Ultragenyx Pharmaceutical announced positive clinical trials for UX111 (rebisufligene etisparvovec), an investigational AAV9 gene therapy targeting Sanfilippo syndrome Type A, or mucopolysaccharidosis type IIIA (MPS IIIA), a fatal neurodegenerative lysosomal storage disorder. The data demonstrate sustained biomarker improvements and meaningful functional benefits in children, offering potential hope for a condition with no current approved treatments.
Trial specifics
The Transpher A study enrolled 28 patients across multiple dose cohorts, with a primary focus on children under two years or with early-stage disease. Using the highest dose of 3×10^13 vg/kg, researchers observed significant clinical improvements compared to natural disease progression.
Key efficacy outcomes included:
- 63.98% median reduction in cerebrospinal fluid heparan sulfate (p<0.001)
- Cognitive score improvement of 23.2 points (p<0.0001)
- Improvements across communication, motor, and functional domains
Notably, eight children reached a 36-month cognitive developmental age—a milestone not achieved in untreated patient populations. For older patients with more advanced disease, the therapy demonstrated remarkable skill retention, with most patients maintaining communication, ambulation, and self-feeding capabilities beyond typical disease progression.
The gene therapy demonstrated a favorable safety profile across 28 patients, with a median follow-up of 4.8 years. Most adverse events were mild, primarily involving transient liver enzyme elevations. No serious complications like thrombotic microangiopathy or malignancies were observed.
Research context
UX111 represents a precision gene therapy approach targeting the underlying genetic cause of Sanfilippo syndrome. By delivering a functional copy of the SGSH gene using an AAV9 vector, the therapy aims to restore sulfamidase enzyme activity and prevent heparan sulfate accumulation in the brain.
The molecular strategy addresses a critical unmet need in a rare genetic disorder characterized by rapid neurodegeneration. With an estimated 3,000-5,000 patients in accessible geographies, this approach could potentially transform treatment paradigms for a devastating childhood neurological condition.
Ultragenyx previously filed a Biologics License Application (BLA) for UX111 with the US FDA in 2024, but was met with a Complete Response Letter requesting additional CMC data and long-term clinical data in June 2025. The long-term safety data is included in a resubmitted BLA filed in January, with the firm expecting a review period of up to six months and potential FDA decision in Q3 2026. The asset has already received several critical designations, including Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug status in the US and EU.