At a Glance
- UX111 yields +23.2-point Bayley-III cognitive gains (p<0.0001) in early-stage MPS IIIA patients vs. natural history.
- Advanced cases retain communication, ambulation, and self-feeding beyond typical loss ages in untreated peers.
- Median 63.98% CSF heparan sulfate reduction (p<0.001), well-tolerated over 4.8-year median follow-up.
- BLA resubmitted to FDA; PDUFA expected Q3 2026 for accelerated approval.
Written By: Sana Khan BPharm
Reviewed By: Pharmacally Editorial Team
Ultragenyx Pharmaceutical Inc. announced promising long-term data from clinical studies of UX111 (rebisufligene etisparvovec), an investigational AAV9 gene therapy targeting Sanfilippo syndrome Type A (MPS IIIA), a fatal neurodegenerative lysosomal storage disorder with no approved treatments. The results show sustained biomarker reductions and functional gains across age groups and disease stages, with follow-up extending up to 8.5 years.
Clinical Improvements in Early-Stage Patients
In younger children or those with early-stage disease (n=17), UX111 delivered a +23.2-point improvement in Bayley-III cognitive raw scores versus natural history data (p<0.0001), alongside gains in receptive communication (+8.1 points, p=0.0076), expressive communication (+11.1 points, p=0.0008), fine motor (+9.0 points, p=0.0026), and gross motor skills (+3.9 points, p=0.070). Caregiver-reported Vineland-2 outcomes echoed these benefits in communication, motor, and personal domains. Eight treated children reached a 36-month cognitive age, a milestone unmet in natural history controls.
Functional Retention in Advanced Cases
Older patients or those with advanced disease (n=10) retained key skills longer than untreated peers, including communication in all cases (median age 9.7 years vs. 7.6 years loss in natural history), independent ambulation in 9/10 (median 9.05 years vs. 11.3 years), and self-feeding in 9/10. These outcomes counter the typical progressive loss seen in late childhood.
Biomarker and Safety Data
UX111 reduced CSF heparan sulfate by a median 63.98% (p<0.001) in 27 patients, with over 80% achieving ≥50% drops regardless of baseline age or severity. The therapy proved well-tolerated (N=33, median 4.8-year follow-up), with mild, transient liver enzyme elevations as primary adverse events and no serious issues like hypersensitivity, TMA, or malignancy.
UX111 Clinical Program Overview
The Transpher A trial (NCT02716246) dosed 28 patients in three escalating cohorts across five international sites, featuring a high-dose Cohort 3 (3×10^13 vg/kg) with 22 participants, including 17 in the modified intent-to-treat analysis limited to children under 2 years or those over 2 with cognitive quotient of 60+. An additional trial (NCT04088734) treated five high-dose patients, and eligible participants transitioned to a long-term extension study (NCT04360265) for at least five years of post-dosing surveillance.
Regulatory Progress and Background
Ultragenyx resubmitted the BLA to FDA in January 2026, targeting accelerated approval with a PDUFA date in Q3 2026. UX111 delivers a functional SGSH gene via one-time IV infusion to address enzyme deficiency driving HS accumulation and brain damage; it holds multiple FDA and EU designations. Data were presented at WORLD Symposium 2026, highlighting urgency for this 3,000-5,000-patient population facing median 15-year survival.
Understanding Sanfilippo Syndrome Type A
MPS IIIA, a devastating ultra-rare brain disorder, emerges in early childhood due to SGSH gene mutations that impair sulfamidase production, causing heparan sulfate buildup, swift neuron loss, developmental regression in cognition/language/motor function, behavioral challenges, and typically death by age 15 in aggressive cases. Affecting roughly 3,000–5,000 individuals in major markets, it remains untreated despite its toll on young lives.
Reference
Ultragenyx Announces Positive Longer-Term Data Demonstrating Treatment with UX111 Gene Therapy Results in Sustained, Significant Reductions in CSF-HS and Continued Meaningful Improvements in Clinical Function Across Multiple Developmental Domains in Children with Sanfilippo Syndrome (MPS IIIA), 03 February 2026, Ultragenyx Announces Positive Longer-Term Data Demonstrating Treatment with UX111 Gene Therapy Results in Sustained, Significant Reductions in CSF-HS and Continued Meaningful Improvements in Clinical Function Across Multiple Developmental Domains in Children with Sanfilippo Syndrome (MPS IIIA)—Ultragenyx Pharmaceutical Inc.
Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.Hsgsh, ClinicalTrials.gov ID NCT02716246, https://clinicaltrials.gov/study/NCT02716246