UniQure’s FDA submission for its Huntington’s disease therapy thrown into question

A moment of hope, then a sudden jolt: the surprising shift by the FDA on uniQure N.V.'s Huntington's gene therapy

For years, there has been one big hope that could amount to a game-changing therapy for patients with Huntington's disease, an inherited, fatal neurodegenerative disorder. In that context, uniQure's experimental gene therapy AMT‑130 emerged as perhaps one of the most promising candidates. The narrative was hopeful: strong early data, regulatory designations, alignment with the FDA… until this week.

On November 3, 2025, uniQure reported that the FDA had informed them the data from AMT-130's Phase I/II studies — compared against an external control — may no longer be sufficient to serve as the primary evidence for a Biologics License Application. Shares of the company plummeted over 50% in pre-market trading, reflecting the severity of the surprise.

Below is an in-depth look at:

Why AMT-130 once seemed to be on the fast track

What exactly changed with the FDA

The implications for uniQure, patients and the HD field

What remains uncertain and what comes next

Why AMT-130 seemed poised for approval

Before the setback, the pathway looked quite promising. Some of the key pieces:

AMT-130 was given the RMAT designation by the FDA in June 2024, based on the potential of the one-time gene therapy to address a serious unmet need.

AMT-130 was granted Breakthrough Therapy designation in April 2025.

In December 2024, uniQure announced alignment with the FDA that the composite Unified Huntington's Disease Rating Scale (cUHDRS) could serve as an intermediate clinical endpoint for accelerated approval, and that data from ongoing Phase I/II studies - comparing treated patients to an external natural-history control - might form the BLA basis.

In June 2025, uniQure reiterated that they had "alignment" with the FDA on the key components of the statistical-analysis plan and manufacturing/CMC (chemistry, manufacturing, controls) aspects; they plan to submit a BLA in Q1 2026.

Together, it meant one thing for patients and investors: here's a one-time gene therapy for Huntington's with early clinical benefit, regulatory support, and a clear filing plan.

So what went wrong? What changed with the FDA?

The core issue: The FDA now seems to believe that the current data package may not be sufficient to support accelerated approval via a BLA. uniQure described the situation as a “key shift from prior communications” with the FDA.

Some of the critical points:

Previous alignment: The previous alignment (Dec 2024) indicated that the FDA agreed that data from Phase I/II+ an external control may serve as the primary evidence for a BLA under the accelerated approval pathway.

uniQure's June 2025 update reiterated that alignment, specifically noting: "The FDA continued to support … that cUHDRS may serve as an acceptable registrational, intermediate clinical endpoint … The primary efficacy analysis for the BLA will evaluate the 3-year change in cUHDRS in high-dose AMT-130 patients compared to a propensity score-adjusted external control arm."

However, in the November 3 disclosure, uniQure said the FDA indicated that data from the Phase I/II studies compared to an external control may no longer be adequate to support the submission.

In other words: what was presumably agreed upon by the company now seems to have been questioned. Or, in shorter sentences: the regulatory hurdle is higher than expected, or at least the FDA’s interpretation/expectations changed.

Unfortunately, since the detailed minutes of the meeting with the FDA are not yet publicly available, the exact reasons for the FDA's shift haven't been fully disclosed. We can speculate on potential contributing factors:

The size of the treated cohort is relatively small, Phase I/II, open-label.

The use of external natural-history controls has inherent limitations compared with randomized, concurrent controls.

The robustness of the long-term data (3-year follow-up) and whether it fulfils the required evidentiary standard for accelerated approval.

Manufacturing/CMC issues, perhaps unresolved, though uniQure's statements stressed alignment on CMC earlier.

The possibility that the FDA now expects a larger pivotal trial, possibly randomized, rather than relying on an external control comparison.

The implications: company, patients & the field

For uniQure

The immediate result on its share price was dramatic: pre-market plunge > 50%.

The regulatory timeline is uncertain: the company said the timing of BLA submission is unclear and more dialogue with the FDA is planned.

If the FDA requires a larger randomized trial, time, cost and the overall risk of the program go up dramatically. This may impact the company's financing, cash burn, and investor sentiment.

This had been a cornerstone program for uniQure's strategy and valuation; this change raises questions about risk diversification, pipeline robustness, and investor exposure.

