A Study to Assess the Safety and Tolerability of SOBI003 in Pediatric MPS IIIA Patients

Study Overview
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Brief Summary
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MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aims of the present study is to assess the dose related safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SOBI003, a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

Detailed Description
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This is an open-label, non-controlled, parallel, sequential ascending multiple-dose, multicenter study to assess the dose related safety, tolerability, PK and PD of SOBI003 in pediatric MPS IIIA patients. Patients between 1 and 6 years of age who have not received previous treatment for MPS IIIA with an ERT, gene- or stem cell therapy will be eligible to participate in the study. The study is planned to consist of 3 dose cohorts, each comprising 3 patients. Treatment initiations will be staggered within each cohort in order to be able to observe, interpret and treat possible adverse reactions. SOBI003 is administered as weekly i.v. infusions over a period of 24 weeks. Upon completion of the 24-week treatment period with satisfactory tolerability, the patient is offered to receive continued SOBI003 treatment by participation in an extension study.

Official Title
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An Open, Non-controlled, Parallel, Ascending Multiple-dose, Multicenter Study to Assess Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SOBI003 in Pediatric MPS IIIA Patients

Conditions
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Sanfilippo Syndrome Type A (MPS IIIA)

Intervention / Treatment
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* Drug: SOBI003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained from the patient's legally authorized representative(s) Patients with MPS IIIA, as confirmed by both: A documented deficiency in sulfamidase enzyme activity in concordance with a diagnosis of MPS IIIA, and Normal enzyme activity level of at least one other sulfatase measured in leukocytes Chronological age of ≥12 and ≤72 months (i.e., 1 to 6 years) at the time of the first SOBI003 infusion and a developmental age ≥12 months at screening as assessed by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Medically stable patient who is expected to be able to comply with study procedures Exclusion Criteria: At least one S298P mutation in the SGSH gene Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI scans and/or lumbar punctures History of poorly controlled seizures Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results Significant non-MPS IIIA-related central nervous system (CNS) impairment or behavioral disturbances, which in the investigator's opinion, would confound the scientific integrity or interpretation of study assessments Prior administration of stem cell or gene therapy, or ERT for MPS IIIA Concurrent or prior (within 30 days of enrolment into this study) participation in a study involving invasive procedures

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 72 Months

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study was designed to include three arms, up to 20 mg/kg. After a company decision to end the development of the compound it was decided to not start a third cohort, but if stated safe the dose could increase up to 20 mg/kg in cohort 1 and 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose group 1<br>SOBI003 dose 3 mg/kg once weekly for 24 weeks | Drug: SOBI003<br>* Weekly i.v.infusion<br>* Other names: Modified recombinant human sulphamidase;|
| Experimental: Dose group 2<br>SOBI003 dose 10 mg/kg once weekly for 24 weeks | Drug: SOBI003<br>* Weekly i.v.infusion<br>* Other names: Modified recombinant human sulphamidase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Measured by Adverse Events Frequencies (by Type and Severity) | Number of adverse events, by type and severity, from start of infusion up to 24 weeks | From start of first infusion up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Observed Serum Concentration Immediately Before the Start of Infusion of SOBI003 | The observed serum concentration immediately before the start of infusion of SOBI003 (CPre-dose). | Weeks 1, 2, 3, 4, 8, 12, and 24 | 
| The Observed Serum Concentration at the End of Infusion of SOBI003 | The observed serum concentration at the end of infusion of SOBI003 (CEnd of inf) | Weeks 1, 2, 3, 4, 8, 12, and 24 | 
| The Time of the End of the Infusion of SOBI003 | The time of the end of infusion of SOBI003 (tEnd of inf) | Weeks 1, 2, 3, 4, 8, 12, and 24 | 
| The Maximum Observed Serum Concentration of SOBI003 | The Maximum Observed Serum Concentration of SOBI003 (Cmax) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Weeks 1, 4, 12, and 24 | 
| The Time at Which the Maximum Serum Concentration of SOBI003 is Observed | The time after start of infusion at which the maximum serum concentration is observed (tmax) | Weeks 1, 4, 12, and 24 | 
| The Minimum Observed Serum Concentration of SOBI003 | The minimum observed serum concentration of SOBI003 (CTrough) | Weeks 1, 4, 12, and 24 | 
| Clearance | Clearance (CL) of SOBI003 | Weeks 1, 4, 12, and 24 | 
| Area Under the Serum Concentration-time Curve From Time 0 to 168 Hours | Area under the serum concentration-time curve from time 0 to 168 hours (AUC 0-168h) | 0,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Weeks 1, 4,12, and 24 | 
| The Half-life | The half-life of SOBI003 in serum (T1/2) | Weeks 1, 4, 12, and 24 | 
| SOBI003 Concentration in Cerebrospinal Fluid | SOBI003 concentration in cerebrospinal fluid | Weeks 12 and 24 | 
| Number of Patients Having Anti-drug Antibodies in Serum | Number of patients in each dose group having anti-drug antibodies in serum | Weeks 2,4,8,12 and 24 | 
| Patients Having Anti-drug Antibodies in Cerebrospinal Fluid | Percent of patients having anti-drug antibodies in cerebrospinal fluid | Weeks 12 and 24 | 
| Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid | Change from baseline, in percent, of Heparan Sulfate levels in cerebrospinal fluid | Baseline, weeks 12, and 24 | 
| Change From Baseline in Heparan Sulfate Levels in Serum | Change from baseline in Heparan sulfate levels in serum | Weeks 2, 3, 4, 8, 12 and 24 | 
| Change From Baseline in Heparan Sulfate Levels in Urine | Change from baseline in Heparan sulfate levels in urine | Weeks 2, 3, 4, 8, 12 and 24 | 
| Change From Baseline in Neurocognitive Development Quotient | Quotient between age equivalent score and age, 0 - 100%, where high values are desirable. The age equivalent score represent the age of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development. | Week 24 | 
| Change From Baseline in Age-equivalence Score | The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development. | Week 24 | 
| Change From Baseline in Age-equivalence Score as Assessed by VABS-II | The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by Vineland™ Adaptive Behavior Scales, Expanded Interview Form, Second edition (VABS-II). The Vineland is designed to measure adaptive behavior of individuals from birth to age 90. The Vineland-II contains 5 domains each with 2-3 subdomains. The main domains are: Communication, Daily Living Skills, Socialization, Motor Skills, and Maladaptive Behavior. | Week 24 | 
| Change From Baseline in Gray Matter Volume | Grey matter contains most of the brain's neuronal cell bodies. The grey matter includes regions of the brain involved in muscle control, and sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control. The gray matter volume will be measured by volumetric magnetic resonance imaging (MRI). | Week 24 | 
| Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Total Score | Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. Lower scores indicate better functioning. Min score = 0, and max score = 144. | Week 24 | 
| Change From Baseline in PedsQL™ Family Impact Module Total Score | Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The measure includes a scale, from where the categorical score 4, 3, 2, 1, and 0 was reversed and linearly transformed to a 0-100 scale to 4=0, 3=25, 2=50, 1=75 and 0=100, where 100 = minimum and 0 = maximum. The Total Score is the sum of all 36 items in the test divided by the number of items answered. Higher scores indicate better functioning. | Week 24 |