Shares of uniQure plummeted more than 40% in premarket trading Monday after the company confirmed the FDA has rejected its current data package for AMT-130, a highly anticipated gene therapy for Huntington’s disease.
The FDA does not agree with uniQure’s plan of using phase 1/2 studies, compared to external control, to support an application for AMT-130, the company said, citing final meeting minutes from a meeting with the FDA on Jan. 30, 2026.
“The FDA strongly recommended uniQure conduct a prospective, randomized, double-blind, sham surgery-controlled study,” the company said in a March 2 release.
By demanding a phase 3 trial, the FDA has effectively closed the door on a near-term approval despite what experts called “game-changing” data, albeit based on natural history as the comparator. The requirement adds years to the development timeline for a therapy that many in the Huntington’s community had hoped would reach the market through an expedited pathway.
“While we respect the agency’s perspective and share its commitment to rigorous science, we believe it’s appropriate to fully and carefully consider how regulatory flexibility is applied in the context of a rare, monogenic, slow-progressive and ultimately fatal neurodegenerative disorder for which there are no approved disease-modifying treatments,” uniQure CEO Matt Kapusta said on an investor call Monday, March 2.
“Our focus now is on constructive engagement with the FDA to further define a clear and efficient regulatory path forward,” Kapusta said. “We are actively evaluating the agency's recommendations, including potential phase 3 study designs, while preserving our commitment to advancing the program responsibly and expeditiously.”
In its communication, the FDA highlighted the phase 1/2 study’s lack of treatment effects relative to sham subjects after 12 months, uniQure’s chief medical officer, Walid Abi-Saab, M.D., told investors on the call. But, in patients with early Huntington’s, it’s “generally insufficient to reliably detect a meaningful progression of their disease” after just one year, making it “virtually impossible” for a drug designed to slow progression to demonstrate any treatment effect, he said.
Abi-Saab argued that a multiyear sham-controlled study “could impose significant risks and burden to patients,” and some may consider it unethical.
The company plans to request another meeting with the FDA in the second quarter “to further discuss potential phase 3 study design approaches that address the agency’s feedback, while also considering feasibility and patient risk,” the uniQure CMO said.
In the meantime, uniQure plans to update its phase 1/2 statistical analysis plan to add a four-year analysis, which is expected to happen in the third quarter, to further demonstrate AMT-130’s treatment durability and magnitude of effect.
A surprised uniQure first telegraphed the FDA’s current view in November following a pre-biologics license application (BLA) meeting, sending shock waves through the biotech sector.
At that time, uniQure CEO Matt Kapusta called the FDA’s feedback “a drastic change” from the agency’s previous guidance. The gene therapy biotech had disclosed a year prior that the FDA had “stated in writing that we may use the data from the phase 1/2 study, in comparison to an external control, as the primary basis for a BLA submission,” Kapusta recalled on the call.
Using an external control derived from the Enroll-HD natural history dataset, uniQure reported a statistically significant 75% reduction in Huntington’s disease progression three years after a one-time treatment with AMT-130 at a high dose. The massive treatment effect tripled uniQure’s stock price at the time.
The FDA did not seem to have any issues with the Enroll-HD database, Kapusta said, noting that the database includes more than 30,000 participants collected over 14 years, which makes it “clinical-grade.”
“It’s puzzling to us, other than the fact that a sham control study is certainly gold-standard science,” Kapusta said.
“We believe that this body of real-world evidence provides a strong foundation to inform efficient and scientifically rigorous study designs, making a long-term sham control study of a one-time administered therapy difficult to justify,” Abi-Saab said.
AMT-130 sits on a growing list of drug candidates for rare diseases that have recently received negative feedback from the FDA, causing mounting concerns that the agency is raising the bar despite public statement from senior officials of their commitment to the field.
The FDA in February also declined to approve Regenxbio’s Hunter syndrome gene therapy, RGX-121, citing concerns about its clinical trial’s ability to properly define a patient population, the use of natural history control arm and the use of biomarker as a surrogate endpoint, according to the company.
In November, the agency denied approval for Biohaven’s troriluzole in spinocerebellar ataxia after the company said the two sides had agreed on the potential to use real-world evidence to support a submission—and a positive readout from such a study. According to Biohaven, the FDA’s complete response letter “cited issues that can be inherent to real-world evidence and external control studies.”
Patient communities have been critical of the FDA’s seemingly tightened policies on rare diseases. On Change.org, a petition for the FDA to approve AMT-130 started by Katie Jackson, a Huntington’s family member, has collected more than 40,000 verified signatures as of Monday morning.
The FDA has fought back. Speaking during an interview on the CNBC’s “Squawk Box” last week, FDA Commissioner Martin Makary, M.D., took a shot at an unnamed therapy that involves burr hole surgery, which is how AMT-130 is delivered.
“There was a product where the researchers drilled a burr hole, literally a hole in people’s skulls, to inject intrathecally into the ventricle a therapy,” Makary said. “At the end of the randomization period, it found no benefit, and yet this is one of the drugs that we were pressured to approve.”
The FDA’s rejection of uniQure’s regulatory plan is even more puzzling considering that the FDA has just unveiled the “plausible mechanism pathway” to facilitate the development of individualized gene editing therapies for rare diseases. AMT-130 would have met all the criteria that the agency set force in a draft guidance document—it targets a defined genetic cause (silences the huntingtin gene), showed clinical benefit in several patients and utilizes a well-characterized natural history for comparison.
In response to an earlier question by Fierce Biotech on the apparent discordance between the FDA’s view toward AMT-130 and that it stated in the new pathway, Center for Biologics Evaluation and Research Director Vinay Prasad, M.D., pointed to how AMT-130 is one treatment designed for all Huntington’s patients, whereas under the plausible mechanism pathway, each treatment is designed specifically for an individual.
Referring to the FDA in a statement to Fierce Biotech, Stephen Majors, VP of global communications and investor relations at the Alliance for Regenerative Medicine, said uniQure represents “another clear sign that the Agency has increased the regulatory requirements for rare disease gene therapies, despite saying for months that it was committed to regulatory flexibility.”
“Just last week, Agency leaders released proposed guidance for individualized therapies in which they explicitly touted natural history as a valid control. But they’ve just told UniQure that a natural history comparison is unacceptable for a therapy that can help thousands of patients right now,” Majors added.
“ARM implores the FDA to back up its positive rhetoric about cell and gene therapies and rare diseases with concrete, common-sense actions that will quickly restore confidence among patients, companies, and investors. Without a serious course correction, US patients will increasingly be denied access to transformative therapies even as these medicines become available to patients in other countries.”
Editor's note: Darren Incorvaia contributed to reporting. The story was updated at 11:45 ET with a statement from the Alliance for Regenerative Medicine.