Evaluation of Cryopreserved Autologous CD34+ Cells Transduced with Lentiviral Vector ARSA cDNA for Early Onset Metachromatic Leukodystrophy Treatment
- Trial ID
- 2024-511970-66-00
- Protocol
- 205756
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical study is to evaluate the **clinical efficacy** of the cryopreserved formulation of OTL-200 in patients with early onset **Metachromatic Leukodystrophy (MLD)**. This is clinically relevant as MLD is a severe genetic disorder that affects the nervous system, and effective treatments are limited. The study aims to assess whether the cryopreserved formulation can provide therapeutic benefits in managing the disease.
Secondary objectives include:
- Evaluating the clinical efficacy of the cryopreserved formulation of OTL-200 through other endpoints.
- Assessing the engraftment of the cryopreserved formulation of OTL-200.
- Evaluating the pharmacodynamic effect of the cryopreserved formulation of OTL-200.
- Assessing the safety and tolerability of the cryopreserved formulation of OTL-200.
Participants
The clinical trial involves participants diagnosed with **Metachromatic Leukodystrophy (MLD)**, a rare genetic disorder. The study population includes both male and female subjects, with an age range primarily focused on children under 6 years old. The trial population is considered vulnerable due to the young age and the nature of the disease. Participants were selected based on a documented biochemical and molecular diagnosis of MLD, characterized by ARSA activity below the normal range and the presence of two disease-causing ARSA alleles. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet and physical activity are not specified, but the inclusion criteria emphasize the early onset of symptoms or a pre-symptomatic diagnosis in children likely to benefit from gene therapy. The trial aims to evaluate the clinical efficacy of the cryopreserved formulation of OTL200.
Plans and Procedures
The clinical trial is designed as a **single-arm, open-label** study to evaluate the clinical efficacy of a cryopreserved formulation of OTL-200 in patients with early onset **Metachromatic Leukodystrophy (MLD)**. The trial involves the administration of autologous CD34+ cells transduced with a lentiviral vector containing human ARSA cDNA. The study is not categorized as low intervention and is classified as a Phase III trial. The trial is expected to run from December 1, 2017, to July 8, 2025, with the primary endpoint being the Gross Motor Function Measure (GMFM) score at 24 months post-gene therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on documented biochemical and molecular diagnosis of MLD. The inclusion criteria require ARSA activity below the normal range and identification of two disease-causing ARSA alleles. Eligible participants must either have an older sibling affected by MLD or be diagnosed pre-symptomatically with a strong suggestion of early onset MLD. The study will include multiple follow-up visits to assess secondary endpoints, such as GMFM scores, clinical efficacy, and safety measures, including adverse events and hematological recovery.
The expected length of participant involvement is approximately 24 months, with regular assessments to monitor the efficacy and safety of the treatment. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or failure to meet the study's safety criteria. The study aims to provide comprehensive data on the efficacy and safety of the gene therapy, with secondary endpoints including assessments of neurological function, nerve conduction velocity, brain MRI parameters, and ARSA activity in various biological samples.
Treatment
The clinical trial involves the administration of **Libmeldy**, a dispersion for infusion containing **atidarsagene autotemcel** as the active substance. This investigational medicinal product is formulated as a dispersion for infusion and is administered via **direct intravenous injection**. The dosage of Libmeldy is specified as 2-10 x 10^6 cells/mL, with a maximum daily dose and total dose amounting to 30,000,000 cells per kilogram of body weight. The treatment period is limited to a single administration. The active substance, atidarsagene autotemcel, is a structurally diverse substance used in cell therapy, specifically targeting somatic cells and hematopoietic stem cells. The gene of interest in this therapy is the Human Arylsulfatase A (ARSA) gene, delivered via a lentiviral vector. This product is not a pediatric formulation and has been designated as an orphan drug.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is designed as a single-arm, open-label study, focusing on the treatment of early-onset Metachromatic Leukodystrophy (MLD). Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The investigational product is manufactured by Orchard Therapeutics (Netherlands) B.V., and the trial aims to evaluate the clinical efficacy of the cryopreserved formulation of OTL200.
Efficacy
Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the Gross Motor Function Measure (GMFM) score evaluated at 24 months post-gene therapy. This measure will provide a quantitative assessment of motor function improvement in patients with early onset **Metachromatic Leukodystrophy (MLD)**.
Secondary endpoints include a range of clinical and laboratory assessments conducted at multiple timepoints post-gene therapy. These include the Gross Motor Function Classification (GMFC)-MLD score, neurological examinations, nerve conduction velocity (NCV) assessments, and brain magnetic resonance imaging (MRI) parameters such as the Modified Loes Score. Neurocognitive assessments will also be performed to evaluate broader neurological function.
Additional laboratory measures will include the percentage of lentivirus (LV) positive clonogenic progenitors in bone marrow at Day 30, vector copy number (VCN) in bone marrow mononuclear cells at Day 30, and VCN in peripheral blood mononuclear cells at Day 60. Arylsulfatase A (ARSA) activity will be measured in total peripheral blood mononuclear cells, CD15+ cells, CD14+ cells at Day 60, and in cerebral spinal fluid at Day 90. These assessments will be conducted at multiple visits over time to monitor the persistence and efficacy of the gene therapy.
Safety and tolerability will be monitored through adverse event reporting, including conditioning regimen-related toxicity and non-conditioning related adverse events. Hematological recovery, incidence and titers of antibodies against ARSA, absence of malignancy or abnormal clonal proliferation due to insertional oncogenesis, and absence of replication competent lentivirus (RCL) will also be evaluated as part of the efficacy and safety assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles, either known or novel mutations. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
- Eligible participants must have EITHER: a) an older sibling affected by MLD (index case), whose age of symptom onset was ≤6 years of age (i.e. had not celebrated 7th birthday). Participants will be classified as Late Infantile, Early Juvenile or Intermediate LI/EJ based on age of symptom onset in the index case and their ARSA genotype: i. LI: symptom onset in index case ≤30 months of age; genotype typically 0/0 ii. EJ: symptom onset in index case >30 months and ≤6 years of age; genotype typically 0/R iii. Intermediate LI/EJ: symptom onset in index case ≤6 years of age but unable to unambiguously characterize index case as LI or EJ OR b) If MLD is diagnosed in a pre-symptomatic child without an older affected sibling, (e.g. incidentally or via newborn screening) and the totality of the data available to the investigator strongly suggest that the patient has an early onset variant of MLD likely to benefit from gene therapy, and the patient is ≤6 years of age (i.e. has not celebrated 7th birthday), the patient may be considered eligible after discussion and approval by the Orchard Therapeutics (Europe) Ltd. Medical Monitor (Orchard-MM)
Exclusion Criteria
- If LI MLD variant, clinical manifestations of the disease defined as EITHER of the following: i. Delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation OR ii. Documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioral functional impairment or regression (substantiated by neurological examination and/or neuropsychological tests appropriate for age)
- If EJ MLD variant, symptoms of MLD resulting in the loss of capacity of walking independently as defined by a GMFC level ≥2 or symptoms consistent with cognitive impairment as defined by an IQ<85 using age-appropriate neurocognitive instruments
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Dec 2017 | 10 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Libmeldy 2-10 x 10^6 cells/mL dispersion for infusion | Test | DISPERSION FOR INFUSION | DIRECT INTRAVENOUS INJECTION | 30000000 | 1 | PRD8611603 |