Gene Therapy AMT-130 Shows Potential Benefit in Phase 1/2 Clinical Trials for Huntington Disease


In newly released data, AMT-130 showed a manageable safety profile at both low and high doses in patients with Huntington disease, supporting the gene therapy's continued development.

 Edward Wild, PhD, FRCP, professor of neurology at University College London Queen Square Institute of Neurology, consultant neurologist at National Hospital for Neurology & Neurosurgery, and associate director of UCL Huntington’s Disease Center

Edward Wild, PhD, FRCP

New 30-month interim data from the ongoing U.S. and European multi-center phase 1/2 clinical trials assessing AMT-130 (uniQure), an investigational gene therapy for Huntington disease (HD), showed evidence of potential dose-dependent clinical benefit relative to the nonconcurrent criteria-matched natural history. The combined data presented from these trials has a cut-off date of September 30, 2023, and does not include efficacy and biomarker data from the control patients who crossed over to treatment.1

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, 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).

Clinical Takeaways

  • AMT-130 gene therapy demonstrated potential dose-dependent clinical benefits and positive trends in key measures for Huntington Disease over a 30-month period.
  • Despite transient increases in neurofilament light chain levels, AMT-130 remained generally well-tolerated with manageable safety profiles at both low and high doses.
  • The results prompt further exploration, with plans for a third cohort assessing both doses in combination with perioperative immune suppression and upcoming regulatory interactions.

“The results from these phase 1/2 trials continue to be very encouraging as they show positive-trending, potentially dose-dependent signals across multiple key clinical and functional measures, in conjunction with further declines in NfL,” Edward Wild, PhD, FRCP, professor of neurology at University College London Queen Square Institute of Neurology, consultant neurologist at National Hospital for Neurology & Neurosurgery, and associate director of UCL Huntington’s Disease Center, said in a statement.1

READ MORE: Huntington Therapy Valbenazine Demonstrates Significant, Long-Term Benefits in KINECT-HD Open-Label Extension

In 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 the U.S and European 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.

“The clinical assessment trends in the ongoing studies of AMT-130 look very promising and continue to show disease stability in HD patients treated with this 1-time administered gene therapy, several of whom have now been followed more than 2 years,” Walid Abi-Saab, MD, chief medical officer at uniQure, said in a statement.1 “We are observing favorable trends in evaluation of motor skills, functional independence, and composite rating scores as compared to a nonconcurrent criteria-matched natural history cohort.”

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.

“While there are well-known complexities associated with analyzing and interpreting other biomarkers in HD, these NfL data are consistent with the clinical data suggesting possible disease stability and support the continued development of AMT-130,” Wild said in a statement.1 “The HD community has endured a prolonged and challenging wait for disease-modifying treatment options, and we enthusiastically embrace this potentially important advancement for this devastating disease.”

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.

“We also are pleased to observe further declines in levels of NfL, a measurement of neuronal degradation and disease progression, with low-dose patients below baseline at 30 months of follow-up and high-dose patients near baseline at 18 months,” Abi-Saab said in a statment.1 “Importantly, AMT-130 continues to be generally well-tolerated with a manageable safety profile at both its low and high doses. We will continue to follow these patients and look forward to initiating regulatory interactions next year.”

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.

In its release statement, the company noted that they began the enrollment of patients for a third cohort on exploring both doses in combination with perioperative immune suppression, focusing on the evaluation of near-term safety. In this cohort, up to 12 patients will be treated with AMT-130 using the current, established stereotactic neurosurgical delivery procedure. In the first quarter of 2024, uniQure noted that the company plans to begin regulatory interactions to discuss the data from both of the trials and potential strategies for ongoing development of AMT-130. Then in mid-2024, the company expects to present new data from the ongoing phase 1/2 studies of AMT-130, including additional follow-up data from treated patients.

1. uniQure Announces Update on Phase I/II Clinical Trials of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News Release. Published December 19, 2023. Accessed December 19, 2023.

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