The data for AMT-130 are indeed impressive.

Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by chorea, unsteady gait, and significant cognitive and psychiatric symptoms (including depression and anxiety). Patients gradually lose independence and typically die 10 to 20 years after onset.

In the U.S., an estimated 4.1–5.2 individuals per 100,000 are affected. There are currently no curative treatments, only symptomatic management.

AMT-130 is delivered via an adeno-associated virus (AAV), a non-pathogenic viral vector. The therapy is administered through specialized neurosurgery, injected directly into the striatum—one of the brain regions most vulnerable to Huntington’s disease.

In September 2025, uniQure released clinical data showing that 12 patients treated with a high dose of AMT-130 experienced a 75% slowdown in disease progression and a 60% reduction in functional decline over three years of follow-up. Critically, levels of neurofilament light chain (NfL) in cerebrospinal fluid decreased by an average of 8.2%, suggesting potential inhibition of neurodegeneration.

Hailed as a “game-changing” breakthrough by Huntington’s disease specialists, the results sent uniQure’s stock soaring 248% in a single day. The company had previously announced alignment with the FDA on a potential accelerated approval pathway.

However, in a pre-BLA meeting in November 2025, the FDA’s position unexpectedly shifted.

The FDA’s core objection centered on the use of external controls in the Phase I/II study, which are prone to bias and deemed inadequate as primary efficacy evidence for approval.

In its feedback, the FDA stated that the Phase I/II study failed to show a treatment effect relative to a placebo group after 12 months.Walid Abi-Saab, uniQure’s CMO, explained to investors on a conference call that for early Huntington’s disease patients, one year is “generally insufficient to reliably detect meaningful disease progression,” making it “nearly impossible” for a disease-modifying drug to show efficacy within that window.

This controversy reflects a disconnect between the FDA’s regulatory logic and clinical reality, especially in rare diseases.

Oncology accepts single-arm and external control studies because disease trajectories are relatively well-defined, rapid, and linear, with surrogate endpoints (e.g., tumor shrinkage) thoroughly validated against clinical benefit (e.g., survival).

Huntington’s disease is the opposite: a complex, heterogeneous neurodegenerative disorder whose natural history is influenced by genotype and other unknown factors. External controls struggle to account for such variability, and even randomized trials require extremely long follow-up to detect differences.

Abi-Saab also noted that a multi-year placebo-controlled study “could pose significant risks and burdens to patients” and raise ethical concerns—not least because some participants would undergo sham surgery without receiving treatment.

Leerink analyst Joseph Schwartz highlighted the contradiction: the FDA expresses worry over complications from craniotomy, yet insists on a sham-surgery control group.

In any case, the FDA’s position is clear, and near-term approval of AMT-130 is off the table. uniQure must adjust its strategy. The company plans to continue discussions with the FDA on a Phase III trial and intends to request a Type B meeting in Q2 2026 to further explore potential study designs.

But all this takes time.And for Huntington’s patients, time is the most precious resource of all.

Taking a broader view, AMT-130 is far from an isolated case.

In February 2026, the FDA rejected Regenxbio’s gene therapy RGX-121 for Hunter syndrome (MPS II). In the complete response letter (CRL), the FDA’s key concerns included an ill-defined patient population, reliance on natural history controls, and the use of biomarkers as surrogate endpoints.

RGX-121’s trial enrolled 13 patients with severe neurological involvement. Regenxbio classified patients using either genetic analysis or cognitive scores on the Bayley Scales of Infant and Toddler Development. The FDA found both approaches flawed: the same genetic mutation can lead to variable clinical presentations, and the cognitive threshold lacked consensus.

“Although we agreed to the protocol in principle, we expressed concerns throughout your development program,” the FDA wrote in the CRL.

Another point of contention was biomarkers. Regenxbio sought to use heparan sulfate as a biomarker to substitute for clinical efficacy, but the FDA did not accept it. This has raised alarm among other companies using similar markers.

For example:

• Denali Therapeutics’ tividenofusp, an enzyme replacement therapy for Hunter syndrome, was expected to be approved in October 2025 but was delayed, with a decision now expected next month.
• Ultragenyx’s rare disease gene therapy UX111 for Sanfilippo syndrome Type A was rejected by the FDA in July 2025 over CMC issues and has since been resubmitted.

