Not recruitingRare disease

Study of Atidarsagene Autotemcel for Treating Early Onset Metachromatic Leukodystrophy (MLD) in Patients

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is focused on studying a rare genetic disorder called Metachromatic Leukodystrophy (MLD). MLD affects the nervous system and can lead to a decline in motor and cognitive functions. The study is testing a new treatment called OTL-200, which is a type of gene therapy. This treatment involves using a specially prepared form of the patient's own cells, which are modified with a lentiviral vector containing the human Arylsulfatase A (ARSA) gene. The goal is to help the body produce the enzyme it lacks, which is necessary for breaking down certain fats in the body.

The purpose of the study is to evaluate how effective this gene therapy is in treating early onset MLD. Participants in the study will receive the treatment through a direct intravenous injection, which means it is delivered directly into the bloodstream. The study will follow participants over a period of time to monitor their progress and assess the treatment's impact on their motor functions and overall health. This will include regular check-ups and various assessments, such as neurological exams and imaging tests like MRI scans, to see how the treatment is working.

Throughout the study, researchers will also keep track of any side effects or adverse events to ensure the safety and tolerability of the treatment. The study aims to provide valuable information on the potential benefits of this gene therapy for individuals with MLD, offering hope for a condition that currently has limited treatment options.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Initial assessment
The trial begins with an initial assessment to confirm eligibility. This includes a documented biochemical and molecular diagnosis of Metachromatic Leukodystrophy (MLD). The diagnosis is based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles.
Participants must meet specific criteria, such as having an older sibling affected by MLD or being diagnosed with MLD in a pre-symptomatic stage. The age of symptom onset and genetic factors are considered.
Step 2
Gene therapy administration
The treatment involves the administration of Libmeldy, a dispersion for infusion containing atidarsagene autotemcel. This is delivered through a direct intravenous injection.
The therapy uses a cryopreserved formulation of OTL-200, which is a gene therapy product designed to treat early onset MLD.
Step 3
Post-treatment monitoring
After the gene therapy, the patient's gross motor function is measured at 24 months to evaluate the primary outcome.
Secondary outcomes include assessments of motor function, neurological examinations, nerve conduction velocity, brain imaging, and neurocognitive assessments at multiple visits over time.
Step 4
Safety and efficacy evaluations
Safety and tolerability are monitored through adverse event reporting. This includes any side effects related to the conditioning regimen and other non-conditioning related events.
Hematological recovery is assessed by checking the reconstitution of absolute neutrophil count and bone marrow recovery by day 60 post-gene therapy.
Step 5
Long-term follow-up
Long-term follow-up includes monitoring for the absence of malignancy or abnormal clonal proliferation, and ensuring there is no replication competent lentivirus.
The trial is expected to continue until July 2025, with ongoing assessments to ensure the safety and effectiveness of the treatment.

Who can join the trial?

7 criteria

The patient must have a confirmed diagnosis of **Metachromatic Leukodystrophy (MLD)**. This is done by checking the activity of an enzyme called **ARSA**. If the activity is lower than normal and two specific changes (mutations) in the ARSA gene are found, the diagnosis is confirmed. If a new mutation is found, a 24-hour urine test must show high levels of a substance called **sulfatide**.
The patient must meet one of the following conditions:
- Have an older brother or sister with MLD who started showing symptoms at or before the age of 6. The patient will be classified based on the age when the sibling started showing symptoms and their ARSA gene type:
  - **Late Infantile (LI)**: Symptoms in the sibling started at or before 30 months of age; the ARSA gene type is usually 0/0.
  - **Early Juvenile (EJ)**: Symptoms in the sibling started after 30 months but at or before 6 years of age; the ARSA gene type is usually 0/R.
  - **Intermediate LI/EJ**: Symptoms in the sibling started at or before 6 years of age, but it is unclear if they are LI or EJ.
  - If the patient is diagnosed with MLD before showing symptoms and does not have an older sibling with MLD, the patient may still be eligible if they are diagnosed early (for example, through newborn screening) and are likely to benefit from gene therapy. The patient must be 6 years old or younger, and this must be approved by a medical monitor from Orchard Therapeutics.
  - The study is open to both male and female patients.
  - The study includes patients who may be considered vulnerable, meaning they might need extra care or protection.

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Verified sites

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Verified
Ospedale San Raffaele S.r.l.
Milan, Italy

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Investigated drugs

OTL200 is a treatment being studied for its effectiveness in treating early onset Metachromatic Leukodystrophy (MLD). It involves using a patient's own CD34+ cells, which are collected and then modified with a lentiviral vector that contains human ARSA cDNA. This process aims to correct the genetic defect causing MLD, potentially slowing or stopping the progression of the disease.

Atidarsagene Autotemcel

What is already known about the treatment

OTL200 – This medication is administered through a process involving the infusion of cryopreserved autologous CD34+ cells that have been genetically modified using a lentiviral vector containing human ARSA cDNA. It is currently being studied in clinical trials for its potential to treat early onset Metachromatic Leukodystrophy (MLD). The main therapeutic indication is to address the genetic deficiency causing MLD by introducing a functional copy of the ARSA gene into the patient's cells. At the molecular level, the mechanism of action involves the integration of the ARSA gene into the patient's genome, allowing for the production of the ARSA enzyme, which is deficient in individuals with MLD. This medication falls under the pharmacological classification of gene therapy.

Investigated diseases

Metachromatic Leukodystrophy (MLD) – Metachromatic Leukodystrophy is a rare genetic disorder that affects the nervous system. It is caused by a deficiency of the enzyme arylsulfatase A, leading to the accumulation of sulfatides, which are toxic to the nervous system. This accumulation results in the progressive destruction of the myelin sheath, the protective covering of nerve cells. As the disease progresses, individuals may experience a decline in motor skills, muscle weakness, and difficulties with coordination and balance. Cognitive functions may also be affected, leading to changes in behavior and mental abilities. The progression of symptoms can vary, but it typically worsens over time.