RARE Daily

UniQure Reports Positive Updated Data on Phase 1/2 Clinical of Gene Therapy for Huntington’s Disease

June 21, 2023

Rare Daily Staff

UniQure said updated interim data, which included up to 24 months of follow-up from 26 patients enrolled in the ongoing U.S. phase 1/2 study, showed evidence of clinical and functional benefits of its experimental gene therapy AMT-130 for the treatment of the rare, neurodegenerative condition Huntington’s disease.

Huntington’s disease leads to motor symptoms including chorea, behavioral abnormalities, and cognitive decline resulting in progressive physical and mental deterioration. The disease is an autosomal dominant condition with a disease-causing CAG repeat expansion in the first exon of the huntingtin gene that leads to the production and aggregation of abnormal protein in the brain. There are no currently approved therapies to delay the onset or to slow the disease’s progression.

AMT-130 is the first one-time administered gene therapy to enter clinical testing for the treatment of HD. It is administered by neurosurgical procedure. The gene therapy uses an adeno-associated viral vector to deliver a gene encoding a miRNA that will recognize, bind, and non-selectively lower the human huntingtin protein. miRNA are small pieces of genetic material that can prevent production of a given protein. The gene therapy lowers the production of both the disease-causing mutant and normal huntingtin protein.

“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,” said Sarah Tabrizi, professor of clinical neurology and director of the University College London’s Huntington’s Disease Center. “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.”

A total of 26 patients with early-manifest Huntington’s disease have been enrolled in the multi-center, U.S. phase 1/2 clinical trial of AMT-130, including a 10-patient low-dose cohort (6 treated, 4 control) and a 16-patient, high-dose cohort (10 treated, 6 control). Patients were randomized to treatment with AMT-130 or an imitation (sham) surgery. The study consists of a blinded 12-month core study period followed by unblinded long-term follow-up of five years for treated patients. To date, four of the six control patients in the high dose cohort have been crossed over to treatment. Efficacy and biomarker data from the crossover patients are not included in the summary below.

AMT-130 was generally well-tolerated, with a manageable safety profile in patients treated with the lower dose vector genomes and the higher dose of vector genomes. The most common adverse events in the treatment groups were related to the surgical procedure. No treatment emergent adverse events led to discontinuation of patient follow-up.

As previously reported, there were two serious adverse events unrelated to AMT-130 (post-operative delirium and major depression) in the low-dose cohort, one serious adverse event in the high-dose cohort (back pain), and one serious adverse event (deep vein thrombosis) in the control group. In addition, there were two suspected unexpected serious adverse events (severe headache, central nervous system inflammation) in the high-dose cohort. All the events have resolved.

Clinical and functional measurements for treated patients in each dose cohort were compared to baseline measurements. Early clinical data demonstrate trends consistent with a potential clinical benefit of AMT-130 at both doses of AMT-130. Compared to baseline measurements, clinical function was generally preserved at 24 months for patients in the low-dose cohort and at 12 months for patients in the high-dose cohort. Compared to natural history, patients in both dose cohorts demonstrated benefits in each of Total Motor Score, Total Functional Capacity and the composite Unified Huntington’s Disease Rating Scale.

Based on the data from the interim analysis, UniQure said it will advance the clinical development of AMT-130. It expects in the second half of 2023 to initiate a third cohort in the ongoing U.S. clinical trial to explore both doses in combination with perioperative immunosuppression with a focus on evaluating near-term safety.

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