In a strikingly blunt briefing, a senior FDA official accused uniQure of pushing “distorted” data to mask a “failed” therapy for Huntington’s disease.
Speaking on a call with reporters Thursday, the senior FDA official defended the agency’s demand that uniQure conduct another sham-controlled trial for its Huntington’s gene therapy and disputed the biotech’s characterization of the agency’s past communication with the company.
“We only ask for randomized data when a condition is heterogeneous, when the will to believe is strong, when the therapy is invasive or potentially harmful, when the effect size is difficult to detect and when the possibility you are fooling yourself is high,” the FDA official said, standing firmly behind a longtime agency policy for Huntington’s candidates.
On a March 2 conference call, uniQure leaders argued that a sham control study “could impose significant risks and burden to patients—some might even consider this trial design to be unethical.”
The one-time uniQure therapy, called AMT-130, is given directly into the brain through small holes in the skull.
“We asked uniQure to take their product and randomize patients to getting the treatment the way they give the treatment, which requires a skin incision, a hole in the skull and an intracranial injection of the product, versus a control arm, where all they do is anesthetize the patient and put one to three nicks in the scalp,” the official said. “We did not ask them to compare against a partial sham burr hole.”
The procedure requested by the FDA, the official added, would theoretically be done in just 30 minutes under anesthesia.
The Department of Health and Human Services requested that the senior FDA official not be named.
UniQure has accused the FDA of raising the bar after agreeing in writing, according to the company, that it can use data based on an external control as the primary basis for an approval application.
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But the FDA official said the agency has always wanted an internal control arm, stating that the approach has been the “long-standing policy for at least two decades” for Huntington’s treatments.
These include Roche and partner Ionis Pharmaceuticals’ antisense drug tominersen, which, like AMT-130, was designed to reduce the production of the huntingtin protein but failed in a phase 3 placebo-controlled trial in 2021.
“Instead of doing the right thing and running the correct clinical study, uniQure is performing a distorted or manipulated comparison in the mind of FDA,” the FDA official said.
“Did FDA ever agree to accept this distorted comparison? No, I’ve asked our people to look for any written or verbally transcribed or minutes of a meeting that document such a promise, and there is no such promise made,” the official said. “Moreover, FDA, as a general rule, never makes such assurances. FDA will always say, ‘Well, we have to see the data when we get it.’”
FDA argues its case
The agency believes a placebo-controlled study is necessary because Huntington’s is heterogeneous and patients are susceptible to a placebo effect, especially as the endpoints are very subjective.
Instead of a sham-controlled trial, uniQure relied on data from a phase 1/2 trial showing a 75% slowing of disease progression on the Unified Huntington’s Disease Rating Scale after three years when compared with an external control of patients with matching characteristics based on a natural history database.
The problem with comparing to that database is that those people don’t get a placebo effect because they weren’t under the impression that they received any treatments, the FDA official pointed out.
“We do not dispute the claim that it’s 75% better than those people,” he said. “What FDA disputes is that those people are a fair comparator. They are not a fair comparator.”
The FDA leader further questioned the validity of the database by flagging a seeming contradiction.
Part of uniQure’s proposed dataset also includes sham-controlled data from a small group of U.S. patients 12 months after treatment. In its feedback, the FDA highlighted that AMT-130 lacks a treatment effect relative to sham subjects in that cohort after 12 months, according to uniQure. During an investor call Monday, uniQure’s chief medical officer, Walid Abi-Saab, M.D., argued that it is “virtually impossible” for a drug designed to slow progression to demonstrate a treatment effect after just one year because study-controlled patients with early Huntington’s did not show clinical worsening after one year.
However, when compared with external control, AMT-130 demonstrated a benefit after one year, according to the FDA official.
“If both of those statements are true, why do we see a benefit at one year in the external controlled data, but not in the randomized data?” the FDA official asked Thursday.
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Still, the agency’s rejection of uniQure’s regulatory plan seems to go against the spirit of the newly unveiled “plausible mechanism pathway,” which is designed to enable the development of individualized gene therapies.
UniQure’s Huntington’s candidate, though not customized for each patient, appears to meet all the primary criteria for the plausible mechanism pathway—it targets a defined genetic cause, showed clinical benefit in several patients and utilizes a well-characterized natural history for comparison.
In response to Fierce’s question on that discord, the FDA official stressed that AMT-130 is not a bespoke therapy tailored for each individual patient.
Besides, instead of a “light-switch effect size” that baby KJ experienced, which inspired the plausible mechanism approach, what uniQure had was a “stone-cold and negative” randomized trial after one year and a “failed product,” the official added.
The FDA’s rejection of uniQure’s gene therapy drew the ire of former senior agency official Janet Woodcock, M.D., who called the decision “truly evil” in an interview with The New York Times.
“Dr. Woodcock is an esteemed regulator who worked at the U.S. FDA for at least two decades in this position,” the official said, referring to Woodcock’s long tenure at the agency.
“There are many commenters who I don’t expect better from, but Dr. Woodcock I do expect better from,” the official added. The FDA’s current stance “is the exact same position that she held for the 20 years she was in office,” according to the federal leader.
Normally, in cases where data are complicated or with rare diseases where the FDA is unlikely to have much internal expertise, the agency will call an advisory committee of outside experts to provide input. But the rate of these adcomms has dropped sharply during the second Trump administration. Zero adcomms have been held since July 2025, and overall rates have dropped by 65% from 2024 to 2025.
Asked about this on the call, the senior official said adcomms are costly, slow and “often use oomph and flash instead of scientific truth.”
“The industry puts tremendous incentive in curating the speakers” who deliberate on drug applications at adcomms, the official said. “There have been many papers, and, in my prior life, I published some of those papers, on the characteristics of the public speakers, who pays for them to go, the characteristics of their comments and who’s sort of controlling the public narrative.”
Historically, adcomms are convened when there is a complex decision that needs to be worked through between a sponsor and the agency. It also is an opportunity for rare disease patients to share their experiences related to their condition and receiving an investigational treatment.
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The rare disease community has taken issue with the current FDA leadership for some time. Last summer, Vinay Prasad, M.D, director of the Center for Biologics Evaluation and Research, was briefly ousted from the FDA following a high-stakes regulatory dispute over Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy Elevidys. Although the agency initially halted all shipments following patient deaths, it later reversed its stance to allow sales for ambulatory patients. Prasad departed as Duchenne advocacy groups reportedly escalated their opposition to his restrictive policies all the way to President Donald Trump.
Now, Prasad is facing renewed backlash after a string of controversial agency decisions again regarding rare disease treatments and Moderna’s mRNA flu shot.
Pointing to the FDA’s recent rejections of Disc Medicine’s drug candidate for the rare genetic disease of erythropoietic protoporphyria and Regenxbio’s gene therapy for Hunter syndrome, The Wall Street Journal’s editorial board bemoaned that while FDA Commissioner Marty Makary, M.D., talks about accelerating new drugs, “biologics chief Vinay Prasad quietly scuttles them,” arguing that “as long as Vinay Prasad is running the biologics shop and has such broad influence at the FDA, faster cures will die in his bureaucratic reviews.”
