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

• ClinicalTrials.gov Identifier: NCT02716246
• Recruitment Status: Active, not recruiting
• First Posted: March 23, 2016
• Last Update Posted: November 10, 2022
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Abeona Therapeutics, Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Tracking Information

• First Submitted Date: March 17, 2016
• First Posted Date: March 23, 2016
• Last Update Posted Date: November 10, 2022
• Actual Study Start Date: March 2016
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2019)

• Product safety [ Time Frame: 24 months ]
  Determination of safety based on the development of unacceptable toxicity: defined as the occurrence of two or more unanticipated Grade III or higher treatment-related adverse events.
• Change from baseline in age equivalent developmental score [ Time Frame: 24 months ]
  Change from baseline in the Age Equivalent Developmental Score calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, based on developmental age, compared with natural history study data at 6, 12, 18, and 24 months

Original Primary Outcome Measures (submitted: March 17, 2016)

Development of unacceptable toxicity: [ Time Frame: 24 months ]

Determination of safety based on the development of unacceptable toxicity: defined as the occurrence of two or more unanticipated Grade III or higher treatment-related toxicity.

Current Secondary Outcome Measures (submitted: September 3, 2019)

• Change from baseline of CSF heparan sulfate after treatment [ Time Frame: 24 months ]
  Change from baseline of CSF heparan sulfate after treatment at 1, 6, 12, and 24 months
• Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment [ Time Frame: 24 months ]
  Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment at Month 1, 6, 12, 18, 24
• Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment [ Time Frame: 24 months ]
  Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment at Month 1, 6, 12, 24
• Change from baseline in liver and/or spleen volumes after treatment [ Time Frame: 24 months ]
  Change from baseline in liver and/or spleen volumes after treatment as measured by MRI at Month 1, 6, 12, 24
• Change from baseline in brain volume after treatment [ Time Frame: 24 months ]
  Change from baseline in brain volume after treatment as measured by MRI at Month 1, 6, 12, 24
• Change from baseline in Cognitive Age Equivalent (Developmental Age) [ Time Frame: 24 months ]
  Change from baseline in Cognitive Age Equivalent (Developmental Age) compared to natural history study calculated using the Bayley Scales of Infant and Toddler Development or the Kaufman Assessment Battery for Children at Month 6, 12, 18, 24
• Change from baseline in Adaptive Age Equivalent score [ Time Frame: 24 months ]
  Change from baseline in Adaptive Age Equivalent score after treatment compared to natural history study data, as assessed by parent report using the Vineland Adaptive Behavior Scale II Survey form at Month 6, 12, 18, 24
• Change from baseline Developmental Quotient [ Time Frame: 24 months ]
  Change from baseline Developmental Quotient after treatment compared to natural history study data assessed by Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, based on chronological and developmental age, at Month 6, 12, 18, 24
• Change from baseline in the Sanfilippo Behavior Rating Scale [ Time Frame: 24 months ]
  Change from baseline in the Sanfilippo Behavior Rating Scale at Month 6, 12, 18, 24
• Change from baseline in the Leiter International Performance Scale - Revised [ Time Frame: 24 months ]
  Change from baseline in the Leiter-R at Month 6, 12, 18, 24
• Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score [ Time Frame: 24 months ]
  Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score at Month 6, 12, 18, 24
• Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed. [ Time Frame: 24 months ]
  Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed short form (PSI-4) at Month 12, 24
• Determination of vector shedding analysis [ Time Frame: 24 months ]
  Determination of vector shedding in plasma, saliva, urine, and feces to provide preliminary data for the Environmental Risk Assessment

Original Secondary Outcome Measures (submitted: March 17, 2016)

• Increase in CSF and blood leukocyte SGSH enzyme activity levels at 6 and/or 12 months [ Time Frame: 12 months ]
• Reduced liver and spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI) [ Time Frame: 12 months ]
• Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months, as assessed by parent report using the Vineland Adaptive Behavior Scale [ Time Frame: 12 months ]
• Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale and the Mullen Scales of Early Learning [ Time Frame: 12 months ]
• Reduction of urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment [ Time Frame: 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
• Official Title: Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA
• Brief Summary: Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

Detailed Description

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. A tapering course of prophylactic enteral prednisone or prednisolone will be administered for a period of at least two months.

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

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• MPS IIIA
• Sanfilippo Syndrome
• Sanfilippo A
• Mucopolysaccharidosis III

Intervention

Biological: ABO-102

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
• UX111

Study Arms

• Experimental: Cohort 1 Low Dose
  Dose of 0.5 X 10^13 vg/kg
  Intervention: Biological: ABO-102
• Experimental: Cohort 2 Mid Dose
  Dose of 1 X 10^13 vg/kg
  Intervention: Biological: ABO-102
• Experimental: Cohort 3 High Dose
  Dose of 3 X 10^13 vg/kg
  Intervention: Biological: ABO-102

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 11, 2022): 28
• Original Estimated Enrollment (submitted: March 17, 2016): 9
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
• Age: From birth to 2 years or children older than 2 years with a minimum cognitive Developmental Quotient (DO) of 60 or above (calculated by Bayley Scales of lnfant and Toddler Development - Third Edition)

Exclusion Criteria:

• Inability to participate in the clinical evaluation as determined by PI
• Identification of two nonsense or null variants on genetic testing of the SGSH gene
• At least one S298P mutation in the SGSH gene
• Has evidence of an attenuated phenotype of MPS IIIA
• 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
• Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
• Subjects with a positive response for the ELISPOT for T-cell responses to AAV9
• Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
• 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 or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
• Uncontrolled seizure disorder
• Any item (braces, etc.) which 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
• Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
• Female participant who is pregnant or demonstrates a positive urine or bhCG result at screening assessment (if applicable)
• Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone)
• Previous treatment by Haematopoietic Stem Cell transplantation
• Previous participation in a gene/cell therapy or ERT clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Spain, United States
• Removed Location Countries: France, Germany

Administrative Information

• NCT Number: NCT02716246
• Other Study ID Numbers: ABT001; UX111-CL301 ( Other Identifier: Ultragenyx Pharmaceutical Inc ); 2015-003904-21 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: There is no plan to share data

• Current Responsible Party: Ultragenyx Pharmaceutical Inc
• Original Responsible Party: Kevin Flanigan, Nationwide Children's Hospital, Professor of Pediatrics
• Current Study Sponsor: Ultragenyx Pharmaceutical Inc
• Original Study Sponsor: Kevin Flanigan
• Collaborators: Abeona Therapeutics, Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

• PRS Account: Ultragenyx Pharmaceutical Inc
• Verification Date: November 2022