A study to investigate the efficacy and safety of OTL-203 in subjects with mucopolysaccharidosis type I, Hurler syndrome (MPS-IH) compared with standard of care with allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Phase 1

• Conditions: Mucopolysaccharidosis type I, Hurler Syndrome; MedDRA version: 20.0Level: LLTClassification code: 10020471Term: Hurler's syndrome Class: 10010331; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]; Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

• Registration Number: CTIS2022-500306-17-00
• Lead Sponsor: Orchard Therapeutics (Europe) Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-10-31
• Last Update Posted: 22 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

Written informed consent by parent/legal guardian., Male or female subject with age at enrolment: = 28 days to =30 months. Note: In addition, subjects aged above 30 months shall be considered for enrolment and treatment with OTL-203 in EU/UK only, if they meet all the eligibility criteria and upon agreement with the Medical Monitor (MM), to comply with the EU/UK PIP. Any subject aged > 30 months enrolled and treated with OTL-203 will be followed as per the SoA of the study but will not be included in the primary statistical analysis., Norm-referenced cognitive standard score of =70 evaluated within the Screening period of the study and measured by age-appropriate cognitive domains of Bayley Scale of Infant Development (BSID)-III or Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-IV (visual spatial index” for WPPSI-IV)., Confirmed laboratory diagnosis of MPS-IH as demonstrated by biallelic mutation(s) in the gene coding for IDUA enzyme (at a CLIA-accredited laboratory): a. homozygosity or compound heterozygosity for two known severe alleles, both of which must be associated with a severe (Hurler) phenotype according to the literature, or b. If mutation(s) are unknown/novel, either of the following: i. sibling known to have MPS-IH with severe phenotype, or ii. presence of somatic features (confirmed by an MPS-I specialist) presenting in the first two years of life, which are consistent with MPS-IH severe phenotype [including but not limited to frequent ear infections, frequent upper respiratory infections, umbilical/inguinal hernia, kyphosis/gibbus, corneal clouding, hepatosplenomegaly, dysostosis multiplex, cognitive impairment, cardiac valve abnormalities, joint contractures], Final confirmation of MPS-IH diagnosis by Diagnostic Review Committee (DRC), following the review of: a. gene mutation analysis b. documented biochemical evidence of a deficiency in IDUA enzyme activity c. documented evidence of altered GAG metabolism d. somatic manifestations of the disease.

Exclusion Criteria

Previous allo-HSCT or gene therapy., Subjects who have contraindications for MRI scans (for example, but not limited to, cardiac pacemaker, metal implants)., Current enrollment or past treatment in any other study/trial using a novel investigational agent for which the washout cannot be confirmed by the time of anticipated treatment., Evidence of: a. Positivity to serological testing for: i. Human immunodeficiency virus (HIV-1 or HIV-2), ii. Human T lymphotropic virus (HTLV-1 or HTLV-2), iii. Hepatitis B virus (HBV) core. Subjects positive for Hepatitis B core antibodies due to prior resolved disease may be enrolled, if a confirmatory negative Hepatitis B surface antigen and negative HBV deoxyribonucleic acid test are obtained iv. Hepatitis C virus (HCV). Subjects who have previously tested positive for antibodies against HCV may be enrolled, provided ongoing infection is excluded using nucleic acid testing v. Mycoplasma, unless ongoing infection can be excluded (e.g., on the basis of a negative result on a repeat serological testing or molecular testing (polymerase chain reaction) and the investigator’s assessment); b. Active tuberculosis (TB) c. Not meeting the microbiology biological screening requirements for drug product (DP) manufacturing., Malignant neoplasia (except local skin cancer). Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Sponsor’s MM., Myelodysplastic syndrome (MDS)/ 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 (for example, but not limited to, general anesthesia, mobilization of CD34+ cells from the bone marrow into the peripheral circulation using G-CSF ± plerixafor, leukapheresis and myeloablative conditioning with busulfan and fludarabine)., 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., Subjects with any of the following: • Alanine transaminase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN), • Total bilirubin >1.5 × ULN at screening unless the subject has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin, • Renal creatinine clearance <30 mL/min, • Left ventricular ejection fraction (LVEF) < 45% by echo or diagnosis of severe pulmonary hypertension, • 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Assessing the event-free survival with OTL-203 in comparison to Standard of Care (SoC; allo-HSCT);Secondary Objective: Assessing the pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT) (Key secondary endpoint)., Assessing the effects of OTL-203 on relevant MPS-IH symptomatic manifestations (disease burden”) in comparison to SoC (allo-HSCT)., Assessing the effects of OTL-203 and SoC on health-related quality of life and health resource utilization., Assessing the engraftment and pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT)., Assessing the safety and tolerability of gene therapy with OTL-203 in comparison to SoC (allo-HSCT procedure).;Primary end point(s): Event-free survival (EFS; composite endpoint) at Year 2 (the primary analysis timepoint) defined by the following events: 1. Death post-treatment 2. Rescue allo-HSCT 3. Treatment Failure 4. Immunological complications 5. Severe Cognitive Impairment 6. Short Stature.