An investigational, one-time gene therapy appears to slow the progression of Huntington disease (HD), results of a new phase 1/2 trial suggest.

A press release issued by uniQure, the drug's manufacturer, reports AMT-130 is delivered directly into the brain via a neurosurgical procedure 

Topline results showed that a single dose of AMT-130 was associated with a 75% reduction in disease progression at 36 months on the composite Unified HD Rating Scale (cUHDRS), compared to a score-matched external control, meeting the pre-specified primary endpoint.

AMT-130 was also associated with a significant slowing of disease progression on Total Functional Capacity (TFC) over the same period. Additionally, mean cerebrospinal fluid (CSF) neurofilament levels remained below baseline.

Co-investigator Erin Furr Stimming, MD, professor and neurologist at UTHealth Houston, told Medscape Medical News that she is cautiously optimistic about the findings.

Furr Stimming, who is also director of the Huntington's Disease Society of America (HDSA) Center of Excellence at UTHealth, said the therapy's early results are exciting and provide hope for continued progress.

AMT-130 was granted a regenerative medicine advanced therapy designation by the FDA in 2024 and a breakthrough device designation in April. The company is now planning to submit a biologics license application (BLA) for the drug in early 2026. 

Further study details will be presented next week at the 2025 HD Clinical Research Congress in Nashville, Tennessee, Furr Stimming noted. 

Disease Progression Slowed

The study included 29 patients with HD, 17 of whom received a high dose of AMT-130 and 12 a low dose. All but five patients in the high-dose group completed 36 months of follow-up.

The investigational drug is designed to reduce production of the toxic mutant huntingtin (mHTT) protein that causes Huntington disease. AMT-130 was administered once directly into the brain's striatum using MRI-guided, convection-enhanced stereotactic neurosurgery.

Furr Stimming's center was one of the study sites, but with only three surgical sites in the US, her patients were referred to one of those locations for the procedure, which can take up to 12 hours.

With a small number of participants, each active dose group was compared with a propensity score-matched control from the Enroll-HD natural history dataset (n = 1,566).

The high-dose AMT-130 group showed a 75% slowing of HD progression at 36 months on the cUHDRS (P = .003) and a 60% slowing on the TFC (P = .03) compared with controls.

Although not statistically significant, secondary endpoints showed an 88% slowing of disease progression on the Symbol Digit Modalities Test and a 59% slowing on the Total Motor Score. There was also a 113% slowing on the Stroop Word Reading Test, but its P value of.002 was deemed "nominal."

CSF NfL was reduced from baseline by a mean of 8.2%, which is significant because increasing levels have been strongly associated with greater Huntington disease severity, the company noted.

It added that the "variable trends" observed in the low-dose AMT-130 group may reflect a dose-dependent response to the drug.

Both doses were generally well-tolerated, with no new drug-related serious adverse events (SAEs). The most common AEs were related to the administration procedure, but all resolved. 

'Profound' Interim Results

"These interim results from a study that is ongoing were profound. And the numbers were more significant than what we've previously seen in other clinical trials" for HD, Furr Stimming said. However, she noted that the study was "quite small" and said larger studies are needed. 

If, down the road, the treatment is approved, there could be practical challenges due to the lengthy administration time and the limited number of sites currently able to provide it. 

Furr Stimming emphasized that access to the therapy will be a key consideration, noting that many institutions already have the infrastructure to deliver it and other approved treatments.

"This positive interim analysis will allow us to prepare. I think we'll then work collaboratively as a community to ensure that we can provide this therapy and more to individuals at risk for or living with HD," she added.

She noted that the company is exploring ways to reduce the lengthy delivery time of the procedure.

Cautious Optimism

In a statement sent to Medscape Medical News, the HDSA noted that the positive TFC finding was especially meaningful because "it directly relates to a person's ability to maintain independence in their daily life." Also, the reduction in NfL "provides strong evidence that the therapy is working to slow the underlying nerve cell degeneration," the organization said.

It added that it also appreciated the favorable safety profile, especially for a treatment delivered directly to the brain. 

Amy Gray, HDSA's president and CEO, said the study's findings offer "cautious but immense hope."

"For decades, there have been no therapies to slow disease progression — only treatment to manage symptoms," she said. "This data brings us closer than ever to a future where we can change the course of HD." 

In a statement, Zosia Miedzybrodzka, PhD, professor of medical genetics at the University of Aberdeen, Scotland, expressed similar measured optimism.

"This is a very exciting and important breakthrough. However, it is still early days and a lot more testing is needed to see if there are side effects of this gene therapy, how long the benefits last, and how well it works in the long term," said Miedzybrodzka, who is also co-chair at the Scottish Clinical Genomics Forum.