For patients and the Huntington’s community

Expectations had been high, and many patients viewed AMT-130 as possibly the first disease-modifying therapy for HD. This sudden regulatory setback brings disappointment, delays and uncertainty with it.

But it's not a cancellation of the program because, in actuality, uniQure remains engaged with the FDA, and the underlying data continue to appear promising.

It raises broader conversations about risk/benefit, the design of gene-therapy trials in rare diseases, and regulatory standards for accelerated approval in neurodegeneration.

For the gene-therapy/rare-disease ecosystem

This case further reinforces the fact that, even with designations such as RMAT and Breakthrough Therapy, accelerated approval is not assured, particularly for complex neurodegenerative diseases.

Regulators may increasingly demand more robust evidence-randomized controls, larger cohorts, longer follow-up-even in cases where unmet need is high.

It underlines the tension between urgency-for the patients-and rigor-for the regulators-and the need for transparency and clarity with regard to trial design, controls, and endpoints.

What's still unanswered and what comes next

Unanswered questions

What exactly motivated the change in the FDA's position? Without meeting minutes, we cannot know which factor-data size, control arm, manufacturing or something else-promoted the doubt.

Will the FDA now require an RCT? If so, that would meaningfully change timeline and cost.

What are the implications for the efficacy data of AMT-130? Strong 3-year data (~75% slowing of decline in higher-dose patients) were publicised. Does the FDA question durability, the external-control comparison, or clinical meaningfulness?

Manufacturing/CMC readiness is where the company has previously claimed alignment, but in gene therapies, this can often become a bottleneck. Will that now become the gating issue?

Commercial strategy & reimbursement: Delays will raise questions around pricing, value proposition, patient access, and payor support.

Global strategy: How will this FDA change affect regulatory strategy in Europe, other jurisdictions?

What happens next

uniQure has indicated that it will “urgently interact” with the FDA to chart a way forward. The next step will be meetings to clarify the agency’s expectations.

The company still expects top-line 3-year data in Q3 2025, which could further strengthen its case.

If a larger trial becomes necessary, then uniQure will have to raise additional funding, plan trial design-likely RCT or improved control arm-and extend its timeline.

From the patient's perspective, what will matter is sustained engagement, advocacy, and realistic expectation-management-conveying that this setback is indeed real, but the door is not shut.

Why this matters — beyond just one company

Even if you're not following uniQure closely, this moment shines a light on wider issues in drug development-especially in gene therapy for neurodegenerative disease. Accelerated-approval pathways: these represent important tools to get therapies faster to patients with high unmet needs. But this case also reminds us that they do still require firm evidence. Even "fast-track" does not mean "fast & easy". External control arms: Using natural history data versus treated patients is popular in rare diseases (where randomized trials may be harder). Yet regulators appear cautious: is the data robust enough? Is bias sufficiently controlled? Is the endpoint meaningful and validated? Trial size, durability & outcome measurement: In conditions like Huntington's, the goal is to slow disease progression, but metrics matter-e.g., cUHDRS-sample size matters, and long-term follow-up matters. Gene therapy manufacturing & scalability: A one-time brain surgery gene therapy promises major benefits but also brings complexity in manufacturing, delivery, cost, and access. The regulators may well regard the preparedness of manufacturing or real-world execution as important as clinical efficacy. Patient hope and regulatory realism: Patients and families often consider these therapies as breakthroughs. Regulators have to balance hope with evidence and safety. Clear communication is thus indispensable. Closing thoughts The story of uniQure's AMT-130 program has been one of exhilarating promise followed by unexpected uncertainty. On one hand, it's a gene therapy that showed dramatic slowing of disease progression in early data, regulatory designations signalling expedited review, and hope for a disease with no disease-modifying treatments. On the other hand, this week's jolt shows how quickly things can change in the regulatory landscape-even with prior alignment and seemingly strong data. The next few months are very crucial for uniQure. They need to iron out the issues pointed out by the FDA, whether to carry out a bigger pivotal study and finance it, and readjust the timeline and expectations. To the patients and families living with Huntington's disease, the message is sobering but not fatalistic: while the path has grown more complex, the underlying science remains promising, and the quest continues. In many ways, this is not a moment about one therapy; it is a moment about how we, as a society, approach high-stakes and high-risk therapies in rare, devastating diseases. It is a moment about how the frameworks of regulatory science adapt to gene therapies, how trials are designed, how data is judged, and how hope and evidence are balanced.