Long-Term Safety and Efficacy of Intrathecal Cebsulfase Alfa in Pediatric Patients with Late Metachromatic Leukodystrophy: An Extension of Study HGT-MLD-070

The primary objective of this study is to collect long-term **safety** data in patients with Late Metachromatic Leukodystrophy (MLD) who are receiving HGT-1110 and have participated in Study HGT-MLD-070 through Week 40. This is clinically relevant as it aims to ensure the continued safety of the intrathecal administration of HGT-1110, a treatment involving enzyme replacement therapy, which is crucial for managing the progression of MLD.

Secondary objectives include:

• Evaluating the effects of intrathecal (IT) administration of HGT-1110 on gross motor function.
• Assessing the effects on adaptive behavior, noting that the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) will not be collected as of 12 October 2021.
• Evaluating the effects on health status and the ability to carry out activities of daily life.
• Assessing repeated-dose pharmacokinetics (PK) of HGT-1110 in serum.
• Determining concentrations of HGT-1110 in cerebrospinal fluid (CSF).

The clinical trial involves a total of **6 participants** diagnosed with **Late Metachromatic Leukodystrophy (MLD)**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on their prior involvement in Study HGT-MLD-070 through Week 40, ensuring they have no safety or medical issues that contraindicate further participation. The trial population is considered vulnerable, and informed consent was obtained from the patients or their legally authorized representatives. No specific lifestyle considerations such as diet or physical activity were highlighted for this study.

The clinical trial is designed as an open-label extension study to evaluate the long-term safety and efficacy of **intrathecal** administration of HGT-1110 in patients with Late **Metachromatic Leukodystrophy** (MLD). The trial follows a non-randomized, open-label design, allowing for the collection of extended safety data from participants who have completed the initial Study HGT-MLD-070 through Week 40. The trial is expected to conclude by December 31, 2024, with recruitment having commenced on April 1, 2013.

Participants eligible for this study must have completed the prior study HGT-MLD-070 and must not present any safety or medical issues that contraindicate further participation. Written informed consent is required from the patient or their legally authorized representative before any study-related activities are conducted. The primary endpoints focus on safety, including the reporting of treatment-emergent adverse events, changes from baseline in clinical laboratory tests, vital signs, and the presence of anti-HGT-1110 antibodies in cerebrospinal fluid (CSF) and/or serum. Secondary endpoints include changes in motor function and adaptive behavior scores, as well as pharmacokinetic parameters of HGT-1110 in serum and CSF.

The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility and obtain consent. Follow-up visits are scheduled to monitor safety and efficacy parameters, with assessments including laboratory tests, physical examinations, and motor function evaluations. The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted. The expected duration of participant involvement varies, contingent on individual progression and response to treatment. Conditions that may lead to early termination from the study include the emergence of significant adverse events or the participant reaching a Gross Motor Function Classification System (GMFCS) level 5, at which point certain motor function assessments will no longer be collected.

The clinical trial involves the administration of the experimental medication **rhASA**, which contains the active substance **cebsulfase alfa**. This medication is formulated as a **solution for injection** and is specifically designed for **intrathecal use**. The administration of rhASA is facilitated through the SOPH-A-PORT Mini S device, which provides long-term, intermittent access to the intrathecal space for the delivery of the investigational drug. The medication is not a pediatric formulation and is classified as an orphan drug, with the designation number EU/3/10/813. The sponsor product code for rhASA is TAK-611, and it is authorized by SHIRE HUMAN GENETIC THERAPIES, INC.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the long-term safety and efficacy of the intrathecal administration of rhASA in patients with **metachromatic leukodystrophy**. The trial does not specify a maximum daily dose, total dose, or treatment period, indicating that dosing schedules may be individualized based on patient response and clinical judgment. Participant compliance with the treatment regimen is monitored through regular assessments and follow-up visits as part of the study protocol.

Efficacy in this clinical trial will be assessed through several secondary endpoints. The primary focus will be on the change from baseline at the end of the study in motor function, evaluated using the Gross Motor Function Measure-88 (GMFM-88) total score. Additionally, motor function assessments will include the global impression of motor function-change (GIMF-C) and global impression of motor function-severity (GIMF-S), although these will not be collected once patients reach Gross Motor Function Classification System (GMFCS) level 5. Another key parameter is the change from baseline at the end of the study in the domain-specific Caregiver Observed MLD Functioning and Outcomes Reporting Tool (COMFORT) scores. Furthermore, repeated-dose pharmacokinetic (PK) parameter estimates for HGT-1110 in serum and concentrations of HGT-1110 in cerebrospinal fluid (CSF) at selected time points after repeated investigational drug product administration will be measured. These assessments will provide comprehensive data on the efficacy of the investigational product in patients with **Metachromatic Leukodystrophy**.