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
Promising Preclinical Data
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.
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.
Orphan Drug Designation Granted in the U.S. and Europe
The U.S. Food and Drug Administration has granted orphan drug designation for AMT-130 in Huntington’s disease and AMT-130 has received an Orphan Medicinal Product Designation (OMPD) from the European Medicines Agency for the same indication, 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) has granted Fast Track designation for AMT‑130.
Phase I/II Clinical Trial of AMT-130
The Phase I/II study of AMT-130 for the treatment of Huntington’s disease is a double-blinded, randomized and controlled clinical trial being conducted in the United States.
In June 2022, we announced 12-month safety and biomarker data from 10 patients enrolled in the low-dose cohort of the ongoing Phase I/II clinical trial of AMT-130. AMT-130 has been well-tolerated, with no serious adverse events related to the gene therapy and levels of neurofilament light chain (NfL) – a key biomarker of neuronal damage – approaching baseline. We are pleased to observe trends suggesting target engagement that are supported by the lowering of mHTT protein in evaluable patients receiving AMT-130, with a mean reduction of 53.8% of mutant HTT (mHTT) observed in cerebrospinal fluid (CSF) at 12 months. (View press release.)
We plan to present additional clinical data, including functional outcomes, on patients from the low-dose and high-dose cohorts of this important study in 2023.
We have added a third cohort to the ongoing U.S. study that will explore the use of alternative stereotactic navigation systems to simplify placement of catheters for infusions of AMT-130. This will help us simplify and shorten the surgical procedure.
We have also initiated patient screening in an open-label study in the EU. This Phase Ib/II study of AMT-130 will enroll 15 patients with early manifest Huntington’s disease across the same two doses being explored in the U.S. trial.
Twenty-six patients have been enrolled in the U.S. clinical trial, including all 10 patients in the low-dose cohort and all 16 patients in the high-dose cohort. In the open-label European trial, all 6 patients in the low-dose cohort and 4 of 9 patients in the high-dose cohort have received AMT-130.
In July 2022, we reported to the health authorities suspected unexpected severe adverse reactions in three of the 14 patients treated with the higher dose of AMT-130. While these patients have fully or substantially recovered, and no clear root cause has yet been identified, we believe it’s prudent to temporarily delay additional higher-dose procedures until we put additional monitoring and treatment plans in place and complete our safety review early in the fourth quarter of 2022. The delay is not expected to impact any future lower-dose procedures, as no serious adverse events related to AMT-130 have been reported in any of the additional 12 patients treated at the lower dose, and no impact is expected on the timing of previously guided data read-outs in 2023, including the presentation of one to two-year follow-up on both low and high-dose cohorts in the second quarter of 2023.