Long-term Safety and Tolerability Evaluation of Rebisufligene Etisparvovec in Mucopolysaccharidosis Type IIIA Patients from Gene Therapy Trials

The primary objective of this study is to evaluate the long-term **safety** and tolerability of UX111 in patients diagnosed with Mucopolysaccharidosis type IIIA (MPS IIIA). This is clinically relevant as it aims to ensure that the gene therapy product, ABO-102 (scAAV9.U1a.hSGSH), is safe for prolonged use in this patient population, potentially offering a sustainable therapeutic option for managing this progressive and debilitating condition. There are no secondary objectives outlined for this study.

The clinical trial involves a total of **17 participants** diagnosed with **Mucopolysaccharidosis type IIIA**. 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 a clinical trial where they received UX111. The trial population is considered vulnerable, and the study aims to evaluate the long-term safety and tolerability of UX111 in these patients. The general health status of participants is not specified, and no specific lifestyle considerations such as diet or physical activity are mentioned. Key inclusion criteria include the willingness and ability of the participants' parent(s) or legal guardian(s) to complete the informed consent process and comply with study procedures and visit schedules.

The clinical trial is designed to evaluate the long-term safety and tolerability of **UX111** in patients with **Mucopolysaccharidosis type IIIA**. This study is a follow-up to previous gene therapy clinical trials involving the administration of **ABO-102**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial spans from May 2020 to August 2027, providing a comprehensive assessment over several years.

Participants eligible for this study must have previously participated in a clinical trial where they received **UX111**. The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility based on prior trial participation and the ability of the participant's parent(s) or legal guardian(s) to complete the informed consent process. Follow-up visits are scheduled to monitor the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as to assess efficacy through measures such as the Bayley Scales of Infant and Toddler Development - Third Edition (BSITD-III) cognitive raw score.

The trial includes secondary endpoints that evaluate cerebrospinal fluid (CSF) heparan sulfate (HS) exposure, changes in CSF HS from baseline, and communication scores from the BSITD-III. Additionally, total cortical volume changes and survival rates are monitored. The expected length of participant involvement is aligned with the trial's overall duration, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent by the participant's guardians.

The clinical trial involves the administration of **ABO-102**, a gene therapy product developed by Ultragenyx Pharmaceutical Inc. The active substance in ABO-102 is **rebisufligene etisparvovec**, also known by its alternative names scAAV9.U1a.hSGSH and UX111. This product is formulated as a **suspension for injection** and is administered via the **intravenous route**. The therapy is designed to transduce patient cells, enabling them to produce the N-sulfoglucosamine sulfohydrolase protein, which is intended to restore the damaged metabolic pathway in patients with MPS IIIA. The dosing unit is measured in vector genomes (vg)/mL, with a maximum treatment period of one day. The trial does not specify a maximum daily or total dose amount, indicating that dosing is tailored to individual patient needs within the study parameters.

In this study, ABO-102 is the sole investigational product, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial focuses on evaluating the long-term safety and tolerability of the gene therapy in patients with MPS IIIA. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The gene therapy vector is not classified as a genetically modified organism (GMO) and is administered in vivo, directly to the patient. The study is conducted under orphan drug designation, highlighting its focus on a rare disease.

The efficacy of the clinical trial involving the administration of ABO-102 for patients with **MPS IIIA** will be assessed using several parameters. The primary efficacy endpoint is the Bayley Scales of Infant and Toddler Development - Third Edition (BSITD-III) Cognitive raw score. Secondary efficacy endpoints include cerebrospinal fluid (CSF) heparan sulfate (HS) exposure, CSF HS percentage change from baseline in a prior trial, BSITD-III Receptive Communication raw score, BSITD-III Expressive Communication raw score, total cortical volume annualized percentage change from baseline in a prior trial, and survival.

The BSITD-III is a validated scale used to measure cognitive and communication development in infants and toddlers. The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial. The trial is designed to evaluate the long-term safety and efficacy of the gene therapy product UX111 in patients who have previously participated in a clinical trial involving this treatment. The study will continue until the estimated end date of August 11, 2027.