On 16 June, UniQure announced the enrolment of the first two patients in the higher-dose second cohort of a Phase I/II clinical trial in the US for AMT-130, a micro ribonucleic acid (miRNA) gene therapy being developed as a potential treatment for Huntington’s disease (HD). Though this is a promising step towards advancing the development of this disease-modifying therapy (DMT) in a disease with significant unmet clinical need, AMT-130 still has a long and challenging road to prove its safety and impact on modifying HD progression while also tackling the anticipated high cost of the treatment. But considering the pressing need for a DMT and the limited pipeline candidates, AMT-130 will have a great opportunity to become a game-changer for HD in the next ten years if it is deemed effective in trials.
Gene therapies have evolved as an area of research interest for targeting neurological disorders, especially those with a genetically identified mutation such as HD. Most clinical development efforts of gene therapies within the HD indication, however, have not been met with success to date. In March, the HD pipeline was left lacking DMTs after three promising candidates failed to show their efficacy in Phase II trials. These were Roche’s gene therapy, tominersen, and Wave’s antisense oligonucleotides, rovanersen and lexanersen.
UniQure’s announcement comes at an opportune time, with the HD community eagerly awaiting the development of a potential DMT. With only Teva’s Austedo (deutetrabenazine) and tetrabenazine currently approved for the symptomatic treatment of HD-associated chorea, establishing effective and safe treatments for HD has proved particularly challenging for drug developers for several reasons. The imperfect animal models, which are used in the preclinical phase to test new interventions, are not a good mimic of the more-prevalent adult-onset HD, leading to a high failure rate for drug development. Several candidates that previously showed promise in animal models were not able to translate to a reduction in mutant huntingtin (HTT) gene in larger human brains.
AMT-130’s Phase I/II trial will evaluate its safety and efficacy on HD progression over a five-year period, initially over a 12-month double-blind period that will be followed by an unblinded four-year period with follow-up visits to evaluate the long-term safety and efficacy of the treatment. The trial is looking to enrol a total of 16 patients in the second cohort, of which ten will be given the highest tested dose of the treatment and six will have an imitation surgery. Patient enrolment for the first cohort was completed in May and patients are currently being enrolled for the second cohort.
As noted by key opinion leaders (KOLs) interviewed by GlobalData, patient enrolment has proved to be difficult in HD due to the rarity of the disease and the need to particularly recruit premanifest or early-stage patients for trials investigating DMTs. UniQure has, therefore, laid a good foundation for AMT-130 by already achieving progress in the enrolment process ahead of schedule. The therapy has also secured both orphan drug designation and fast track designation by the US Food and Drug Administration (FDA) in 2017 and 2019 respectively. This allows for frequent meetings with the FDA and the independent safety board regarding the clinical study design, which will be an additional advantage for UniQure considering the repeated failures in trials of other gene pipeline agents.
AMT-130 is designed from an artificial miRNA that is inserted into cells using a modified adeno-associated virus. The miRNA targets the HTT gene, silencing the mutated HTT gene expression. As a result, the therapy, which requires a single brain procedure, is believed to decrease the accumulation of the huntingtin protein, the underlying cause of the disease. KOLs indicated that this mechanism of action and route of administration look robust and cautiously promising, as the drug is still undergoing early stages of clinical development.
Despite this, the HD market, which was valued at $245m in the US last year, is not expected to see any drastic changes over the next ten years. As such, UniQure appears well-positioned to enter the HD market with AMT-130, as any drug that succeeds in demonstrating enough clinical benefits in altering or halting the disease progression is expected to command an exponential market uptake.