Evaluation of the Safety and Efficacy of Atidarsagene Autotemcel Infusion in Late Juvenile Metachromatic Leukodystrophy Patients
- Trial ID
- 2024-511971-13-00
- Protocol
- OTL-200-07
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **pharmacodynamic** effect of OTL-200 in the cerebrospinal fluid (CSF) and brain of patients with Late Juvenile Metachromatic Leukodystrophy (LJ MLD) compared to baseline. This is clinically relevant as it aims to assess the impact of the gene therapy on the central nervous system, which is crucial for understanding its potential therapeutic benefits in altering disease progression in MLD.
Secondary objectives include:
- Evaluating the pharmacodynamic effect of OTL-200 in bone marrow and peripheral blood, as well as on various brain metabolites in LJ MLD patients compared to baseline and/or siblings/untreated historical controls.
- Assessing the engraftment of OTL-200 in LJ MLD subjects.
- Evaluating the clinical efficacy of OTL-200 in LJ MLD subjects compared to baseline and/or siblings/untreated historical controls.
- Assessing the safety and tolerability of the hematopoietic stem cell gene therapy (HSPC-GT) procedure and OTL-200.
Participants
The clinical trial involves participants diagnosed with **Metachromatic Leukodystrophy (MLD)**, an autosomal recessive disorder. The study population includes both male and female subjects, with an age range of less than 17 years, encompassing both symptomatic individuals with disease onset between 7 and 17 years and pre-symptomatic individuals under 17 years of age. Participants are required to have normal cognitive function, defined by an IQ of 85 or higher, and either normal or mildly impaired gross motor function. The trial population is considered vulnerable, and the selection criteria include documented biochemical and molecular diagnosis of MLD, with specific genotypic requirements. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of a single infusion of OTL-200 in patients diagnosed with Late Juvenile Metachromatic Leukodystrophy (MLD). This is an open-label, non-randomized trial, categorized as a Phase 3b study. The primary objective is to assess the pharmacodynamic effect of OTL-200 in cerebrospinal fluid (CSF) and the brain, comparing post-treatment results to baseline levels. The trial is expected to run until January 2035, with recruitment having commenced in January 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as documented biochemical and molecular diagnosis of MLD and normal cognitive function. Following the screening, eligible participants will receive a single infusion of the investigational product, Libmeldy, which contains the active substance **atidarsagene autotemcel**. The infusion is administered intravenously as a dispersion for infusion. Subsequent follow-up visits will be scheduled to monitor the participants' response to the treatment, with primary endpoints including changes in ARSA activity levels in CSF and neuronal metabolite ratios in the brain over a 24-month period post-treatment.
The expected length of participant involvement in the trial is up to 96 months, with regular assessments to evaluate both primary and secondary endpoints, such as changes in neurocognitive function and brain MRI assessments. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of adverse events that compromise participant safety. The trial concludes with an end-of-study visit, where final assessments are conducted to gather comprehensive data on the long-term effects of the treatment.
Treatment
The clinical trial involves the administration of **Libmeldy**, a dispersion for infusion containing the active substance **atidarsagene autotemcel**. This experimental medication is designed for the treatment of Late Juvenile Metachromatic Leukodystrophy (MLD). Libmeldy is formulated as a dispersion for infusion, with a concentration of 2-10 x 10^6 cells/mL. The route of administration is **intravenous use**, and the maximum total dose is 30,000,000 cells per kilogram of body weight. The treatment period is limited to a maximum of 96 weeks. The active substance, atidarsagene autotemcel, is a structurally diverse substance used in cell therapy, specifically targeting the human arylsulfatase A (ARSA) cDNA through lentiviral vector-mediated gene transfer into haematopoietic stem cells. This product is classified as an orphan drug and is not a pediatric formulation.
In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the safety and efficacy of the single infusion of OTL-200, which is the investigational name for Libmeldy. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial is open-label and non-randomized, aiming to assess the pharmacodynamic effects of OTL-200 in the cerebrospinal fluid (CSF) and brain of subjects with Late Juvenile MLD compared to baseline measurements.
Efficacy
Efficacy in the clinical trial evaluating the safety and efficacy of a single infusion of OTL-200 in patients with Late Juvenile Metachromatic Leukodystrophy (MLD) will be assessed using specific pharmacodynamic endpoints. The co-primary efficacy endpoints include the change in **ARSA** activity levels in cerebrospinal fluid (CSF) from baseline to 24 months post-treatment, and the change in the neuronal metabolite ratio NAA:Cr in white matter regions of interest in the brain over the same period. Secondary endpoints encompass a range of measures, including changes in CSF ARSA, neuronal metabolite ratios, ARSA in PBMC, CD14+ & CD15+, and engraftment. Additional secondary measures include VCN in bone marrow and PBMC, changes in severity scale for brain MRI assessments, neurocognitive function, and GMFC-MLD. The trial will also monitor conditioning-related toxicity, non-conditioning adverse events, hematological reconstitution, incidence of infusion-related reactions, and the presence and titers of ARSA antibodies. The absence of replication-competent lentivirus (RCL) and other site analysis findings will also be evaluated. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, which is estimated to conclude by January 2035.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1.Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease causing ARSA alleles. Novel mutations will be analysed with in silico prediction tool 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. 2. O/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD. 3. a) if symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. before their 17th birthday) OR b) if pre-symptomatic: subject must be <17 years of age at treatment (i.e before their 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLD variant based on age at disease onset (≥7 and <17 years of age i.e before sibling's 17th birthday), with biochemical and molecular diagnosis. 4. Normal cognitive function as defined by an IQ≥ 85 on age appropriate cognitive scales. 5.a) If the subject is <7 years age (i.e before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and normal neurological examination (if applicable based on the age of the subject, GMFC-MLD =0) OR b) If the subject is ≥ 7 years, normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e subject is able to walk independently). NOTE: The following will not be exclusionary if present alone: i.Seizures ii.Signs of the disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MRI) 6. If applicable, subject willing and capable of compliance with contraceptive requirements as detailed further in Protocol Section 7.1. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 7. Subject (or if applicable, parent/legal guardian) providing signed informed consent or assent if applicable as described in Section 17.4 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion Criteria
- Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies). 2.Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Orchard-MM. 3.Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders. 4.Subjects currently enrolled in other interventional trials. 5.Has previously undergone allogeneic HSCT and has evidence of residual cells of donor origin. 6.Previous gene therapy. 7.Has symptomatic herpes zoster, not responsive to specific treatment. 8.Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON-TB Gold test and microbiological evidence. 9.Acute or chronic stable Hepatitis B (HBV) as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to onset of conditioning and/or positive HBV DNA. 10.Presence of positive Hepatitis C RNA test result at screening. 11.End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgement of the investigator, would make the subject inappropriate for entry into this study. 12. In addition to the potential infections tested per protocol, the PI should consider testing for other transmissible infectious agents listed in the EU Cell and Tissue Directive as clinically appropriate and results must be discussed with the Orchard-MM prior to stem cell harvest. 13. Subjects with alanine transferase (ALT) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN may be included only after discussed and agreed with the Orchard-MM and considered in the context of the criterion for excluding subjects with other severe disease. Isolated elevation of total bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Jan 2022 | 6 |
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 | INTRAVENOUS USE | 30000000 | 96 | PRD8611603 |