A Study to Assess the Safety, Tolerability, and Efficacy of Long-term SOBI003 Treatment 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 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).

Detailed Description
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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.

Official Title
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An Open, Single-arm, Multicenter Extension Study to Assess the Safety, Tolerability, and Efficacy of Long-term SOBI003 Treatment 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: Completion of study SOBI003-001 Informed consent obtained from the patient´s legally authorized representative Exclusion Criteria: If, in the opinion of the investigator, there are patient specific safety concerns that contraindicates further treatment with SOBI003

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 78 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOBI003<br>SOBI003 solution, 20 mg/mL, is mixed with NaCl 0.9% infusion solution prior to administration. For a bodyweight < 25 kg, the total infusion volume is 100 mL. For a bodyweight ≥ 25 kg, the total infusion volume is 250 mL. SOBI003 is administered as i.v. infusions given once weekly for a duration of 80 weeks (from Week 25 until Week 104 following the first 24 weeks of SOBI003 administration in the FIH study (SOBI003-001) study. The SOBI003 dose will be adjusted to the highest dose that has been declared safe by the safety review committee on the FIH study.Hence, dose adjustments may occur a couple of times on the extension study until the final decided dose has been determined. | 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 week 25 up to week 104 | From infusion week 25 up to week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Weeks 38, 52, 78 and 104 | 
| SOBI003 Concentration in Cerebrospinal Fluid | Concentration of SOBI003 in cerebrospinal fluid | 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 | 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 | 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 | 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 | 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 | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Week 52 and 104 |