Phase I/II Clinical Trial of Atidarsagene Autotemcel Gene Therapy for Metachromatic Leukodystrophy in Hematopoietic Stem Cell Transplantation

The primary objective of this Phase I/II clinical trial is to evaluate the **safety** of gene therapy in subjects with Metachromatic Leukodystrophy (MLD). This includes assessing the safety of the conditioning regimen and the infusion of LV-transduced cells, both in the short and long term. Additionally, the trial aims to evaluate the efficacy of the gene therapy by measuring the reduction in the progression of clinical motor impairment in treated subjects compared to untreated MLD patients. This is clinically relevant as motor impairment in MLD is a direct consequence of central and peripheral nervous system involvement. The efficacy will be further supported by a significant increase in residual ARSA activity, measured on hematopoietic cells, which is expected to correlate with improved motor function as assessed by the GMFM scoring system.

The secondary objectives include: - Evaluation of the procedure's efficacy in reducing the progression of demyelination and atrophy in the central and peripheral nervous system, using validated instrumental parameters, total brain MRI score, and NCV Index at ENG recordings. - Assessment of the procedure's efficacy in reducing the progression of clinical motor impairment, as measured by GMFC-MLD, compared to historical controls. - Evaluation of the procedure's efficacy in reducing cognitive impairment, assessed through neuropsychological tests. - Assessment of the biological efficacy of the procedure, focusing on the sustained engraftment of transduced cells, which is crucial for clinical benefit. - Evaluation of correlations between transduced cell engraftment levels and busulfan exposure.

The clinical trial focuses on evaluating the safety and efficacy of gene therapy in subjects diagnosed with **Metachromatic Leukodystrophy (MLD)**. The study population includes both male and female participants, encompassing pre-symptomatic late infantile and pre- or early-symptomatic early juvenile patients. The age range of participants is categorized under code "2," which typically refers to a specific pediatric age group, although the exact age range is not specified. The trial involves a vulnerable population, indicating that special ethical considerations are in place. Participants were selected based on specific inclusion criteria, including the requirement for parental or guardian consent. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **Phase I/II** study to evaluate the safety and efficacy of hematopoietic stem cell gene therapy for the treatment of **Metachromatic Leukodystrophy (MLD)**. The trial employs a **randomized, double-blind, controlled** methodology to ensure unbiased results. The estimated duration of the trial extends until June 30, 2025, with recruitment having commenced on April 9, 2010. Participants will be involved in the study for a period of up to 36 months, depending on their individual treatment and follow-up schedules.

The sequence of study visits begins with an inclusion (screening) visit, where potential participants are assessed against the principal inclusion criteria, which include being pre-symptomatic late infantile patients or pre- or early-symptomatic early juvenile patients, along with obtaining informed consent from parents or guardians. Following successful screening, participants will undergo the treatment phase, which involves the administration of **atidarsagene autotemcel** via **intravenous injection**. Subsequent follow-up visits are scheduled to monitor safety and efficacy endpoints, with primary endpoints focusing on the safety of the conditioning regimen and lentiviral-transduced cell infusion, as well as the efficacy measured by improvements in gross motor function and **Arylsulfatase A (ARSA)** activity. Secondary endpoints include assessments of immune response, nerve conduction velocity, brain MRI scores, and intelligence quotient values.

The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted to evaluate long-term outcomes. Participants may be subject to early termination from the study if they experience significant adverse events or fail to comply with study protocols. The trial aims to provide comprehensive data on the potential benefits and risks associated with this innovative gene therapy approach for MLD.

The clinical trial involves the administration of **Libmeldy**, a dispersion for infusion containing **atidarsagene autotemcel** as the active substance. This investigational medicinal product is a gene therapy designed for the treatment of Metachromatic Leukodystrophy (MLD). The pharmaceutical form of Libmeldy is a dispersion for infusion, with a concentration of 2-10 x 10^6 cells/mL. The route of administration is via **intravenous injection**. The therapy involves the use of lentivirus-transduced hematopoietic stem cells, specifically targeting the Human Arylsulfatase A (ARSA) gene. The product is classified as a structurally diverse substance, specifically a cell therapy, and is not a pediatric formulation. The administration schedule and dosing frequency are determined based on the trial protocol, with compliance monitored through standard clinical trial procedures.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the safety and efficacy of the gene therapy in reducing the progression of clinical motor impairment in MLD patients. The trial aims to assess the increase in residual ARSA activity post-treatment compared to pre-treatment levels. Monitoring of participant compliance and safety is conducted through regular assessments and follow-ups as outlined in the trial protocol. The investigational product is authorized under the marketing authorization number EU/1/20/1493/001 and is developed by Orchard Therapeutics (Netherlands) B.V.

Efficacy in this clinical trial will be assessed through several key endpoints. The primary efficacy endpoints include an improvement of ≥ 10% in the total score of the Gross Motor Function Measure (GMFM) when compared to scores from age-matched untreated patients with Metachromatic Leukodystrophy (MLD). This assessment will be conducted 24 months post-treatment. Additionally, a significant increase in **Arylsulfatase A (ARSA)** activity will be measured in total peripheral blood mononuclear cells, also evaluated 24 months after treatment, compared to pre-treatment values.

Secondary efficacy endpoints involve multiple parameters. These include the Nerve Conduction Velocity Index at 24 months post-treatment, compared to historical control data, and total brain MRI scores at the same time point. The GMFC-MLD levels will be assessed at various ages in treated subjects against historical controls. Intelligence Quotient (IQ) values will be measured at 24, 30, and 36 months post-treatment, with a focus on maintaining values above 55. Engraftment of transduced cells above 4% in bone marrow-derived clonogenic progenitor cells will be evaluated at 12 months post-transplant. Vector copy number (VCN) per cell in total peripheral blood mononuclear cells, total bone marrow, and peripheral blood and bone marrow cell subpopulations will also be assessed. Correlations between transduced cell engraftment levels and busulfan exposure will be evaluated to further understand the treatment's efficacy.