Some Dose-Dependent Neurological Benefits Seen With AMT-130 Huntington Disease Gene Therapy


uniQure plans to initiate regulatory discussions in the US and Europe in the first quarter of 2024.

Interim data from uniQure's phase 1/2 clinical trials of AMT-130 gene therapy in patients with Huntington disease (HD) has shown evidence of preserved neurological function and dose-dependent clinical benefits.

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

The data, current as of September 30, 2023, are from 30 months of follow-up of 39 patients enrolled in the US (n = 26) and European trials (n = 13) of AMT-130 randomized to treatment with AMT-130 administered by stereotactic neurosurgical delivery procedure or an imitation (sham) surgery. The US trial had a low dose (6 treated, 4 control) and high dose (10 treated, 6 control) cohort and the European trial had a low dose (n = 6) and high dose (n = 7) cohort. In the high-dose cohort, 4 control participants were later crossed over to treatment and the other 2 did not meet inclusion criteria; these participants are not included in the new analysis.

Investigators found evidence of a dose-dependent clinical benefit in treated patients, which improvements in neurological function in the high dose cohort and preserved neurological function in the low dose cohort. On the composite Unified Huntington’s Disease Rating Scale (cUHDRS) the low dose cohort (6x1012 vg) had a difference of 0.39 points at 30 months from baseline and the high dose (6x1013 vg) cohort had a difference of 1.24 points at 18 months, compared with baseline values of 14.1 and 14.9, respectively.On the Total Functional Capacity (TFC) scale the low dose cohort had a differenceof 0.95 points at 30 months and the high dose cohort had a difference of 0.49 points at 18 months compared with baseline values of 11.9 and 12.2, respectively. On Total Motor Score (TMS) scale, the low dose cohort had a difference of 2.80 points at 30 months and the high dose cohort had a difference of 1.70 points at 18 months compared with baseline values of 13.3and 12.1, respectively.

READ MORE: uniQure Expanding Clinical Pipeline to Fabry Disease

“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 added. “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.”

Participants had cerebrospinal fluid (CSF) neurofilament Light Chain (NfL) levels below baseline through month 30 (mean, 6.6%) in the low dose cohort and through month 18 (near baseline) in the high dose cohort. There have been no conclusive trends with mutant Huntingtin Protein (mHTT) in the CSF and uniQure also stated that there were some changes in total brain volume after treatment which trended below natural history.

In general, AMT-130 was well-tolerated at both dose levels with common adverse events (AEs) related to the surgical procedure. There were 4 serious AEs unrelated to AMT-130 in the low dose cohort; these were post-operative delirium, major depression, suicidal ideation and epistaxis. There were 6 unrelated SAEs in the high-dose cohort: back pain, hypothermia, post procedural hematoma, post-lumbar puncture syndrome (n=2), and pulmonary embolism. There was one SAE of deep vein thrombosis in the control group. There were related serious AEs in the high dose cohort of central nervous system inflammation (n=3), and severe headache (1) that was retrospectively also attributable to central nervous system inflammation. Inflammation improved with glucocorticoid medication and 6 participants in the high-dose cohort have received perioperative steroids to reduce the risk of inflammation.

“The results from these Phase I/II 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, University College London (UCL) Queen Square Institute of Neurology, and consultant neurologist, National Hospital for Neurology & Neurosurgery, and associate director, UCL Huntington’s Disease Centre, added to the statement. “While there are well-known complexities associated with analyzing and interpreting other biomarkers in Huntington’s disease, these NfL data are consistent with the clinical data suggesting possible disease stability and support the continued development of AMT-130. The Huntington’s disease 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.”

uniQure has begun enrolling patients in a third cohort to further investigate both doses in combination with perioperative immune suppression in up to 12 patients. The company plans to initiate regulatory interactions in the US and Europe in the first quarter of 2024 and to present another clinical update in mid-2024.

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