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

An Open Label, Non-randomized Trial to Evaluate the Safety and Efficacy of a Single Infusion of OTL-200 in Patients With Late Juvenile (LJ) Metachromatic Leukodystrophy (MLD).

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lysosomal Storage Diseases; Metachromatic Leukodystrophy
• Intervention / Treatment: Genetic: OTL-200

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Orchard Clinical Trials; Phone Number: +44 (0) 20 3808 8286; Email: medinfo@orchard-tx.com
• Study Contact Backup: Name: Orchard Clinical Trials; Email: medinfo@orchard-tx.com

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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.
• 0/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).

NOTE: The following will not be exclusionary if present alone: 1.) Seizures 2.) Signs of the disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MR)

• 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

Exclusion Criteria:

• 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.
• Has symptomatic herpes zoster, not responsive to specific treatment. NOTE: Participants with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the Medical Monitor.
• Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing. Participants with latent tuberculosis, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such participants must be discussed and approved by the Medical Monitor.
• 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. NOTE: Participants with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such participants must be discussed and approved by the Medical Monitor.
• Presence of positive Hepatitis C RNA test result at screening. NOTE: Patients who have previously tested positive for antibodies to hepatitis C can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of ≤15 international units/ml. Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for Hepatitis C, with the final test conducted no more than 3 days prior to cell harvest. Inclusion, monitoring and treatment of hepatitis in such participants must be discussed and approved by the Medical Monitor.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OTL-200 Gene Therapy; 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; All subjects will receive OTL-200 gene therapy and will be followed up for 8 years following treatment with OTL-200.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ARSA activity levels in CSF from baseline	Measured to assess the pharmacodynamic activity of OTL-200 in the Central Nervous System (CNS) post-treatment	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	Measured to assess the pharmacodynamic activity of OTL-200 in neuronal metabolite ratio of NAA to Cr in white matter regions of interest of the brain post-treatment	multiple visits up to 8 years post gene-therapy
Change from baseline in ARSA levels in total peripheral blood mononuclear cells (PBMCs)	Measured to assess the pharmacodynamic activity of OTL-200 in circulating total PBMCs post-treatment	24 months and multiple visits up to 8 years post gene-therapy
Change from baseline in ARSA levels in PB CD14+	Measured to assess the pharmacodynamic activity of OTL-200 in circulating CD14+ post-treatment	24 months and multiple visits up to 8 years post gene-therapy
Change from baseline in ARSA levels in PB CD15+	Measured to assess the pharmacodynamic activity of OTL-200 in circulating CD15+ post-treatment	24 months and multiple visits up to 8 years post gene-therapy
Neuronal metabolite ratios as compared to baseline, siblings and/or untreated historical controls (may include but not limited to Cho:Cr, mIns:Cr, Lac: Cr, Cho: NAA, NAA: H2O, Cho: H2O, mIns: H2O, Lac: H2O) in white matter regions of interest	Measured to assess the pharmacodynamic activity of OTL-200 in neuronal metabolite ratios in white matter regions of interest of the brain post-treatment compared to siblings and/or untreated historical controls	24 months and multiple visits up to 8 years post gene-therapy
Engraftment as measured by percent lentiviral positive (%LV+) in bone marrow (BM) progenitors	Engraftment of transduced cells will be determined by measuring the percentage of hematopoietic colony-forming cells harboring the integrated vector by quantitative polymerase chain reaction (qPCR).	At D30 and multiple visits up to 8 years post gene-therapy
Vector copy number (VCN) in BM mononuclear cells	Engraftment of transduced cells will be determined by measuring the VCN per genome in BM-derived cells.	At D30 and multiple visits up to 8 years post gene-therapy
VCN in Peripheral blood PBMCs	Engraftment of transduced cells will be determined by measuring the VCN per genome in PBMCs.	At D60 and multiple visits up to 8 years post gene-therapy
Change in severity scale for brain magnetic resonance imaging (MRI)	Brain MRI will be assessed using modified Loes Score and demyelination load on T1w, T2w and FLAIR imaging.	24 months and multiple visits up to 8 years post gene-therapy
Change in neurocognitive function	Neurocognitive assessments will use Bayley Scale of Infant and Toddler Development (BSID), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC), or Wechsler Adult Intelligence Scale (WAIS) according to the age of the participant to encompass performance, verbal, full scale IQ measures, processing speed and working memory indices	24 months and multiple visits up to 8 years post gene-therapy as compared to baseline
Change in full neurological clinical examination (NCE)	Neurological examinations will be performed to evaluate the effect of OTL-200 on the onset or progression of MLD disease.	24 months and multiple visits up to 8 years post gene-therapy
Change in Gross Motor Function Classification (GMFC)-MLD	GMFC-MLD will evaluate the change in motor function according to seven clinically relevant levels of walking, sitting, locomotion, trunk and head control. The scoring range is from 0 (walking without support with quality of performance normal for age) to 6 (loss of any locomotion as well as loss of any head and trunk control).	24 months and multiple visits up to 8 years post gene-therapy
Change in NCV	NCV will be assessed by electroneurography which is a technique used to test and quantify the nerve conduction and impulse propagation along motor and sensory peripheral nerves.	24 months and multiple visits up to 8 years post gene-therapy
Vineland Adaptive Behavior Scale (VABS)	VABS will assess the individual's ability to undertake daily activities appropriate for their age group.	24 months and multiple visits up to 8 years post gene-therapy
Conditioning regimen related toxicity and AEs	To evaluate the safety and tolerability of the HSPC GT procedure.	up to 8 years post gene-therapy
Non-conditioning related AEs	To evaluate the safety and tolerability of OTL-200.	up to 8 years post gene-therapy
Hematological reconstitution	Hematological reconstitution defined as absolute neutrophil count [ANC] ≥ 500/µL and platelet count ≥20,000 platelets/μL with associated evidence of BM recovery	By Day 60 post-gene therapy
Incidence of infusion related reactions	To evaluate the safety and tolerability of the HSPC GT procedure.	up to 8 years post gene-therapy
Immune response (e.g. anti-ARSA antibodies)	Plasma samples will be collected for anti-ARSA antibody analysis	up to 8 years post gene-therapy
Abnormal Clonal Proliferation (ACP)	Malignancy or ACP due to insertional oncogenesis will be evaluated using different tests and procedures.	up to 8 years post gene-therapy
Replication Competent Lentivirus (RCL	Molecular monitoring of RCL will be assessed via enzyme-linked immunosorbent assay (ELISA) test for serum human immunodeficiency virus (HIV) p24 antigen. A positive HIV p24 test result is subject to second level testing including: a) DNA PCR for vesicular stomatitis virus G (VSV-G) envelope (PBMC), and b) reverse transcription (RT)-PCR for serum HIV-pol ribonucleic acid (RNA) (plasma).	baseline, 1, 3, 6, and 12 months, then once a year up to 8 years post gene-therapy
Integration Site analysis findings	Detailed analysis of LV integrations will be performed on PB and BM cells, to monitor the nature and distribution of Integration Sites	6, 12 months, then once a year up to 8 years post gene-therapy

Collaborators and Investigators

• Sponsor: Orchard Therapeutics
• Collaborators: Ospedale San Raffaele
• Investigators: Study Director: Orchard Clinical Trials, Orchard Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2022
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): March 31, 2031

Study Registration Dates

• First Submitted: February 13, 2020
• First Submitted That Met QC Criteria: February 24, 2020
• First Posted (Actual): February 25, 2020

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Gene therapy; OTL-200; Cryopreserved formulation; MLD; late juvenile; atidarsagene autotemcel
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Leukoencephalopathies; Hereditary Central Nervous System Demyelinating Diseases; Sulfatidosis; Lysosomal Storage Diseases; Leukodystrophy, Metachromatic
• Other Study ID Numbers: OTL-200-07

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No