Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Patients with Hunter Syndrome (Mucopolysaccharidosis Type II)

The primary objective of this study is to characterize the **safety** and tolerability of DNL310 in pediatric participants with **Hunter Syndrome** (Mucopolysaccharidosis Type II [MPS II]). This is clinically relevant as it aims to ensure that the treatment is safe for use in this vulnerable population, potentially leading to improved management of the disease.

Secondary objectives include:

• Characterizing the central nervous system (CNS) effects of DNL310 on **heparan sulfate** (HS) concentrations in cerebrospinal fluid (CSF).
• Assessing the CNS effects of DNL310 on adaptive behaviors using the Vineland Adaptive Behavior Scale.
• Characterizing the pharmacokinetics (PK) of once-weekly intravenous infusions of DNL310 in serum.
• Evaluating the immunogenicity of DNL310 in serum.
• Characterizing the peripheral effects of DNL310 on HS concentrations in urine.
• Assessing the peripheral effects of DNL310 on liver volume as measured by magnetic resonance imaging (MRI).

The clinical trial involves a total of **43 male pediatric participants** diagnosed with **Hunter Syndrome (Mucopolysaccharidosis Type II [MPS II])**. The study population is exclusively male, with an age range that includes various cohorts: participants aged 1 to 18 years, with specific subgroups for those aged 5 to 10 years, under 4 years, and those with a history of prior hematopoietic stem cell transplantation or gene therapy. The trial population was selected based on a confirmed diagnosis of MPS II, with additional criteria such as the presence of neuronopathic or non-neuronopathic forms of the disease, and preexisting conditions like hepatomegaly. Participants are required to have tolerated a minimum of 4 months of intravenous iduronate 2-sulfatase enzyme replacement therapy prior to screening. The study focuses on a vulnerable population, emphasizing the safety and tolerability of DNL310 in these pediatric subjects.

The clinical trial is a **Phase 1/2**, multicenter, open-label study designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of DNL310 in pediatric participants diagnosed with **Hunter Syndrome** (Mucopolysaccharidosis Type II [MPS II]). The trial aims to characterize the safety and tolerability of DNL310 across various cohorts of pediatric participants. The study involves the administration of DNL310 via **intravenous infusion**. The trial is expected to run from June 2021 to July 2027, with participant involvement potentially extending up to 261 weeks, depending on the cohort and study phase.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, phenotype of MPS II, and prior treatment history. The trial includes multiple cohorts, each with specific inclusion criteria, such as age range and previous treatment exposure. Following the screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety and efficacy endpoints. These visits will assess the incidence and severity of treatment-emergent adverse events (TEAEs), infusion-related reactions (IRRs), and changes in urine total glycosaminoglycan (GAG) concentration, among other parameters.

The primary endpoints focus on the safety profile of DNL310, while secondary endpoints include pharmacokinetic parameters and measures of disease progression, such as changes in cerebrospinal fluid (CSF) heparan sulfate levels and liver volume. Participants will also be evaluated for immunogenicity through the incidence of anti-drug antibodies (ADAs). The study includes a safety extension and an open-label extension to further assess long-term outcomes.

Participant involvement may be terminated early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial is not categorized as low intervention, reflecting its exploratory nature in human pharmacology and therapeutic contexts. The study is conducted under the sponsorship of Denali Therapeutics Inc., with DNL310 being the investigational product under evaluation.

The clinical trial involves the administration of an **experimental medication** known as DNL310, developed by Denali Therapeutics Inc. 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 formulation is designed for intravenous infusion, allowing direct delivery into the bloodstream. The medication is not a pediatric formulation, and it is not classified as an orphan drug. The trial aims to evaluate the safety, pharmacokinetics, and pharmacodynamics of DNL310 in pediatric participants diagnosed with Hunter Syndrome, also known as Mucopolysaccharidosis II (MPS II).

In addition to the experimental treatment, the study may include the use of standard-of-care therapies as deemed necessary by the clinical investigators. These therapies are not specified in the trial data but are typically administered according to established medical guidelines for managing Hunter Syndrome. The trial does not mention the use of a placebo or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure accurate assessment of the medication's effects. The frequency and specific dosing schedule for DNL310 are not detailed in the provided data.

The efficacy of DNL310 in pediatric participants with **Hunter Syndrome** will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs) and infusion-related reactions (IRRs) throughout the study period, which extends to a safety extension at Week 104 and an open-label extension at Week 261. Additionally, changes from baseline in urine total glycosaminoglycan (GAG) concentration and concomitant medication use will be evaluated over the same timeframes.

Secondary endpoints focus on various pharmacokinetic (PK) parameters and other clinical measures. These include the percent change from baseline in cerebrospinal fluid (CSF) heparan sulfate levels over 24 weeks, and improvements in disease progression as measured by the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score and subdomain scores over 49 weeks. PK parameters such as maximum observed concentration (Cmax), trough concentration (Cmin), time to maximum observed concentration (tmax), and area under the concentration-time curve (AUC) will be measured in serum over 24 weeks. The study will also assess the immunogenicity of DNL310 by measuring the incidence of anti-drug antibodies (ADAs) relative to baseline. Additional assessments include percent change from baseline in urine heparan sulfate concentration, liver volume normalization, and percentage change in liver volume over 24 and 49 weeks.