Long-term Safety and Efficacy Evaluation of Pabinafusp Alfa in Patients with Mucopolysaccharidosis Type II (Hunter Syndrome)

The primary objective of this study is to evaluate the long-term **efficacy** of JR-141 on central nervous system (CNS) symptoms in subjects with **Hunter Syndrome** (Mucopolysaccharidosis II). This is clinically relevant as CNS involvement in Hunter Syndrome can lead to significant neurological impairments, and assessing the efficacy of JR-141 could provide insights into potential therapeutic benefits for managing these symptoms.

Secondary objectives include:

• Evaluating the long-term efficacy of JR-141 on somatic symptoms in subjects with MPS II. This is important for understanding the broader impact of the treatment on physical manifestations of the disease.
• Assessing the long-term safety of JR-141 in subjects with MPS II, which is crucial for determining the risk-benefit profile of the treatment over extended use.

The clinical trial involves a total of **45 participants** diagnosed with **Hunter Syndrome**, also known as **Mucopolysaccharidosis II**. The study population includes both male and female subjects, with an age range encompassing children, adolescents, and adults. Participants were selected based on their prior involvement in the Parent Study (JR-141-GS31) and successful completion of specific assessments, with no safety concerns as determined by the principal investigator. The trial includes individuals from a vulnerable population, necessitating careful consideration of informed consent and assent procedures. Participants are required to adhere to medically accepted, highly effective methods of contraception if applicable. The study aims to evaluate the long-term efficacy of JR-141 on central nervous system symptoms in subjects with MPS II.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the long-term safety and efficacy of JR-141 in subjects with **Hunter Syndrome** (Mucopolysaccharidosis II). The trial will extend treatment with JR-141 following the completion of a previous study, JR-141-GS31. The primary objective is to assess the long-term efficacy of JR-141 on central nervous system symptoms in subjects with MPS II. The trial is expected to commence on April 1, 2024, and conclude by April 30, 2029, with a maximum treatment period of 60 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior participation in the parent study and the absence of safety concerns. Subsequent visits will include regular follow-up assessments to monitor primary endpoints, such as cerebrospinal fluid heparan sulfate and dermatan sulfate concentrations, neuropsychological assessments, and quality of life evaluations. Secondary endpoints will include liver and spleen volume, shoulder range of motion, and six-minute walk tests, among others. Safety endpoints will be continuously assessed through adverse event monitoring, laboratory tests, and physical examinations.

The expected length of participant involvement is up to 60 months, with conditions for early termination including the emergence of significant safety concerns or withdrawal of consent. Participants will be required to adhere to a medically accepted, highly effective method of contraception if applicable. The study will conclude with an end-of-study visit to perform final assessments and ensure participant safety. The trial will utilize JR-141, a lyophilized powder for preparation for injection, administered via intravenous injection, with a maximum daily dose of 2.0 mg/kg.

The clinical trial involves the administration of the experimental medication **JR-141**, which contains the active substance **pabinafusp alfa**. This medication is provided in the form of a **lyophilized powder for preparation for injection**. The pharmaceutical form is specifically designed for intravenous injection. The dosing regimen for JR-141 is set at a maximum daily dose of 2.0 mg/kg, with the same maximum total dose amount. The treatment period is limited to a maximum of 60 days. The medication is not formulated specifically for pediatric use, although it is being evaluated for its effects on **Mucopolysaccharidosis Type II (Hunter Syndrome)**, a condition that can affect children. The active substance, pabinafusp alfa, is a protein of other origin, and the medication has been designated as an orphan drug, indicating its use in rare diseases.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and efficacy of JR-141 in subjects with Mucopolysaccharidosis Type II. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to assess the impact of JR-141 on central nervous system symptoms associated with the disease.

The efficacy of JR-141 in the treatment of **Mucopolysaccharidosis Type II (Hunter Syndrome)** will be assessed through a series of primary and secondary endpoints. Primary endpoints include the measurement of cerebrospinal fluid (CSF) heparan sulfate (HS) and dermatan sulfate (DS) concentrations, as well as the opening pressure. Neuropsychological assessments will also be conducted, alongside evaluations of quality of life (QoL), sleep disturbances, and global impressions at various time points in Cohort A and Cohort B. Additionally, the time course of therapeutic activity scores (TAS) and continuous assessments of narrative reports from subjects or caregivers will be included.

Secondary endpoints will focus on the evaluation of liver and spleen volume, shoulder range of motion, and the six-minute walk test. Serum and urinary concentrations of HS and DS will be measured, and pulmonary function will be assessed in Cohort B if deemed feasible by the principal investigator. Other secondary measures include the time course of cardiac function parameters such as left ventricular mass index (LVMI), interventricular septal thickness (IVST), and posterior wall thickness (PWT) at each time point in both cohorts. The time course of the Test of Variables of Attention (T.O.V.A.®) will be monitored in Cohort B. Safety endpoints will involve continuous assessment of adverse events (AEs), periodic laboratory tests, vital signs, 12-lead ECG, anti-JR-141 antibodies, and physical and neurological examinations.