The FDA accepted uniQure’s application for priority review, while questions about four-year results and the need for confirmatory evidence remain.
The FDA’s acceptance of uniQure’s application for ifezuntirgene inilparvovec puts the Huntington’s disease gene therapy on a path to a decision by May 1. The agency granted Priority Review to the Biologics License Application (BLA), a significant shift after it had questioned whether the company’s earlier trial data could support approval. Acceptance means the application will be reviewed; it doesn’t settle the debate over the evidence.
The FDA has also told uniQure it is tentatively planning to bring the application before an advisory committee, likely the Cellular, Tissue, and Gene Therapies Advisory Committee. No meeting date had been set when the company announced the review. If held, the committee discussion would put the trial design and interpretation of the clinical results under public scrutiny ahead of the agency’s action date.
A change in the FDA’s position
uniQure submitted the BLA in September, alongside a Marketing Authorization Application to the United Kingdom’s Medicines and Healthcare products Regulatory Agency. The FDA’s current review follows months of shifting signals. In November 2025, the agency told uniQure that its Phase I/II findings might not be enough to establish effectiveness. On March 2, the FDA recommended a prospective, randomized, double-blind study with sham surgery controls, saying the earlier comparison against an external control did not provide sufficient primary evidence for approval.
The company’s position changed again in June, when Karim Mikhail was acting director of the Center for Biologics Evaluation and Research (CBER). The FDA then accepted the three-year analysis from the two Phase I/II trials as the primary basis for a BLA seeking accelerated approval. Mikhail has since become CBER’s permanent director.
Leadership shifts also formed part of the backdrop. Vinayak (Vinay) Prasad, MD, who had opposed the application, resigned as CBER director and FDA chief medical and scientific officer, effective April 30. FDA Commissioner Martin A. Makary, MD, resigned effective May 12. The sequence has made the FDA’s reversal a central part of the story, though the application still faces review and a possible advisory committee meeting.
uniQure CEO Matt Kapusta called acceptance “an important milestone for the Huntington’s disease community, which has waited generations for a treatment that changes the course of this devastating disease.” William Blair healthcare research analyst Lachlan Hanbury-Brown also viewed the move as reducing regulatory risk for the candidate.
What the therapy does and how it is delivered
Ifezuntirgene inilparvovec uses uniQure’s miQURE® gene-silencing platform. It carries a microRNA designed to suppress the huntingtin gene and the potentially toxic exon 1 protein fragment. Treatment involves a single administration delivered directly to the striatum—the caudate and putamen—using MRI-guided, convection-enhanced stereotactic neurosurgery.
The intervention is therefore a one-time procedure aimed at changing the disease’s progression, rather than a recurring medicine. Its delivery method and the risks associated with the ongoing trials remain part of the questions investors and reviewers will weigh. The company’s planned confirmatory study is designed to provide randomized evidence using standard of care as the comparison.
Under the design agreed with the FDA on key elements, the trial is expected to enroll about 200 patients, randomized in a 2:1 ratio to gene therapy or standard of care. Total Functional Capacity (TFC) at 36 months is the proposed primary endpoint. uniQure says it plans to begin screening patients in the United States by the end of 2026.
The application also carries the FDA’s Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), and Fast Track designations, in addition to Priority Review. Those designations shape the review pathway, but the central issue remains whether the clinical evidence supports the proposed benefit.
Three-year and four-year results tell different parts of the story
In the Phase I/II program, the high dose—6×1013 gc per subject—was associated with a statistically significant 75% slowing of disease progression on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) at 36 months. The comparison used a propensity score-matched external control drawn from the Enroll-HD natural history database. The result exceeded the study’s primary endpoint, but it came from a comparison that the FDA later said could not serve as the primary evidence of effectiveness for approval.
The findings came from U.S. and European studies, listed at NCT04120493 and NCT05243017. The design and control group matter: results against an external natural-history cohort can suggest a treatment effect, while the FDA’s call for a randomized comparison reflects its concern about relying on that approach to establish benefit.
Four-year results, reported last month, showed continued slowing on some measures, but the size and statistical strength of the findings varied by endpoint. At 48 months, uniQure reported 44% slowing on cUHDRS, which was not statistically significant (p=0.144), and 61% slowing on TFC, with a nominal p-value of 0.008. The company said the absolute treatment benefit on TFC was maintained at month 48 and that differences between the high and low doses on both measures were consistent with a dose-dependent effect.
Hanbury-Brown said the high-dose cUHDRS result had softened between years three and four, which could indicate a weakening effect, but argued that concerns about that measure were overstated given analysis caveats and its different role in the confirmatory trial and current BLA. He pointed to the TFC results, saying the separation from the external control group increased between years three and four. Those views underscore why the FDA’s review of the endpoints and longer-term data will matter.
Trial enrollment and investor reaction
The two Phase I/II studies have treated 51 patients, according to uniQure. In the U.S. randomized study, 26 patients enrolled: six received the low dose, 10 the high dose, and 10 underwent a sham procedure. Four control participants later crossed over to treatment after about 12 months.
The European open-label study enrolled 13 patients, six at the low dose and seven at the high dose. A third cohort of 12 patients explored both doses alongside immunosuppression. A fourth U.S. cohort, comprising six patients, is evaluating the high dose in people with lower striatal volumes than participants in earlier cohorts.
Despite the FDA’s acceptance, uniQure shares fell 3% to $24.03 at 10:56 a.m. ET, from Friday’s close of $24.83. Investor discussions cited the later-than-expected May 1 action date, the weaker cUHDRS slowing at four years compared with the three-year result, and continuing trial-risk concerns. The stock had already swung sharply after the FDA’s March recommendation, dropping 42% on March 2 and 3 before rebounding 58% by March 6.
The FDA’s acceptance gives uniQure a defined review milestone, but it leaves the central evidence question open. The agency’s decision will test how it weighs the earlier external-control results against the four-year data, and whether the proposed randomized study addresses its concerns. For the Huntington’s disease field, the next concrete signals are the advisory committee plans, if confirmed, and the FDA’s May 1 action.
Background: FDA questions about uniQure’s data, the earlier progression findings, analyst forecasts, the stock’s March movements, and the FDA’s June acceptance of the three-year analysis.
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