Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH

Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA

The main objective of this study is to evaluate the efficacy and safety of UX111 for the treatment of MPS IIIA.

Study Overview

• Status: Recruiting
• Conditions: Mucopolysaccharidosis III; Sanfilippo Syndrome; MPS IIIA; Sanfilippo A
• Intervention / Treatment: Biological: UX111; Drug: Prophylactic Immunomodulatory (IM) Therapy; Drug: Adjuvant IM Therapy; Drug: Optimized Prophylactic IM Therapy

Detailed Description

Open-label, single dose, dose-escalation clinical trial of UX111 (scAAV9.U1a.hSGSH) injected intravenously through a peripheral limb vein. A limited course of prophylactic immunomodulatory (IM) therapy will be administered. At approved sites adjuvant IM therapy may be administered to selected participants. The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.

This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Patients Contact: Trial Recruitment; Phone Number: 1-888-756-8657; Email: trialrecruitment@ultragenyx.com
• Study Contact Backup: Name: HCPs Contact: Medical Information; Phone Number: 1-888-756-8657; Email: medinfo@ultragenyx.com

Study Locations

• Australia
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Completed
      • Women's and Children's Hospital
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall d'Hebron Barcelona Hospital Campus
    • Principal Investigator: Mireia del Toro, MD
    • Contact: Mireia del Toro, MD; Email: mireia.deltoro@vallhebron.cat
  • Santiago de Compostela, Spain, 15706
    • Recruiting
    • Hospital Clínico Universitario de Santiago
    • Contact: Eines Monteagudo, MD; Email: eines.monteagudo.vilavedra@sergas.es
    • Principal Investigator: Maria Luz Couce, MD
    • Contact: Beatriz Martín López-Pardo, MD; Email: beatriz.martin.lopezpardo@sergas.es
• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Completed
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Completed
      • Children's Hospital of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of MPS IIIA confirmed by the following methods:

  • No detectable or significantly reduced SGSH enzyme activity by leukocyte assay, and
  • Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)

• Age:

  • For Cohort 1-3: From birth (participating sites in USA and Australia) OR 6 months (participating sites in Spain) to 2 years of age with no BSITD-III Cognitive Development Quotient (DQ) requirement, or older than 2 years with a BSITD-III Cognitive DQ of 60 or above (participating sites globally).
  • For Cohort 4 (participating sites in Spain): 3 months to ≤ 2 years of age with no BSITD-III Cognitive DQ requirement or > 2 years of age with a BSITD-III Cognitive DQ ≥ 60 (n = up to 6). Up to 2 additional subjects > 2 years and ≤ 5 years of age with a BSITD-III Cognitive DQ < 60 may also be enrolled. •Subjects must be ≥ 6 months of age before UX111 administration. However, subjects may be consented and initiate relevant Screening Procedures and IM treatment < 6 months of age. Refer to Section 8.2 for relevant screening procedures •For children ≤ 24 months chronological age who were born prematurely, defined as born at < 36 weeks gestational age, the corrected gestational age must be used for determining inclusion •The BSITD-III Cognitive DQ is assessed during the onsite Screening visit, for subjects who require it •The age of the child on the date of the Screening BSITD-III assessment is used to determine the requirement for the BSITD-III Cognitive DQ score.
• Cohort 4 only: Vaccination status based on age according to country-specific guidelines that is up to date 30 days prior to Enrollment as verified by documentation from the subject's primary care physician, and willing to defer vaccines through 6 months after completion of the subject's IM medication, or longer per Principal Investigator (PI) judgment. Emergency use authorization or conditional marketing authorization of coronavirus disease (COVID) vaccines is included unless there is an accepted medical exemption.

Exclusion Criteria:

• Inability to participate in the clinical evaluation as determined by PI
• Cohorts 1 to 3 only: Identification of two nonsense or null variants on genetic testing of the SGSH gene (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)
• At least one S298P mutation in the SGSH gene (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)
• Has evidence of an attenuated phenotype of MPS IIIA, in the judgement of the PI
• Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
• Active viral infection based on clinical observations
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer or precludes the child from participating in the protocol assessments and follow up
• Cohorts 1 to 3 only: Subjects with total anti-AAV9 antibody titers ≥ 1:100 equivalent to a positive screen as determined by ELISA binding assay in serum
• Cohorts 1-3 only: Subjects with a positive response for the enzyme-linked immunosorbent spot assay (ELISpot) for T-cell responses to AAV9
• Cohorts 1-3 only: Serology consistent with exposure to human immunodeficiency virus (HIV), or serology consistent with active hepatitis B or C infection, Cohort 4: Current clinically significant infections (including any requiring systemic treatment including, but not limited to, HIV; hepatitis A, B, or C; varicella zosters virus; human T-cell lymphotropic virus type 1 [HTLV-1]; tuberculosis; or COVID-19) that would interfere with participation in the study.
• Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy
• Visual, hearing, or other impairment sufficient to preclude cooperation with neurodevelopmental testing
• Uncontrolled seizure disorder
• Any item (braces, etc.) or circumstance that would exclude the subject from being able to undergo MRI according to local institutional policy
• Any other situation that precludes the subject from undergoing procedures required in this study
• Subjects with cardiomyopathy or significant congenital heart abnormalities
• The presence of significant non-MPS IlIA related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study

• Cohorts 1-3: Abnormal laboratory values Grade 2 or higher as defined in common terminology criteria for adverse events (CTCAE) v4.03 for gamma-glutamyl transferase (GGT), total bilirubin, creatinine, hemoglobin, white blood cell (WBC) count, platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT), Cohort 4: Any of the following abnormal laboratory values from screening assessment:

