FDA Sets May 1 PDUFA Date for uniQure Huntington's Gene Therapy BLA

The FDA has set a May 1 PDUFA action date for uniQure's Huntington's disease gene therapy ifezuntirgene inilparvovec, accepting the company's Biologics License Application under Priority Review and putting the candidate on track to become the first treatment shown to modify the fatal, inherited neurodegenerative disorder. PDUFA is the statute under which the agency commits to review deadlines for drug applications.

The acceptance, announced Monday, completes a reversal of agency opposition that surfaced last year and hardened earlier this year. The FDA cautioned uniQure that it tentatively plans to discuss the BLA at a future advisory committee meeting, most likely the Cellular, Tissue, and Gene Therapies Advisory Committee. No date had been set at deadline; uniQure said the FDA will notify it when one is.

uniQure submitted the BLA in September, alongside a Marketing Authorization Application to the UK's Medicines and Healthcare products Regulatory Agency.

"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," CEO Matt Kapusta said in a statement.

Why did the market not cheer?

Investors stayed cautious. uniQure shares dipped 3% to $24.03 by 10:56 a.m. ET on Monday, from $24.83 at Friday's close, despite the positive news. Chatter on investor websites pointed to three concerns:

• The PDUFA date arrived later than expected.
• Four-year data showed less slowing of disease progression than the three-year data.
• Questions persist about risk in the ongoing trials.

Lachlan Hanbury-Brown, healthcare research analyst with William Blair, framed the acceptance differently: "We see the acceptance of the BLA as an important milestone for ifezuntirgene inilparvovec as it further removes regulatory risk," he wrote in a research note.

How does the therapy work?

Ifezuntirgene inilparvovec is built on uniQure's miQURE gene-silencing platform and carries a microRNA (a small regulatory RNA molecule) designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment. Patients receive a single administration through MRI-guided, convection-enhanced stereotactic neurosurgery directly into the striatum — the caudate and putamen regions central to Huntington's pathology.

The two Phase I/II trials, one in the U.S. (NCT04120493) and one in Europe (NCT05243017), have dosed 51 patients. The U.S. randomized study enrolled 26: six at low dose, 10 at high dose, and 10 in a sham procedure, with four controls crossing over to treatment after roughly 12 months. The European open-label study enrolled 13 — six low dose, seven high. A third cohort of 12 patients tested both doses with immunosuppression, and a fourth cohort of six U.S. patients is evaluating the high dose in patients with lower striatal volumes.

What changed at the FDA?

Under Vinayak (Vinay) Prasad, MD, the FDA stunned uniQure in November 2025, telling the company that data it had called "game-changing" in September — showing significant slowing of disease progression — might not suffice for approval. That September data had prompted one analyst to predict $4 billion in peak worldwide annual sales by 2032 for the candidate, then known as AMT-130, while a consensus of other analysts forecast $1.7 billion.

The key Phase I/II result was a statistically significant 75% slowing of disease progression on the composite Unified Huntington's Disease Rating Scale (cUHDRS) at 36 months in patients given the high dose of 6×10¹³ genome copies per subject, compared with a propensity score-matched external control drawn from the Enroll-HD natural history database.

On March 2, the FDA escalated, issuing what uniQure called a "strong" recommendation to run a prospective, randomized, double-blind, sham surgery-controlled study, concluding the external-control Phase I/II data were not sufficient as primary evidence of effectiveness. The stock plummeted 42% across March 2 and 3, then rebounded 58% by March 6 as Prasad announced plans to resign. Prasad relinquished his roles as CBER director and FDA chief medical and scientific officer, with his resignation effective April 30; Martin A. Makary, MD, resigned effective May 12.

In June, with Karim Mikhail as acting CBER director, the FDA reversed course and accepted the three-year analysis as the primary basis for a BLA seeking accelerated approval. Mikhail has since been appointed permanent CBER director.

What do the four-year data show?

Last month, uniQure reported 48-month results showing continued slowing of disease progression. cUHDRS showed a 44% slowing (non-significant, p=0.144), while Total Functional Capacity (TFC) — the primary measure of the planned confirmatory study — showed a 61% slowing (nominal p=0.008), with absolute treatment benefit maintained. Dose-dependent differences between high and low doses held on both measures.

"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, adding that TFC separation from the external control widened between years 3 and 4.

The confirmatory study design, aligned with the FDA, will randomize roughly 200 patients in a 2:1 ratio to ifezuntirgene inilparvovec or standard of care, with TFC at 36 months as the primary endpoint. uniQure plans to begin U.S. patient screening by the end of 2026. The BLA also carries Breakthrough Therapy, Regenerative Medicine Advanced Therapy, and Fast Track designations.

The May 1 action date, and any advisory committee meeting before it, will determine whether the first disease-modifying Huntington's treatment reaches patients.