A Treatment Study of Mucopolysaccharidosis Type IIIB

Study Overview
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Brief Summary
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The study's primary objectives are to evaluate the safety and tolerability of AX 250 administered to subjects with MPS IIIB via an ICV reservoir and catheter and to evaluate the impact of AX 250 on cognitive function in patients with MPS IIIB as assessed by the Development Quotient.

Official Title
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A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Intracerebroventricular AX 250 in Patients With Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)

Conditions
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MPS III B, Mucopolysaccharidosis Type IIIB

Intervention / Treatment
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* Drug: AX 250


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals eligible to participate in Part 1 of this study must meet all of the following criteria: Has deficient NAGLU enzyme activity at Screening. Blood for NAGLU enzyme activity will be collected and analyzed centrally. Is ≥ 1 and < 11 years of age (at least 1 of the 3 subjects in Part 1 must be ≥ 1 and < 6 years of age) Has presented with signs/symptoms consistent with MPS IIIB; for individuals who have not presented with signs/symptoms of disease (eg, siblings of known patients), the determination of eligibility will be at the discretion of the BioMarin medical monitor in conjunction with the site investigator. Written informed consent from parent or legal guardian and assent from subject, if required Has the ability to comply with protocol requirements, in the opinion of the investigator Individuals eligible to participate in Part 2 of this study must meet all of the following criteria: Participated in and met protocol requirements for transitioning from Study 250-901 or participated in Part 1 of Study 250-201 Written informed consent from parent or legal guardian and assent from subject, if required Exclusion Criteria: Individuals who meet any of the following exclusion criteria are ineligible to participate in Part 1 of the study: Has received stem cell, gene therapy or ERT for MPS IIIB Has contraindications for neurosurgery (eg, congenital heart disease, severe respiratory impairment, or clotting abnormalities) Has contraindications for MRI scans (eg, cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain) Has a history of poorly controlled seizure disorder Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts Has received any investigational medication within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data. Is pregnant at any time during the study Individuals who meet any of the following exclusion criteria are ineligible to participate in Part 2 of this study: Has received stem cell, gene therapy or ERT for MPS IIIB Has contraindications for neurosurgery (eg, congenital heart disease, severe respiratory impairment, or clotting abnormalities) Has contraindications for MRI scans (eg, cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain) Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts Has received any investigational medication within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data. Is pregnant at any time during the study

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 10 Years

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: AX 250<br>In Part 1, patients will receive up to 3 escalating doses of AX 250 (30, 100 and 300 mg) via ICV infusion every week until the maximum tolerated tested dose (MTTD) is established. In Part 2, patients will receive weekly doses of AX 250 via ICV infusion that will continue for 48 weeks at the MTTD established in Part 1. | Drug: AX 250<br>* Chimeric fusion of recombinant human alpha-N-acetylglucosaminidase and truncated human insulin-like growth factor 2 (rhNAGLU-IGF2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluation of weekly infusions of AX 250 (Part 1 & Part 2) - Number of participants with abnormal clinical laboratory values and/or Adverse Events that are related to treatment. | Number of participants with abnormal clinical laboratory values and/or Adverse Events that are related to treatment. | Entire study period, up to 124 weeks | 
| Development Quotient (DQ) as efficacy variable with analysis of rate of change of DQ score on treatment vs. rate of change of DQ score prior to treatment. |  | Assessed at study end, up to 124 weeks. Collected at: Part 1 - Baseline; Part 2 - Weeks 12, 24, 36, & 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize maximum concentration (Cmax) of AX 250 in cerebrospinal fluid (CSF) and plasma as relevant through completion of Part 1 and Part 2 |  | Study end, up to 124 weeks. Collected at: Pre-dose, 0, 4, 10, 24, 48, 72, 96, 168 hours post-dose for the first dose during each dose escalation in Part 1. Pre-dose, 0, 4, 10, 24, 48, 72, 96, 168 hours post-dose for Baseline, Weeks 5, 12, 36 in Part 2. | 
| Characterize area under concentration curve (AUC) of AX 250 in cerebrospinal fluid (CSF) and plasma as relevant through completion of Part 1 and Part 2 |  | Study end, up to 124 weeks. Collected at: Pre-dose, 0, 4, 10, 24, 48, 72, 96, 168 hours post-dose for the first dose during each dose escalation in Part 1. Pre-dose, 0, 4, 10, 24, 48, 72, 96, 168 hours post-dose for Baseline, Weeks 5, 12, 36 in Part 2. | 
| Characterize immunogenicity of AX 250 total anti-drug anti-body (TAb) in cerebrospinal fluid (CSF) and serum as relevant through completion of Part 1 and Part 2 |  | Assessed at study end, up to 124 weeks. Collected at: First dose during each dose escalation in Part 1, and Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 in Part 2 | 
| Evaluate GAG levels in cerebrospinal fluid (CSF) |  | Assessed at study end, up to 124 weeks. Collected at: Each weekly visit as relevant through completion of Part 1 and Part 2 | 
| Evaluate GAG levels in plasma |  | Assessed at study end, up to 124 weeks. Collected at: Each weekly visit as relevant through completion of Part 1 and Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, as relevant in Part 2 | 
| Evaluate GAG levels in urine |  | Assessed at study end, up to 124 weeks. Collected at: Each weekly visit as relevant through completion of Part 1 and Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, as relevant in Part 2 | 
| Evaluate the impact of AX 250 treatment on brain structure assessed by magnetic resonance imaging (MRI) |  | Assessed at study end, up to 124 weeks. Part 1 - Screening and Baseline; Part 2 - Screening, Baseline, Week 24, and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sanfilippo Syndrome Type B