Clinical trial NCT04088734: Gene Transfer Study of ABO-102 in Patients With Middle and Advanced Phases of MPS IIIA Disease
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: MPS IIIA
Sanfilippo Syndrome
Sanfilippo A
Mucopolysaccharidosis III
Keywords: MPS IIIA
Sanfilippo
Gene therapy
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
Collaborators: name: Abeona Therapeutics, Inc
First posted: 2019-09-13
Enrollment: 5
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility 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

Primary outcomes:
measure: Incidence, Type and Severity of Related Treatment-Emergent Adverse Events (TEAEs) by Time Frame
timeFrame: From the first dose of study drug to <30 days postdose, Day 30, 60, 90, 180 and Month 12
measure: Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame
timeFrame: From signing of informed consent through Day 60, 90, 180 and up to Day 454 (> 12 months)
measure: Change From Baseline (BL) in Multiples of Normal of Liver and Spleen Volumes After Treatment
timeFrame: Baseline, Day 30, 180, Month 12
measure: Change From BL in Cerebrospinal Fluid (CSF) Heparan Sulfate Levels After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
Secondary outcomes:
measure: Change From Baseline in Plasma Heparan Sulfate After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Change From Baseline in Urine Glycosaminoglycans After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Change From Baseline in Urine Heparan Sulfate After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Change From Baseline in CSF N-Sulfoglucosamine Sulfohydrolase (SGSH) Enzyme Activity Levels After Treatment
timeFrame: Baseline, Day 30, Day 180, and Month 12
measure: Change From Baseline in Heparan N-Sulfatase (Type A) After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Change From Baseline in Plasma SGSH After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Change From Baseline in Brain Volumes After Treatment
timeFrame: Baseline, 12 months
measure: Change From Baseline in Brain Volumes After Treatment: Average Total Cortical Thickness
timeFrame: Baseline, 12 months
measure: Change From Baseline in Sleep Pattern as Measured by the Modified Children's Sleep Habits Questionnaire (CSHQ) Subscore Total After Treatment
timeFrame: Baseline, Day 180, Month 12
measure: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales Total Score
timeFrame: Baseline, Day 180, Month 12
measure: Change From Baseline in Parent Quality of Life, Using the Parenting Stress Index, 4th Edition (PSI-4) Total Stress Raw Score
timeFrame: Baseline, Day 180, Month 12
measure: Change From Baseline in Gastrointestinal Symptoms Using the PedsQL™ Gastrointestinal (GI) Symptoms Scales Score
timeFrame: Baseline, Day 180, Month 12
measure: Change From Baseline in Parent Global Impression (PGI) Total Score
timeFrame: Baseline, Day 180, Month 12
measure: Clinical Global Impression Improvement Scale at Day 180 and Month 12
timeFrame: Day 180, Month 12
measure: Change From Baseline in Parent Symptoms Score Questionnaire
timeFrame: Baseline, Day 180, Month 12
measure: Percent Change From Baseline in Body Mass Index After Treatment
timeFrame: Baseline, Day 30, Day 180, Month 12
measure: Number of Participants With Abnormalities in Standard Awake 45-Minutes-Electroencephalogram (EEG) Monitoring at Baseline and Day 180
timeFrame: Baseline, Day 180
measure: Change From Baseline in Vector Shedding Analysis in Plasma, Saliva, Stool and Urine
timeFrame: Baseline, Day 30, Day 180, Month 12
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: North Adelaide
country: Australia
facility: Adelaide Women's and Children's Hospital
state: South Australia
city: Santiago De Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.