Efficacy and Safety Evaluation of Iduronate-2-Sulfatase-Fc Polypeptide vs Idursulfase in Pediatric Mucopolysaccharidosis Type II

The primary objective of this study is to evaluate the **central nervous system (CNS)** activity of DNL310 compared to idursulfase in pediatric participants with neuronopathic Mucopolysaccharidosis Type II (nMPS II). This is assessed by measuring the cerebrospinal fluid (CSF) concentration of heparan sulfate (HS). The clinical relevance of this objective lies in determining the potential of DNL310 to address CNS manifestations of nMPS II, which are not adequately managed by current treatments.

Secondary objectives include:

• Evaluating the clinical CNS efficacy of DNL310 versus idursulfase on neurocognitive development, as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) cognitive domain in nMPS II participants.
• Assessing the clinical CNS efficacy on adaptive behavior using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) in nMPS II participants.
• Evaluating the efficacy on neuronal injury in nMPS II participants.
• Assessing the clinical efficacy on physical endurance as measured by the 6-Minute Walk Test (6MWT) in participants with non-neuronopathic MPS II (nnMPS II).
• Evaluating the onset and durability of peripheral efficacy as measured by the urine concentration of total glycosaminoglycans (GAGs) in both nMPS II and nnMPS II participants.
• Assessing the efficacy on liver and spleen volume as measured by MRI in both nMPS II and nnMPS II participants.

The clinical trial involves a total of **32 participants** diagnosed with **Mucopolysaccharidosis Type II (MPS II)**. The study population includes both male and female subjects, with an age range of **2 to 26 years**. Participants are divided into two cohorts: Cohort A consists of individuals aged 2 to less than 6 years, and Cohort B includes those aged 6 to less than 26 years. All participants have a confirmed diagnosis of MPS II, with Cohort A focusing on neuronopathic MPS II (nMPS II) and Cohort B on non-neuronopathic MPS II (nnMPS II). The trial population was selected based on their current treatment regimen, requiring that non-run-in participants in both cohorts be on maintenance enzyme replacement therapy (ERT) and have tolerated a minimum of 4 months of idursulfase therapy prior to screening. The study includes a vulnerable population, reflecting the specific needs and considerations of individuals with this rare genetic disorder. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 2/3**, multicenter, double-blind, randomized study designed to evaluate the efficacy and safety of DNL310 compared to idursulfase in pediatric participants with **Mucopolysaccharidosis Type II (MPS II)**. The trial involves two cohorts: Cohort A includes participants aged 2 to less than 6 years with neuronopathic MPS II, and Cohort B includes participants aged 6 to less than 26 years with non-neuronopathic MPS II. The study aims to assess the central nervous system (CNS) activity and clinical efficacy of DNL310 versus idursulfase, with primary endpoints focusing on changes in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration and adaptive behavior as measured by the Vineland-3 scale.

The trial is structured to include an initial screening visit to confirm eligibility based on the inclusion criteria, such as age and confirmed diagnosis of MPS II. Participants must have been on maintenance enzyme replacement therapy (ERT) and tolerated a minimum of 16 weeks of idursulfase therapy prior to screening. The study duration is estimated to conclude by December 2025, with participant involvement lasting up to 96 weeks. The trial includes regular follow-up visits to monitor safety and efficacy, with assessments at key intervals such as Week 24 and Week 96 for primary and secondary endpoints. These assessments include changes in CSF HS concentration, adaptive behavior, and other clinical measures such as the Bayley Scales of Infant and Toddler Development and the 6-Minute Walk Test (6MWT).

Participants will receive either DNL310 or idursulfase via **intravenous infusion**, with dosing regimens tailored to each product's specifications. The maximum treatment period is 96 weeks, with the potential for early termination if participants experience adverse events or fail to comply with study protocols. The end-of-study visit will involve comprehensive evaluations to assess the long-term impact of the treatments. The trial's design ensures rigorous control and blinding to maintain the integrity of the data collected, with the ultimate goal of advancing therapeutic options for individuals with MPS II.

The clinical trial involves the administration of two treatments to evaluate their efficacy and safety in pediatric participants with neuronopathic or non-neuronopathic **Mucopolysaccharidosis Type II**. The experimental medication, identified as DNL310, is a **solution for infusion** containing the active substance **iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor**. This biologic product is administered intravenously. The dosing regimen for DNL310 is set at a maximum daily dose of 15 mg/kg, with a total maximum dose of 1440 mg/kg over a treatment period of 96 weeks. The formulation is specifically designed for pediatric use, and participant compliance is monitored throughout the study to ensure adherence to the dosing schedule.

The comparator treatment in this study is Elaprase, a 2 mg/ml concentrate for solution for infusion, containing the active substance **idursulfase**. This biologic product is also administered intravenously. The dosing for Elaprase is established at a maximum daily dose of 0.5 mg/kg, with a total maximum dose of 48 mg/kg over the same 96-week treatment period. Elaprase is not specifically formulated for pediatric use in this trial. Both treatments are administered under double-blind conditions to maintain the integrity of the study, and participant compliance is closely monitored to ensure accurate assessment of the treatments' efficacy and safety.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the therapeutic impact of DNL310 compared to idursulfase in pediatric participants with neuronopathic or non-neuronopathic **Mucopolysaccharidosis Type II** (MPS II). The primary endpoints include the percent change from baseline in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration at Week 24 for Cohort A, and the change from baseline in the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) at Week 96 for the same cohort.

Secondary endpoints will further assess efficacy through various measures. For Cohort A, these include changes from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and serum neurofilament light chain (NfL) levels at Week 96, as well as changes in the Vineland-3 Adaptive Behavior Composite (ABC) score. For Cohort B, efficacy will be evaluated by the change from baseline in the distance walked in the 6-Minute Walk Test (6MWT) at Week 48. Both cohorts will be assessed for percent changes from baseline in the sum of urine HS and dermatan sulfate (DS) concentrations at Weeks 24 and 48, liver and spleen volume normalization as measured by magnetic resonance imaging (MRI) at Week 48, and improvement in the Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II at Week 48.