Gene Therapy AMT-130 Shows Promising Results on Several Outcomes in Phase 1/2 Study of Huntington Disease


Following the positive results, uniQure expects to initiate a third cohort in the ongoing trial to further investigate both low and high doses of AMT-130 in combination with perioperative immunosuppression.

Ricardo Dolmetsch, PhD, president of research and development at uniQure

Ricardo Dolmetsch, PhD

Recently, uniQure, the drug makers of AMT-130, a gene therapy in development for Huntington disease (HD) announced positive findings from a phase 1/2 trial (NCT04120493), with patients showing preserved function and reductions in relevant biomarkers over a 24-month period. Based on these data, the company anticipates initiating a third cohort to evaluate the impact of low and high dose AMT-130 when used in combination with perioperative immunosuppression.

The company also noted that it expects to present new clinical data from the phase 1/2 studies of AMT-130, including addition follow-up data from the treated patients in the US trial and the 12-month follow-up data from the low-dose patients in the European trial, to come in the fourth quarter of 2023. Patient enrollment in the high-dose cohort of the European clinical trial is expected to be complete by the third quarter of this year after it was briefly paused in November 2022.

A total of 26 patients with early-manifest HD were enrolled in the US trial of AMT-130, with 10 patients in the low-dose cohort (AMT-130: n = 6; placebo: n = 4) and 16 in the high-dose cohort (AMT-130; n = 10; placebo: n = 6). The randomized controlled trial included a 12-month blinded core study period, followed by an unblinded long-term follow-up of 5 years for treated patients. Clinical and functional measurements were compared with baseline, controls, and a natural history cohort, which was developed by uniQure in collaboration with the Cure Huntington’s Disease Initiative using the TRACK-HD natural history study of patients with HD.

All told, findings showed that compared with baseline, clinical function was generall preserved at 24 months in the low-dose treated group and at 12 months for the high-dose treated group. At 24 months, those in the low-dose cohort showed mean improvements of 1.8 and 0.8 points in Total Motor Score (TMS) and Total Functional Capacity (TFC), respectively. At 12 months, investigators observed mean improvements of 2.7 and 0.5 points in TMS and TFC, respectively, following treatment with AMT-130.

Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a statement that, "We are very pleased with the data from the interim analysis of our U.S. Phase I/II clinical trial of AMT-130, a one-time administered investigational gene therapy for Huntington’s Disease." He added, "We plan to engage with regulators to advance this promising clinical program as we collect more data from these patients and from our European study."

While treated patients continued to improve on functional scales, those on placebo experienced a worsening of TMS at 12 months compared with baseline and natural history. After experiencing a transient and expected increase in neurofilament light (NfL) following treatment administration, patients on AMT-130 showed subsequent declines, with mean levels that were 12.9% lower than baseline for those in the low-dose cohort. In comparison, natural history estimates showed a 22.9% increase over that time.

Investigators observed more variable findings in the high-dose cohort, with mean increase in NfL of 51.5% compared with baseline. Half of the 8-patient cohort with at least 12 months of follow up had NfL levels below baseline, while 2 patients with 18 months of follow-up demonstrated a continued decline in cerebrospinal fluid (CSF) NfL to 27.4% above baseline. Over 12 months, the control group showed NfL levels that were 6.83% below baseline.

"Today’s encouraging interim update shows early signs of a potential clinical benefit of AMT-130 and supportive trends in neurofilament light chain, a key marker of neuronal damage that has proven useful across multiple neurodegenerative disorders," Sarah Tabrizi, MD, PhD, FRCP, professor of clinical neurology and director of the University College London Huntington’s Disease Center, said in a statement. "Despite the small patient numbers, I am encouraged to see that patients treated with either dose of AMT-130 appear to have largely preserved function and are trending favorably to natural disease course at up to 24 months."

She added, "These interim results provide early hope for patients suffering from this devastating disease, and I look forward to additional clinical updates and the further investigation of AMT-130 as a potentially important treatment option for patients with Huntington’s disease."

READ MORE: Huntington Agent PTC518 Demonstrates Significant Reduction in Key Biomarker in Phase 2 Study

Over 12 months, those in the control, low-dose and high-dose AMT-130 cohorts showed declines of 0.74%, 1.02%, and 1.23%, respectively, in mean total brain volume. Additionally, at 24 months, those in the low-dose treated cohort had CSF mutant huntingtin protein (mHTT) reductions of 8.1%. Significant variability was once again shown in the high-dose cohort, with a mean increase of 39.7% above baseline at the 12-month time point compared with a 4.7% increase among controls. Despite this, 3 of the 9 treated patients in the high-dose cohort had CSF mHTT reduction below baseline at their last measurement.

In terms of safety, the therapy showed a tolerable profile, with the most common adverse events that were related to the surgical procedure. There were 2 serious AEs of post-operative delirium and major depression in the low-dose cohort, both unrelated to active treatment, as well as 1 serious AE of back pain in the high-dose cohort and 1 serious AE of deep vein thrombosis in the control group. Of note, investigators observed 2 suspected unexpected serious AEs of severe headache and central nervous system inflammation in the high-dose cohort; however, all the events were resolved.

There were 4 patients, 3 in the high-dose and 1 in the low-dose cohort, that crossed over to treatment. All of these individuals received a short course of immunosuppression therapy concurrent with the administration of AMT-130. Following a review of the interim data, the Data Safety Monitoring Board concluded that there are no safety concerns with either dose and recommended continued development of AMT-130.

1. uniQure announces update on US Phase 1/2 clinical trial of AMT-130 gene therapy for the treatment of Huntington’s disease. June 21, 2023. Accessed June 23, 2023.
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