Clinical trial NCT03423186: A Study to Assess the Safety and Tolerability of SOBI003 in Pediatric MPS IIIA Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Sanfilippo Syndrome Type A (MPS IIIA)
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
First posted: 2018-02-06
Enrollment: 6
Sex: ALL
Minimum age (years): 12
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent obtained from the patient's legally authorized representative(s)
2. 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
3. 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)
4. Medically stable patient who is expected to be able to comply with study procedures

Exclusion Criteria:

1. At least one S298P mutation in the SGSH gene
2. Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI scans and/or lumbar punctures
3. History of poorly controlled seizures
4. Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results
5. 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
6. Prior administration of stem cell or gene therapy, or ERT for MPS IIIA
7. Concurrent or prior (within 30 days of enrolment into this study) participation in a study involving invasive procedures

Primary outcomes:
measure: Safety as Measured by Adverse Events Frequencies (by Type and Severity)
timeFrame: From start of first infusion up to Week 24
Secondary outcomes:
measure: The Observed Serum Concentration Immediately Before the Start of Infusion of SOBI003
timeFrame: Weeks 1, 2, 3, 4, 8, 12, and 24
measure: The Observed Serum Concentration at the End of Infusion of SOBI003
timeFrame: Weeks 1, 2, 3, 4, 8, 12, and 24
measure: The Time of the End of the Infusion of SOBI003
timeFrame: Weeks 1, 2, 3, 4, 8, 12, and 24
measure: The Maximum Observed Serum Concentration of SOBI003
timeFrame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Weeks 1, 4, 12, and 24
measure: The Time at Which the Maximum Serum Concentration of SOBI003 is Observed
timeFrame: Weeks 1, 4, 12, and 24
measure: The Minimum Observed Serum Concentration of SOBI003
timeFrame: Weeks 1, 4, 12, and 24
measure: Clearance
timeFrame: Weeks 1, 4, 12, and 24
measure: Area Under the Serum Concentration-time Curve From Time 0 to 168 Hours
timeFrame: 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
measure: The Half-life
timeFrame: Weeks 1, 4, 12, and 24
measure: SOBI003 Concentration in Cerebrospinal Fluid
timeFrame: Weeks 12 and 24
measure: Number of Patients Having Anti-drug Antibodies in Serum
timeFrame: Weeks 2,4,8,12 and 24
measure: Patients Having Anti-drug Antibodies in Cerebrospinal Fluid
timeFrame: Weeks 12 and 24
measure: Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid
timeFrame: Baseline, weeks 12, and 24
measure: Change From Baseline in Heparan Sulfate Levels in Serum
timeFrame: Weeks 2, 3, 4, 8, 12 and 24
measure: Change From Baseline in Heparan Sulfate Levels in Urine
timeFrame: Weeks 2, 3, 4, 8, 12 and 24
measure: Change From Baseline in Neurocognitive Development Quotient
timeFrame: Week 24
measure: Change From Baseline in Age-equivalence Score
timeFrame: Week 24
measure: Change From Baseline in Age-equivalence Score as Assessed by VABS-II
timeFrame: Week 24
measure: Change From Baseline in Gray Matter Volume
timeFrame: Week 24
measure: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Total Score
timeFrame: Week 24
measure: Change From Baseline in PedsQL™ Family Impact Module Total Score
timeFrame: Week 24
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Childrens's Hospital and Research Center
state: California
city: Chapel Hill
country: United States
facility: University of North Carolina Hospitals
state: North Carolina
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Ankara
country: Turkey
facility: Gazi University Hospital
Study officials:
affiliation: Childrens's Hospital and Research Center Oakland
name: Paul Harmatz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Harmatz P, Muenzer J, Ezgu F, Dalen P, Huledal G, Lindqvist D, Gelius SS, Wiken M, Onnestam K, Broijersen A. Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study. Mol Genet Metab. 2022 Aug;136(4):249-259. doi: 10.1016/j.ymgme.2022.06.008. Epub 2022 Jun 28.