Mucopolysaccharidosis IH
Conditions
Keywords
Mucopolysaccharidosis IH, Gene Therapy, Transplantation, Autologous, Lentiviral vector
Brief summary
This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant
Detailed description
Pediatric patients with mucopolysaccharidosis type I will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow if mobilization is not feasible) and transduced with IDUA lentiviral vector encoding for the human α-L-iduronidase gene. Participants will be followed for up to 15 years post treatment (per regulatory guidelines for follow up of patients treated with ATMPs, under this study (TigetT10\_MPSIH) or via enrollment into a separate long term follow-up (LTFU) study for the overall OTL-203 Clinical Development Program, if one is set up prior to their Year 15 visit.
Interventions
GENETICFrozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LVV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.
The drug product target dose is more or equal to 8x10\^6 CD34+ cells/Kg, with a minimum dose of 4x10\^6 CD34+ cells/Kg and a maximum dose of 35x10\^6 CD34+ cells/Kg. The product will be injected intravenously.
Sponsors
Orchard Therapeutics
Fondazione Telethon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 11 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent by parent/legal guardian * Sex: Males and Females * Age: ≥ 28 days and ≤ 11 years old * Biochemically and molecularly proven MPS IH * Lansky index \>80% * Indication to hematopoietic stem cell transplant * Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10\^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). * Adequate cardiac, renal, hepatic and pulmonary functions
Exclusion criteria
* Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents) * Severe, active viral, bacterial or fungal infection at eligibility evaluation * Patients affected by neoplasia or family history of familial cancer syndromes * Cytogenetic alterations associated with high risk of developing hematological malignancies * History of uncontrolled seizures * 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 * 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 * Patients with DQ/IQ \<70 * Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product * Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | Assessed at multiple timepoints up to 15 years post-treatment | Number and percentage of subjects alive at the end of the trial |
| Achievement of haematological engraftment | within day +45 after gene therapy | Percentage of subjects with both neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days) on 3 consecutive blood counts in the first 45 days from ATIMP injection. |
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Short term tolerability | 0-24 hours from ATIMP injection | Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions |
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of Replication Competent Lentivirus | Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated | Percentage of subjects without Replication Competent Lentivirus |
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of malignancy or abnormal clonal proliferation | Assessed at multiple timepoints up to 15 years post-treatment | Percentage of subjects without abnormal clonal proliferation |
| Overall safety and tolerability (AE) | Assessed at multiple timepoints up to 15 years post-treatment | The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated. |
| IDUA activity in blood (up to supraphysiologic levels) at 1-year post-treatment | At 1 year post-treatment | IDUA activity measured on peripheral dried blood spot |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-IDUA antibody immune response | Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated | Presence or absence and titer of anti-IDUA antibody on plasma or serum |
| Achievement of supraphysiologic IDUA activity in blood | Assessed at multiple timepoints up to 15 years post-treatment | IDUA activity measured on peripheral dried blood spots up to supraphysiologic levels as compared with healthy donors. A supraphysiologic IDUA level is defined as \>24.31 μmol/L/h, which is the 97.5th percentile of the IDUA distribution in healthy children |
| IDUA activity in plasma | Assessed at multiple timepoints up to 15 years post-treatment | IDUA activity measured on plasma samples from peripheral blood. |
| Engraftment of transduced cells ≥ 0.30 VCN/genome | Assessed at multiple timepoints up to 15 years post-treatment | Percentage of subjects with engraftment of transduced cells ≥ 0.30 VCN/genome on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM) progenitor cells. |
| Normalization of urinary GAGs | Assessed at multiple timepoints up to 15 years post-treatment | Percentage of subjects achieving normalization of urinary GAG levels (heparan sulfate and dermatan sulfate) measured by HPLC |
| Normalization of spleen and liver | Assessed at multiple timepoints up to 15 years post-treatment | Percentage of subjects with normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound |
| Growth velocity | Assessed at multiple timepoints up to 15 years post-treatment | Length/height for age (cm) per month vs. WHO percentiles |
Countries
Italy
Outcome results
None listed