FDA Grants Regenerative Medicine Advanced Therapy Designation for AMT-130 Gene Therapy in Huntington Disease

Recently, the FDA granted regenerative medicine advanced therapy (RMAT) designation to uniQure’s investigational Huntington disease (HD) gene therapy AMT-130 based on interim data from a phase 1/2 trial (NCT04120493) and a comparison analysis of the data to a nonconcurrent criteria-matched natural history cohort.¹ The company anticipates to provide an update of the interim data from the ongoing U.S. and European phase 1/2 studies investigating the agent in mid-2024, which will include up to 3 years of follow-up on 29 treated patients.

In December 2023, 30-month interim data from such trials showed evidence of potential dose-dependent clinical benefit relative to the nonconcurrent criteria-matched natural history.² Among 39 patients in the both trials, treatment with AMT-130 resulted in a 0.39-point difference on composite Unified Huntington’s Disease Rating Scale (cUHDRS) at 30 months and a 1.24-point difference at 18 months for the low- and high-dose groups, respectively (baseline values; low-dose, 14.1; high-dose, 14.9).

Notably, the therapy demonstrated a 0.95-points difference on Total Functional Capacity (TFC) at 30 months in the low-dose group and 0.49-points difference at 18 months in the high-dose (baseline values; low-dose, 11.9; high dose, 12.2). Additionally, patients on active therapy showed a 2.80-point difference in Total Motor Score (TMS) at 30 months in the low-dose and 1.70-point difference in the high-dose at 18 months (baseline values; low-dose, 13.3; high-dose, 12.1).

“We’re thrilled to receive the first ever RMAT designation for an investigational therapy for Huntington’s disease,” Matt Kapusta, MBA, chief executive officer at uniQure, said in a statement.¹ “This achievement is a significant milestone for the program and supports the potential for AMT-130 to address the high unmet medical need of those suffering from this devastating disease.”

The U.S. trial enrolled 26 patients with early manifest HD, including an initial 10-patient low-dose cohort (treated, n = 6; control, n = 4) with up to 30 months of follow-up, and a subsequent 16-patient high-dose cohort (treated, n = 10; control, n = 6) with up to 18 months of follow-up. Patients were randomized to be treated with AMT-130 or sham. This study consists of a blinded 12-month core study period followed by unblinded long-term follow-up of 5 years for treated patients. Researchers had 4 control patients from the high-dose cohort cross over to treatment while the remaining 2 patients failed to meet the study’s inclusion criteria.

The Europe and the UK trial enrolled 13 patients with the same early manifest criteria for HD as the U.S. study. Investigators had 6 patients treated with AMT-130 in the initial low-dose cohort and 7 patients treated in the subsequent high-dose cohort. In each dose cohort of both trials, clinical and functional measurements for treated patients were compared with baseline measurements, as well as to control patients for up to 12 months, and a nonconcurrent criteria-matched natural history cohort (n = 31). Investigators measured neurological function using cUHDRS in patients receiving the high dose, and TMS and TFC in patients receiving the low dose.

Top Clinical Takeaways

The FDA has granted regenerative medicine advanced therapy (RMAT) designation to uniQure's investigational Huntington disease gene therapy AMT-130.
The designation was based on interim data from a phase 1/2 trial and a comparative analysis with a natural history cohort.
An update on the interim data from ongoing U.S. and European phase 1/2 studies, which will include up to three years of follow-up on 29 treated patients, is expected in mid-2024.

For the low-dose cohort, the mean CSF neurofilament light chain (NfL) remained 6.6% below baseline through month 30; however, this declined in the high-dose cohort at month 18, being near the baseline. These findings suggest a reduction in neurodegeneration with AMT-130 as compared with an expected increase from baseline in CSF NfL based on the natural history data. As expected by the investigators, all patients treated with AMT-130 experienced a transient increase in CSF NfL related to the surgical procedure that peaked at approximately 1 month after the procedure and declined thereafter. It was noted by the company that the transient increases were not dose-dependent.

Given AMT-130 is directly administered deep within the brain, the pharmacodynamics of Mutant Huntingtin Protein (mHTT) in the CSF are not believed to be materially representative of mHTT in the targeted brain regions. Mean changes in mHTT levels measured in CSF samples compared to baseline continue to be variable and impacted by baseline levels near or below the lower limit of quantification. Changes in the total brain volume of patients treated with AMT-130 were observed after the surgical procedure and trended below natural history. According to the company, observed volumetric changes do not appear to be clinically meaningful or associated with protracted increases in neurodegeneration as measured by NfL.

At both the lower dose and higher dose, AMT-130 was generally well-tolerated and demonstrated a manageable safety profile among the participants in the trials. The most common adverse events (AEs) in the treated groups were related to the surgical procedure. Overall, there were 4 serious AEs in the low-dose cohort, 6 in the high-dose cohort, and 1 in the control group not related to the therapy candidate. In the low-dose cohort, the SAEs reported included post-operative delirium, major depression, suicidal ideation and epistaxis. As for the SAEs in the high dose group, the SAEs reported included back pain, hypothermia, post procedural hematoma, post-lumbar puncture syndrome (n = 2), and pulmonary embolism. The investigators noted that the only SAE reported in the control group was deep vein thrombosis.

There also were 4 AMT-130-related SAE in the high-dose cohort which included central nervous system inflammation (n = 3), and severe headache (n = 1) that, retrospectively, was attributable to central nervous system inflammation. The participants with symptomatic central nervous system inflammation improved with glucocorticoid medication. Additionally, the investigators noted that 6 high-dose patients received perioperative steroids with the administration of AMT-130 to reduce the risk of inflammation.

“The RMAT designation, which was based on the comparison of the two-year AMT-130 data to a natural history cohort, marks a promising start to our FDA interactions,” Walid Abi-Saab, MD, chief medical officer at uniQure, said in a statement.¹ “Importantly, RMAT designation allows for increased collaboration with the FDA to accelerate development, potentially facilitating earlier access for patients with life-threatening medical conditions. I’m incredibly proud of the team at uniQure for this accomplishment, and we look forward to presenting updated interim data from our ongoing Phase I/II studies in the middle of the year.”