FDA Grants Breakthrough Therapy Designation to AMT-130 to Treat Huntington Disease

The FDA granted a breakthrough therapy designation to AMT-130 (uniQuire) for the treatment of Huntington disease. Previously, AMT-130 was also granted a regenerative medicine advanced therapy designation and orphan drug designation for this indication.¹

Image credit: Dr_Microbe | stock.adobe.com

Huntington disease is a rare, inherited neurodegenerative disorder that leads to motor symptoms, such as chorea, behavioral abnormalities, and cognitive decline, which results 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, which facilitates the production and aggregation of an abnormal protein within the brain. Approximately 70,000 people have been diagnosed with Huntington disease in the US and Europe, according to experts, with many others at risk of inheriting the disease. Currently, there are no FDA-approved therapies to delay the onset or to slow the progression of Huntington disease.^1,2

AMT-130 is a gene therapy candidate that consists of an AAV5 vector, which carries an artificial micro-RNA that is specifically tailored to silence the huntingtin gene. Its goal is to inhibit the production of the mutant protein through the use of AAV vectors that deliver micro-RNAs directly to the brain for non-selective knockdown of the huntingtin gene. The designation follows clinical data from the ongoing phase 1/2 clinical trials—a proof-of-concept (POC) study (NCT04120493) and safety and efficacy study (NCT05243017)—evaluating AMT-130 as a treatment in adults with Huntington disease.^1-4

The POC randomized, multicenter, multiple-dose, double-blind, imitation surgery, first-in-human study (NCT04120493) in which participants in cohort 3 will receive either a high or low dose of AMT-130 based on randomization. They will also receive an immunosuppression regimen that consists of dexamethasone, sirolimus, and rituximab. Cohorts 1 and 2 involve a blinded 12-month core study period to evaluate the safety and potential impact of AMT-130 on the progression of Huntington disease.³

The safety and efficacy trial (NCT05243017) aims to build upon the safety demonstrated in the first-in-human study. In addition to safety and efficacy, the randomized, double-blind study explores the tolerability of multiple doses of AMT-130.⁴

According to 24-month follow-up data from 29 treated patients, the high dose of AMT-130 had statistically significant slowing of disease progression, as measured by the composite Unified Huntington’s Disease Rating Scale (cUDHRS; -0.2) compared to patients in the control group (-1.0). This represented an about 80% slowing of disease progression (p = .007). Additionally, the mean change in cUDHRS for patients receiving the low-dose of AMT-130 was -0.7 compared to -1.0 for patients in the propensity score-weighted external control, representing a 30% slowing of disease progression (p = .21).⁵

The experts noted that, based on these data, AMT-130 was generally well-tolerated, with a manageable safety profile at both doses. There were also no new serious adverse events reported that were believed to be related to AMT-130.⁵ At the time of the breakthrough designation, the experts treated a total of 45 patients with AMT-130.¹

“Receiving [a] breakthrough therapy designation underscores both the urgent need for effective treatments for Huntington disease and the encouraging interim data demonstrating that AMT-130 has the potential to slow disease progression,” Walid Abi-Saab, MD, chief medical officer of uniQure, said in a news release. “It’s a powerful recognition of the promise of AMT-130 and the important progress we’ve made. We deeply value the FDA’s continued commitment to advancing innovative gene therapies for patients with critical unmet needs, and we look forward to working closely with the agency to bring AMT-130 to the Huntington disease patient community as quickly as possible.”¹

REFERENCES

1. GlobeNewswire. uniQure Announces FDA Breakthrough Therapy Designation Granted to AMT-130 for the Treatment of Huntington’s Disease. News release. April 17, 2025. Accessed April 18, 2025. https://www.globenewswire.com/news-release/2025/04/17/3063262/0/en/uniQure-Announces-FDA-Breakthrough-Therapy-Designation-Granted-to-AMT-130-for-the-Treatment-of-Huntington-s-Disease.html

2. uniQure. Huntington’s Disease. Accessed April 18, 2025. https://www.uniqure.com/programs-pipeline/huntingtons-disease

3. Safety and Proof-of-Concept (POC) Study with AMT-130 in Adults with Early Manifest Huntington's Disease. ClinicalTrials.gov identifier: NCT04120493. Updated March 10, 2025. Accessed April 18, 2025. https://clinicaltrials.gov/study/NCT04120493

4. Safety and Efficacy of AMT-130 in European Adults with Early Manifest Huntington's Disease. ClinicalTrials.gov identifier: NCT05243017. Updated March 10, 2025. Accessed April 18, 2025. https://clinicaltrials.gov/study/NCT05243017

5. uniQure. uniQure Announces Positive Interim Data Update Demonstrating Slowing of Disease Progression in Phase I/II Trials of AMT-130 for Huntington’s Disease. News release. July 9, 2024. Accessed April 18, 2025. https://www.globenewswire.com/en/news-release/2024/07/09/2910220/0/en/uniQure-Announces-Positive-Interim-Data-Update-Demonstrating-Slowing-of-Disease-Progression-in-Phase-I-II-Trials-of-AMT-130-for-Huntington-s-Disease.html