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

Sponsor

Orchard Therapeutics (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06149403

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

5.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
MPS-IH (Hurler Syndrome)	Genetic: Experimental: OTL-203 Genetic: Active Comparator: Allo-HSCT	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel assignmentParallel assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

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)

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2028

Anticipated Study Completion Date :

Mar 1, 2031

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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 urinary heparan sulfate levels, defined as ratio to the upper limit of normal [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

28 Days to 30 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 HIV-1 or HIV-2, HTLV-1 or HTLV-2, HBV core, HCV, mycoplasma, active 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
2	University of Minnesota, Pediatrics	Minnesota	Minnesota	United States	55455
3	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19041
4	Ospedale San Raffaele	Milan		Italy	20131
5	Princess Maxima Center	Utrecht		Netherlands	3584 CS
6	UMC Utrecht	Utrecht		Netherlands	3584 CX
7	Manchester University NHS Foundation Trust Blood and Marrow Transplant Programme, Royal Manchester Children's Hospital	Manchester		United Kingdom	M13 9WL