A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome

Study Overview
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Brief Summary
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This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant enzyme replacement therapy (ERT), designed to treat both the peripheral and CNS manifestations of Mucopolysaccharidosis type II (MPS II; Hunter syndrome). Participants, whose physicians feel they are deriving benefit, will have the opportunity to be reconsented into a safety extension and then an open-label extension for continued evaluation.

Official Title
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A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants With Hunter Syndrome

Conditions
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Mucopolysaccharidosis II

Intervention / Treatment
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* Drug: tividenofusp alfa


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of MPS II Cohort A: Participants aged ≥5 to ≤10 years with neuronopathic MPS II Cohort B: Participants aged ≥1 to ≤18 years with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype Cohort C: Participants aged <4 years with neuronopathic MPS II (this cohort can include participants ≥4 to ≤18 years of age if participant is a blood relative of a participant <4 years of age) Cohort D: Participants aged ≤18 years with non-neuronopathic MPS II or neuronopathic MPS II with preexisting hepatomegaly who have never taken standard-of-care ERT Cohort E: neuronopathic MPS II participants aged ≥6 years at screening, non-neuronopathic MPS II participants <6 or ≥17 years at screening, and neuronopathic MPS II participants ≥1 to ≤18 years at screening with a history of prior haematopoietic stem cell transplantation or gene therapy who have completed at least 48 weeks in Study DNLI-E-0001 For participants receiving intravenous iduronate 2-sulfatase (IDS) ERT, tolerated a minimum of 4 months of therapy during the period immediately prior to screening. Key Exclusion Criteria: Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments Use of any CNS-targeted MPS II ERT within 3 months before study start for participants aged ≥5 years, and within 6 months before study start for participants aged <5 years Use of IDS gene therapy or stem cell therapy at any time (except for participants in Cohort E) Clinically significant thrombocytopenia, other clinically significant coagulation abnormality, or significant active bleeding, or required treatment with an anticoagulant or more than two antiplatelet agents Contraindication for lumbar punctures Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not MPS II-related within 1 year of screening Have had a ventriculoperitoneal (VP) shunt placed, or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening Have any clinically significant CNS trauma or disorder that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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Male

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>|
| Experimental: Cohort B<br>A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants. | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>|
| Experimental: Cohort C<br>A consistent dose level in participants with neuronopathic MPS II | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>|
| Experimental: Cohort D<br>A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>|
| Experimental: Cohort E<br>A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II | Drug: tividenofusp alfa<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) |  | 24 weeks, 104 weeks, and 261 weeks | 
| Change from baseline in urine total glycosaminoglycan (GAG) concentrations |  | 24 weeks, 104 weeks, and 261 weeks | 
| Incidence and severity of infusion-related reactions (IRRs) |  | 24 weeks, 104 weeks, and 261 weeks | 
| Change from baseline in concomitant medications |  | 24 weeks, 104 weeks, and 261 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate |  | 24 weeks | 
| Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score |  | 49 weeks | 
| Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores |  | 49 weeks | 
| PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Trough concentration (Cmin) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum |  | 24 weeks | 
| PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum |  | 24 weeks | 
| Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline |  | 24 weeks | 
| Percent change from baseline in urine concentration of heparan sulfate (HS) |  | 24 weeks | 
| Participants with liver volume in the normal range |  | 24 weeks and 49 weeks | 
| Percentage change from baseline in liver volume |  | 24 weeks and 49 weeks | 

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