Despite unanticipated regulatory hurdles following promising clinical results with a novel investigational treatment for Huntington’s Disease, the significance of the gene therapy’s impact remains strong, as per an expert.
Earlier this month, uniQure announced that in a Type A meeting the FDA said it does not consider the Phase I/II study data adequate to support a marketing application for the gene therapy, ifezuntirgene inilparvovec or AMT-130. The FDA recommended UniQure to conduct a prospective, randomised, double-blind, sham surgery-controlled study.
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“What happened with the FDA was unexpected,” said Edward Wild, professor of Neurology at UCL’s Huntington’s Disease Centre, who was involved in the program evaluating AMT-130. Wild made these comments during a fireside chat on the second day of the Advanced Therapies conference, which took place 17–18 of March in London, UK.
The company’s Huntington’s Disease program consists of two Phase I/II trials. The US study (NCT04120493) is double-blind sham-controlled in two cohorts, while the European study (NCT05243017) is open label.
In September 2025, a 75% slower progression of Huntington’s Disease in 17 patients across both trials treated at the high dose of the therapy was reported at three years in comparison to the external control arm. While the disease was not reversed, patients that were expected to need a wheelchair in two years would need it in eight years after receiving treatment, Wild emphasised about the significance of the trial result.
Ethical considerations behind sham controls
This was the first trial of any gene therapy in Huntington’s, and was designed cautiously with safety in mind, according to Wild. The trial criteria outlined specific requirements for the striatal MRI volume per hemisphere, because it needed to be large enough for the surgeons to inject the gene therapy. Patients had to meet a certain score on the Diagnostic Confidence Level (DCL) scale for Huntington’s disease used to indicate disease progression.
Based on the disease trajectory, if left untreated, patients were expected to be significantly more disabled three years down the line, potentially requiring a wheelchair or assistance to walk.
On the topic of why a sham surgery was not conducted in the control arm of the UniQure trial, Wild said designing the study was “new territory and different regulators gave different answers”. In 2018, the FDA insisted on a sham control—skin incisions—so there was a sham control for 12 months and then patients were rolled over to the treatment arm, he said. In Europe, the EMA said implementing a sham control would be unethical and thus there was no sham arm, he explained. The control arm in the study was a natural history study of 2,500 patients suitable for inclusion.
Wild said the sponsor and the FDA agreed on a timeline for accelerated approval if the results were positive with no other trial needed. Thus, the decision to require sham surgery for the full duration of the trial was unexpected, with the regulators “changing their mind and previous statements no longer being applicable”, he said.
UniQure has said it will request a Type B meeting with the FDA in Q2 2026 to explore next steps.
Overall, it is difficult to reconcile regulatory requirements between the US and Europe, especially for gene therapies, he said. Wild drew parallels with HIV treatments in the early 90s. “For the first time you recognise you have a foot in the door, but it will be difficult to actualise for the patients who need it”.
Next steps and barriers to access
Macro events like national elections play an influential role, and the sector should adopt the attitude of hoping for the best while planning for the worst, said Wild on the huge learning curve with gene therapy development. Sponsors need to create trials to be scientifically robust, and keep an eye on the shifting political and regulatory landscape and engage early with regulators to ensure success, he said.
In terms of access barriers, in the case of AMT-130, the bottleneck will come from surgical delivery as the MRI-guided surgery necessary to deliver the gene therapy may not be possible in all countries, said Wild.
In the case of Huntington’s disease, treating early with a gene therapy can not only significantly impact the patient’s life, but also reduce the burden on the healthcare system, and overall costs, said Wild. Huntington’s is a good case study in estimating disease trajectories, because researchers can predict the age at which the disease manifests in patients using emerging mutation modifiers and potentially using polygenic risk scores, he added.
Despite recent challenges, Wild is optimistic about other potential therapies and the progress of different modalities in the Huntington’s disease space.
