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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Weekly i.v.infusion
Childrens's Hospital and Research Center
Oakland, California, United States
University of North Carolina Hospitals
Chapel Hill, North Carolina, United States
University Medical Center Hamburg-Eppendorf
Hamburg, Germany
Gazi University Hospital
Ankara, Turkey (Türkiye)
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
Time frame: From start of first infusion up to Week 24
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).
Time frame: 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)
Time frame: 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)
Time frame: Weeks 1, 2, 3, 4, 8, 12, and 24
The Maximum Observed Serum Concentration of SOBI003
The Maximum Observed Serum Concentration of SOBI003 (Cmax)
Time frame: 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)
Time frame: Weeks 1, 4, 12, and 24
The Minimum Observed Serum Concentration of SOBI003
The minimum observed serum concentration of SOBI003 (CTrough)
Time frame: Weeks 1, 4, 12, and 24
Clearance
Clearance (CL) of SOBI003
Time frame: 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)
Time frame: 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)
Time frame: Weeks 1, 4, 12, and 24
SOBI003 Concentration in Cerebrospinal Fluid
SOBI003 concentration in cerebrospinal fluid
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, weeks 12, and 24
Change From Baseline in Heparan Sulfate Levels in Serum
Change from baseline in Heparan sulfate levels in serum
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Week 24
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