A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II)

Study Overview
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Brief Summary
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This is a Phase 2/3, multiregional, two-arm, double-blind, randomized, active (standard-of-care)-controlled study of the efficacy and safety of tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant enzyme-replacement therapy (ERT) for mucopolysaccharidosis type II (MPS II). Participants may also qualify to enter an open-label treatment phase with DNL310 or idursulfase based on pre-specified criteria.

Official Title
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A Phase 2/3, Multicenter, Double-Blind, Randomized Study to Determine the Efficacy and Safety of DNL310 vs Idursulfase in Pediatric Participants With Neuronopathic or Non-Neuronopathic Mucopolysaccharidosis Type II

Conditions
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Mucopolysaccharidosis II

Intervention / Treatment
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* Drug: tividenofusp alfa
* Drug: idursulfase


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <17 years (Cohort B) Confirmed diagnosis of MPS II (for Cohort A, nMPS II; for Cohort B, nnMPS II) Be on maintenance enzyme replacement therapy (ERT) and have tolerated idursulfase for a minimum of 4 months prior to screening Key Exclusion Criteria: Have a documented mutation of other genes or genetic diagnosis accounting for developmental delay Previously received an iduronate 2-sulfatase (IDS) gene therapy or stem cell therapy Received any CNS-targeted MPS ERT within 6 months prior to screening Have a contraindication for lumbar punctures and/or magnetic resonance imagings (MRIs) Participated in any other investigational drug study or used an investigational drug within 60 days prior to screening or intend to receive another investigational drug during the study

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 16 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Participants with nMPS II<br> | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>Drug: idursulfase<br>* Intravenous repeating dose<br>|
| Experimental: Cohort B: Participants with nnMPS II<br> | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>Drug: idursulfase<br>* Intravenous repeating dose<br>|
| Experimental: Open-label Treatment Phase<br>Participants who meet pre-specified criteria may receive DNL310 or idursulfase | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>Drug: idursulfase<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration (Cohort A only) |  | 24 weeks | 
| Change from baseline in the Vineland Adaptive Behavior Scale, Third Edition (Vineland-3)(Cohort A only) |  | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)(Cohort A only) |  | 96 weeks | 
| Change from baseline in distance walked in the Six-Minute Walk Test (6MWT; Cohort B only) |  | 48 weeks | 
| Percent change from baseline in the sum of urine HS and dermatan sulfate (DS) concentrations (Cohorts A and B) |  | up to 48 weeks | 
| Liver volume within the normal range (normal vs abnormal) as measured by magnetic resonance imaging (MRI) (Cohorts A and B) |  | 48 weeks | 
| Spleen volume within the normal range (normal vs abnormal) as measured by MRI (Cohorts A and B) |  | 48 weeks | 
| Improvement in Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II (Cohorts A and B) |  | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hunter Syndrome, MPS II, nMPS II, nnMPS II