Long-Term Safety, Tolerability, and Efficacy of Iduronate-2-Sulfatase-Fc Polypeptide in Mucopolysaccharidosis Type II Patients from DNLI-E-0002/0007 Studies

The primary objective of this study is to assess the long-term **safety** and **tolerability** of DNL310 in patients diagnosed with Mucopolysaccharidosis Type II (MPS II). This is clinically relevant as it aims to ensure that the therapeutic intervention is safe for prolonged use in this patient population, addressing potential adverse effects and overall patient well-being.

Secondary objectives include: - Evaluating the long-term central nervous system (CNS) activity of DNL310 by measuring cerebrospinal fluid (CSF) concentration of heparan sulfate (HS). - Assessing the long-term clinical CNS efficacy of DNL310 on adaptive behavior using the Vineland Adaptive Behavior Scales, Third Edition (Vineland 3), Adaptive Behavior Composite (ABC). - Evaluating the long-term clinical CNS efficacy on neurocognitive development with the Bayley Scales of Infant and Toddler Development, Third Edition (BSID III), cognitive domain. - Assessing the long-term clinical efficacy on physical endurance using the Six Minute Walk Test (6MWT). - Evaluating the onset and durability of peripheral efficacy by measuring urine concentration of total glycosaminoglycans (GAGs) through mass spectrometry-based detection. - Assessing the long-term efficacy on liver and spleen volume using magnetic resonance imaging (MRI). - Evaluating the parent's/caregiver's assessment of long-term efficacy through the Parent/Caregiver Global Impression of Change (CaGI-C).

The clinical trial involves a total of **70 participants** diagnosed with **Mucopolysaccharidosis Type II (MPS II)**. The study population includes both male and female subjects, with an age range that encompasses children and adolescents. Participants were selected based on their completion of previous related studies, specifically Study DNLI-E-0002 and Study DNLI-E-0007, without early discontinuation of the study intervention. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of participants. The primary objective of the trial is to assess the long-term safety and tolerability of DNL310 in patients with MPS II. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **DNL310**, a **solution for infusion** administered via **intravenous use**, in patients with **Mucopolysaccharidosis Type II (MPS II)**. This open-label extension study follows participants from previous studies DNLI-E-0002 and DNLI-E-0007. The trial is structured as a non-randomized, open-label study, focusing on the collection of safety and efficacy data over an extended period. The trial is expected to last until July 2027, with recruitment starting in December 2023.

Participants eligible for inclusion must have completed specific prior study requirements, such as the Week 49 visit in Study DNLI-E-0002 or the treatment period in Study DNLI-E-0007. The primary endpoints include the incidence and intensity of treatment-emergent adverse events (TEAEs), clinically significant changes in urine total glycosaminoglycan (GAG) concentrations, and the incidence and intensity of infusion-related reactions (IRRs), all assessed over a five-year period. Secondary endpoints involve various measures of clinical improvement and biochemical changes, such as percent change from baseline in cerebrospinal fluid heparan sulfate concentration and changes in cognitive and physical performance metrics.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, summarizing the collected data and assessing the overall impact of the treatment. Participant involvement is expected to last up to five years, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The study aims to provide comprehensive data on the long-term use of DNL310 in the treatment of MPS II, contributing to the understanding of its therapeutic potential and safety profile.

The clinical trial involves the administration of an **experimental medication** known as DNL310, developed by Denali Therapeutics Inc. This medication is a **solution for infusion** and is specifically formulated for pediatric use. The active substance in DNL310 is **iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor**. This biologic agent is designed for **intravenous use**. The dosing regimen allows for a maximum daily dose of 15 mg/kg, with a total maximum dose of 3600 mg/kg over the course of the treatment period, which can extend up to 240 days. The medication is classified as a protein of other origin, indicating its complex biological nature.

In this study, DNL310 is being evaluated for its long-term safety, tolerability, and efficacy in patients with **Mucopolysaccharidosis Type II (MPS II)**. The trial is an open-label extension, meaning that all participants receive the experimental treatment, and there is no placebo or comparator treatment involved. The focus is on monitoring the participants' response to the treatment over an extended period, ensuring adherence to the dosing schedule, and assessing any potential adverse effects. Compliance with the treatment regimen is closely monitored to ensure the integrity of the trial data and the safety of the participants.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints over a period of five years. The primary endpoints include the incidence and intensity of treatment-emergent adverse events (TEAEs), clinically significant changes in urine total glycosaminoglycan (GAG) concentrations, and the incidence and intensity of infusion-related reactions (IRRs). These parameters will be monitored throughout the treatment period to evaluate the long-term safety and tolerability of DNL310 in patients with **Mucopolysaccharidosis Type II (MPS II)**.

Secondary endpoints will focus on various measures of clinical improvement and biomarker changes. These include the percent change from baseline in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration, changes in the Vineland-3 Adaptive Behavior Composite (ABC), and changes in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID III) cognitive raw score. Additionally, the trial will assess changes in the distance walked in the 6-Minute Walk Test (6MWT), percent change from baseline in the sum of urine HS and dermatan sulfate concentrations, and liver and spleen volumes as measured by MRI. Improvement in the Caregiver Global Impression of Change (CaGI C) Overall MPS II will also be evaluated, defined as much improved or a little improved.