Gene Transfer Study of ABO-102 in Patients With Middle and Advanced Phases of MPS IIIA Disease

• ClinicalTrials.gov Identifier: NCT04088734
• Recruitment Status: Terminated
• First Posted: September 13, 2019
• Last Update Posted: August 15, 2022
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Abeona Therapeutics, Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Study Description

Brief Summary:

Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

Condition or disease	Intervention/treatment	Phase
MPS IIIA; Sanfilippo Syndrome; Sanfilippo A; Mucopolysaccharidosis III	Drug: ABO-102	Phase 1; Phase 2

Detailed Description:

This is an open-label, single dose clinical trial. All participants will receive 3 X 10^13 vg/kg of ABO-102 delivered one time through a venous catheter inserted into a peripheral limb vein. The target population includes MPS IIIA participants with a DQ lower than 60 in middle and advanced phases of the disease. Similar numbers of MPS IIIA participants with age equivalent above and below 18 months of age will be enrolled to ensure a representation of middle and advanced phases of the disease.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Open Label, Single-dose, Gene Transfer Study of scAAV9.U1a.hSGSH (ABO-102) in Patients With Middle and Advanced Phases of MPS IIIA Disease
• Actual Study Start Date: September 18, 2019
• Actual Primary Completion Date: March 10, 2022
• Actual Study Completion Date: March 10, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: ABO-102; Dose of 3x10^13 vg/kg	Drug: ABO-102; Single dose of ABO-102 (scAAV9.U1a.hSGSH) administered by intravenous injection through a peripheral limb vein at a dose of 3 X 10^13 vg/kg; Other Names: scAAV9.U1a.hSGSH; UX111

Outcome Measures

Primary Outcome Measures :

1. Adverse Events and Serious Adverse Events [ Time Frame: 24 months ]
   The incidence, type, and severity of treatment-related adverse events and serious adverse events
2. CSF Heparan Sulfate [ Time Frame: 1, 6, 12, 24 months ]
   Change from baseline in CSF heparan sulfate levels after treatment
3. Liver and/or Spleen Volumes [ Time Frame: 1, 6, 12, 24 months ]
   Change from baseline in liver and/or spleen volumes after treatment, as measured by MRI

Secondary Outcome Measures :

1. Glycosaminoglycans or Heparan Sulfate [ Time Frame: 1, 6, 12, 18, 24 months ]
   Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after treatment
2. SGSH Enzyme Activity [ Time Frame: 1, 6, 12, 24 Months ]
   Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment
3. Brain Volume [ Time Frame: 12, 24 months ]
   Change from baseline in brain volume after treatment, as measured by MRI
4. Age Equivalent [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in the Age Equivalent after treatment compared to Natural History Study data calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, 2nd edition, based on chronological and developmental age
5. Mullen Developmental Quotient [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in the Developmental Quotient (DQ) after treatment compared to Natural History Study data calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, 2nd edition, based on chronological and developmental age
6. Cognitive Age Equivalent [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in the Cognitive Age Equivalent after treatment compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development - Third edition or the Kaufman Assessment Battery for Children. Second Edition, based on developmental age
7. Bayley Developmental Quotient [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in the Developmental Quotient after treatment compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development - Third edition or the Kaufman Assessment Battery for Children. Second Edition, based on developmental age
8. Adaptive Age Equivalent Score [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in the 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
9. Sleep Pattern [ Time Frame: 6, 12, 18, 24 months ]
   Change from baseline in sleep pattern as measured by the modified Children's Sleep Habits Questionnaire (CSHQ)
10. Pediatric Quality of Life Inventory Core [ Time Frame: 6, 12, 18, 24 months ]
    Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales total score
11. Parent Quality of Life [ Time Frame: 6, 12, 18, 24 months ]
    Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4)
12. Pediatric Quality of Life Inventory Gastrointestinal [ Time Frame: 6, 12, 18, 24 months ]
    Change from baseline in gastrointestinal symptoms using the PedsQL™ Gastrointestinal Symptoms Scales
13. Parent Global Impression Score [ Time Frame: 6, 12, 18, 24 months ]
    Parent Global Impression Score at different time points
14. Clinical Global Impression Improvement Scale [ Time Frame: 6, 12, 18, 24 months ]
    Clinical Global Impression Improvement Score at different time points.
15. Parent Symptoms Score Questionnaire [ Time Frame: 6, 12, 18, 24 months ]
    Change from baseline in Parent Symptoms Score Questionnaire
16. Body Mass Index [ Time Frame: 6, 12, 18, 24 months ]
    Change from baseline in Body Mass Index after treatment
17. EEG Monitoring [ Time Frame: 6, 12, 18, 24 months ]
    Incidence and Change from baseline in abnormalities in standard awake 45-minutes- EEG monitoring
18. AAV9 Viral DNA Detection [ Time Frame: 24 months ]
    Detection of the AAV9 viral DNA in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment (ERA)

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of MPS IIIA confirmed by the following methods:

  1. No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and
  2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene
• Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition)
• Must be ambulatory, though may receive assistance with ambulation
• Age range of 2 years up to 18 years (excluded)

Exclusion Criteria:

• Inability to participate in the clinical evaluation as determined by Principal Investigator
• 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
• Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay
• Participants 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
• Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy
• Any other situation that precludes the participant from undergoing procedures required in this study
• Participants 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 (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
• Female participant who is pregnant or demonstrates a positive urine or beta-hCG 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
• Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration
• Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03

Contacts and Locations

Locations

United States, Pennsylvania

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

Australia, South Australia

Adelaide Women's and Children's Hospital

North Adelaide, South Australia, Australia, 5006

Spain

Hospital Clínico Universitario de Santiago

Santiago De Compostela, Spain, 15706

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Abeona Therapeutics, Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

More Information

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.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT04088734
• Other Study ID Numbers: ABT-003; UX111-CL201 ( Other Identifier: Ultragenyx Pharmaceutical Inc ); 2018-000504-42 ( EudraCT Number )
• First Posted: September 13, 2019
• Last Update Posted: August 15, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Ultragenyx Pharmaceutical Inc:

MPS IIIA; Sanfilippo; Gene therapy

Additional relevant MeSH terms:

Mucopolysaccharidoses; Mucopolysaccharidosis III; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases