Autologous CD34+ haematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the alpha-L-iduronidase cDNA for Mucopolysaccharidosis type I (Hurler syndrome)

Inclusion criteria

• {"criterion_text":"- Written informed consent by parent/legal guardian."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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]"}
• {"criterion_text":"- 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

• {"criterion_text":"- Previous allo-HSCT or gene therapy."}
• {"criterion_text":"- Subjects who have contraindications for MRI scans (for example, but not limited to, cardiac pacemaker, metal implants)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML)."}
• {"criterion_text":"- History of uncontrolled seizures."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"EFS is a composite endpoint assessed at Year 2; events constituting failure are enumerated in the endpoint text (death post-treatment, rescue allo-HSCT, treatment failure, immunological complications, severe cognitive impairment, short stature)."}

Secondary endpoints

• {"endpoint_text":"- • Change from Baseline (CFB) to Year 2 in IDUA activity in leukocytes • CFB to Year 2 in urinary heparan sulfate levels, defined as ratio to the upper limit of normal (ULN).","definition_or_measurement_approach":"Change from baseline to Year 2 in leukocyte IDUA activity and urinary heparan sulfate levels (ratio to ULN)."}
• {"endpoint_text":"- Long Term EFS at the time of the final analysis.","definition_or_measurement_approach":"Event-free survival assessed long-term at final analysis (no further definition provided)."}
• {"endpoint_text":"- The following endpoints will be assessed at each visit scheduled in the SoA: Cognitive Function, Joint Range Motion, Dysostosis Multiplex, Auditory function, Visual function and corneal clouding, Imaging, Presence of cardiac abnormalities associated with MPS-I, Motor Function, Functional Capacity, Auxological measurements, Quality of Life (QoL) and Activities of Daily Living (ADLs).","definition_or_measurement_approach":"Multiple clinical and functional assessments scheduled per the Schedule of Assessments (SoA); individual measures assessed at each visit as listed."}
• {"endpoint_text":"- Healthcare resource utilization (HRU) and Surgical Burden.","definition_or_measurement_approach":"Assessment of healthcare resource use and surgical burden; specific measurement approach not detailed in the available extract."}
• {"endpoint_text":"- Assessments of Engraftment and Pharmacodynamic Effects.","definition_or_measurement_approach":"Assessments to evaluate engraftment and pharmacodynamic outcomes; methods not fully detailed in the extract."}
• {"endpoint_text":"- Safety of OTL-203 compared to allo-HSCT procedure as measured by: overall incidence of adverse events (AEs), NIMP/AxMP-related AEs, Study Procedure-related AEs, Disease-related AEs, Treatment related AEs, Serious adverse events (SAEs). Immune response against IDUA enzyme (anti-IDUA antibodies), evaluated via immunoassay. Malignancy or Abnormal Clonal Proliferation (ACP). Emergence of Replication Competent Lentivirus (RCL).","definition_or_measurement_approach":"Safety measured by incidence and categorization of AEs/SAEs, immunoassay for anti-IDUA antibodies, monitoring for malignancy/ACP and emergence of RCL."}

Netherlands

Earliest CTIS Part Ii Submission Date

09-02-2024

Latest Decision Or Authorization Date

25-06-2024

Processing Time Days

137

Number Of Sites

2

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

07-02-2024

Latest Decision Or Authorization Date

20-06-2024

Processing Time Days

134

Number Of Sites

1

Number Of Participants

7

Primary sponsor

Full Name

Orchard Therapeutics (Europe) Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Psi Cro AG

Responsibilities

codes: 1,11,12,13,15,5,9; value: Vendor management; Translations; DRC, DSMB and EAC management

Name

Bioclinica Inc.

Responsibilities

codes: 15; value: Imaging/Ophtalmology

Name

Medidata Solutions Inc.

Responsibilities

codes: 3,7

Name

Medidata Solutions International Limited

Responsibilities

codes: 3,7

Name

CluePoints SA

Responsibilities

codes: 15; value: Risk-Based Management

Name

Labcorp Early Development Laboratories Limited

Responsibilities

codes: 4

Name

Labcorp Central Laboratory Services LP

Responsibilities

codes: 4

Name

Labcorp Central Laboratory Services S.a.r.l.

Responsibilities

codes: 4

Third parties

• {"country":"United States","full_name":"Greenwood Genetic Center Inc.","duties_or_roles":"codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Genosafe S.A.S.","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"San Raffaele Telethon Institute for Gene Therapy, Tiget Clinical Laboratory","duties_or_roles":"codes: 4","organisation_type":"Health care"}
• {"country":"Switzerland","full_name":"Psi Cro AG","duties_or_roles":"codes: 1,11,12,13,15,5,9; value: Vendor management; Translations; DRC, DSMB and EAC management","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"AGC Biologics S.p.A.","duties_or_roles":"codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"codes: 3,7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Italy","full_name":"Ospedale San Raffaele S.r.l.","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Lithuania","full_name":"Insuvia UAB","duties_or_roles":"codes: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Mayo Clinic Hospital Rochester","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"codes: 15; value: Imaging/Ophtalmology","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Protagene Cgt GmbH","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"University Of Manchester","duties_or_roles":"codes: 15; value: Imaging/Ophtalmology","organisation_type":"Educational Institution"}
• {"country":"Belgium","full_name":"CluePoints SA","duties_or_roles":"codes: 15; value: Risk-Based Management","organisation_type":"Health care"}
• {"country":"United Kingdom","full_name":"Medidata Solutions International Limited","duties_or_roles":"codes: 3,7","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)","duties_or_roles":"codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Clinical Outcomes Solutions Limited","duties_or_roles":"codes: 15; value: Entry & Exit Interviews","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Vivos Technology Limited","duties_or_roles":"codes: 6","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Labcorp Early Development Laboratories Limited","duties_or_roles":"codes: 4","organisation_type":"Pharmaceutical company"}