While the FDA appears to be adamant that uniQure conduct a sham surgery–controlled Phase 3 trial before AMT-130 can be considered for approval, experts believe there is an alternate path forward for the therapy, perhaps even based on precedent from the recent drama surrounding Moderna’s mRNA flu vaccine.
UniQure’s highly anticipated gene therapy for Huntington’s disease may still have another path forward despite the FDA’s insistance on an additional sham surgery–controlled Phase 3 trial, some market watchers believe.
“I’m not convinced that there isn’t a path forward on [upcoming] 48-month data,” Courtney Rice, principal at Acadia Strategy Partners, told BioSpace. UniQure plans to conduct a four-year analysis for patients in AMT-130’s Phase 1/2 study in the third quarter of this year. “I think that the final story has yet to be written here.”
During the company’s full-year 2025 earnings call on Monday, uniQure executives appeared open to a new trial for the one-time gene therapy. “If there is a study that we believe is feasible and ethical, we’re going to do everything we can to drive AMT-130 forward,” CEO Matt Kapusta said on the call.
Chief Medical Officer Walid Abi-Saab echoed this sentiment, saying the company plans to request a Type B meeting with the FDA in the second quarter of this year “to further discuss potential Phase 3 study design approaches that address the agency’s feedback, while also considering feasibility and patient risk.”
But whether that trial will ever materialize—and if it needs to in order for AMT-130 to reach the market—is far from certain. H.C. Wainwright analyst Patrick Trucchio told BioSpace he believes uniQure needs to try to negotiate a path forward for AMT-130 without a Phase 3 trial.
“They have to act in what’s in the best interest of the shareholders and that clearly would be in the best interest,” he said. “So I think they have to, even if it’s an uphill climb from here.”
Reversal of Guidance
UniQure animated the Huntington’s disease community in September 2025, reporting that AMT-130, a one-time gene therapy in development for the intractable neurodegenerative disease, slowed disease progression by 75% after three years. With these data in hand, the biotech appeared to be on track for a biologics license application (BLA) submission in the first quarter of 2026. Five weeks later, however, the FDA said not so fast.
During a pre-BLA meeting, the agency told uniQure it “no longer agrees” that data from the company’s Phase 1/2 trial are “adequate to provide the primary evidence in support of a BLA submission,” the company revealed in early November. This, despite the two parties having previously agreed on the protocols and statistical analyses used.
The new feedback was a “drastic change” from FDA guidance provided to uniQure in 2024, the company insisted. Previously, the regulator had said that data from the trial, compared to a natural history external control, could serve as the primary basis for a BLA submission under the agency’s accelerated approval pathway, Kapusta said in a statement at the time.
The FDA’s reversal appears to be based on the fact that the 12-month sham-controlled cohort of the Phase 1/2 trial did not show benefit at that time point, H.C. Wainwright analysts wrote in a note to investors on Monday.
But recent precedent suggests the FDA could be convinced with new evidence.
As Steven Grossman, president of HPS Group, wrote in an email to BioSpace after the FDA reversed its refusal-to-file letter for Moderna’s mRNA-based flu vaccine, “An important feature of FDA decisionmaking is its willingness to consider additional information and insights. A seeming no that becomes a nuanced yes is a common occurrence.
“Over the last year, the agency has moved away from this, resulting in a lot of decisions that feel like fiat,” Grossman continued. “Hopefully [the RTF reversal] marks a return to considering all points of view.”
UniQure received its initial guidance regarding AMT-130’s regulatory path from the FDA under the Biden administration. Holly Fernandez Lynch, associate professor of Medical Ethics and Health Policy at the University of Pennsylvania School of Medicine, acknowledged that a reversal of FDA guidance under a new administration is “challenging” for uniQure from a business perspective.
“If they’re making business decisions based on what FDA said, they need to be able to rely on that from administration to administration,” she told BioSpace. However, she added that current FDA leadership is not necessarily obligated to follow previous guidance. “Just because the FDA said something doesn’t mean that future FDAs should not be able to say, ‘That was wrong. We have an obligation to not approve a drug that doesn’t work.’”
FDA, Is That Your Final Answer?
Abi-Saab said during uniQure’s earnings call that he wouldn’t count on the four-year data altering the FDA’s decision.
“We don’t believe that there’s any reason we have today to believe that this will change the FDA’s position regarding the Phase 1/2 trials,” he told investors.
H.C. Wainwright struck a different tone, however, in the Monday note. “While the FDA appears to be enforcing a full sham surgery-controlled Phase 3 trial in Huntington’s, we believe an alternative path forward may be negotiated given the strong AMT-130 data generated to-date,” the analysts wrote. The 4-year data “should further inform the durability and magnitude of effect observed to date.”
After the FDA’s Moderna reversal, Commissioner Marty Makary appeared to leave the door open to a more fluid regulatory review process. During a drug industry event on February 17, Makary said the RTF was “part of a conversation” with the company, Politico reported.
“I have a hard time believing why [AMT-130] can’t do the same about-face that so many other previous ones have done, including Moderna,” Rice said.
The Ethics of a Sham Study in HD
If a Phase 3 trial is required, what it will entail remains to be seen, and uniQure—and the Huntington’s community—have concerns.
“We believe that this body of real-world evidence provides a strong foundation to inform efficient and scientifically rigorous study design, making a long-term sham control study of a one-time administered therapy difficult to justify,” Abi-Saab said on Monday’s call.
The type of sham study the FDA is requesting requires patients to be anesthetized for 10 to 12 hours while a surgeon cuts through the skin and makes a superficial [burr] hole in the skull, he explained.
“All of these elements represent risk for these patients,” Abi-Saab continued, especially in a two- to three-year study where the sham selection is unknown to the patients, who are given around 12–18 years to live from the time of diagnosis. Sometimes, clinical trials will offer the study drug to patients who received placebo at the end of the testing period. But in the case of AMT-130, the disease may have progressed too far for patients to benefit from the therapy by the end of the trial, Abi-Saab said.
Department of Health and Human Services spokesperson Andrew Nixon disputed Abi-Saab’s characterization of the surgical procedure on social media, saying that the study could be based on a sham procedure in which the patient would receive a small scalp incision, Reuters reported on Wednesday.
Notably, the sham cohorts in uniQure’s Phase 1/2 study involved a simulated surgical procedure with skin incisions only, as opposed to burr holes through the skull.
“To go back in a rare disease for sham surgeries is unethical,” Katie Jackson, president and CEO of Help 4 HD International, told BioSpace. “You’re asking people to get a sham surgery and sit in a placebo-like hold for one year, two years, three years,” preventing patients from participating in other clinical trials or from being able to receive AMT-130 in a future open label extension study if they become too ill.
Fernandez Lynch agreed that ethical questions surround the FDA’s decision because there are data available that support the treatment’s efficacy. In general, she said, “It is not unethical to do a placebo-controlled trial just because the disease is severe. You are not harming them by not giving them something that you don’t know is going to help them.”
But when data for the investigational drug are available, “you start to get into the ethical questions about how much evidence is enough evidence for us to feel like we know that this drug works.”
Fernandez Lynch added that a sham trial might be infeasible because it can be difficult to convince patients to enroll in the study. “On the other hand, if it’s the only way that they have a chance of getting the drug, then they’re likely to enroll.”
These are all issues uniQure must balance as it heads into the Type B meeting for AMT-130.
“If this is feasible and the patient community support it,” Kapusta said on the investor call, “we have a moral obligation given the strength of our data to continue to pursue this.”
