A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)

NCT03392987 | Completed Phase 2

• 2 other identifiers: 2057562017-001730-26
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

OTL-200 is autologous CD34+ cells transduced with lentiviral vector containing human arylsulfatase A (ARSA) complementary deoxyribonucleic acid (cDNA) used for the treatment of MLD. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. This study will assess safety and efficacy of treatment using cryopreserved formulation of OTL-200 in pediatric subjects with pre-symptomatic Early Onset MLD (Late Infantile (LI) to Early Juvenile (EJ) MLD) and early symptomatic EJ MLD.

Conditions

Metachromatic Leukodystrophy; Lysosomal Storage Disease

Keywords

OTL-200; Cryopreserved formulation; Gene therapy; Metachromatic leukodystrophy; MLD; Previously GSK2696274

Outcome Measures

Primary Outcomes (1)

• Change in Gross Motor Function Measure (GMFM) score

  GMFM will evaluate subject's ability to perform specific tasks in different positions. The scoring range is between 100 percent and 0 percent, with 0 percent corresponding to loss of all voluntary movement.

  At 24 months post gene-therapy

Secondary Outcomes (18)

• Change in Gross Motor Function Measure (GMFM) score

  At 24 months and multiple visits up to 5 years post-gene therapy

• Change in Gross Motor Function Classification (GMFC)-MLD score

  At 24 months and multiple visits up to 5 years post-gene therapy

• Change in neurological examinations

  At 24 months and multiple visits up to 5 years post-gene therapy

• Change in Nerve Conduction Velocity (NCV)

  At 24 months and multiple visits up to 5 years post-gene therapy

• Change in total score for brain magnetic resonance (MR) imaging

  At 24 months and multiple visits up to 5 years post-gene therapy

Study Arms (1)

OTL-200 gene therapy

EXPERIMENTAL

Eligible subjects will receive intravenous (IV) infusion of OTL-200 gene therapy. Subjects will also receive conditioning regimen with busulfan.

Genetic: OTL-200

Interventions

OTL-200 GENETIC

OTL-200 is an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with lentiviral vector that encodes for the human ARSA cDNA sequence

Also known as: Previously GSK2696274

OTL-200 gene therapy

Eligibility Criteria

• Age: Up to 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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 subjects must have EITHER
• 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). Subjects will be classified as LI, EJ or intermediate LI/EJ based on age of symptom onset in the index case and their ARSA genotype; LI: symptom onset in index case \<=30 months of age and genotype typically 0/0; EJ: symptom onset in index case \>30 months and \<= 6 years of age with genotype typically 0/R; Intermediate LI/EJ: symptom onset in index case \<= 6 years of age but unable to unambiguously characterize index case as LI or EJ OR
• 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 subject has an early onset variant of MLD likely to benefit from gene therapy, and the subject is \<=6 years of age (i.e., has not celebrated 7th birthday), the subject may be considered eligible after discussion and approval by the Orchard medical monitor.
• Parental/guardian signed and dated informed consent.

You may not qualify if:

• If LI MLD variant, clinical manifestations of the disease defined as EITHER of the following:
• delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation
• Or documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioural 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.
• Seizures
• Signs of the disease revealed at instrumental evaluations (Electroneurography \[ENG\] and brain MR)
• Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
• Malignant neoplasia (except local 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 Medical monitor.
• Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), or other serious hematological disorders.
• Subjects currently enrolled in other interventional trials.
• Has previously undergone allogeneic hematopoietic stem cell transplantation 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 subject inappropriate for entry into this study. In addition to the potential infections 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 discussed with the medical monitor prior to cell harvest.
• 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 medical monitor 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 percent 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

Related Publications (1)

• Fumagalli F, Calbi V, Gallo V, Zambon AA, Recupero S, Ciotti F, Sarzana M, Fraschini M, Scarparo S, De Mattia F, Miglietta S, Pierini C, Soncini M, Morena F, Montini E, Barzaghi F, Consiglieri G, Ferrua F, Migliavacca M, Tucci F, Fratini ES, Ippolito A, Silvani P, Calvi MR, Clerici A, Corti A, Facchini M, Locatelli S, Sangalli M, Zancan S, Miotto F, Natali Sora MG, Baldoli C, Martino S, Cordoba-Claros A, Moro SL, Gollop ND, Abate J, Yarzi MN, Nutkins P, Shenker A, Calissano M, Brooks J, Richardson A, Campbell L, Filippi M, Naldini L, Cicalese MP, Ciceri F, Bernardo ME, Aiuti A. Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy. N Engl J Med. 2025 Apr 24;392(16):1609-1620. doi: 10.1056/NEJMoa2405727.

  PMID: 40267426 DERIVED

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 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This will be a single arm study. All subjects will receive OTL-200 gene therapy and will be followed up for 5 years post-gene therapy.

Study Record Dates

• First Submitted: December 12, 2017
• First Posted: January 8, 2018
• Study Start: January 25, 2018
• Primary Completion: April 6, 2022
• Study Completion: March 10, 2026
• Last Updated: March 16, 2026

Record last verified: 2025-01

Locations

IT (1)