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)

• ClinicalTrials.gov Identifier: NCT06149403
• Recruitment Status: Recruiting
• First Posted: November 29, 2023
• Last Update Posted: April 16, 2024
• Sponsor: Orchard Therapeutics
• Information provided by (Responsible Party): Orchard Therapeutics

Tracking Information

• First Submitted Date: November 17, 2023
• First Posted Date: November 29, 2023
• Last Update Posted Date: April 16, 2024
• Actual Study Start Date: December 11, 2023
• Estimated Primary Completion Date: March 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 27, 2023)

Event-free survival [ Time Frame: 2 years ]

Defined by events of death, rescue transplant, treatment failure, immunological complications, severe cognitive and/or growth impairment.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 27, 2023)

• Change from baseline to Year 2 in α-L-iduronidase (IDUA) activity in leukocytes [ Time Frame: 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 urinary heparan sulfate levels, defined as ratio to the upper limit of normal [ Time Frame: 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 [ Time Frame: 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). [ Time Frame: 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) [ Time Frame: Up to 5 years post-treatment ]
  Presence of RCL will be evaluated in subjects treated with OTL-203
• Immune response against IDUA enzyme [ Time Frame: Up to 5 years post-treatment ]
  Anti-IDUA antibodies analysis will be evaluated in all subjects.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Investigate the Efficacy and Safety of OTL-203 in Subjects With MPS-IH Compared With Standard of Care With Allogeneic HSCT
• Official Title: 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)
• 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 Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel assignment

Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment

• Condition: MPS-IH (Hurler Syndrome)

Intervention

• 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
• Genetic: Active Comparator: Allo-HSCT
  Active Comparator: Allogeneic hematopoietic stem cell transplantation

Study Arms

• 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.
  Intervention: Genetic: Experimental: OTL-203
• 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.
  Intervention: Genetic: Active Comparator: Allo-HSCT

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 27, 2023): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2031
• Estimated Primary Completion Date: March 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
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 for drug product (DP) manufacturing.
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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 28 Days to 30 Months (Child)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Italy, Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT06149403
• Other Study ID Numbers: OTL-203-02
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Orchard Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Orchard Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Orchard Therapeutics
• Verification Date: April 2024