Abstract Details

Title Treatment with UX111 Reduced Cerebrospinal Fluid (CSF) Heparan Sulfate (HS) Exposure and Stabilized or Improved Functioning Across Dose, Age, and Stage of MPS IIIA

Topic Child Neurology and Developmental Neurology

Presentation(s) S19 - Emerging Therapies in Child Neurology (5:06 PM-5:18 PM)

Poster/Presentation
Number 009

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

Background MPS IIIA (Sanfilippo type A) is a progressive neurodegenerative disease characterized by developmental arrest, regression, and early death. UX111 (rebisufligene etisparvovec) is an AAV9 viral vector encoding human SGSH under investigation for MPS IIIA.

Design/Methods Data were analyzed across 2 open-label studies (NCT02716246, NCT0408873) and the ongoing long-term follow up (NCT04360265). Children received a single UX111 infusion IV at low (0.5x10¹³ vg/kg, n=3), mid (1x10¹³ vg/kg, n=3), or high dose (3x10¹³ vg/kg, n=27).The mITT set (n=17) included children treated with high dose and either ≤2 years old or >2 years old with a BSID-III cognitive developmental quotient ≥60. CSF HS exposure was defined as time-normalized area under the curve of percentage change from baseline. Data cutoff was 01Aug2024.

Results

33 children received UX111. Median (min-max) follow up was 43.96 (7.00-77.14) months. Median (95% CI) CSF HS exposure decreased by 57.86% (33.15, 61.44) relative to baseline for low dose, 42.81% (39.74, 62.75) for mid dose, 64.51% (56.29, 71.25, p<0.0001) for high dose, and 65.96% (56.86, 74.16, p<0.0001) for the mITT set.

In the mITT set, mean change in model-estimated BSID-III raw scores from 24-60 months of age was significantly improved for treated children vs Natural History for cognitive (22.7 points, p<0.0001), receptive communication (7.4 points, p=0.0212), and expressive communication (15.9 points, p=0.0011). Fine and gross motor skills showed separation from Natural History (7.3 points, p=0.050 and 2.0 points, p=0.360, respectively). Older children and those with more advanced disease at treatment (n=10) retained key communication, ambulation, and/or eating/self-feeding skills.

Most UX111-related TEAEs were mild to moderate and resolved spontaneously.

Conclusions UX111 showed a positive treatment effect and manageable safety across UX111 doses, age, and stage of disease at the time of treatment. LTFU continues with additional data forthcoming.

Authors/Disclosures
Heather Lau, MD (Ultragenyx) PRESENTER	Dr. Lau has received personal compensation for serving as an employee of Ultragenyx. Dr. Lau has or had 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 Ultragenyx. The institution of Prof. Fuller has received research support from Paradigm. The institution of Prof. Fuller has received research support from Sanofi.
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 $500-$4,999 for serving as a Consultant for Solid. 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 Armatus. 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 Avidity. 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 Dyne. The institution of Dr. Flanigan has received research support from Ultragenyx . The institution of Dr. Flanigan has received research support from Solid Biosciences. The institution of Dr. Flanigan has received research support from Dyne Therapeutics. The institution of Dr. Flanigan has received research support from Avidity.

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