Abstract Details

Title Treatment with UX111 Gene Therapy Rapidly Reduced Heparan Sulfate (HS) Exposure in Cerebrospinal Fluid (CSF) and Improved Long-term Cognitive Function in Children with Mucopolysaccharidosis IIIA (MPS IIIA)

Topic Child Neurology and Developmental Neurology

Presentation(s) S31 - Hot Topics in Child Neurology (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

Background

MPS IIIA is a rare, progressive, childhood-onset neurodegenerative lysosomal storage disease resulting in toxic accumulation of HS in the brain leading to irreversible neurocognitive decline and early death. UX111 is an AAV9 viral vector encoding human SGSH being investigated for efficacy and safety in children with MPS IIIA.

Objective Describe safety and efficacy of a single administration of UX111 in children with MPS IIIA

Design/Methods

UX111-CL301 (NCT04088734) is an ongoing, open-label phase 1/2/3 trial. Children received a single IV injection of UX111 and were followed for 24 months (parent study) then for at least 5 years after UX111 administration in the long-term follow up study (NCT04360265). The primary efficacy endpoint was CSF HS exposure, measured by time-normalized area under the curve (AUC). A key secondary endpoint was BSITD-III cognitive raw score. Data cutoff was 01Aug2024.

Results Seventeen children were in the mITT group (3.0 x 1013 vg/kg UX111 and ≤24 months of age or >24 month with a baseline Bayley cognitive DQ ≥60). Baseline mean (SD) age was 21.8 (9.9) months. Median CSF HS exposure was significantly reduced by >50% relative to baseline, and these reductions were rapid and sustained, with a median follow up of 31 months. Gangliosides GM2 and GM3 also showed rapid and sustained decreases relative to baseline. BSITD-III cognitive raw scores were significantly improved relative to untreated children with MPS IIIA during the ages when untreated children tend to plateau or lose skills. Similar improvements were seen across BSITD-III domains, including receptive and expressive communication and gross and fine motor. The only treatment-related adverse event ≥grade 3 was one event of increased alanine aminotransferase that resolved.

Conclusions UX111 appears safe and effective in children with MPS IIIA leading to reduced CSF HS exposure and improved cognitive function.

Authors/Disclosures
Heather Lau, MD (Ultragenyx) PRESENTER	Dr. Lau has received personal compensation for serving as an employee of Ultragenyx. Dr. Lau has stock in Ultragenyx.
Kaushik Patra, PhD	Dr. Patra has received personal compensation for serving as an employee of Ultragenyx. Dr. Patra has stock in Ultragenyx.
Melissa Wolf, PT	Mrs. Wolf has received personal compensation for serving as an employee of Ultragenyx Pharmaceutical. Mrs. Wolf has stock in Ultragenyx Pharmaceutical.
Nicholas Smith, MBBS, PhD, FRACP	The institution of Dr. Smith has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Forge Bio. The institution of Dr. Smith has received research support from Ultragenyx. The institution of Dr. Smith has received research support from Cyclotherapeutics. The institution of Dr. Smith has received research support from BluebirdBio. The institution of Dr. Smith has received research support from Sanfilippo Children's Foundation. The institution of Dr. Smith has received research support from Medical Research Future Fund. The institution of Dr. Smith has received research support from Women's and Children's Hospital Foundation.
María Luz Couce, MD, PhD	Prof. Couce has nothing to disclose.
Deepa S. Rajan, MD, FAAN (Childrens Hospital of Pittsburgh)	Dr. Rajan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Rajan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Rajan has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Medlink Neurology. The institution of Dr. Rajan has received research support from National Scleroderma Foundation. The institution of Dr. Rajan has received research support from Denali Therapeutics. The institution of Dr. Rajan has received research support from Ultragenyx . The institution of Dr. Rajan has received research support from Regenxbio. The institution of Dr. Rajan has received research support from Takeda. The institution of Dr. Rajan has received research support from Prevail Therapeutics. The institution of Dr. Rajan has received research support from Children's Neuroscience Institute. Dr. Rajan has received intellectual property interests from a discovery or technology relating to health care.
Kristen Truxal, MD	The institution of Dr. Truxal has received research support from Ultragenyx. The institution of Dr. Truxal has received research support from Inozyme Therapeutics.
María Jose Lopez, MD, PhD	Dr. Lopez has nothing to disclose.
Maria Fuller, PhD	The institution of Prof. Fuller has received research support from Alexion. The institution of Prof. Fuller has received research support from Ultragenyx. The institution of Prof. Fuller has received research support from Sanofi. The institution of Prof. Fuller has received research support from Paradigm.
Eines Monteagudo, MD	Mrs. Monteagudo has nothing to disclose.
Lucy Dougherty, MD	Ms. Dougherty has nothing to disclose.
Mireia del Toro, MD	Dr. del Toro has nothing to disclose.
Kevin M. Flanigan, MD, FAAN (Nationwide CHildrens Hospital)	Dr. Flanigan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta. Dr. Flanigan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apic Bio. Dr. Flanigan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AavantiBio. Dr. Flanigan has stock in 4D Molecular Therapeutics. The institution of Dr. Flanigan has received research support from Abeona Therapeutics. The institution of Dr. Flanigan has received research support from Sarepta Therapeutics. The institution of Dr. Flanigan has received research support from Astellas Therapeutics. Dr. Flanigan has received intellectual property interests from a discovery or technology relating to health care.

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