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Huntington Disease Gene Therapy Promotes Reduction in Mutant Huntington Protein, Neurofilament Light

NfL peaked 1-month post-treatment as expected and returned to near baseline at 12 months.

AMT-130, uniQure’s gene therapy candidate for Huntington disease (HD), has been well-tolerated with promising biomarker activity, according to updated data from the low-dose cohort of a phase 1/2 clinical trial (NCT04120493).

Participants treated with 6x1012 vg AMT-130 in the trial showed reductions in cerebrospinal fluid (CSF) neurofilament light (NfL), with levels near or below baseline at 12 months. Participants also exhibited a mean decrease of mutant Huntingtin protein (mHTT) of 53.8% from baseline at 12 months post-treatment (range, 44-71).

“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, uniQure, said in a statement. “Thus far in the clinical trial, AMT-130 has been well-tolerated, with no serious adverse events related to the gene therapy and NfL levels approaching baseline. We are also pleased to observe trends suggesting target engagement that are supported by the lowering of mHTT protein in evaluable patients receiving AMT-130. We look forward to presenting additional clinical data, including functional outcomes, on all patients from this important study next year.”

The low-dose cohort of the phase 1/2 trial has enrolled 10 patients with HD, 6 of which were treated with AMT-130 and 4 of which received sham surgery. Patients’ ages ranged from, 24 to 58 years and 4 were male and 6 were female. All participants were clinically diagnosed with early-stage HD with CAG repeats between 40-44, baseline Total Functional Capacity scores of 10-13, and Total Motor Scores of 7-23. Demographics were similar between treatment and sham arms.

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At 12 months, all patients were evaluable for NfL measurements while 4 treated and 1 control patient were evaluable for CSF mHTT measurements (other participants did not have a measurable baseline value).

AMT-130 was generally well-tolerated in this cohort. There were no serious, treatment-related adverse events (AEs). Two serious AEs unrelated to treatment, deep-vein thrombosis and transient post-operative delirium, did occur. These AEs resolved with anticoagulants and supportive care, respectively. MRI imaging at 1-year post-treatment did not reveal any clinically meaningful safety findings.

In the control arm, mean CSF NfL remained stable or slightly declined (range, +1% to –35%) over 12 months. In treated patients, CSF NfL increased as expected following the surgical procedure (peak at 1-month post-treatment) and approached baseline at 12 months. Two treated participants were at or below baseline at 12 months post-treatment and 3 were at or below baseline at 15- and 18-months post-treatment. Altogether, treated participants had an 8% increase compared to baseline (range, +46 to -14).

Mean CSF mHTT declined from baseline in 4 evaluable treated patients with a 53.8% reduction from baseline at 12 months post-treatment (range, 44-71). Three evaluable control patients experienced a mean increase in CSF mHTT from base line at 1, 3, 6, and 9 months and then a 16.8% decrease from baseline at 12 months (range, 35-47).

The trial has completed enrollment in its 2 cohorts with 26 total patients, 16 of which are in the high-dose cohort. uniQure also plans to initiate a third cohort of up to 18 patients in the trial that will evaluate the use of alternative stereotactic navigation systems to simplify placement of catheters for AMT-130 infusions. Participants will receive the high 6x1013 vg dose. This cohort is planned to complete enrollment by the end of 2023. In an additional, open-label trial being conducted in Europe, all 6 patients in the low-dose cohort and 4 of 9 patients in the high-dose cohort have received AMT-130.

“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,” Matt Kapusta, chief executive officer, uniQure, added to the statement. “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.”

uniQure announces update on low-dose cohort in phase i/ii clinical trial of AMT-130 gene therapy for the treatment of Huntington’s disease. News release. uniQure. June 23, 2022. https://www.globenewswire.com/news-release/2022/06/23/2467860/0/en/uniQure-Announces-Update-on-Low-Dose-Cohort-in-Phase-I-II-Clinical-Trial-of-AMT-130-Gene-Therapy-for-the-Treatment-of-Huntington-s-Disease.html