AMT-130 for Huntington’s disease

Last updated June 5, 2024, by Marisa Wexler, MS
Fact-checked by Marta Figueiredo, PhD

What is AMT-130 for Huntington’s disease?

AMT-130 is an experimental gene therapy being developed by uniQure to slow the progression of Huntington’s disease.

The medication received orphan drug designation for the treatment of Huntington’s in the U.S. in 2017 and in Europe the following year. In the U.S., it also was given fast track status in 2019 and a regenerative medicine advanced therapy (RMAT) designation in 2024 for the same indication. All of these designations are meant to expedite the therapy’s clinical development and regulatory review by providing a range of financial incentives and regulatory support.

Therapy snapshot

How does AMT-130 work in Huntington’s disease?

Huntington’s is caused by mutations in the huntingtin (HTT) gene, which provides instructions for making the huntingtin protein. This gene contains CAG repeats, a series of three DNA building blocks that are repeated 10 to 35 times in a row. But in Huntington’s, these CAG repeats are present at excessive numbers, often 40 or more.

The result is an abnormal version of the huntingtin protein that is longer than usual and prone to forming toxic clumps in nerve cells, causing a range of motor and nonmotor disease symptoms.

AMT-130 is designed to reduce the production of both normal and mutated huntingtin protein by targeting the HTT gene’s messenger RNA (mRNA), which is an intermediary molecule derived from DNA that guides protein production.

The gene therapy uses a modified and noninfectious viral vector called adeno-associated virus serotype 5 (AAV5) to deliver to cells a human-made piece of genetic material known as microRNA. The microRNA is designed to bind to HTT mRNA molecules and prevent their use to produce huntingtin.

To target mostly brain nerve cells, AMT-130 is administered directly into the caudate nucleus and the putamen, two deep brain regions that are heavily impacted by Huntington’s.

By lowering production of the toxic huntingtin protein in the brain, the one-time gene therapy is expected to ease symptoms and slow or stop disease progression in people with Huntington’s disease.

How will AMT-130 be administered in Huntington’s disease?

In Huntington’s clinical trials, AMT-130 has been tested at a low dose (6 trillion vector genomes, or virus units) and a high dose (60 trillion vector genomes). The therapy was administered directly into the caudate nucleus and putamen via a surgical procedure.

The procedure involved inserting a very small catheter (tube) to deliver the gene therapy into three different parts of these deep structures, and on each side of the brain. The infusions are given over a period of eight to 10 hours, and clinicians use magnetic resonance imaging (MRI) to track the therapy’s delivery.

Research suggests that, after administration, the gene therapy spreads throughout the caudate nucleus and putamen before moving outward to other parts of the brain.

AMT-130 in Huntington’s disease clinical trials

The safety, tolerability, and efficacy of AMT-130 are being evaluated in two ongoing Phase 1/2 clinical trials: a placebo-controlled study taking place in the U.S. (NCT04120493) and an open-label trial in Europe (NCT05243017).

Both trials are designed to test the therapy in adults, ages 25-65, with early Huntington’s — up to 36 adults in the U.S. trial and 15 in the European study. All patients are expected to receive a single administration of AMT-130, after which they will be followed up for up to five years.

In both studies, a first group of participants is given a low dose of AMT-130 (6 trillion vector genomes) and a second group is given a higher dose (60 trillion vector genomes).

But in the U.S. study, patients recruited for the first two groups are randomly assigned to either an AMT-130 infusion or an imitation (sham) surgical procedure. After one year, these patients will know what they received, and those assigned to the sham procedure have the option of receiving the gene therapy; they will be followed up until the study’s end.

For both trials, the main goal is to assess the therapy’s safety and tolerability, while the secondary goal is to evaluate how long AMT-130 stays in the brain.

Changes in measures of disease severity, functional capacity, motor skills, brain parameters, and quality of life will also be evaluated. Researchers also will measure changes in the levels of mutant huntingtin and a nerve damage marker called neurofilament light chain (NfL).

The U.S. trial has completed enrollment of 10 patients in the first group, and 16 adults in the second group. The European study, meanwhile, has enrolled six participants in its low-dose group and as many as nine will make the high-dose group.

One-year interim data showed that AMT-130 given at low-dose halved the levels of mutated huntingtin in the cerebrospinal fluid, the liquid that flows around the brain and spinal cord.

Additional findings from all 39 enrolled patients were announced in late 2023. At that point, patients in the low-dose group had been followed for up to 30 months (about 2.5 years), and those in high-dose groups had been followed for up to 18 months (about 1.5 years).

In the low-dose group, patients’ motor function and ability to perform daily activities at last follow-up were comparable with pre-treatment measures, implying relatively stable disease. In the high-dose group, neurological function measures showed stability or improvement over follow-up.

In addition, patients treated with AMT-130 had relatively preserved neurological and functional abilities compared with an external group of untreated early Huntington’s patients participating in the observational TRACK-HD study.

NfL levels showed a temporary increase after either dose of the therapy, which peaked after one month and then declined, reaching levels around those seen before treatment. This suggests no worsening in neurodegeneration, which also strongly contrasts with the gradual increase in NfL levels over time observed in untreated patients.

In both studies, a third group of patients will be randomly assigned to AMT-130 at either low or high dose, along with an immunosuppression regimen given before and after surgery to see if this approach reduces the risk of adverse events.

Both studies are expected to end in 2029.

Common side effects of AMT-130

In clinical testing so far, a single administration of AMT-130 has been found to be safe and well tolerated. The most commonly reported adverse events in treated patients are complications related to the surgical procedure that’s used to administer the gene therapy. In some patients, AMT-130 was reported to cause serious side effects associated with inflammation in the central nervous system, the brain and spinal cord.

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