AMT-130 slows progression in early Huntington’s, 2-year trial data show
Benefits of gene therapy candidate seen in clinical trials in US, Europe
The investigational gene therapy AMT-130 is slowing disease progression for people with early-stage Huntington’s disease, as well as lowering levels of neurofilament light chain (NfL), a marker of nerve cell damage.
That’s according to two-year data from two Phase 1/2 clinical trials: one in the U.S. (NCT04120493) and another in Europe (NCT05243017). The findings were also shared in a webcast held by uniQure, AMT-130’s developer, on July 9.
“We are very pleased with these new data. … We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration,” Walid Abi-Saab, MD, uniQure’s chief medical officer, said in a company press release.
uniQure expects to meet with the U.S. Food and Drug Administration (FDA) this year to present updated results and discuss the fastest pathway forward for the therapy’s development. This interaction is facilitated by the FDA’s designation, last month, of AMT-130 as a regenerative medicine advanced therapy (RMAT) for Huntington’s. Such status, which aims to speed the therapy’s development and regulatory review, comes with more frequent communication with the FDA.
Meanwhile, the U.S. trial is enrolling a new group of patients, in whom it will be tested whether immunosuppressive treatment has an effect on the safety of the surgical procedure used to deliver the experimental therapy.
uniQure expects that enrollment will wrap up by year’s end, and that safety data will be presented in the first half of 2025. The company also plans to provide three-year data from both trials in the first half of next year.
Interventional studies are longest in Huntington’s to date
Huntington’s disease is caused by mutations in the HTT gene, which is responsible for making the huntingtin protein. These mutations cause production of an abnormal, mutated version of huntingtin that toxically clumps in nerve cells and drives their damage and death.
While there are approved treatments for managing the symptoms of Huntington’s, there are, to date, no available disease-modifying therapies that directly target its underlying cause.
AMT-130 is a gene therapy designed to suppress production of all forms of huntingtin. It delivers a small piece of genetic material that binds to HTT‘s mRNA — an intermediate molecule that serves as a blueprint for making a protein from DNA — promoting its breakdown.
The one-time treatment is delivered directly into brain regions particularly affected in Huntington’s via a surgical procedure. By lowering huntingtin levels, AMT-130 aims to slow disease progression and improve life quality for patients.
Both Phase 1/2 trials involve early-stage Huntington’s patients, ages 25-65. In the U.S. trial, 26 participants received one of two doses of AMT-130 or a sham surgical procedure. Those given the sham procedure can opt to receive AMT-130 after a year. The European trial enrolled 13 patients, all of whom received one of the two AMT-130 doses.
Previous interim data showed that AMT-130 lowered levels of mutated huntingtin and helped stabilize clinical and motor function.
Now, most patients have been followed for up to three years, making the trials “the longest interventional study in Huntington’s disease to date,” Abi-Saab said in the company webcast.
As of March 31, 12 patients given the low dose and nine who received the high dose in either of the ongoing trials had been followed for at least two years.
Their data were compared with an external group of 154 untreated Huntington’s patients who participated in natural history studies. This external control group was matched closely to the trial’s participants in terms of demographic and clinical characteristics at the study’s start.
Treatment with AMT-130 high dose slowed disease progression 80%
Two-year results showed that AMT-130’s high dose led to a significant, 80% slowing of disease progression relative to the external control group. Progression was assessed by the composite Unified Huntington’s Disease Rating Scale (cUHDRS), in which higher scores indicate worse disability.
Specifically, AMT-130 was associated with a mean decline of 0.2 points, while the control group experienced a one-point drop, the data showed.
“Reaching statistical significance with such a small sample size is impressive,” Abi-Saab said, adding that “if these effects are maintained over time, AMT-130 has the potential to be a groundbreaking treatment for Huntington’s.”
Patients in the low-dose group experienced a 0.7-point reduction. This represents a 30% slowing of disease progression relative to the control group, although the difference was not statistically significant.
Across most of cUHDRS’ individual components, including motor and cognitive function, patients treated with the high dose also showed better scores than did the external control group.
Reaching statistical significance with such a small sample size is impressive. … If these effects are maintained over time, AMT-130 has the potential to be a groundbreaking treatment for Huntington’s.
Victor Sung, MD, of the University of Alabama Birmingham and a trial principal investigator, noted that unchanged motor and cognitive function during a time when substantial declines would be expected is “both impressive and unprecedented.”
Moreover, AMT-130 treatment resulted in a significant reduction, by 11%, in the levels of NfL in the fluid surrounding the brain and spinal cord. The natural history group, meanwhile, experienced a 26% increase, according to the company.
After two years, both AMT-130 doses resulted in mean NfL levels below those observed at the study’s start — “a result that has never been seen before in a clinical trial therapeutic setting in Huntington’s disease,” Abi-Saab said.
uniQure believes this further demonstrates the therapy’s ability to slow neurodegeneration.
AMT-130 continued to be well tolerated with longer follow-up, without any new safety concerns, and with a manageable safety profile.
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