uniQure NASDAQ: QURE used its fourth-quarter and full-year 2025 earnings call to outline next steps for its lead Huntington’s disease gene therapy program AMT-130 after receiving additional regulatory feedback from the U.S. Food and Drug Administration, while also providing updates across its Fabry disease and epilepsy pipelines and reviewing year-end financial results.
AMT-130: company highlights three-year data while responding to FDA feedback
CEO Matt Kapusta reiterated the company’s view that AMT-130 has generated “groundbreaking” three-year Phase I/II results in Huntington’s disease, citing outcomes previously disclosed in September 2025. Kapusta said the dataset showed a statistically significant 75% slowing of disease progression on the Composite Unified Huntington’s Disease Rating Scale, a statistically significant 60% slowing on Total Functional Capacity, a reduction in neurofilament light (NfL) from baseline, and supportive trends across other endpoints.
Management emphasized that these outcomes were assessed against a “carefully and methodically constructed patient-matched external comparator” derived from Enroll-HD, a large natural history dataset with longitudinal data on more than 30,000 participants.
However, leadership spent much of the call discussing the regulatory implications of FDA feedback. Kapusta said the company previously disclosed that during an October 2025 pre-BLA meeting, the FDA conveyed that Phase I/II data were “unlikely” to provide the primary evidence needed to support a biologics license application. The company then held a Type A meeting with the agency on January 30, and received the official meeting minutes on February 27.
Chief Medical Officer Dr. Walid Abi-Saab said the meeting minutes stated that FDA could not agree that Phase I/II data compared to an external control would be sufficient as the primary evidence of effectiveness for a marketing application. Abi-Saab added that FDA highlighted “the absence of treatment effects relative to sham subjects” in the U.S. Phase I/II study after 12 months, and the agency “strongly recommended” a Phase III randomized, double-blind, sham surgery-controlled trial.
Debate over sham surgery, external controls, and trial feasibility
Abi-Saab said uniQure has a different interpretation of the one-year sham-controlled data, arguing that in early Huntington’s disease, a one-year window is generally too short to reliably detect meaningful progression in control patients. He said evidence of disease slowing began to emerge in the second year and became more pronounced in the third year, and he pointed to precedents in rare diseases where external controls and natural history datasets have supported approvals.
The company also raised ethical and practical concerns with a multiyear sham-controlled design for a one-time administered therapy. Abi-Saab said such a study could impose “significant risks and burden,” and noted that the Huntington’s patient community has communicated concerns to regulators. In response to analyst questions, he described the burdens of a sham surgery as including extended anesthesia and surgical steps such as cutting through skin and potentially drilling a superficial hole, adding that patients could worsen during a long blinded period and potentially lose the opportunity to benefit.
Kapusta said the company has worked to educate FDA around AMT-130’s safety profile and procedure-related considerations, including volumetric MRI changes that management said were not associated with clinical consequences. Kapusta stated that the company has not seen disease or clinical safety events associated with AMT-130 since December 2022, while acknowledging earlier events related to the surgical procedure.
Looking ahead, uniQure said it plans to request a Type B meeting in the second quarter of 2026, with the primary goal of discussing Phase III study designs. Abi-Saab said the company hopes to leverage the extensive Enroll-HD database to “strengthen study designs” and potentially avoid approaches that are difficult for patients, while still addressing FDA’s feedback. Management said it is too early to provide specific details on endpoints, duration, costs, or enrollment timelines given that a Phase III design has not yet been defined.
Four-year follow-up analysis planned; publication efforts underway
uniQure said it intends to update its Phase I/II Statistical Analysis Plan to incorporate a four-year analysis, which Kapusta said is expected to be conducted in the third quarter of 2026. Abi-Saab told analysts the company informed FDA it will amend the protocol or statistical analysis plan and submit it, and that the analysis would include the 12 patients who reach four years of follow-up as well as additional patients who by then reach three years, presenting the “totality of the data.”
Abi-Saab cautioned that the company has no reason to believe the four-year dataset will change FDA’s current position regarding the Phase I/II trials, but said longer observation could further demonstrate durability and clinical meaningfulness over time.
He also noted that after presenting three-year data in September 2025, the company received unsolicited outreach from ex-U.S. regulators and has initiated discussions with several agencies. In addition, he referenced a February 2026 presentation at the CHDI meeting describing new analyses supporting the company’s propensity score matching methodology, and said uniQure is preparing a manuscript detailing the three-year analysis for anticipated peer-reviewed publication later in 2026.
