A Study to Investigate the Efficacy and Safety of OTL-203 in Subjects With MPS-IH Compared With Standard of Care With Allogeneic HSCT

Study Overview
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Brief Summary
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A multi-center randomized clinical trial to compare OTL-203 (gene therapy) with stem cell transplant (standard of care) in patients with MPS-IH (Hurler syndrome).

Detailed Description
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The study is a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL-203 in patients with mucopolysaccharidosis type I, Hurler syndrome (MPS-IH) compared to standard of care with allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 40 patients with a confirmed diagnosis of MPS-IH who meet the study inclusion criteria will be randomized to receive either OTL-203 or allo-HSCT. The trial will comprise of a screening, baseline, and treatment period, with a follow-up period of 5 years post-treatment, and primary analysis performed at 2 years follow-up of the last treated subject.

Official Title
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A Multi-center, Randomized, Active Controlled Clinical Trial to Evaluate the Efficacy and Safety of OTL-203 in Subjects With Mucopolysaccharidosis Type I, Hurler Syndrome (MPS-IH) Compared to Standard of Care With Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

Conditions
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MPS-IH (Hurler Syndrome)

Intervention / Treatment
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* Genetic: Experimental: OTL-203
* Genetic: Active Comparator: Allo-HSCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Norm-referenced cognitive standard score of ≥70 measured by age-appropriate cognitive domains of either Bayley Scale of Infant Development (BSID)-III or Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-IV Confirmed laboratory diagnosis of MPS-IH as demonstrated by biallelic mutation(s) in the gene coding for IDUA enzyme Final confirmation of MPS-IH diagnosis by a Diagnostic Review Committee (DRC) Exclusion Criteria: Previous allo-HSCT or gene therapy Current enrollment or past treatment in any other interventional study/trial using a novel investigational agent Positivity to serological testing for Human Immunodeficiency Virus (HIV)-1 or HIV-2, Human T Lymphotropic Virus (HTLV)-1 or HTLV-2, Hepatitis B Virus (HBV) core, Hepatitis C Virus (HCV), mycoplasma, active tuberculosis (TB) and not meeting the microbiology biological screening requirements for drug product (DP) manufacturing. Malignant neoplasia (except local skin cancer) Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) History of uncontrolled seizures Subjects with an active infection not responsive to treatment, end-organ damage, or any other disease that contraindicates performance of any of the procedures detailed in the protocol, or medical conditions or extenuating circumstances that, in the opinion of the Investigator, might compromise the subject's well-being or safety, or the interpretability of the subject's clinical data. Subjects, who in the opinion of the Investigator, may not be able to comply with protocol requirements or cooperate fully with the study procedures and necessary long- term follow up

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 30 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OTL-203<br>Eligible subjects randomized to Arm 1 will receive an intravenous (IV) infusion of OTL-203 gene therapy. Subjects will receive conditioning regimen with busulfan and fludarabine prior to OTL-203 infusion. | Genetic: Experimental: OTL-203<br>* Experimental: OTL-203: Autologous CD34+ enriched cell fraction that contains hematopoietic stem and progenitor cells transduced ex vivo using lentiviral vector encoding the human IDUA gene<br>|
| Active Comparator: Allo-HSCT<br>Eligible subjects randomized to Arm 2 will receive allogeneic hematopoietic stem cell transplantation. Subjects will receive conditioning regimen with busulfan and fludarabine prior to allo-HSCT. | Genetic: Active Comparator: Allo-HSCT<br>* Active Comparator: Allogeneic hematopoietic stem cell transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Defined by events of death, rescue transplant, treatment failure, immunological complications, severe cognitive and/or growth impairment. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Year 2 in α-L-iduronidase (IDUA) activity in leukocytes | IDUA activity in leukocytes will be used to measure post-treatment systemic correction of the biochemical defect that causes the disease | Day 30 and multiple visits up to 5 years post-treatment | 
| Change from baseline to Year 2 in urinary heparan sulfate levels, defined as ratio to the upper limit of normal | Urinary heparan sulfate levels will be used to measure post-treatment clearance of glycosaminoglycans accumulated within tissues and organs due to IDUA enzymatic deficiency | Day 30 and multiple visits up to 5 years post-treatment | 
| Safety of OTL-203 compared to allo-HSCT procedure | Measured by Overall incidence of adverse events (AEs) whether or not considered related to the study treatment, including conditioning regimen-related AEs, Study Procedure-related AEs, Disease-related AEs, Treatment related AEs, Serious adverse events (SAEs) | Up to 5 years post-treatment | 
| Malignancy or abnormal clonal proliferation (ACP) using different tests and procedures (e.g., general clinical evaluation, blood counts, and specialized assessments such as integration site analysis). | Malignancy or ACP due to insertional oncogenesis will be evaluated in subjects treated with OTL-203. | Up to 5 years post-treatment | 
| Replication Competent Lentivirus (RCL) | Presence of RCL will be evaluated in subjects treated with OTL-203 | Up to 5 years post-treatment | 
| Immune response against IDUA enzyme | Anti-IDUA antibodies analysis will be evaluated in all subjects. | Up to 5 years post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPS-IH, Hurler, MPS-I, Mucopolysaccharidoses, Mucopolysaccharidosis type I, Hurler syndrome, Mucopolysaccharidosis IH, Gene Therapy, Transplantation, Autologous Lentiviral vector