to repair." NuNerve's clinical lead, Associate Professor Antony Winkel, said the study had been carefully designed to determine whether NUN-004 could meaningfully change the course of the disease, combining measures of everyday function with respiratory, neurophysiological and biomarker assessments.

The trial is a test of an idea as much as of a drug. If blocking EphA4 can protect motor neurons and allow nerve connections to recover, it would open a new approach not only for motor neurone disease but potentially for other conditions in which nerve connections are damaged. For now, though, the researchers are cautious: a Phase 2 trial is designed to test whether a treatment works and is safe in a larger group, not to prove a cure, and many promising early signals do not survive larger trials.

NuNerve says it intends to seek international investment and partnerships to progress NUN-004 into Phase 3 and towards potential regulatory approval in major global markets. For the estimated tens of thousands of people living with motor neurone disease around the world, and for the families who care for them, the start of the Australian trial is a moment of guarded hope — a new idea, backed by decades of research, finally being tested at scale.

What happens next will be decided by the data. Recruitment is under way at the six Australian sites, and the trial's double-blind phase will run for 24 weeks before the open-label extension. If the results confirm the early signal of stabilisation and functional improvement, the therapy could move towards the larger Phase 3 trials that regulators require before approval. If they do not, researchers will still learn something valuable about EphA4 and the biology of the disease. Either way, the trial marks a rare moment of momentum in a field where progress has been painfully slow.