Huntington’s Disease (HD): A Rare and Deadly Disorder
uniQure is developing a gene therapy for Huntington’s disease (HD), a rare, fatal, neurodegenerative genetic disorder that affects motor function and leads to behavioral symptoms and cognitive decline in young adults, resulting in total physical and mental deterioration. HD is caused by the expansion of CAG trinucleotide in exon 1 of a multifunctional gene coding for protein called huntingtin.
According to the EMA, Huntington’s disease affects approximately 70,000 people in the U.S. and Europe, making this one of the largest clinical unmet needs in the rare disease field. Despite the clear etiology of the disease, there are no therapies available to treat the disease, delay its onset, or slow the progression of a patient’s decline.
uniQure’s AMT-130 for Huntington’s Disease
Our gene therapy product candidate AMT-130 consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene, leveraging our proprietary miQURE™ silencing technology. The therapeutic goal is to inhibit the production of the mutant protein (mHTT). Using AAV vectors to deliver micro-RNAs directly to the brain for non-selective knockdown of the huntingtin gene represents a highly innovative and promising approach to treating Huntington’s disease.
AMT-130 administration animated video
Animated illustration of how AMT-130 is administered into the caudate and striatum regions of the brain via a micro-catheter
A Differentiated Gene Therapy Approach
uniQure’s gene therapy candidate for Huntington’s disease is differentiated in that:
AMT-130 targets the deep brain structures known for the disease pathology onset.
AMT-130 silences mutant huntingtin protein at levels not demonstrated in other studies.
AMT-130 targets the accumulation of the exon 1 HTT fragment, the most toxic source of abnormal protein aggregation in Huntington’s disease.
We are very encouraged by the significant reductions in mutant huntingtin protein, and believe that knock-down of this magnitude has the potential to significantly alter the course of the disease.
AMT-130 Granted RMAT, Orphan Drug, and Fast Track Designations
In June 2024, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation for AMT-130 based on the potential of AMT-130 to address the major unmet medical need among patients with Huntington’s disease. The designation follows the FDA’s review of interim Phase I/II clinical data for AMT-130 announced in December 2023 and is based on an analysis comparing these 24-month clinical data to a non-concurrent criteria-matched natural history cohort. RMAT designation allows for increased collaboration with the FDA to accelerate development, potentially facilitating earlier access for patients with life-threatening medical conditions. AMT-130 is the first therapeutic candidate to receive RMAT Designation for Huntington’s disease.
Previously, the FDA granted orphan drug designation for AMT-130 in Huntington’s disease, and AMT-130 has also received an Orphan Medicinal Product Designation (OMPD) from the European Medicines Agency, making it the first investigational AAV gene therapy in Huntington’s disease to receive such designation. In April 2019, we announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for AMT‑130, underscoring the high unmet medical need for patients suffering from Huntington’s disease.
Phase I/II Clinical Trial of AMT-130
The U.S. Phase I/II clinical trial of AMT-130 for the treatment of Huntington’s disease is exploring the safety, tolerability, and efficacy signals in 26 total patients with early manifest Huntington’s disease split into a 10-patient low-dose cohort followed by a 16-patient high-dose cohort; patients are randomized to treatment with AMT-130 or an imitation (sham) surgery. The multi-center trial consists of a blinded 12-month core study period followed by unblinded long-term follow-up for five years. A total of 16 patients in the clinical trial were randomized to treatment and received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen). An additional four control patients in the high-dose cohort crossed over to treatment. Additional details are available on www.clinicaltrials.gov (NCT04120493).
The European, open-label Phase Ib/II study of AMT-130 enrolled 13 patients with early manifest Huntington’s disease across two dose cohorts; a low-dose cohort of six patients and a high-dose cohort of seven patients. Together with the U.S. study, the European study is intended to establish safety, proof of concept, and the optimal dose of AMT-130 to take forward into Phase III development or into a confirmatory study should an accelerated registration pathway be feasible.
In July 2024 we announced promising interim data demonstrating slowing of disease progression in our ongoing Ph. I/II clinical trials.
A statistically significant, dose-dependent, slowing in disease progression measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS) was observed through 24 months in patients receiving the high dose of AMT-130. cUHDRS has been demonstrated to be the most sensitive measurement of clinical progression in Huntington’s disease patients. Trends in measurements of motor and cognitive function showed near-baseline stability throughout the 24 months of follow-up in patients receiving the high dose of AMT-130.
A statistically significant reduction of NfL in cerebrospinal fluid (CSF) was observed in patients treated with AMT-130. Patients treated with AMT-130 had a mean reduction in CSF NfL of 11% compared to baseline (p=0.02) at 24 months, and mean CSF NfL levels for both high and low doses were below baseline at 24 months. CSF NfL is a well-characterized biomarker of neurodegeneration that has been shown to be strongly associated with the clinical severity of Huntington’s disease.
Importantly, AMT-130 remains generally well-tolerated, with a manageable safety profile at both doses. There were no new AMT-130-related serious adverse events reported.
Based on the encouraging data, uniQure expects to hold a Type B, multi-disciplinary RMAT meeting with U.S. Food and Drug Administration (FDA) in 2024 to present the updated data and discuss potential expedited clinical development pathways and accelerated approval.
In February 2019, uniQure presented 12-month follow-up data in a Huntington’s disease minipig model, the largest available animal model for the disease. The data demonstrated that a single administration of AMT-130 resulted in a dose-dependent and sustained reduction of mutant huntingtin protein (mHTT) in the deep structures of the brain – including the striatum and the putamen, where Huntington’s disease is known to manifest, and the cortex. Once administered, AMT-130 was observed to spread to the cerebral cortex and lowered mHTT in the frontal areas of the brain that show neuropathological changes later in the course of the disease, providing evidence that AMT-130 spread from the injection sites to the cerebral cortex.
Preclinical studies using a non-invasive technique, Magnetic Resonance Spectroscopy (MRS), demonstrate that in addition to significant knock-down of mHTT, a single administration of AMT-130 also leads to an improvement in brain cell function, a reversal in HD neuropathology, and a partial reversal of volume loss in a key brain area involved in memory, called the hippocampus.
