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 aim of the present study is to assess the safety, tolerability and efficacy of long-term SOBI003 treatment. SOBI003 is a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).
This is an open, single-arm, multicenter extension study to assess the safety, tolerability and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA patients. The study is an extension of the First in Human (FIH) SOBI003-001 study, allowing continuous treatment of SOBI003 for up to 2 years. Study patients who complete Week 24 of the FIH study (SOBI003-001) will be invited to continue to Week 25 in the extension study. When entering the extension study, these patients will receive the highest dose that has been declared safe in the ongoing FIH study (SOBI003-001). Upon completion of the FIH study, an analysis aimed at selecting the dose for forthcoming studies will take place. Once the dose has been selected, this dose will be applied to all patients enrolled in the extension study. The total duration of the extension study for an individual patient is 80 weeks, resulting in a total of 104 weeks (2 years) of SOBI003 treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
weekly i.v. infusion
Children´s Hospital and research center
Oakland, California, United States
University of North Carolina hospitals
Chapel Hill, North Carolina, United States
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 week 25 up to week 104
Time frame: From infusion week 25 up to week 104
The Observed SOBI003 Serum Concentration Immediately Before the Start of Infusion of SOBI003
The observed SOBI003 serum concentration immediately before the start of infusion of SOBI003 (CPre-dose) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
The Observed SOBI003 Serum Concentration at the End of Infusion of SOBI003
The observed SOBI003 serum concentration at the end of infusion of SOBI003 (CEnd of inf) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
The Time of the End of the Infusion of SOBI003
The time of the end of infusion of SOBI003 (tEnd of inf) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
The Maximum Observed Serum Concentration of SOBI003
The maximum observed serum concentration of SOBI003 (Cmax) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
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) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
The Minimum Observed Serum Concentration of SOBI003
The minimum observed serum concentration of SOBI003 (CTrough) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
Clearance
Clearance (CL) of SOBI003 Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
Area Under the SOBI003 Serum Concentration-time Curve From Time 0 to168 Hours
Area under the SOBI003 serum concentration-time curve from time 0 to 168 hours (AUC 0-168h) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: 0,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Weeks 38, 52, 78 and 104
The Half-life
The half-life of SOBI003 in serum (T1/2) Blood samples for serum PK analysis were collected either by centrally (i.e., using a catheter in the central venous port) or peripheral (i.e., by venipuncture). Central venous sampling is more convenient than repeated venipuncture.
Time frame: Weeks 38, 52, 78 and 104
SOBI003 Concentration in Cerebrospinal Fluid
Concentration of SOBI003 in cerebrospinal fluid
Time frame: Weeks 52 and 104
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 38, 52, 78 and 104
Number of Patients Having Anti-drug Antibodies in Cerebrospinal Fluid
Number of patients in each dose group having anti-drug antibodies cerebrospinal fluid
Time frame: Weeks 52 and 104
Change From Baseline in Heparan Sulfate Concentration in Cerebrospinal Fluid
Change from baseline, in percent, of Heparan Sulfate levels in cerebrospinal fluid
Time frame: Weeks 52 and 104
Change From Baseline in Heparan Sulfate Levels in Serum
Change from baseline in Heparan sulfate, in mg/L, levels in serum
Time frame: Weeks 38, 52, 78 and 104
Change From Baseline in Heparan Sulfate Levels in Urine
Change from baseline in Heparan sulfate levels, in g/mol, in urine
Time frame: Weeks 38, 52, 78 and 104
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. These results are truly "unitless"/"dimensionless" because they represents quotients of values from the same scale, which means that the units in the denominator and
Time frame: Weeks 52 and 104
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 52 and 104
Age-equivalence Score as Assessed Either by the BSID-III, Cognitive Subtest, or the KABC-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 52 and 104
Change From Baseline in Age-equivalence Score as Assessed Either by the BSID-III, Cognitive Subtest, or the KABC-II.
The age equivalent score represents 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 either by the Bayley Scales of Infant and Toddler Development®, third edition, (BSID-III) cognitive subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) depending on chronological age of the subject. Quotient between age equivalent score and age, 0 - 100%, where high values are desirable. The BSID-III is an individually administered test designed to assess developmental functioning of infants and toddlers. The BSID-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The KABC-II is a clinical instrument for assessing cognitive development. The unit and measurement is the same in both scales (BSID-III and KABC-II): Age-equivalent score.
Time frame: Week 52 and 104
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 52 and 104
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 52 and 104
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) at weeks 52 and 104.
Time frame: Week 52 and 104
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 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 52 and 104
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. Higher scores indicate better functioning. Min score = 0, and max score = 144.
Time frame: Week 52 and 104
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 Total Score is the sum of all 36 items in the test divided by the number of items answered. Higher scores indicate better functioning. Min score = 0, and max score = 144.
Time frame: Week 52 and 104
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 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 52 and 104
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