FDA Sets May 1 PDUFA Action Date for uniQure’s Huntington’s Disease Gene Therapy

The FDA has set a May 1 target action date under the Prescription Drug User Fee Act (PDUFA) for uniQure’s Huntington’s disease gene therapy candidate ifezuntirgene inilparvovec—which, if approved, would be the first treatment shown to modify the fatal, inherited neurodegenerative disorder—after accepting the company’s Biologics License Application (BLA) under Priority Review.

The action by the FDA, announced Monday, marks a complete reversal of agency opposition that surfaced last year and hardened earlier this year.

The FDA did caution uniQure, however, that it was tentatively planning to discuss the BLA at a future advisory committee meeting, most likely the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC). No date for such a meeting had been set at deadline, though uniQure said it was told it would be notified by the agency when that happens.

uniQure submitted its BLA to the FDA in September, as well as a Marketing Authorization Application (MAA) to the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).

“The FDA’s acceptance of our BLA for review marks an important milestone for the Huntington’s disease community, which has waited generations for a treatment that changes the course of this devastating disease,” uniQure CEO Matt Kapusta said in a statement.

One analyst offered another reason for the significance of the FDA action: “We see the acceptance of the BLA as an important milestone for ifezuntirgene inilparvovec as it further removes regulatory risk,” Lachlan Hanbury-Brown, research analyst, healthcare with William Blair, wrote in a research note.

Investor caution

However, investors appeared more cautious, as uniQure shares dipped 3% to $24.03 as of 10:56 am. ET from $24.83 at Friday’s close despite the positive news. Chatter on investor websites suggested several possible reasons why investors were reluctant to buy uniQure stock:

• The PDUFA target action date was later than expected.
• Four-year data for the gene therapy showed lower slowing of disease progression than earlier three-year data.
• Continuing concerns about risk in the ongoing trials.

Ifezuntirgene inilparvovec uses the company’s gene-silencing miQURE^® platform and incorporates a microRNA designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment. Patients receive a single administration through targeted, MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen).

uniQure has aligned with the FDA on what the company calls key elements of the confirmatory study design: The study is being designed as a randomized, standard-of-care trial enrolling approximately 200 patients in a 2:1 ratio of ifezuntirgene inilparvovec to standard of care, with Total Functional Capacity (TFC) at 36 months serving as the primary endpoint.

uniQure said it plans to begin patient screening in the United States by the end of 2026.

In addition to Priority Review, uniQure’s BLA for ifezuntirgene inilparvovec has been granted the FDA’s Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), and Fast Track designations.

The FDA reversal follows a change in leadership at the Center for Biologics Evaluation and Research (CBER) as Vinayak (Vinay) Prasad, MD, who opposed uniQure’s BLA, resigned for the second time in March, effective April 30. Prasad relinquished his roles as CBER director and FDA chief medical and scientific officer under Martin A. Makary, MD, who resigned effective May 12.

FDA stunner

Under Prasad, the FDA stunned uniQure in November 2025 when it told the company that what it had called “game-changing” data in September, showing significant slowing of HD progression in patients treated with the gene therapy candidate, may not be enough to secure FDA approval. The data prompted one analyst to predict ifezuntirgene inilparvovec (then known as AMT-130) would generate $4 billion peak worldwide annual sales by 2032, though a consensus of other analysts forecasted just $1.7 billion in peak sales.

Key among uniQure’s Phase I/II results was the statistically significant 75% slowing of disease progression as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS) at 36 months in patients treated with the high dose of 6×10¹³ gc/subject of ifezuntirgene inilparvovec, compared to a propensity score-matched external control derived from the Enroll-HD natural history database. That more than met the primary endpoint of the Phase I/II study, which consisted of trials in the United States (NCT04120493) and Europe (NCT05243017).

The FDA stepped up its public criticism against uniQure on March 2, when it issued what the company termed a “strong” recommendation to conduct a prospective, randomized, double-blind, sham surgery-controlled study to support a future marketing application for AMT-130. The FDA concluded that data from uniQure’s earlier Phase I/II study, which compared ifezuntirgene inilparvovec to an external control, were not sufficient to provide the primary evidence of effectiveness needed for the agency to approve the gene therapy candidate.

UniQure stock responded to the FDA jawboning by plummeting 42% on March 2 and 3, then flattening in the middle of that week, before rebounding 58% by March 6. The stock gyrations followed Prasad announcing his resignation plans.

In June, with Karim Mikhail then serving as acting CBER director, the FDA reversed itself and accepted the three-year analysis from the two Phase I/II trials as the primary basis of a Biologics License Application (BLA) for accelerated approval of ifezuntirgene inilparvovec. Mikhail has since been appointed permanent CBER director.

Four-year data

Last month, uniQure reported positive four-year data for ifezuntirgene inilparvovec showing a continued slowing of disease progression based on the two ongoing Phase I/II studies. At 48 months TFC, the primary measure of uniQure’s confirmatory study, showed consistent slowing of functional decline, with absolute treatment benefit maintained in Month 48. Differences seen between the high and low doses on both composite cUHDRS and TFC were consistent with a dose-dependent treatment effect, uniQure said.

The primary endpoint of cUHDRS showed a 44% slowing of disease progression (non-significant p=0.144) while TFC showed a 61% slowing of disease progression (nominal p=0.008), according to uniQure.

“While efficacy in the high-dose group as measured by the cUHDRS softened from year 3 to year 4 and thus could point to a weakening of treatment effect, we see concerns from this endpoint as overdone given several caveats in the analysis, and the fact that it is not the primary endpoint of the confirmatory study or the basis for the current BLA,” Hanbury-Brown commented.

“We believe the additional 48-month results from the ongoing Phase I/II study of AMT-130 in HD continue to show a positive clinical benefit, especially around the more important regulatory endpoint of TFC, which increased separation from the external control group from 3 to 4 years following treatment,” Hanbury-Brown added.

In its announcement Monday, uniQure said the two trials have dosed 51 patients with ifezuntirgene inilparvovec. The U.S. randomized study enrolled 26 patients, of which six received a low dose of ifezuntirgene inilparvovec, 10 a high dose, and 10 a sham procedure. Four control patients subsequently crossed over to treatment after approximately 12 months.

The European open-label study enrolled 13 patients—six receiving low-dose ifezuntirgene inilparvovec and seven, the high dose. A third cohort of 12 patients explored both doses in combination with immunosuppression, while and a fourth cohort of six U.S. patients is evaluating the high dose in patients with lower striatal volumes compared to those enrolled in previous cohorts.

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