If confirmed, AMT-130 could mark the first real step toward changing the trajectory of Huntington’s disease.
An investigational gene therapy has delivered the most convincing clinical evidence yet that a one-time treatment can slow the relentless course of Huntington’s disease, with patients in a Phase I/II trial showing a 75% reduction in disease progression at 36 months.
The pivotal study, conducted by gene therapy company uniQure, found that high-dose AMT-130 met its primary endpoint on the composite Unified Huntington’s Disease Rating Scale and also slowed functional decline by 60% on Total Functional Capacity (TFC), a clinical rating scale used to measure a person’s ability to function independently in daily life. It is part of the Unified Huntington’s Disease Rating Scale (UHDRS) and is one of the most widely used tools to stage disease progression.
The results, though yet to be peer-reviewed or published, have been recognised by experts as unprecedented and potentially transformative.
Among those experts was Dr Sophie Andrews, a healthy brain and neurocognition expert and clinical neuropsychologist at the University of the Sunshine Coast Thompson Institute. Dr Andrews has published more than 20 research papers on Huntington’s Disease.
“To detect such a large effect in such a small patient group is incredibly promising,” she said.
“If this is reflected in a large patient group, this could be a major breakthrough in the search for effective treatment for such a devastating disease.”
Dr Andrews noted that this was only a small trial, with data from 12 patients who received the high-dose of AMT-130 available for analysis, but the results were nevertheless “impressive”.
“These patients were in the early diagnosed stage of the disease, and compared to a larger group of people with HD who were at a similar stage of progression, the treatment group showed significant slowing of disease progress measured across multiple gold-standard measures of severity, including their clinical symptoms (cUHDRS), their everyday function (TDF) and their cognitive function, specifically, their speed of information processing,” she said.
“Motor symptoms were not significantly slowed in this analysis, however, keep in mind these are very small samples. Although preliminary, these positive findings across multiple measures after three years indicate that this really could be a promising, long-lasting treatment for this devastating disease.
“Further, although AMT-130 is invasive, as it involves brain surgery, it is potentially a permanent treatment, which would be a huge bonus for patients who commonly need regular visits to specialists, and regular adjustments to medications, as the disease progresses.
“It will be very exciting to see where this leads as it progresses to Phase III, where it would be testing in a much larger group of patients.”
uniQure said in a statement that high-dose AMT-130 not only met the trial’s prespecified primary endpoint but also produced consistent signals across multiple secondary measures.
Patients treated with the high dose experienced a 75% slowing of decline on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) compared with a propensity score–matched external control group drawn from the Enroll-HD dataset.
The mean decline in cUHDRS was -0.38 in treated patients versus -1.52 in controls (p=0.003). The therapy also slowed functional decline by 60% on Total Functional Capacity (TFC), with a mean decline of -0.36 compared to -0.88 in controls (p=0.033). Together, these findings provide compelling clinical evidence of durable disease modification.
Beyond the primary outcomes, AMT-130 produced favourable trends in cognition and motor function, including an 88% slowing of decline on the Symbol Digit Modalities Test, a 113% slowing on the Stroop Word Reading Test and a 59% slowing on the Total Motor Score.
Patients also demonstrated a mean reduction of 8.2% in cerebrospinal fluid neurofilament light protein (CSF NfL), a well-characterised biomarker of neurodegeneration and disease severity in HD. These converging data suggest that AMT-130 is exerting a biologically meaningful effect on the underlying pathology, the company said.
Safety outcomes further reinforced the therapy’s potential clinical utility, it said. AMT-130 was generally well-tolerated across both dose groups, with no new drug-related serious adverse events since December 2022.
The most common adverse events were related to the neurosurgical administration procedure and resolved without long-term impact. Taken together, the data point toward a favourable long-term risk–benefit profile for high-dose AMT-130.
“We are incredibly excited about these topline results and what they may represent for individuals and families affected by Huntington’s disease,” said uniQure chief medical officer Dr Walid Abi-Saab.
“These findings reinforce our conviction that AMT-130 has the potential to fundamentally transform the treatment landscape for Huntington’s disease, while also providing important evidence supporting one-time, precision-delivered gene therapies for the treatment of neurological disorders.”
He said the company was eager to discuss the data with the FDA later this year, with the goal of submitting a BLA in the first quarter of 2026. AMT-130 has been granted Breakthrough Therapy designation and Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA.
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Dr Nela Durisic, a research fellow at the Queensland Brain Institute at The University of Queensland said the data revealing a 75% slowing of clinical progression over three years was “unprecedented and genuinely transformative, as it targets the disease’s root cause”.
Current therapies mainly manage symptoms like movement difficulties and mood changes but do not alter disease progression. These symptom-relief drugs will remain vital, especially as patients live longer, making improved and safer symptomatic treatments an urgent research priority. Monitoring and mitigating gene therapy side effects, such as inflammation and neurological issues, was also crucial, she said.
“This breakthrough gene therapy for Huntington’s disease represents a historic advance in neurodegenerative medicine,” Dr Durisic said.
“A bold next step is prevention trials in gene-positive people before symptoms appear, involving young individuals undergoing 12–18 hours of delicate brain surgery.
“Ethical and safety challenges are significant, requiring careful patient selection and close monitoring.
“Nevertheless if successful, this could shift treatment from symptom management to stopping Huntington’s before it starts, revolutionising patient care.
“This comprehensive approach: combining gene therapy, better symptom management, and prevention research, heralds a new era of hope for those affected by Huntington’s disease.”
Associate Professor Lyndsey Collins-Praino, head of the Cognition, Ageing and Neurodegenerative Disease Laboratory (CANDL) at the University of Adelaide, said the therapy had the potential to “transform how we think about HD and its treatment”.
“It is important to acknowledge, however, that it is still early days, and key questions remain, such as the long-term effects of the treatment and its potential cost,” she said.
“At this stage, results have also not yet been peer-reviewed. The 12–18-hour complex brain surgery required to deliver the treatment may also limit its availability. Despite these caveats, however, the preliminary results offer real hope for those affected by HD and their families.”
Dr Bryce Vissel, a Professor in the School of Clinical Medicine at UNSW and director of the Centre for Neuroscience and Regenerative Medicine at St Vincent’s Hospital Sydney, said the report was to his knowledge, the first public claim of statistically significant slowing on both the composite clinical scale and the functional scale over three years in a clinical Huntington’s study, albeit using an externally matched comparison rather than a concurrent randomised control.
“It requires independent scrutiny and, ideally, confirmation,” he said.
“For families who carry this gene, the future has too often felt pre-written. The data reported today do not prove success, but they make a credible case for hope grounded in biology and careful clinical measurement. This is very exciting.”
