atidarsagene autotemcel for Metachromatic leukodystrophy|Late juvenile metachromatic leukodystrophy

Inclusion criteria

• {"criterion_text":"- 1.Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease causing ARSA alleles. Novel mutations will be analysed with in silico prediction tool and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.\n- 2. O/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.\n- 3. a) if symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. before their 17th birthday) OR b) if pre-symptomatic: subject must be <17 years of age at treatment (i.e before their 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLD variant based on age at disease onset (≥7 and <17 years of age i.e before sibling's 17th birthday), with biochemical and molecular diagnosis.\n- 4. Normal cognitive function as defined by an IQ≥ 85 on age appropriate cognitive scales.\n- 5.a) If the subject is <7 years age (i.e before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and normal neurological examination (if applicable based on the age of the subject, GMFC-MLD =0) OR b) If the subject is ≥ 7 years, normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e subject is able to walk independently). NOTE: The following will not be exclusionary if present alone: i.Seizures ii.Signs of the disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MRI)\n- 6. If applicable, subject willing and capable of compliance with contraceptive requirements as detailed further in Protocol Section 7.1. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.\n- 7. Subject (or if applicable, parent/legal guardian) providing signed informed consent or assent if applicable as described in Section 17.4 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol."}

Exclusion criteria

• {"criterion_text":"- 1. Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).\n- 2.Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. 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 Orchard-MM.\n- 3.Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.\n- 4.Subjects currently enrolled in other interventional trials.\n- 5.Has previously undergone allogeneic HSCT and has evidence of residual cells of donor origin.\n- 6.Previous gene therapy.\n- 7.Has symptomatic herpes zoster, not responsive to specific treatment.\n- 8.Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON-TB Gold test and microbiological evidence.\n- 9.Acute or chronic stable Hepatitis B (HBV) as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to onset of conditioning and/or positive HBV DNA.\n- 10.Presence of positive Hepatitis C RNA test result at screening.\n- 11.End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgement of the investigator, would make the subject inappropriate for entry into this study. \n- 12. In addition to the potential infections tested per protocol, the PI should consider testing for other transmissible infectious agents listed in the EU Cell and Tissue Directive as clinically appropriate and results must be discussed with the Orchard-MM prior to stem cell harvest.\n- 13. Subjects with alanine transferase (ALT) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN may be included only after discussed and agreed with the Orchard-MM and considered in the context of the criterion for excluding subjects with other severe disease. Isolated elevation of total bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total."}

Primary endpoints

• {"endpoint_text":"- Change in ARSA activity levels in CSF from baseline to 24 months post treatment.\n- Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain from baseline to 24 months post-treatment.","definition_or_measurement_approach":"Co-primary pharmacodynamic efficacy endpoints measured as change from baseline to 24 months post-treatment. ARSA activity levels measured in CSF; neuronal metabolite ratio NAA:Cr assessed in defined white matter regions of interest in the brain (change from baseline to 24 months)."}

Secondary endpoints

• {"endpoint_text":"- Change in CSF ARSA\n- Change in neuronal metabolite ratio\n- Change in ARSA in PBMC, CD14+ & CD15+\n- Engraftment\n- VCN in BM & PBMC\n- Change in severity scale for brain MRI asses\n- Change in neurocog function\n- Full NCE\n- Change in GMFC-MLD\n- Change in NCV\n- Conditioning related toxicity/AEs\n- Non-conditioning AEs\n- Hem.reconstitution\n- Incidence of inf. related reactions\n- Incidence & titers of ARSA antibodies\n- Abn.clonal proliferation\n- Absence of RCL\n- site analysis findings\n- ELFC-MLD\n- Add Brain MRI analyses","definition_or_measurement_approach":"Most secondary endpoints are changes or incidences measured from baseline; examples explicitly indicate specimen/source where applicable (e.g., CSF ARSA; ARSA in PBMC, CD14+ & CD15+; VCN measured in bone marrow (BM) & PBMC). Several endpoints relate to imaging (brain MRI/MRS) and clinical scales (GMFC-MLD, neurocognitive function). Specific measurement methods are not detailed in the provided JSON."}

Italy

Earliest CTIS Part Ii Submission Date

20-03-2024

Latest Decision Or Authorization Date

11-04-2025

Processing Time Days

387

Number Of Sites

1

Number Of Participants

6

Primary sponsor

Full Name

Orchard Therapeutics (Europe) Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

PPD Development L.P.

Responsibilities

Support with CTIS system; operational support (sponsor duties codes 1,12,15)

Name

Bioclinica Inc.

Responsibilities

Brain MRI/MRS storage and facilitation of analysis

Third parties

• {"country":"United States","full_name":"Alliance Pharma Inc.","duties_or_roles":"Anti-ARSA Antibody","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Vivos Technology Limited","duties_or_roles":"Codes: 10, 6","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Italy","full_name":"Ospedale San Raffaele S.r.l.","duties_or_roles":"Clinical chemistry,Clinical haematology,Clinical microbiology,karyotyping, p24 HIV ELISA and reverse transcription PCR for HIV-Pol RNA for RCL evaluation.; Primary/ surrogate endpoint test, Brain magnetic resonance imaging; Clinical chemistry,Clinical haematology,Clinical microbiology,karyotyping, p24 HIV ELISA and reverse transcription PCR for HIV-Pol RNA for RCL evaluation.","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"France","full_name":"Genosafe S.A.S.","duties_or_roles":"VSV-G RNA PCR testing for RCL evaluation","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development L.P.","duties_or_roles":"Codes: 1, 12, 15; Support with CTIS system","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Istituto San Raffaele","duties_or_roles":"Spec. assays for ARSA(PBandBM only),vector copy number,%LV in bone marrow, TCR,Analytical chemistry,Primary/ surrogate endpoint test","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"NMDP Collection Services LLC","duties_or_roles":"Shipment of cellular source material from the QTC and drug product from the CMO to the QTC","organisation_type":"Patient organisation/association"}
• {"country":"Italy","full_name":"IRCCS Istituto Giannina Gaslini","duties_or_roles":"Urinary Sulfatides","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Italy","full_name":"Universita' Degli Studi Di Perugia","duties_or_roles":"ARSA-CSF analysis","organisation_type":"Educational Institution"}
• {"country":"Lithuania","full_name":"Insuvia UAB","duties_or_roles":"Pharmacovigilance vendor (MRI/MRS) storage, facilitation of analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"ProtaGene CGT GmbH","duties_or_roles":"Insertion Site Analysis (ISA)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Biocair International Limited","duties_or_roles":"Shipment of Samples","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Fondazione IRCCS Policlinico San Matteo","duties_or_roles":"Busulfan PK analysis","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Brain Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) storage, facilitation of analysis","organisation_type":"Laboratory/Research/Testing facility"}