UniQure is facing uncertainty regarding the regulatory path for its gene therapy candidate AMT-130, developed for Huntington’s disease, after the FDA requested an additional sham surgery–controlled Phase 3 trial. The company and industry analysts are considering whether new data could provide an alternative route to approval.
Courtney Rice, principal at Acadia Strategy Partners, commented on the upcoming four-year analysis from the Phase 1/2 study, which is expected in the third quarter of this year. “I’m not convinced that there isn’t a path forward on [upcoming] 48-month data,” Rice told BioSpace. “I think that the final story has yet to be written here.”
During uniQure’s full-year 2025 earnings call, CEO Matt Kapusta said, “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.” Chief Medical Officer Walid Abi-Saab added that uniQure will 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.”
The necessity of another trial remains unclear. H.C. Wainwright analyst Patrick Trucchio suggested uniQure should attempt to move forward 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.”
In September 2025, uniQure reported that AMT-130 slowed Huntington's disease progression by 75% over three years. This led many to expect a biologics license application (BLA) submission in early 2026. However, following a pre-BLA meeting, the FDA stated it no longer agreed that data from uniQure’s Phase 1/2 trial were sufficient as primary evidence for accelerated approval—a reversal from previous guidance.
The FDA had earlier indicated that comparing trial results with external natural history controls would suffice for BLA submission under its accelerated pathway. UniQure described this change as drastic and noted it was inconsistent with prior agreements on protocols and statistical analyses.
H.C. Wainwright analysts wrote that this shift appears related to a lack of benefit seen at twelve months in the sham-controlled cohort of the Phase 1/2 trial.
Steven Grossman, president of HPS Group, observed via email after another recent FDA decision reversal: “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.” He continued: “Over the last year, the agency has moved away from this, resulting in a lot of decisions that feel like fiat. Hopefully [the RTF reversal] marks a return to considering all points of view.”
Holly Fernandez Lynch, associate professor at University of Pennsylvania School of Medicine, noted business challenges when regulatory guidance changes between administrations but acknowledged current leadership may revise previous decisions: “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.’”
Abi-Saab cautioned investors during uniQure’s earnings call against expecting four-year data alone to change FDA’s position: “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.” H.C. Wainwright analysts suggested negotiations could still yield an alternative pathway based on strong existing data.
Rice compared AMT-130's situation with Moderna's mRNA-based flu vaccine review process: “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.”
If required by regulators, details about any future sham-controlled Phase 3 trial remain unresolved. Abi-Saab argued against long-term sham studies involving invasive procedures for patients with limited life expectancy: “We believe that this body of real-world evidence provides a strong foundation... making a long-term sham control study... difficult to justify.” He described risks associated with surgical shams involving anesthesia and skull incisions.
A Department of Health and Human Services spokesperson disputed some descriptions of these procedures online; Reuters reported suggestions for less invasive methods such as small scalp incisions rather than burr holes through bone.
Katie Jackson, president and CEO of Help 4 HD International, criticized placebo-like sham surgeries as unethical due to patient risk and delays accessing treatment or joining other trials: “You’re asking people to get a sham surgery and sit in a placebo-like hold for one year, two years, three years,” she said.
Fernandez Lynch addressed broader ethical considerations: "It is not unethical to do a placebo-controlled trial just because the disease is severe... But when data for the investigational drug are available, you start to get into ethical questions about how much evidence is enough." She added recruitment challenges might make such trials infeasible unless patients see participation as their only chance at receiving treatment.
Kapusta concluded during his investor call: "If this is feasible and the patient community support it... we have a moral obligation given the strength of our data to continue to pursue this."