In January of this year, the FDA rejected Atara’s cell therapy Ebvallo for the second time, citing “insufficient evidence of efficacy.”

Ebvallo, which treats EBV-positive post-transplant lymphoproliferative disorder, was approved in the EU in 2022. Its first U.S. submission in 2025 was rejected over CMC issues. After Atara transferred rights to Pierre Fabre and resubmitted, the therapy was again denied.

STAT reported that a former FDA employee revealed that, in late 2024, reviewers considered Ebvallo’s data sufficient, with the only issue being manufacturing facilities. The shift to “insufficient evidence of efficacy” was attributed to changes in FDA leadership.

Last July, the FDA rejected Capricor Therapeutics’ cell therapy deramiocel for DMD-related cardiomyopathy due to a lack of supporting data. Capricor’s CEO expressed “surprise” at the CRL, noting that prior to rejection, “the review was proceeding smoothly with no major issues identified.”

Behind this string of rejections lies ongoing turmoil within the FDA.

Since Marty Makary became FDA Commissioner, he has pushed for accelerated review and regulatory simplification, alongside rapid turnover in key departments. Over the past year, CDER has had five acting directors, including Richard Pazdur, who served just over one month.

Meanwhile, Peter Marks, the long-time head of CBER and a key champion of cell and gene therapy approvals, left in 2025. His successor, Vinay Prasad, has been skeptical of the flexibility and leniency in some earlier CGT approvals, raising industry concerns about the sector’s outlook.

Fears about the CGT sector’s outlook have proven justified. Over the past year, the FDA’s regulation of CGT has been in flux.

In September 2025, the FDA issued two draft guidelines related to CGTs, including Innovative Clinical Trial Designs for Cell and Gene Therapy Products for Small Populations. This document, targeting CGTs for small patient populations (typically rare diseases), systematically outlines six innovative trial designs:single-arm trials, disease progression modeling, external control studies, adaptive designs, Bayesian designs, and master protocols.

The FDA also explored methods for collecting post-marketing data for CGT products. Given that many CGTs are approved based on limited clinical data, the guideline clarified post-approval data collection to confirm long-term safety and efficacy.

Specific approaches include:

• using real-world evidence;
• leveraging electronic health records and insurance claims to track long-term outcomes;
• establishing patient registries to monitor durability and malignancy risk;
• decentralized data collection beyond traditional trial sites.

The core logic: limited pre-approval evidence can be balanced by robust post-approval data.

In January this year, the FDA formally announced flexible regulatory approaches for CMC requirements of CGT products.

• During clinical development, full compliance with cGMP is not required before Phase II/III; process validation and analytical methods can be refined iteratively.
• For commercial release criteria, given the small patient populations for CGTs, traditional standards based on large numbers of production batches are impractical. The FDA will exercise discretion in reviewing release specifications in BLAs, and companies may request revisions post-approval if stability is demonstrated.
• For process validation, the FDA explicitly stated it “does not require three PPQ batches,” and will judge batch adequacy based on the sponsor’s overall process understanding.

Marty Makary stated: “Regulatory policies must be tailored for highly complex and personalized CGT products.”

On paper, the FDA is indeed loosening constraints and providing greater flexibility for CGTs.In practice, however, enforcement is tightening.

According to the Pink Sheet database, in early 2026, at least 56 new molecular entities (NMEs) and novel biologics were under FDA review, compared to over 60 in each year from 2023 to 2025. CBER had only 8 novel therapeutic biologics in review—nearly halved from at least 14 in early 2025—while CDER’s pipeline remained largely stable.

The fate of AMT-130, together with the recent wave of rejections, likely marks the end of CGT’s “wild growth” era. The FDA’s new policies have opened space for flexible regulation, but this does not mean lower standards. If anything, requirements for clinical evidence are becoming stricter.

For investigational CGT therapies, the current dilemma is clear: policy incentives appear attractive, yet the new regulatory boundaries remain undefined.The priority going forward is to re‑evaluate clinical strategies and identify the FDA’s true bottom line within the new policy framework.

This round of regulatory reshaping has only just begun.