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

Phase 3

Active, not recruiting

• Conditions: MPS-IH (Hurler Syndrome)

• Registration Number: NCT06149403
• Lead Sponsor: Orchard Therapeutics

Brief Summary

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

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 Timeline

• Study First Submitted: 2023-11-17
• Study First Submitted QC: 2023-11-27
• Study First Posted: 2023-11-29
• Study Start: 2023-12-11
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-11
• Last Update Posted: 2025-06-15
• Primary Completion: 2028-03
• Study Completion: 2031-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 41

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Event-free survival	2 years	Defined by events of death, rescue transplant, treatment failure, immunological complications, severe cognitive and/or growth impairment.

Secondary Outcome Measures

Name	Time	Method
Change from baseline to Year 2 in α-L-iduronidase (IDUA) activity in leukocytes	Day 30 and multiple visits up to 5 years post-treatment	IDUA activity in leukocytes will be used to measure post-treatment systemic correction of the biochemical defect that causes the disease
Change from baseline to Year 2 in the ratio to the upper limit of normal (ULN) of urinary heparan sulfate levels	Day 30 and multiple visits up to 5 years post-treatment	Urinary heparan sulfate levels will be used to measure post-treatment clearance of glycosaminoglycans accumulated within tissues and organs due to IDUA enzymatic deficiency
Safety of OTL-203 compared to allo-HSCT procedure	Up to 5 years post-treatment	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)
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).	Up to 5 years post-treatment	Malignancy or ACP due to insertional oncogenesis will be evaluated in subjects treated with OTL-203.
Replication Competent Lentivirus (RCL)	Up to 5 years post-treatment	Presence of RCL will be evaluated in subjects treated with OTL-203
Immune response against IDUA enzyme	Up to 5 years post-treatment	Anti-IDUA antibodies analysis will be evaluated in all subjects.

Trial Locations

Locations (5)

University of Minnesota, Pediatrics; 🇺🇸 Minneapolis, Minnesota, United States

Ospedale San Raffaele; 🇮🇹 Milan, Italy

Princess Maxima Center; 🇳🇱 Utrecht, Netherlands

UMC Utrecht; 🇳🇱 Utrecht, Netherlands

Manchester University NHS Foundation Trust Blood and Marrow Transplant Programme, Royal Manchester Children's Hospital; 🇬🇧 Manchester, United Kingdom