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":"- Sex: Males and Females"}
• {"criterion_text":"- ≥ 28 days and ≤ 11 years old"}
• {"criterion_text":"- Biochemically and molecularly proven MPS-IH"}
• {"criterion_text":"- Lansky Index > 80 %"}
• {"criterion_text":"- Indication to HSCT"}
• {"criterion_text":"- Lack of a non-heterozygous (for mutated IDUA) human leukocyte antigens (HLA) -matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5x10^7 Total Nucleated Cells (TNC)/Kg after 1-month search. This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantation."}
• {"criterion_text":"- Adequate cardiac, renal, hepatic and pulmonary functions"}

Exclusion criteria

• {"criterion_text":"- Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)"}
• {"criterion_text":"- Controindications to Products equivalent to the IMP (PeIMP): G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab"}
• {"criterion_text":"- Severe, active viral, bacterial, or fungal infection at eligibility evaluation"}
• {"criterion_text":"- Patients affected by malignant neoplasia or family history of familial cancer syndromes"}
• {"criterion_text":"- Cytogenetic alterations associated with high risk of developing hematological malignancies"}
• {"criterion_text":"- History of uncontrolled seizures"}
• {"criterion_text":"- Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study"}
• {"criterion_text":"- Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection"}
• {"criterion_text":"- Patients with DQ/IQ <70 (also referred as, “cognitive standard score”, measured using Cognitive Scale for Bayley Scale of Infant Development and Performance IQ for WPPSI and WISC)"}
• {"criterion_text":"- Previous allogeneic HSCT or gene therapy with a different product"}

Primary endpoints

• {"endpoint_text":"- Overall survival from Advanced Therapy Investigational Medicinal Product (ATIMP) injection","definition_or_measurement_approach":""}
• {"endpoint_text":"- Achievement of hematological engraftment less than or equal to day +45 from Advanced Therapy Investigational Medicinal Product (ATIMP) injection. Hematologic engraftment is defined as the first of 3 consecutive days with neutrophil count > 500/mm3 and platelets > 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days).","definition_or_measurement_approach":"Hematologic engraftment defined as first of 3 consecutive days with neutrophil count >500/mm3 and platelets >20,000/mm3 (without platelet transfusion for seven consecutive days); measured up to day +45 post-ATIMP injection."}
• {"endpoint_text":"- Safety of the administration of autologous HSPC transduced with LVV-IDUA. This will be measured as: a) short-term tolerability (0-24 hours from ATIMP injection); b) absence of Replication Competent Lentivirus (RCL); c) absence of malignancy or abnormal clonal proliferation due to insertional mutagenesis.","definition_or_measurement_approach":"Safety measured via (a) short-term tolerability 0-24 hours post-injection; (b) testing for absence of Replication Competent Lentivirus (RCL); (c) monitoring for absence of malignancy or abnormal clonal proliferation attributable to insertional mutagenesis."}
• {"endpoint_text":"- Overall safety and tolerability measured by Adverse Event (AE) recording.","definition_or_measurement_approach":"Overall safety/tolerability assessed by collection and recording of adverse events."}
• {"endpoint_text":"- IDUA activity in blood (dried blood spot, DBS) (up to supraphysiologic levels) at 1-year posttreatment","definition_or_measurement_approach":"Measurement of IDUA enzyme activity in blood using dried blood spot (DBS) samples at 1 year posttreatment; target includes up to supraphysiologic levels."}

Secondary endpoints

• {"endpoint_text":"- Achievement of supraphysiologic IDUA activity in blood (DBS)","definition_or_measurement_approach":"Measurement of IDUA activity in DBS to assess attainment of supraphysiologic levels."}
• {"endpoint_text":"- IDUA activity in plasma","definition_or_measurement_approach":"Measurement of IDUA enzyme activity in plasma samples."}
• {"endpoint_text":"- Engraftment of transduced cells >= 0.30 vector copy number (VCN)/genome","definition_or_measurement_approach":"Molecular assessment of vector copy number (VCN) per genome in transduced cells; threshold >=0.30 VCN/genome."}
• {"endpoint_text":"- Normalization of urinary GAGs","definition_or_measurement_approach":"Measurement of urinary glycosaminoglycans (GAGs) to assess normalization."}
• {"endpoint_text":"- Normalization of spleen and liver (for age)","definition_or_measurement_approach":"Assessment of spleen and liver size relative to age-based norms (imaging/clinical evaluation) to determine normalization."}
• {"endpoint_text":"- Growth velocity","definition_or_measurement_approach":"Measurement of longitudinal growth parameters to calculate growth velocity."}
• {"endpoint_text":"- Anti-IDUA antibody immune response before and after infusion of IDUA LVV-transduced cells","definition_or_measurement_approach":"Serologic assessment of anti-IDUA antibodies pre- and post-infusion to characterize immune response."}

Italy

Earliest CTIS Part Ii Submission Date

25-06-2024

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

658

Number Of Sites

1

Number Of Participants

8

Primary sponsor

Full Name

Orchard Therapeutics (Europe) Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

CTI Clinical Trial and Consulting Services Europe GmbH

Responsibilities

codes: 1,12,5

Third parties

• {"country":"Germany","full_name":"CTI Clinical Trial and Consulting Services Europe GmbH","duties_or_roles":"codes: 1,12,5","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"TransPerfect Translations Limited","duties_or_roles":"code: 15 (electronic trial master file)","organisation_type":"Industry"}
• {"country":"Italy","full_name":"Azienda Ospedaliera Universitaria Meyer IRCCS","duties_or_roles":"code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Lithuania","full_name":"Insuvia UAB","duties_or_roles":"code: 8","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Genosafe S.A.S.","duties_or_roles":"code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"codes: 6,7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Labcorp Early Development Laboratories Limited","duties_or_roles":"code: 4","organisation_type":"Pharmaceutical company"}