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

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ClinicalTrials.gov Identifier: NCT03392987
Recruitment Status : Recruiting
First Posted : January 8, 2018
Last Update Posted : May 20, 2019
Sponsor:
Collaborator:
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Information provided by (Responsible Party):
Orchard Therapeutics

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).

Condition or disease Intervention/treatment Phase
Lysosomal Storage Disease Metachromatic Leukodystrophy Genetic: OTL-200 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This will be a single arm study. All subjects will receive OTL-200 gene therapy and will be followed up for 8 years post-gene therapy.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Open Label, Clinical Study of Cryopreserved Autologous CD34+ Cells Transduced With Lentiviral Vector Containing Human ARSA cDNA (OTL-200), for the Treatment of Early Onset Metachromatic Leukodystrophy (MLD)
Actual Study Start Date : January 25, 2018
Estimated Primary Completion Date : August 22, 2022
Estimated Study Completion Date : August 23, 2028


Arm Intervention/treatment
Experimental: OTL-200 gene therapy
Eligible subjects will receive intravenous (IV) infusion of OTL-200 gene therapy. Subjects will also receive conditioning regimen with busulfan.
Genetic: OTL-200
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
Other Name: Previously GSK2696274




Primary Outcome Measures :
  1. Change in Gross Motor Function Measure (GMFM) score [ Time Frame: At 24 months post gene-therapy ]
    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.


Secondary Outcome Measures :
  1. Change in Gross Motor Function Measure (GMFM) score [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    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.

  2. Change in Gross Motor Function Classification (GMFC)-MLD score [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    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).

  3. Change in neurological examinations [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Neurological examinations will be performed to identify any signs and symptoms of MLD disease.

  4. Change in Nerve Conduction Velocity (NCV) [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    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.

  5. Change in total score for brain magnetic resonance (MR) imaging [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Brain MR will be assessed using modified Loes score where normal brain has a score of zero and increasing score reflects worsening disease and demyelination.

  6. Change in neurocognitive function (Intelligence Quotient [IQ]) [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Standardized, age-appropriate IQ tests will be administered.

  7. Engraftment measured by percent Lentiviral (LV) positive clonogenic progenitors in bone marrow [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    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).

  8. Vector copy number (VCN) level in bone marrow mononuclear cells [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Engraftment of transduced cells will be determined by measuring the VCN per genome in bone marrow-derived cells.

  9. VCN level in peripheral blood mononuclear cell (PBMCs) [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Engraftment of transduced cells will be determined by measuring the VCN per genome in PBMCs.

  10. Change in ARSA activity in total PBMCs [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Measured to assess the pharmacodynamic activity of GSK2696274 in circulating total PBMCs post-treatment.

  11. Change in ARSA activity in PB CD15+ cells [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Measured to assess the pharmacodynamic activity of GSK2696274 in circulating CD15+ cells post-treatment.

  12. Change in ARSA activity in PB CD14+ cells [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Measured to assess the pharmacodynamic activity of GSK2696274 in circulating CD14+ cells post-treatment.

  13. Change in ARSA activity in cerebrospinal fluid (CSF) [ Time Frame: At multiple visits up to 8 years post-gene therapy ]
    Measured to assess the pharmacodynamic activity of GSK2696274 in the CNS post-treatment.

  14. Safety and tolerability as measured by recording of adverse events (AEs) [ Time Frame: Up to 8 years post-gene therapy ]
    An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as an SAE.

  15. Safety and tolerability as measured by number of subjects not achieving hematological recovery by Day 60 (i.e., engraftment failure) [ Time Frame: By Day 60 post-gene therapy ]
    Hematological recovery will be defined as reconstitution of absolute neutrophil count (ANC ) > 500 neutrophils per microliter, associated with evidence of bone marrow recovery by Day 60.

  16. Safety and tolerability as measured by number of subjects with incidences and titers of antibodies against ARSA [ Time Frame: Up to 8 years post-gene therapy ]
    Serum samples will be collected for anti-ARSA antibody analysis.

  17. Safety and tolerability as measured by number of subjects with abnormal clonal proliferation (ACP) [ Time Frame: Up to 8 years post gene-therapy ]
    Malignancy or ACP due to insertional oncogenesis will be evaluated using different tests and procedures.

  18. Safety and tolerability as measured by number of subjects with replication competent lentivirus (RCL) [ Time Frame: Up to 8 years post gene-therapy ]
    Molecular monitoring of RCL will be carried out using enzyme-linked immunosorbent assay (ELISA) test for serum human immunodeficiency virus (HIV) p24 antigen, DNA PCR for vesicular stomatitis virus G (VSV-G) env, reverse transcription (RT)-PCR for serum HIV-pol ribonucleic acid (RNA) and anti-HIV p24 antibodies.



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Ages Eligible for Study:   up to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

    1. 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
    2. 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.

Exclusion Criteria:

  • Symptoms of MLD, defined as EITHER of the following:

    1. delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation OR
    2. documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioral functional impairment or regression (substantiated by neurological examination and/or neuropsychological tests appropriate for age).
  • 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.
  • Has symptomatic herpes zoster, not responsive to specific treatment. Subjects 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 i.e. QuantiFERON-TB Gold test and microbiological evidence. Subjects 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 subjects must be discussed and approved by the medical monitor.
  • Acute or chronic stable Hepatitis B 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 hepatitis B virus (HBV) DNA. Subjects with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative Hepatitis B surface antigen and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the medical monitor.
  • Presence of positive Hepatitis C RNA test result at screening; subjects who have previously tested positive for antibodies against 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/milliliter (IU/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 subjects 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 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03392987


Contacts
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Contact: Orchard Medical Information +44 (0) 20 3808 8286 medinfo@orchard-tx.com
Contact: Orchard Clinical Trials medinfo@orchard-tx.com

Locations
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Italy
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET) Recruiting
Milan, Italy, 20132
Contact: Orchard Clinical Trials         
Sponsors and Collaborators
Orchard Therapeutics
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Investigators
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Study Director: Orchard Clinical Trials Orchard Therapeutics

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Responsible Party: Orchard Therapeutics
ClinicalTrials.gov Identifier: NCT03392987     History of Changes
Other Study ID Numbers: 205756
2017-001730-26 ( EudraCT Number )
First Posted: January 8, 2018    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Orchard Therapeutics:
OTL-200
Cryopreserved formulation
Gene therapy
Metachromatic leukodystrophy
MLD
Previously GSK2696274

Additional relevant MeSH terms:
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Leukodystrophy, Metachromatic
Lysosomal Storage 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
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders