Huntington Disease Gene Therapy Shows Improvements in Total Motor Score, Inconsistent Effect on Mutant Huntingtin


uniQure deemed the safety profile for AMT-130 to be manageable.

uniQure's AMT-130, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Huntington disease (HD), has demonstrated preservation of function and other signs of efficacy among patients treated in a phase 1/2 clinical trial (NCT04120493) being carried out in the United States; although, inconsistent results on some measures were observed between dose cohorts.1

The interim efficacy analysis for the trial included 6 patients treated with AMT-130 at the study’s lower dose (6x1012 vector genomes) and 10 patients treated at the study’s higher dose (6x1013 vector genomes). The study also included 4 patients who received a sham injection in the lower dose cohort and 6 patients who received a sham injection in the higher dose cohort. uniQure reported that a mean improvement of 1.8 points in Total Motor Score (TMS) at 24 months posttreatment was observed in the lower dose cohort, compared to a natural history cohort developed by the company and the Cure Huntington’s Disease Initiative. This natural history cohort included 31 patients meeting the trial’s inclusion criteria for CAG repeat expansion length, age, Total Functional Capacity (TFC), Diagnostic Classification Level, and minimum striatal volumes. Patients in the higher dose cohort showed a 2.7 point mean improvement in TMS at 12 months posttreatment compared to the natural history cohort. In terms of total functional capacity, patients in the lower dose cohort showed a mean improvement of 0.8 points at 24 months compared to the natural history cohort and patients in the higher dose cohort showed a 0.5-point improvement at 12 months compared to the natural history cohort. A 0.9-point improvement in Composite Unified Huntington’s Disease Rating Scale (cUHDRS) score compared to the natural history group was also observed in the lower dose cohort at 24 months posttreatment. For the higher dose cohort, a 1.0-point improvement in cUHDRS score compared to the natural history group was observed at 12 months posttreatment. The company noted that in comparison to both baseline measurements and the natural history cohort, a worsening in TMS score was observed in the study’s control group at 12 months posttreatment. Although, TFC and cUHDRS scores were sustained for the control group at this time point.

In the low dose cohort, mean levels of neurofilament light chain (NfL) in the cerebrospinal fluid were 12.9% below baseline at 24 months. By comparison, there was a predicted 22.9% increase in CFS NfL levels in the natural history cohort. On the other hand, a 51.5% mean increase from baseline in CFS NfL levels at 12 months posttreatment was observed in the high-dose cohort. That said, 4 of 8 patients in the high-dose cohort who had at least 12 months of follow-up showed NfL levels lower than baseline and 2 patients who had 18 months of follow-up had levels that had declined to 27.4% above baseline. The mean CFS NfL level for the control cohort was 6.83% below baseline at the 12-month time point. 

The study also looked at levels of mutant Huntingtin protein (mHTT) in the CSF. At 24 months, the low-dose cohort showed a mean reduction of 8.1% in CSF mHTT. At the 12-month time point, the high-dose cohort showed a 39.7% increase from baseline and the control group showed a 4.7% increase from baseline. Although, at the most recent follow-up, 3 patients in the high-dose cohort showed a decrease from baseline in CSF mHTT levels. No significant difference in total brain volume reductions at 12 months posttreatment were observed between the treatment, control, and natural history groups.

“CSF NfL was below baseline and natural history at 24 months in low-dose patients and is declining towards baseline in high-dose patients at 12 months,” Ricardo Dolmetsch, PhD, the president of research and development at uniQure, told CGTLive™. “NfL is a sign of neuronal injury and disease progression in HD and the idea that we may be reducing injury and neuronal death is important. The mhTT data are complex and are confounded by multiple issues including the reliability of the assay and interpatient variability. mHTT levels in CSF were highly variable but showed declines in low-dose patients and several high dose patients.”

The safety profile for AMT-130 was deemed manageable. Adverse events (AEs) related to the neurosurgical administration procedure comprised the most common AEs. No patients discontinued follow-up as a result of AEs experienced during or after treatment. A serious case of post-operative delirium and a serious case of major depression were reported in the lower dose cohort and deemed unrelated to the gene therapy. Furthermore, a patient in the higher dose cohort experienced a serious case of back pain and a patient in the control group experienced a case of serious deep vein thrombosis. Additional suspected serious AEs in the higher dose cohort included a case of severe headache and a case of central nervous system inflammation; uniQure noted that these 2 AEs were unexpected. The company also stated that all previously mentioned AEs are now resolved. The Data Safety Monitoring Board (DSMB) for the trial recommended a continuation of clinical development.

“We are very encouraged by these interim clinical results that show that AMT-130 was generally well-tolerated with a manageable safety profile,” Dolmetsch added. “There is an early indication of a potentially positive clinical effect in this relatively small group of patients treated with AMT-130 with 1 to 2 years of follow up. Patients treated with both doses of AMT-130 show early evidence of preserved function relative to baseline and clinical benefit relative to natural history.”

A separate phase 1/2 clinical trial (NCT05243017) for AMT-130 is also being conducted in several European countries. In August of last year, uniQure paused enrollment for the higher dose cohort in relation to suspected unexpected severe adverse reactions (SUSARs) that occurred in 2 patients treated at a European site and 1 patient treated at a US site.2 Because the US trial had already reached full enrollment in August 2022, it was unaffected by the pause. In October 2022, uniQure resumed higher dose cohort enrollment for the European trial following a DSMB recommendation based on a review of the available safety data.3 At the time, the company noted that the 3 SUSAR events had resolved.

“We look forward to advancing the clinical development of AMT-130 and completing the enrollment of the EU/UK trial in the third quarter and presenting next data in the fourth quarter that will include additional 18- and 30-month data on US cohorts and 12-month follow-up on the low-dose cohort from the EU/UK study,” Dolmetsch continued. “We are pleased with these promising interim results, and we continue to work tirelessly to develop a treatment option for patients suffering from this devastating disease.”

1. uniQure announces update on U.S. phase I/II clinical trial of AMT-130 gene therapy for the treatment of Huntington’s disease. News release. UniQure. June 21, 2023. Accessed June 21, 2023.
2. uniQure Announces Second Quarter 2022 Financial Results and Highlights Recent Company Progress. News release. UniQure. August 8, 2022. Accessed June 21, 2023.
3. uniQure announces third quarter 2022 financial results and highlights recent company progress. News release. UniQure. November 2, 2022. Accessed June 21, 2023.
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