OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)

NCT04283227 | Active Not Recruiting Phase 3

• 1 other identifier: OTL-200-07
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

OTL-200 is a cryopreserved dispersion for infusion containing autologous CD34+ cell enriched population that contains haematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. The aim of this clinical study is to assess the pharmacodynamic effect and long-term clinical efficacy and safety of OTL-200 in Late Juvenile MLD patients.

Conditions

Lysosomal Storage Diseases; Metachromatic Leukodystrophy

Keywords

OTL-200; Cryopreserved formulation; Gene therapy; MLD; late juvenile; atidarsagene autotemcel

Outcome Measures

Primary Outcomes (2)

• Evaluation of OTL-200 Arylsulfatase A (ARSA) activity levels in Cerebrospinal Fluid (CSF)

  Change from baseline in ARSA activity levels in CSF

  24 months after treatment

• Evaluation of OTL-200 on the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of the brain

  Change from baseline in neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of interest of the brain

  24 months after treatment

Secondary Outcomes (23)

• Change in ARSA activity levels in CSF from baseline

  multiple visits up to 8 years post gene-therapy

• Change from baseline in neuronal metabolite ratio of NAA: Cr in white matter regions of interest of the brain

  multiple visits up to 8 years post gene-therapy

• Change from baseline in ARSA levels in total peripheral blood mononuclear cells (PBMCs)

  24 months and multiple visits up to 8 years post gene-therapy

• Change from baseline in ARSA levels in PB CD14+

  24 months and multiple visits up to 8 years post gene-therapy

• Change from baseline in ARSA levels in PB CD15+

  24 months and multiple visits up to 8 years post gene-therapy

Study Arms (1)

OTL-200 Gene Therapy

EXPERIMENTAL

OTL-200 is an autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene.

Genetic: OTL-200

Interventions

OTL-200 GENETIC

All subjects will receive OTL-200 gene therapy and will be followed up for 8 years following treatment with OTL-200.

OTL-200 Gene Therapy

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All the following criteria need to be met:
• 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 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.
• /R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.
• 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: participant 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.
• Normal cognitive function as defined by an IQ≥85 on age appropriate cognitive scales.
• a) If the participant is \<7 years (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 participant is ≥7 years: normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e. patient is able to walk independently).
• If applicable, participant willing and capable of compliance with contraceptive use requirements.
• Participant (or if applicable, parent/legal guardian) providing signed informed consent or assent as applicable

You may not qualify if:

• Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
• Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. Participants 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 Medical Monitor.
• Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.
• Patients currently enrolled in other interventional trials
• Has previously undergone allogeneic HSPC gene therapy (HSPC-GT) and has evidence of residual cells of donor origin.
• Previous gene therapy.
• End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
• In addition to the potential infections tested per protocol, the PI should consider testing for other transmissible infectious agents listed in the European Union (EU) Cell and Tissue Directive as clinically appropriate and results must be discussed with the Orchard medical monitor prior to stem cell harvest.
• Participants 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 medical monitor and considered in the context of the criterion for excluding participants with other severe disease. Isolated elevation of total bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35% of total.

Sponsors & Collaborators

• Orchard Therapeutics: lead
• Ospedale San Raffaele: collaborator

Study Sites (1)

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Milan, 20132, Italy

Location

MeSH Terms

Conditions

Lysosomal Storage Diseases; Leukodystrophy, Metachromatic

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders

Study Officials

• Orchard Clinical Trials

  Orchard Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: All eligible subjects will receive intravenous (IV) infusion of OTL-200 gene therapy. Subjects will also receive conditioning regimen with busulfan.

Study Record Dates

• First Submitted: February 13, 2020
• First Posted: February 25, 2020
• Study Start: January 17, 2022
• Primary Completion: January 31, 2026
• Study Completion (Estimated): March 31, 2031
• Last Updated: September 5, 2025

Record last verified: 2025-08

Locations

IT (1)