  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), GGT, and/or alkaline phosphatase ≥ 2 × upper limit of normal (ULN) and/or total bilirubin > 1.5 × ULN
  • Anemia (hemoglobin < 10 g/dL)
  • Leukopenia or leukocytosis (total WBC count < 3,000/mm3 and > 15,000/mm3 respectively)
  • Abnormal absolute neutrophil count (ANC) of < 1000/mm3
  • Platelet count < 100,000/mm3
  • Coagulopathy (international normalized ratio [INR] > 1.5) or aPTT > 40 seconds
  • Renal impairment, defined as estimated glomerular filtration rate (eGFR) below the lower limit of normal (age and sex appropriate) based on Bedside Schwartz equation
• Female of childbearing potential who is pregnant or demonstrates a positive urine or bhCG result at screening assessment (if applicable)
• Cohorts 1-3: Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone)
• Previous treatment by hematopoietic stem cell transplantation
• Previous participation in a gene/cell therapy or enzyme replacement therapy (ERT) clinical trial

Cohort 4 only:

• Known hypersensitivity, that in the judgment of the PI, places the subject at increased risk for adverse effects.
• Unwilling to avoid consumption of grapefruit juice and the use of strong inhibitors of CYP3A4 and/or P-gp (eg, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin), strong inducers of CYP3A4 and/or P-gp (eg, rifampin, rifabutin, phenobarbital, carbamazepine, or phenytoin), and St. John's Wort from 30 days prior to Screening through completion of the IM regimen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 Low Dose; Dose of 0.5 X 10^13 vg/kg	Biological: UX111; Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein.; Other Names: scAAV9.U1a.hSGSH; ABO-102; rebisufligene etisparvovec; Drug: Prophylactic Immunomodulatory (IM) Therapy; Drug: Adjuvant IM Therapy; The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.
Experimental: Cohort 2 Mid Dose; Dose of 1 X 10^13 vg/kg	Biological: UX111; Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein.; Other Names: scAAV9.U1a.hSGSH; ABO-102; rebisufligene etisparvovec; Drug: Prophylactic Immunomodulatory (IM) Therapy; Drug: Adjuvant IM Therapy; The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.
Experimental: Cohort 3 High Dose; Dose of 3 X 10^13 vg/kg	Biological: UX111; Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein.; Other Names: scAAV9.U1a.hSGSH; ABO-102; rebisufligene etisparvovec; Drug: Prophylactic Immunomodulatory (IM) Therapy; Drug: Adjuvant IM Therapy; The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.
Experimental: Cohort 4 High Dose (Spain Only); Dose of 3 X 10^13 vg/kg	Biological: UX111; Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein.; Other Names: scAAV9.U1a.hSGSH; ABO-102; rebisufligene etisparvovec; Drug: Adjuvant IM Therapy; The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.; Drug: Optimized Prophylactic IM Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid (CSF) Heparan Sulfate (HS) (Disaccharide) Exposure	Exposure is defined as the time-normalized area under the curve (AUC) of the percentage reduction from baseline.	Up to Month 24 Visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Ganglioside Type 2 (GM2) Exposure	Exposure is defined as the time-normalized area under the curve (AUC) of the percentage change from baseline.	Up to Month 24 Visit
CSF Ganglioside Type 3 (GM3) Exposure	Exposure is defined as the time-normalized area under the curve (AUC) of the percentage change from baseline.	Up to Month 24 Visit
Percent Change from Baseline in CSF HS		Baseline, Up to Month 24 Visit
Percent Change From Baseline in Total Cortical Volume		Baseline, Up to Month 24 Visit
Bayley Scales of Infant and Toddler Development-Third Edition (BSITD-III) Cognitive Raw Score Over Time		Up to Month 24 Visit
BSITD-III Receptive Communication Raw Score Over Time		Up to Month 24 Visit
BSITD-III Expressive Communication Raw Score Over Time		Up to Month 24 Visit

Other Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Treatment-Emergent Adverse Events, and Treatment-Emergent Serious Adverse Events	Up to Month 24 Visit

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborators: Abeona Therapeutics, Inc
• Investigators: Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Publications and helpful links

General Publications

• Fu H, Meadows AS, Pineda RJ, Kunkler KL, Truxal KV, McBride KL, Flanigan KM, McCarty DM. Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy. Hum Gene Ther Clin Dev. 2017 Dec;28(4):187-196. doi: 10.1089/humc.2017.109. Epub 2017 Oct 24.
• McCurdy VJ, Johnson AK, Gray-Edwards HL, Randle AN, Bradbury AM, Morrison NE, Hwang M, Baker HJ, Cox NR, Sena-Esteves M, Martin DR. Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease. Gene Ther. 2021 Apr;28(3-4):142-154. doi: 10.1038/s41434-020-00190-1. Epub 2020 Sep 3.
• Fu H, Cataldi MP, Ware TA, Zaraspe K, Meadows AS, Murrey DA, McCarty DM. Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery. Mol Ther Methods Clin Dev. 2016 Jun 8;3:16036. doi: 10.1038/mtm.2016.36. eCollection 2016.

Helpful Links

• Ultragenyx Transparency Commitment

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2016
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: March 17, 2016
• First Submitted That Met QC Criteria: March 17, 2016
• First Posted (Estimated): March 23, 2016

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; MPS IIIA; Sanfilippo
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Mucopolysaccharidosis III; Therapeutics
• Other Study ID Numbers: ABT-001; UX111-CL301 (Other Identifier: Ultragenyx Pharmaceutical Inc); 2015-003904-21 (EudraCT Number); 2023-510032-37-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to share data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No