The 26-patient trial includes 10 individuals with early-manifest Huntington disease on low-dose AMT-130 and 16 in the high-dose cohort, which will continue enrollment after a DSMB found no further safety concerns.
After patient enrollment was briefly paused in the higher-dose level in the European phase 1/2 trial (NCT04120493) of AMT-130 (uniQure), a gene therapy in development for Huntington disease (HD), uniQure announced that the trial’s Data Safety Monitoring Board (DSMB) has recommended that patient enrollment resume at this higher dose.1
This past summer, uniQure was made aware of some unexpected severe reactions shortly after the administration of AMT-130 in the higher-dose group of the trial. After a meeting with the DSMB, the company decided to pause enrollment for that specific dosed group to investigate the safety events and determine any mitigation steps. All unexpected safety events in the 3 identified patients were fully resolved, allowing the DSMB to lift the pause.
"We would like to extend our deepest gratitude to the patients, families and clinical sites that have joined us on our journey to investigate AMT-130 as a possible treatment for HD," Daniel Leonard, senior director of Global Patient Advocacy, uniQure, said in a statement.1 "Without your participation, our mission to deliver transformative therapies would not be possible. We look forward to continuing the work with the HD community and will continue to share updates on the AMT-130 clinical program."
The phase 1/2 trial exploring the safety, tolerability, and efficacy of AMT-130 includes 26 patients with early manifest HD split into a 10-patient, low-dose cohort followed by a 16-patient, high-dose cohort where patients are randomized to either active treatment or sham surgery. AMT-130 is administered through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum. uniQue plans to initiate a third cohort of the study that will assess the use of alternative stereotactic navigation systems to simplify placement of catheters for infusions of AMT-130. Enrollment for this third cohort is expected to be complete by the end of 2023.
Initial data from 4 of the patients included in the study, half of whom received the agent and half of whom experienced sham surgery, were announced in January 2022. AMT-130, an investigational recombinant AAV5 vector gene therapy, was deemed well-tolerated at its lower dose of 6 x 1012 vg, without any serious adverse events (AEs) related to the treatment to date.2
The first grouping of 4 patients was heterogenous in that they represented a variety of Stage I-II early manifest HD, with 41-44 CAG repeats, and baseline Total Functional Capacity scores ranging from 10-13 and Total Motor Scores ranging from 7-23.
Findings also showed increased levels of neurofilament light (NfL), which was considered expected, following the procedure for 2 patients who received AMT-130, with those levels returning to normal afterward. NfL was consistent in the sham group. In the initial data, structural MRI reveal no meaningful safety findings in either group after 1 year of follow-up, and both total and mutant huntingtin (mHTT) protein in the cerebrospinal fluid of the overall cohort were highly variable and thus inconclusive.
Months later, in June 2022, the company announced safety and biomarker data from 10 patients with early-stage HD enrolled in the low-dose cohort of the study. Six of the 10 enrolled patients received AMT-130, and 4 patients received an imitation surgical procedure. All told, the data showed that AMT-130 was well-tolerated, with no serious AEs. Two serious AEs of deep-vein thrombosis in the elbow in 1 patient and transient post-operative delirium in a second patient, were both resolved and deemed unrelated to treatment. Structural MRI also did not reveal any clinically meaningful safety findings in treated patients at 1 year of follow-up.3
At the time, Ricardo Dolmetsch, PhD, president of research and development, uniQure, said in a statement, "We are encouraged by this 12-month update of the patients enrolled in the low-dose cohort."3
Measurements on cerebrospinal fluid NfL, a key biomarker of neuronal damage, increased following the AMT-130 surgical procedure and approached baseline at 12 months. Notably, 2 of the 6 treated patients were at or below baseline levels at 12 months with an additional patient below baseline at 15 and 18 months. In AMT-130-treated patients, the increase in mean cerebrospinal fluid NfL peaked 1 month after the surgical procedure. Thereafter, NfL levels declined and at 12 months and showed an 8% increased relative to baseline. In contrast, NfL levels remained stable or slightly declined for the 4 patients on sham.
Four treated and 3 control patients were evaluable for mHTT protein in the cerebrospinal fluid measurements. In those treated with AMT-130, the mean mHTT decreased 53.8% at 12 months compared with baseline. In controls, mean mHTT showed an increased compared to baseline at 1, 3, 6, and 9 months, and decreased by 16.8% compared with baseline at 12 months.