Trial Update: Low Dose of AMT-130 Safe, Lowers Huntingtin After 1 Year

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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AMT-130 trial update | Huntington's Disease News | update illustration with ringing bells

AMT-130, uniQure’s investigational gene therapy for Huntington’s disease, was generally well-tolerated and led to reductions in the levels of mutant huntingtin protein a year after treatment, according to an update from an ongoing Phase 1/2 trial.

Moreover, levels of neurofilament light (NfL), a biomarker of nerve damage — which were expected to rise after treatment — were elevated but returned to more normal levels over time, uniQure reported.

The clinical trial (NCT04120493) is assessing the safety and tolerability of a single into-the-brain infusion of AMT-130 in people with early-stage Huntington’s. Conducted across 12 U.S. locations, the study is fully enrolled and involves 26 patients in total.

“We are encouraged by this 12-month update on the patients enrolled in the low-dose cohort,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a press release. “We look forward to presenting additional clinical data, including functional outcomes, on all patients from this important study next year.”

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AMT-130 Gene Therapy Given to 1st Patients in European Trial

Huntington’s is caused by mutations in the huntingtin gene. These mutations lead to the formation of an abnormal form of the huntingtin protein that is prone to misfolding and clumping together inside nerve cells, disrupting their function.

AMT-130 contains a small piece of synthetic genetic material, called a microRNA. It is designed to bind to a molecule that carries genetic information needed to form the huntingtin protein, and mark it for degradation. In so doing, the production of mutated huntingtin is lowered.

Packaged into a modified, noninfectious viral carrier called an adeno-associated virus (AAV), AMT-130 is delivered to nerve cells as a one-time infusion into a brain region called the striatum. That region is particularly affected in Huntington’s disease.

The Phase 1/2 trial includes two dosing groups. Of the 10 participants in the lowest dose group, six received AMT-130 at a dose of 6x1o^12 vector genomes. The remaining four received an imitation surgical procedure as part of the control group.

In an update last year, uniQure announced that in two treated patients and two control participants, no significant safety findings were observed.

Now, all 10 participants have received AMT-130 or the sham procedure and have been followed for at least a year. Among this group, four patients are male and six are female, with ages ranging from 34–58.

AMT-130 was generally well-tolerated, with no serious adverse events related to the therapy reported, and no significant safety findings revealed on MRI scans. Two serious adverse events — a blood clot in the elbow and a case of temporary post-surgical delirium — were deemed unrelated to treatment, and were resolved.

NfL levels were increased in the cerebrospinal fluid or CSF — the liquid surrounding the brain and spinal cord — after the surgical procedure in the treated patients. However, these levels returned to near pre-surgical (baseline) levels after a year. Meanwhile, NfL levels remained relatively stable in those who received the sham surgery, similar to earlier findings in the first two treated patients.

In treated patients, mean levels of the biomarker peaked after a month, and reached a mean of 8% above baseline values at 12 months. Two patients were at or below baseline NfL levels after a year, and a third was below baseline at 15-month and 18-month measurements.

Mean mutant huntingtin levels in the CSF declined by 53.8% after a year in four treated patients for whom it was evaluated.

In the three patients in the control group with evaluable data, mean mutant huntingtin initially showed an increase compared with baseline — at one, three, six, and nine months. It decreased by 16.8% after one year, however.

These participants will continue to be monitored for an additional four years of follow-up in an unblinded manner, meaning both the patient and clinician will now be aware of which individuals received AMT-130.

The other 16 trial participants are enrolled in the second, high-dose (6x1o^13 vector genomes) group. Among them, 10 will receive AMT-130 and six the sham surgery.

In Europe, an open-label trial (NCT05243017) is evaluating the effects of the same two AMT-130 doses in 15 Huntington’s patients. All six patients in the low-dose group have been treated, as have four of the nine people in the high-dose group.

“We have made excellent progress in our clinical investigation of AMT-130 and now have a total of 36 patients enrolled across our two Phase I/II clinical studies in the U.S. and Europe,” said Matt Kaputsa, CEO of uniQure.

Added Kaputsa, “Enrollment in the high-dose cohort of our open-label European study is well underway and is expected to be completed by the end of this year. We look forward to continued collaboration with the Huntington’s disease community to advance AMT-130 as a potential treatment for those living with Huntington’s disease.”

In the U.S. study, one-year data from the high-dose group and two-year data from the low-dose group are expected in the first half of 2023.

A third group is planned, comprising up to 18 additional patients, in whom a new surgical technique designed to simplify the infusion methods will be explored. Patient enrollment for that group is expected to complete by the end of 2023, according to uniQure.