Safety and Efficacy Evaluation of γ-globin Reactivated Autologous Hematopoietic Stem Cells

Study Overview
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Brief Summary
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This is a single arm, open label, single-dose, phase 1/2 study in up to 5 participants with β-thalassemia major.The study will evaluate the safety and efficacy of the treatment with γ-globin reactivated autologous hematopoietic stem cells in subjects with β-thalassemia major.

Detailed Description
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γ-globin reactivated autologous hematopoietic stem cells will be manufactured using Glycosylase Base Editors. Subject participation for this study will be 2 year. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 15 years post-transplant.

Official Title
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an Open Label Trial of Evaluation of the Safety and Efficacy of Treatment With γ-globin Reactivated Autologous Hematopoietic Stem Cells in Subjects With β-thalassemia Major

Conditions
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Thalassemia Major

Intervention / Treatment
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* Biological: γ-globin reactivated autologous hematopoietic stem cells


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Fully understand and voluntarily sign informed consent. 3-35years old. At least one legal guardian and/or Subjects to sign informed consent. Clinically diagnosed as β-thalassemia major, phenotypes including β0β0, β+β+、β +β0, βEβ0 genotype. Subjects with no affection with EBV, HIV, CMV, TP, HAV, HBV and HCV. Subjects body condition eligible for autologous stem cell transplant. Key exclusion criteria: Subjects acceptable for allogeneic hematopoietic stem cell transplantation and have an available fully matched related donor. Active bacterial, viral, or fungal infection. Treated with erythropoietin prior 3 months. Immediate family member with any known hematological tumor. Subjects with severe psychiatric disorders to be unable to cooperate. Recently diagnosed as malaria. History of complex autoimmune disease. Persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 X the upper limit of normal (ULN). Subjects with severe heart, lung and kidney diseases. With serious iron overload, serum ferritin>5000mg/ml. Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician or Investigator. Subjects who are receiving treatment from another clinical study, or have received another gene therapy. Subjects or guardians had resisted the guidance of the attending doctor. Subjects whom the investigators do not consider appropriate for participating in this clinical study

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: γ-globin reactivated autologous hematopoietic stem cells<br>each subject will accept one dose of γ-globin reactivated autologous hematopoietic stem cells | Biological: γ-globin reactivated autologous hematopoietic stem cells<br>* gene edited autologous hematopoietic stem cells with γ-globin expression; BRL-103<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving successful neutrophil engraftment within 42 days after BRL-103 infusion |  | From 12 months to 24 months post transplant | 
| Time to neutrophil engraftment |  | From 12 months to 24 months post transplant | 
| Time to platelet engraftment |  | From 12 months to 24 months post transplant | 
| Frequency and severity of adverse events through 100 days after BRL-103 Infusion |  | From 12 months to 24 months post transplant | 
| Proportion of subjects achieving sustained transfusion reduction for at least 3 months (TR3) | TR3 was defined as at least a 50% reduction in monthly red blood cell transfusion volume and transfusion frequency compared to baseline for at least 3 months | From 12 months to 24 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving sustained transfusion independence for at least 3 months (TI3) | Routine transfusion without disease related and with Hb ≥ 90 g/L for at least 3 months | From 12 months to 24 months post transplant | 
| Proportion of subjects achieving TR6 |  | From 12 months to 24 months post transplant | 
| Proportion of subjects achieving TR12 |  | From 12 months to 24 months post transplant | 
| Proportion of subjects achieving sustained transfusion independence for at least 6 months (TI6) |  | From 12 months to 24 months post transplant | 
| Proportion of subjects achieving sustained transfusion independence for at least 12 months (TI12) |  | From 12 months to 24 months post transplant | 
| Incidence of transplant related mortality (TRM) within 100 days and within 1 year |  | From 12 months to 24 months post transplant | 
| Frequency, severity, and relationship to BRL-103 of adverse events over two years following BRL-103 infusion. |  | From 12 months to 24 months post transplant | 
| All-cause mortality |  | From 12 months to 24 months post transplant | 
| Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time |  | From 12 months to 24 months post transplant | 
| Fetal hemoglobin concentration (pre-transfusion) over time |  | From 12 months to 24 months post transplant | 
| Total hemoglobin concentration (pre-transfusion) over time |  | From 12 months to 24 months post transplant | 
| Change in serum ferritin level from baseline over time |  | From 12 months to 24 months post transplant |