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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Mucopolysaccharidosis III, MPS IIIA, Sanfilippo Syndrome, Sanfilippo A

Intervention / Treatment
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* Drug: ABO-102


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABO-102<br>Dose of 3x10^13 vg/kg | Drug: ABO-102<br>* 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<br>* Other names: UX111;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, Type and Severity of Related Treatment-Emergent Adverse Events (TEAEs) by Time Frame | An adverse event (AE) is any untoward medical occurrence or unintended change from the time informed consent form (ICF) is signed, including inter-current illness that occurs during the course of a clinical trial after treatment has started, whether considered related to treatment or not. TEAEs are those that occurred after the start of study drug. Related adverse events were categorized as possible, probable, or definitely. | From the first dose of study drug to <30 days postdose, Day 30, 60, 90, 180 and Month 12 | 
| Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame | An SAE is defined as any untoward medical occurrence that, at any dose: Results in death Is life threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent disability/incapacity Is a congenital anomaly/birth defect Other situations such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Relationship to study drug was defined as unrelated, unlikely, possible, probable, or definitely. | From signing of informed consent through Day 60, 90, 180 and up to Day 454 (> 12 months) | 
| Change From Baseline (BL) in Multiples of Normal of Liver and Spleen Volumes After Treatment | As Measured by Magnetic Resonance Imaging (MRI). Baseline value of multiple of normal is calculated using the baseline values of the Liver volume/Spleen Volume/Height and Weight. Body Surface Area (BSA) (m2)=( Height(cm) * Weight (kg)/3600)1/2. Normal Liver Volume=(689.9 * BSA (m)) - 24.7. Normal Spleen Volume (mL)=(4.6 * Weight (kg)) + 0.7. Liver Volume (multiples of normal)=Subject Liver Volume (mL)/Normal Liver Volume (mL). Spleen Volume (multiples of normal)=Subject Spleen Volume (mL)/Normal Spleen Volume (mL). | Baseline, Day 30, 180, Month 12 | 
| Change From BL in Cerebrospinal Fluid (CSF) Heparan Sulfate Levels After Treatment | Change from baseline in CSF heparan sulfate levels after treatment | Baseline, Day 30, Day 180, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma Heparan Sulfate After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Change From Baseline in Urine Glycosaminoglycans After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Change From Baseline in Urine Heparan Sulfate After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Change From Baseline in CSF N-Sulfoglucosamine Sulfohydrolase (SGSH) Enzyme Activity Levels After Treatment |  | Baseline, Day 30, Day 180, and Month 12 | 
| Change From Baseline in Heparan N-Sulfatase (Type A) After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Change From Baseline in Plasma SGSH After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Change From Baseline in Brain Volumes After Treatment | As measured by MRI | Baseline, 12 months | 
| Change From Baseline in Brain Volumes After Treatment: Average Total Cortical Thickness | As measured by MRI | Baseline, 12 months | 
| Change From Baseline in Sleep Pattern as Measured by the Modified Children's Sleep Habits Questionnaire (CSHQ) Subscore Total After Treatment | CSHQ is a caregiver-completed, 35-item questionnaire that assesses the frequency of behaviors associated with common pediatric sleep difficulties. Eight domains of sleep, including Bedtime Resistance, Sleep Onset Delay, Sleep Duration, Sleep Anxiety, Night Awakenings, Parasomnias, Sleep Disordered Breathing, and Daytime Sleepiness are assessed, producing eight individual subdomain scores and an overall CSHQ subscore total. CSHQ total score is calculated by adding all the 8 subscores, and ranges from 36 to 108. A higher score is indicative of more disturbed sleep. | Baseline, Day 180, Month 12 | 
| Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales Total Score | PedsQL is a brief measure of health-related quality of life in children. The Peds QL Generic Core Scales was used in the study, consisting of 23 items applicable for healthy school and community populations, as well as pediatric populations with acute and chronic conditions. The four scales include Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Item scores are added together and averaged to produce a Core total score, where higher scores on a scale of 0-100 indicate better Health-related Quality of Life (HRQOL). | Baseline, Day 180, Month 12 | 
| Change From Baseline in Parent Quality of Life, Using the Parenting Stress Index, 4th Edition (PSI-4) Total Stress Raw Score | The Parenting Stress Index, 4th Edition evaluates the magnitude and type of stress in a parent/child relationship. The short form version was used in the study, consisting of 36 items divided into three domains: Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI), and Difficult Child (DC), which combine together to form a Total Stress raw score. Total Stress raw scores can range from 36 - 180, with higher raw scores indicating higher levels of stress. | Baseline, Day 180, Month 12 | 
| Change From Baseline in Gastrointestinal Symptoms Using the PedsQL™ Gastrointestinal (GI) Symptoms Scales Score | The PedsQL Gastrointestinal Symptoms Scale is a specific module of the PedsQL that measures gastrointestinal symptoms in patients with acute and chronic health conditions as well as healthy school and community populations. The Parent Report version was used on the study, consisting of 58 items across 10 dimensions, assessing parents' perceptions of their child's GI-specific symptoms. Item scores are added together and averaged to produce a GI symptoms scales score, where higher scores on a scale of 0-100 indicate better GI specific QOL. | Baseline, Day 180, Month 12 | 
| Change From Baseline in Parent Global Impression (PGI) Total Score | The Parent Global Impression scale evaluates all aspects of a patients' health and assesses if there has been an improvement or decline in clinical status, as reported by the parent/caregiver. This study used a modified version with symptoms relevant to the patient population in the trial. Nine symptoms were scored at each visit, using a 7-point rating scale where 3 = much better, 2 = better, 1 = slightly better, 0 = same, -1 = slightly worse, -2 = worse, and -3 = much worse. The nine symptom scores are added together to produce a PGI total score, ranging from -27 to 27. | Baseline, Day 180, Month 12 | 
| Clinical Global Impression Improvement Scale at Day 180 and Month 12 | The Clinical Global Impression of Improvement scale is a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication, specifically looking at whether the patient has demonstrated improvement or not. Assessment of improvement was scored at each visit, using a 7-point rating scale where 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. | Day 180, Month 12 | 
| Change From Baseline in Parent Symptoms Score Questionnaire | The Parent Symptoms Score Questionnaire contains 29 symptoms with an indicator of whether the symptom was present or absent. | Baseline, Day 180, Month 12 | 
| Percent Change From Baseline in Body Mass Index After Treatment |  | Baseline, Day 30, Day 180, Month 12 | 
| Number of Participants With Abnormalities in Standard Awake 45-Minutes-Electroencephalogram (EEG) Monitoring at Baseline and Day 180 | NCS=not clinically significant CS=clinically significant | Baseline, Day 180 | 
| Change From Baseline in Vector Shedding Analysis in Plasma, Saliva, Stool and Urine | Detection of the adeno-associated Virus 9 (AAV9) viral deoxyribonucleic acid (DNA) in plasma, saliva, urine and feces was analyzed. Per protocol, data were not collected for urine at Month 12. | Baseline, Day 30, Day 180, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPS IIIA, Sanfilippo, Gene therapy