Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant

Phase 2Active Not RecruitingNCT03488394

Orchard Therapeutics8 enrolled

Overview

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

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. Patients will be followed for 8 years after gene therapy. After completing participation in this study, subjects will be offered enrollment into an approved long term follow-up (LTFU) study which will enable continued follow-up for up to 15 years post-treatment (per regulatory guidelines for follow up of patients treated with ATMPs).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Mucopolysaccharidosis IH

Interventions

Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.GENETIC

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.

Eligibility

Sex: ALLMin age: 28 DaysMax age: 11 Years

Medical Language ↔ Plain English

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)

Locations (1)

Ospedale San Raffaele

Milan, Italy

Outcomes

Primary Outcomes

Overall survival

Number and percentage of subjects alive at the end of the trial

Time frame: 8 years

Achievement of haematological engraftment

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.

Time frame: within day +45 after gene therapy

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability

Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions

Time frame: 0-24 hours from ATIMP injection

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus

Percentage of subjects without Replication Competent Lentivirus

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation

Percentage of subjects without abnormal clonal proliferation

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Overall safety and tolerability (AE)

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.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Anti-IDUA antibody immune response

Presence or absence and titer of anti-IDUA antibody on serum

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Achievement of supraphysiologic IDUA activity in blood

IDUA activity measured on peripheral 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

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

IDUA activity in plasma

IDUA activity measured on plasma samples from peripheral blood.

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Engraftment of transduced cells ≥ 0.30 VCN/genome

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.

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Normalization of urinary GAGs

Percentage of subjects achieving normalization of urinary GAG levels (heparan sulfate and dermatan sulfate) measured by HPLC

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Normalization of spleen and liver

Percentage of subjects with normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound

Time frame: Assessed at multiple timepoints up to 8 years post-treatment

Growth velocity

length/height for age and cm/year percentiles

Time frame: Assessed at multiple timepoints up to 8 years post-treatment