Pipeline updates: Fabry gene therapy paused at higher doses; epilepsy enrollment progresses
In Fabry disease, Abi-Saab reviewed preliminary safety and exploratory efficacy data from 11 patients in the Phase I/II trial of AMT-191. As of a January 8, 2026 cut-off, all 11 patients across three dose cohorts exhibited elevated alpha-Gal A enzyme activity, and six had successfully withdrawn from enzyme replacement therapy (ERT). Abi-Saab said that as of the call date, all 11 patients have now been withdrawn from ERT.
He said dose-dependent enzyme activity increases were observed and appeared durable over measured follow-up periods, which ranged from more than one year for the longest-followed high-dose patient to four months for a mid-dose patient. He added that stable plasma Lyso-Gb3 levels were maintained post-dose across cohorts through the cut-off date, regardless of ERT status.
On safety, Abi-Saab said AMT-191 had a manageable profile, with no serious adverse events related to the therapy in the low and mid doses. However, two mid-dose patients experienced asymptomatic grade 3 liver enzyme elevations, which were confirmed by an independent data monitoring committee as dose-limiting toxicities per protocol. As a result, uniQure paused dosing at the mid and high doses pending further evaluation. Abi-Saab said both patients responded to corticosteroids and were tapering off without loss of alpha-Gal A activity as of the call.
For mesial temporal lobe epilepsy, Abi-Saab said the company has completed enrollment of five additional patients in the first cohort and has begun enrollment in the second cohort, with enrollment in the second cohort expected to be completed by mid-year. He said uniQure plans a second-quarter update on all six treated patients in the first cohort, including patients with non-dominant and dominant hemisphere lesions, reporting at least six months of safety, tolerability, and seizure frequency outcomes. Management said the study remains early-stage and is focused on safety and pharmacodynamic signals, and did not set expectations for seizure reduction levels.
Abi-Saab also noted that the Phase I/II EPISOD1 trial of AMT-162 for SOD1-ALS remains on voluntary enrollment and treatment hold following an independent data monitoring committee recommendation after a September 2025 review, tied to a dose-limiting toxicity event involving dorsal root ganglion toxicity in one patient in the second cohort.
Financial results: higher cash balance and runway into 2029
CFO Christian Klemt reported full-year 2025 revenue of $16.1 million, down from $27.1 million in 2024, driven primarily by decreases in collaboration revenue and contract manufacturing revenue, partially offset by higher license revenue. Research and development expense was $140.7 million, slightly down from $143.8 million, reflecting lower employee, contractor, severance, and facility costs offset by higher direct R&D spending, including costs related to preparation for a potential AMT-130 BLA submission. Selling, general and administrative expense rose to $65.5 million from $52.7 million, driven mainly by higher professional fees associated with planned U.S. commercialization activities for AMT-130.
Cash, cash equivalents, and investment securities totaled $622.5 million at December 31, 2025, up from $367.5 million a year earlier. Klemt attributed the increase primarily to approximately $404.2 million in proceeds from public offerings of ordinary shares and pre-funded awards, and said the company expects its cash to be sufficient to fund operations into the second half of 2029.
In closing remarks, Kapusta said 2026 priorities include continued engagement with regulators in and outside the U.S. to define the most appropriate path forward for AMT-130, disciplined advancement of pipeline programs, and ongoing data generation. He added that if a Phase III sham-controlled study is deemed feasible and ethical—and supported by the patient community—the company would “seriously” consider moving forward.
About uniQure NASDAQ: QURE
uniQure N.V. is a biotechnology company focused on the development and commercialization of gene therapies for patients with severe medical needs. Using its proprietary adeno‐associated viral (AAV) vector platform, the company designs single‐dose treatments aimed at addressing the underlying genetic causes of disease rather than solely managing symptoms. Its most advanced program, Hemgenix® (etranacogene dezaparvovec), received regulatory approval in the United States and Europe for adult patients with hemophilia B, marking one of the first gene therapies for a bleeding disorder to reach the market.
Beyond hemophilia B, uniQure's pipeline includes preclinical and clinical-stage candidates targeting rare and debilitating conditions such as aromatic l-amino acid decarboxylase (AADC) deficiency, Huntington's disease, and Parkinson's disease.
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