The second half of 2025 is shaping up to be a pivotal period for advanced therapies, with the FDA poised to decide on a wave of gene and cell therapies. The outcomes of these reviews will offer critical insights into the future of Accelerated Approval for gene therapies and signal how new FDA leadership might approach novel treatments for high unmet medical needs in the years ahead. Among these, Ultragenyx’s UX111 (formerly Abeona Therapeutics’ ABO-102) gene therapy for Sanfilippo syndrome type A stands out, not only as one of a potential dozen advanced therapy programs seeking FDA approval this year, but also as one of a handful aiming to secure approval via the FDA’s Accelerated Approval pathway based on surrogate endpoints and one that is close to our hearts. This program will represent a significant advancement in the treatment of MPS IIIA and may pave the way for future gene therapies targeting similar lysosomal storage disorders.
Given the promising clinical data and significant regulatory momentum, RareMoon’s Regulatory Scientific Advisor, Dr. Kaye Spratt, is closely monitoring the progress of UX111. Dr. Spratt, who previously held a leadership role at Abeona Therapeutics, has maintained a deep connection to this program since supporting its early development during her tenure at Abeona.
Development History
UX111 is an investigational gene therapy designed to treat MPS IIIA, a rare and fatal, pediatric-onset lysosomal storage disorder caused by a deficiency of the SGSH enzyme, which leads to toxic accumulation of heparan sulfate (HS) in the central nervous system. By early childhood, MPSIIIA children lose the ability to speak, recognize loved ones, and eventually even walk or feed themselves. Originally developed by Abeona Therapeutics, Ultragenyx acquired global rights to UX111 in May 2022. The therapy utilizes an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH), aiming to restore enzyme activity and reduce the accumulation of HS in the central nervous system. Accomplishing this will make UX111 the first ever FDA-approved treatment for patients suffering from this devastating neurodegenerative disorder, and a victory for the rare disease community.
Clinical Trials and Patient Enrollment
The pivotal Transpher A study (NCT02716246, opened in the US in 2016 with a planned completion date of 2027) is an ongoing Phase 1/2/3 open-label, dose-escalation trial, evaluating the safety and efficacy of UX111. To date, 28 subjects have been treated across three dose cohorts, with 22 subjects receiving the highest dose of 3×10¹³ vg/kg. A modified intent-to-treat (mITT) group includes 17 subjects who were either under 2 years of age or older than 2 with a cognitive developmental quotient (DQ) of 60 or above at enrollment.
Endpoints and Efficacy
- Primary Endpoint: Reduction of HS levels in cerebrospinal fluid (CSF).
- Secondary Endpoints: Neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development (Bayley-III), MRI-based brain volume measurements, and safety evaluations.
In the mITT group, treatment with UX111 resulted in a mean 63% reduction in CSF HS exposure over time. This biochemical improvement correlated with stabilization or gains in cognitive function, with a +22.7 point treatment effect observed in Bayley-III cognitive raw scores compared to natural history data. Additionally, improvements were noted in receptive and expressive communication and fine motor skills.
UX111 has achieved multiple FDA designations
- Regenerative Medicine Advanced Therapy (RMAT), c.2018
- Fast Track Designation, c.2016
- Rare Pediatric Disease (RPD) Designation
- Orphan Drug Designation (ODD), c.2014
In the European Union, UX111 has been granted:
- PRIME, c.2019
- Orphan Designation, c.2016
BLA Submission and FDA Alignment
In December 2024, Ultragenyx submitted a Biologics License Application (BLA) to the FDA seeking Accelerated Approval for UX111. The submission is supported by data from the Transpher A study, with the FDA agreeing to consider CSF HS reduction as a surrogate endpoint for Accelerated Approval. With this approval, Ultragenyx will also be awarded a Priority Review Voucher. This approval will underscore the FDA’s recognition of CSF HS as a biomarker directly linked to disease pathology in MPS IIIA.
Other Gene Therapies RareMoon is Tracking
The regulatory momentum for gene therapies to treat rare genetic diseases continues in the U.S., with 5+ approvals possible in 2025 after seeing eight approvals between 2023 and 2024.
