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

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)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: MPS-IH (Hurler Syndrome)
• Intervention / Treatment: Genetic: Experimental: OTL-203; Genetic: Active Comparator: Allo-HSCT

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20131
    • Ospedale San Raffaele
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • UMC Utrecht
  • Utrecht, Netherlands, 3584 CS
    • Princess Máxima Center
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Manchester University NHS Foundation Trust Blood and Marrow Transplant Programme, Royal Manchester Children's Hospital
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Pediatrics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Confirmed laboratory diagnosis of MPS-IH as demonstrated by biallelic mutation(s) in the gene coding for IDUA enzyme
3. Final confirmation of MPS-IH diagnosis by a Diagnostic Review Committee (DRC).

Exclusion Criteria:

1. Previous allo-HSCT or gene therapy
2. Current enrollment or past treatment in any other interventional study/trial using a novel investigational agent and/or treated with prohibited medications listed in the protocol
3. 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.
4. Malignant neoplasia (except local skin cancer).
5. Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
6. History of uncontrolled seizures
7. 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.
8. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OTL-203; 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; 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
Active Comparator: Allo-HSCT; 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; Active Comparator: Allogeneic hematopoietic stem cell transplantation

What is the study measuring?

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
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
Change from baseline to Year 2 in the ratio to the upper limit of normal (ULN) of urinary heparan sulfate levels	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

Collaborators and Investigators

• Sponsor: Orchard Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: November 17, 2023
• First Submitted That Met QC Criteria: November 27, 2023
• First Posted (Actual): November 29, 2023

Study Record Updates

• Last Update Posted (Actual): December 22, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Gene Therapy; Transplantation; Mucopolysaccharidoses; Hurler; Hurler syndrome; Mucopolysaccharidosis IH; Mucopolysaccharidosis type I; MPS-IH; MPS-I; Autologous Lentiviral vector
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Mucopolysaccharidoses; Mucopolysaccharidosis I
• Other Study ID Numbers: OTL-203-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No