By Gerry Smith and Robert Langreth | Bloomberg
Katie Jackson desperately wants a new treatment for Huntington’s disease. Her husband died from the devastating brain disorder. And because the disease runs in families, her three children have a 50% chance of inheriting the condition. She’s pinned her hopes on a cutting-edge gene therapy from UniQure NV.
But Jackson says Huntington’s patients have no desire to meet a new demand from the US Food and Drug Administration: to enroll in a new clinical trial where some people will undergo fake brain surgery without getting UniQure’s treatment. The FDA’s request, intended to conclusively determine the therapy’s potency, has raised concerns the trial would be both unethical and impractical.
“It is inconceivable to us,” said Jackson, chief executive officer of Help 4 HD International, a Huntington’s advocacy organization. “Subjecting participants to invasive procedures without the prospect of therapeutic benefit is unjustifiable.”
With little support from patients for a new trial, UniQure may have reached an impasse with the FDA over its gene therapy for the fatal neurological condition that leaves people unable to think, walk or talk. The company’s one-time treatment aims to silence a gene that’s linked to the disease. It’s infused into a patient’s brain through burr holes drilled through their skulls.
After showing promising trial results in September, the company announced plans to file for US approval in early 2026, sending the stock soaring. But regulators aren’t convinced that the gene therapy and the arduous procedure to deliver it will make a meaningful difference for patients. They now want a study that compares those who got the treatment to those in a placebo group who undergo a sham surgery, the company said this week.
That request has set off fireworks, with UniQure and the agency openly feuding over what such a study would entail. In order to ensure that patients don’t know if they received the gene therapy, the critical element for such a blinded comparison trial, even those who don’t get it would need to go under anesthesia for about 10 hours, the company said. The agency denies this.
UniQure’s shares rose as much as 7.1% in New York, after falling 42% after the company disclosed the new FDA request through Wednesday’s close.
Placebo effect
Placebos have long been a fixture of clinical trials, used to ensure that the psychological benefits of getting care aren’t mistaken for drug potency. But companies and patient advocates have been pushing the FDA for flexibility with rare diseases because it can be hard to recruit enough people and unethical to withhold treatment from dying patients.
And a placebo comparison for UniQure’s gene therapy is far more complicated than giving someone a sugar pill.
Performing a fake surgery would involve patients undergoing anesthesia for about 10 hours, a UniQure executive said Monday on an earnings call. Doctors would “superficially drill a hole on the skull” without going through the bone, the company said.
The FDA disputes that patients getting the fake surgery would need to be under anesthesia for anywhere near that long, estimating it would be less than 30 minutes.
“The company’s description of what the control arm participants are going through is completely distorted,” Andrew Nixon, a spokesman for the Health and Human Services Department, said in a phone interview Wednesday.
UniQure disagreed. The sham surgery “requires a lengthy anesthesia period,” comparable to that of the actual brain surgery, to prevent patients from knowing if they are in the control arm, a spokesperson said in response to the agency. That has consequences.
Complications
In an early part of UniQure’s testing, doctors performed fake surgeries on 10 patients at the request of the FDA.
On average, those patients were under general anesthesia for 10.3 hours, the company spokesperson said. One participant developed dangerous blood clots from lying on an operating table for too long, according to people familiar with the study who asked not to be identified discussing the private information.
Fake surgeries are unusual but not unprecedented in clinical trials. Researchers drilled holes in patients’ foreheads about two decades ago as part of a sham procedure to study whether fetal tissue transplants are effective for Parkinson’s disease. Some sham surgery studies have proven that treatments are ineffective.
If UniQure were to agree to the new trial, depending on how long it goes, patients in the placebo group may not be eligible to get treated because their disease might have progressed. It could be difficult to recruit trial participants who are willing to accept that risk.
A sham surgery isn’t necessarily unethical, though the potential scientific benefits must justify the risks, said Amy L. McGuire, a professor of biomedical ethics at Baylor College of Medicine.
The FDA should hold an advisory committee meeting to decide whether UniQure’s existing data justifies approval, said Steven Joffe, who chairs the department of medical ethics and health policy at the University of Pennsylvania Perelman School of Medicine.
The FDA “has sent mixed or changing messages,” Joffe said. “I believe they have a responsibility to patients and families to air the data publicly and get expert input.”
Benefits questioned
UniQure’s study was far from ideal. It was small, with only 17 people getting a high dose of the gene therapy. The company has three-year follow-up data for only 12 patients. By comparison, some other trials for Huntington’s drugs have involved hundreds of patients, though they didn’t involve brain surgery.
The initial results from UniQure’s study, released in 2023, weren’t clear cut. After one year, there was no obvious difference between the people who got high doses and those who underwent a fake surgery on a common scale of Huntington’s symptoms. The sham group didn’t decline at all on a rating scale of disease symptoms.
The data has raised questions at the FDA, according to people familiar with the matter. It was a negative study, and staff-level reviewers made the decision that a new trial was needed, said the people, who asked not to be identified discussing deliberations within the agency.
Company researchers concluded that Huntington’s disease progresses too slowly to notice a difference after one year. They needed to look longer to see if the treatment was working. But they couldn’t track the patients who got the fake surgery. They had either quit the trial or gotten the actual treatment.
So the company compared patients who got its therapy to a different control group: a database showing how the disease normally progresses. While that’s a common approach for rare diseases, it isn’t considered as reliable as studies where patients are randomly assigned to get treatment or a placebo.
Changing goals
The study’s original main goal was to determine if the treatment was safe. The company approached the FDA much later, after it was well underway, for permission to compare the fate of patients getting the gene therapy to the expected progression of the disease based on the external data.
After two years, patients given a high dose were doing 80% better than expected based on the external control arm, the company announced in 2024. Later that year, UniQure approached the FDA for guidance. While the agency didn’t make any promises, the company said it reached an agreement that the revamped design could be used as the basis for a fast-track approval without the need for a new study.
UniQure conducted another year of analysis and announced the final results in September 2025.
But by then, the FDA leadership had changed. The division that oversees gene therapies is now led by Vinay Prasad, a well-known critic of companies that don’t test their treatments against placebo controls.
During his watch, the agency has announced multiple new initiatives to speed rare disease drugs. But biotech companies and agency critics have said that behind the scenes the goalposts are shifting and the agency is taking a harder line on some new therapies.
UniQure says it plans to request another meeting with the agency in the second quarter to discuss potential study designs. On a call with investors Monday, Chief Executive Officer Matthew Kapusta said the company “has a moral obligation, given the strength of our data, to continue to pursue this.”
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