RareMoon has spent hundreds of hours strategically supporting and advising Clients on Accelerated Approval strategies, creating databases, and charting trends. This year, we are actively tracking the current gene therapy BLAs in the regulatory pipeline, focusing on whether sponsors and the FDA expect Accelerated Approval based on surrogate or intermediate clinical endpoints. The table below summarizes each program’s regulatory status and the endpoints proposed or accepted for approval. Based on public sources, the programs with a clearly announced expectation of accelerated approval based on a surrogate or intermediate clinical endpoint are Ultragenyx’s UX111 for MPS IIIA, REGENXBIO’s RGX-121 for MPS II, and uniQure, which announced the FDA the agrees that data from ongoing Phase I/II studies may serve as the primary basis for BLA for Accelerated Approval.
| Product (Sponsor) | Indication | Accelerated Approval Expected? | Endpoint Type & Description | Status / Decision Date |
|---|---|---|---|---|
| BLAs under review | ||||
| UX111 (Ultragenyx) | MPS IIIA | Yes | Surrogate: Reduction in CSF heparan sulfate (HS), correlated with neurocognitive outcomes | BLA under review, PDUFA Aug 18, 2025 |
| PRGN-2012 (Precigen) | Recurrent respiratory papillomatosis | Not announced | Clinical: Reduction in number of surgical interventions required per year | BLA under review, PDUFA Aug 27, 2025 |
| Deramiocel (Capricor) | DMD cardiomyopathy | Not announced | Clinical: Cardiac function (e.g., LVEF), biomarkers, and functional endpoints | BLA under review, PDUFA Aug 31, 2025 |
| Avance Nerve Graft (Axogen) | Peripheral nerve discontinuities | Not announced | Clinical: Nerve function recovery, sensory/motor endpoints | BLA under review, PDUFA Sept 5, 2025 |
| RGX-121 (REGENXBIO) | MPS II (Hunter syndrome) | Yes | Surrogate: Reduction in CSF heparan sulfate (HS) D2S6, biomarker of CNS disease burden | BLA under review, PDUFA Nov 9, 2025. |
| Etuvetidigene autotemcel (Fondazione Telethon) | Wiskott-Aldrich Syndrome | Not announced | Clinical: Survival, infection/bleeding reduction, platelet normalization. Surrogate: WASP expression, immune reconstitution, cell engraftment | BLA submitted March 2025, no PDUFA date announced as of yet |
| Anticipated/upcoming BLA submissions | ||||
| AMT-130 (uniQure) | Huntington’s disease | Yes | Clinical: Change in composite Unified Huntington’s Disease Rating Scale (cUHDRS) | Phase 3, BLA not yet submitted |
| RP-A501 (Rocket) | Danon disease | Possible, not announced | Surrogate: Reduction in left ventricular mass index (LVMI), cardiac biomarkers; functional endpoints | Phase 2, BLA not yet submitted |
| ST-920 (Sangamo) | Fabry disease | Possible, not announced | Surrogate: Increase in α-Gal A activity, reduction in plasma/urine GL-3 (Gb3) and lyso-Gb3 | Phase 3, BLA not yet submitted |
Notes:
- “Accelerated Approval Expected?” column reflects public statements or regulatory filings indicating intent to pursue accelerated approval based on surrogate or intermediate endpoints.
- uniQure (AMT-130), Rocket (RP-A501), and Sangamo (ST-920) are in late-stage development but have not yet submitted BLAs.
- ⚠️ Important: Rocket Pharma’s Phase 2 trial was on FDA clinical hold as of late May 2025 due to a patient death.
- uniQure announced FDA alignment on key elements of Accelerated Approval for AMT-130 in Huntington’s Disease in December 2024.
- For PRGN-2012, Deramiocel, Avance Nerve Graft, AMT-130, RP-A501, and ST-920, there is no current public confirmation of accelerated approval via a surrogate endpoint, though some use biomarkers or functional endpoints in pivotal studies.
Contact Us
If you’re evaluating the potential for accelerated approval at any stage in your program, RareMoon can help. Contact us to assess how to approach the FDA, refine your regulatory strategy, and position your data for a successful engagement with the FDA. Or email us at [email protected] to ensure you stay in touch via our newsletter: IMPACT: Regulatory Updates.
