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

• Sponsor: Abeona Therapeutics, Inc
• Information provided by (Responsible Party): Abeona Therapeutics, Inc

Tracking Information

• First Submitted Date: March 17, 2016
• First Posted Date: March 23, 2016
• Last Update Posted Date: February 15, 2019
• Study Start Date: March 2016
• Estimated Primary Completion Date: December 2019 (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.

• Change History: Complete list of historical versions of study NCT02716246 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 12, 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) 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 (PSI-4) at Month 6, 12, 18, 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 Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
• Official Title: Phase I/II 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. The vector will be delivered undiluted over 15 to 45 minutes, under sedation as needed. Dosing volume will be approximately 0.5 to 3 mL/kg, depending on final vector product concentration and subject cohort. A tapering course of prophylactic enteral prednisone or prednisolone will be administered
• 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: Mucopolysaccharidosis Type 3 A Sanfilippo Syndrome

Intervention

Biological: scAAV9.U1a.hSGSH

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.

Study Arms

• Experimental: Cohort 1 Low Dose

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

  • Cohort 1 (Low Dose): 0.5 X 10^13 vg/kg (n=3 subjects)

  Intervention: Biological: scAAV9.U1a.hSGSH
• Experimental: Cohort 2 Mid Dose

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

  • Cohort 2 (Mid Dose): 1 X 10^13 vg/kg (n=3 subjects)

  Intervention: Biological: scAAV9.U1a.hSGSH
• Experimental: Cohort 3 High Dose

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

  • Cohort 3 (High Dose): 3 X 10^13 vg/kg (n=9-16 subjects)

  Intervention: Biological: scAAV9.U1a.hSGSH

• Publications *: Duncan FJ, Naughton BJ, Zaraspe K, Murrey DA, Meadows AS, Clark KR, Newsom DE, White P, Fu H, McCarty DM. Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice. Mol Ther. 2015 Apr;23(4):638-47. doi: 10.1038/mt.2015.9. Epub 2015 Jan 16.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 12, 2019): 22
• Original Estimated Enrollment (submitted: March 17, 2016): 9
• Estimated Study Completion Date: December 2021
• Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age 6 months to 2 years or children older than 2 years with a minimum cognitive Developmental Quotient (DQ) of 60 or above (calculated by Bayley Scales of Infant and Toddler Development - Third Edition)
• Confirmed diagnosis of MPS IIIA by the following methods:
• No detectable or significantly reduced* SGSH enzyme activity by leukocyte assay
• Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene

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 patient from being able to undergo MRI according to local institutional policy
• Any other situation that precludes the subject from undergoing any other procedure 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 v4.0 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

  • Due to the nature of enzyme activity testing, normal ranges and reported units vary from lab to lab. Many laboratories utilize control samples rather than normal ranges, to account for the influence of small day-to-day fluctuations in the laboratory environment.
  • For the purposes of invitation to a screening visit, we will accept "significantly reduced" results as those interpreted as such by any clinical laboratory approved to perform this diagnostic test.

For uniformity of data for analysis, and confirmation of accurate diagnosis before gene transfer, subjects who consent to complete the screening visit will have their blood drawn for confirmatory enzyme activity level to be performed by Greenwood Genetics Center Biochemical Laboratory. Subjects must have an enzyme activity level considered to be in the affected range by Greenwood Genetic Center Biochemical Laboratory to proceed within the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Juan Ruiz, MD, PhD; +34 685895069; infotrials@abeonatherapeutics.com

• Listed Location Countries: Australia, Spain, United States

Administrative Information

• NCT Number: NCT02716246
• Other Study ID Numbers: ABT001
• 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

• Responsible Party: Abeona Therapeutics, Inc
• Study Sponsor: Abeona Therapeutics, Inc
• Collaborators: Not Provided

Investigators

• Principal Investigator: Kevin Flanigan, MD; Nationwide Children's Hospital

• PRS Account: Abeona Therapeutics, Inc
• Verification Date: February 2019