Recently, uniQure announced that it had achieved positive results from its pivotal phase 1/2 study using its one-time gene therapy AMT-130 for the treatment of patients with Huntington’s disease (HD). The positive top-line data released not only brings hopes of a potential disease-modifying therapy for them, but has also demonstrated the ability to significantly slow the rate of disease progression for them. In terms of positive data, it stems from the fact that patients given high-dose AMT-130 for 36 months (3 years) were able to slow their disease progression by 75%.
This slowing of disease progression, over this period of time, was assessed by a scale known as the composite Unified Huntington’s Disease Rating Scale (cUHDRS). Specifically, this measures certain tests for these patients. For instance, it incorporates several functions ranging from the function of daily activities to motor movement and other factors like cognitive decline that may be present for these patients.
I would say that the way the trial was designed played a huge role in the success of this pivotal phase 1/2 study. For instance, it pitted AMT-130 versus a propensity-matched external control from the ENroll-HD trial. In addition, instead of the company testing one dose of AMT-130, it tested two of them. With that being said, the study was split into high-dose gene therapy versus a matched external control in one portion and then a low-dose of gene therapy against a matched external control.
This was a smart move, because the high-dose of AMT-130 was the one that ended up achieving a statistically significant slowing of disease progression versus matched external control. Such statistical significance was achieved with a p-value of p=0.003 with respect to the primary endpoint of slowed disease progression by cUHDRS over a 36-month period. To put this in even better perspective, consider that the mean change of cUHDRS from baseline in patients that took high-dose therapy was -0.38 compared to -1.52 for patients who were in the matched external control arm. Whilst the patients on the one-time gene therapy from uniQure still progressed in disease, they did so at a much slower pace over the same time period.
There is no doubt that this data is a game-changer for the HD treatment landscape. With that being said, it is going to allow the company to advance to the next stage of the trial process, which is a pre-BLA meeting expected during the second half of 2025. The key function of this meeting is to discuss this newly released data with the FDA and for it to potentially be in a position to file a BLA for AMT-130 as a one-time gene therapy for the treatment of these patients with HD in the first quarter of 2026.
The company is playing it safe as it is looking to cover all of its bases. In essence, to make sure that no new issue arises. For instance, this therapy has been shown to be safe and tolerable for patients to take. However, since it uses an adeno-associated virus (AAV) vector to deliver genetic material (payload) to the intended site, there are instances where the immune system reacts in a negative way. To help in this regard, the company is in the process of exploring a third cohort as part of this pivotal phase 1/2 study using AMT-130 in combination with immunosuppression. The end result of this is to add an immunosuppressive agent like dexamethasone and possibly sirolimus and rituximab as well to lower the immune response that occurs with an AAV vector.
Huntington’s disease is a rare neurological disorder whereby a genetic mutation of the mHTT gene causes neuroinflammation in the patient’s brain. The problem with this is that nerve cells in the brain die off, and it leads to movement problems (chorea), cognitive issues, and behavioral issues. The mutation of the mHTT gene leads to the protein aggregation buildup of toxic mHTT protein that causes nerve cell death. This protein occurs as a result of CAG repeats in the gene. Consider that the number of CAG repeats for people in the normal range is 35 or below. However, when a person has HD, there are CAG repeats of this gene by 36 or more.
Besides neuroinflammation, other problems that happen because of HD are oxidative stress and the immune cells of the person’s body reacting in a violent manner. The mechanism of action of AMT-130 involves the delivery of the AAV5 vector with genetic material to the brain, where the goal is to silence the mHTT gene and in turn prevent the production or aggregation of mHTT protein.
Gene therapies are being offered up as one-time gene therapies to eliminate mutations in a variety of disorders. UniQure is already in the process of developing gene therapies to treat patients with Fabry disease and SOD1 amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. These gene therapies are known as AMT-191 and AMT-162, respectively. The latter program of using AMT-162 to target patients with SOD1 ALS is currently in clinical testing in the phase 1/2 EPISOD1 study, and more importantly, initial data from it is expected in the first half of 2026. The stock closed higher by 247% at $47.50 per share, with this data being released on Wednesday, September 24, 2025.
With the huge increase in stock price, the company wasted no time implementing a $200 million proposed public offering. Considering it is moving towards a pre-BLA meeting, this is not a huge surprise, as it is going to need a lot of cash for pre-commercialization efforts. Along with the fact that it is in the process of developing several other gene therapies for the treatment of patients with severe diseases. What remains now is to see if the FDA is going to allow the company to be able to file a BLA of AMT-130 for potential U.S. marketing approval in treating patients with Huntington’s disease. Not only would such a filing be good for the company and its shareholders, but it could also allow uniQure another possible strategic move. The company is seeking to file its BLA under a possible Priority Review Designation. If granted, this could speed up the review process significantly and get this potential one-time disease-modifying therapy approved for these patients in a quicker way.