A clinical trial to evaluate the effect of OTL-200, a gene therapy treatment in patients with Late Juvenile (LJ) Metachromatic Leukodystrophy (MLD)

Phase 1

Conditions: Metachromatic Leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations
MedDRA version: 20.0Level: PTClassification code: 10067609Term: Metachromatic leukodystrophy Class: 100000004850
Therapeutic area: Phenomena and Processes [G] - Genetic Phenomena [G05]

Registration Number: CTIS2024-511971-13-00

Lead Sponsor: Orchard Therapeutics (Europe) Limited

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 6

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

1. 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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the pharmacodynamic effect of OTL-200 in CSF and the brain of subject LJ MLD subjects as compared to baseline.;Secondary Objective: - To evaluate the pharmacodynamic effect of OTL-200 in peripheral blood and on various brain metabolites in LJ MLD subjectsas compared to baseline, siblings and/or untreated historical controls -To evaluate engraftment of OTL-200 -To evaluate the clinical efficacy of OTL-200 in LJ MLD subjects as compared to baseline, untreated historical controls or siblings -To evaluate the safety and tolerability of the HSPC-GT procedure and OTL-200;Primary end point(s): Co-primary pharmacodynamic efficacy endpoints: •Change in ARSA activity levels in CSF from baseline to 24 months post treatment. •Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain from baseline to 24 months post-treatment.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):Change in CSF ARSA, Change in neuronal metabolite ratio, Change in ARSA in PBMC, CD14+ & CD15+, Engraftment, VCN in BM & PBMC, Change in severity scale for brain MRI assessments, Change in neurocog function, Full NCE, Change in GMFC-MLD, Change in NCV, Conditioning related toxicity/AEs, Non-conditioning related AEs, Hematological reconstitution, Incidence of infusion related reactions, Incidence & titers of ARSA antibodies, Abnormal clonal proliferation, Absence of RC

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