A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease

Study Overview
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Brief Summary
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This is a non-randomized, open-label, multi-site, single-dose, Phase 3 study in approximately 35 adults and pediatric subjects ≥2 and ≤50 years of age with sickle cell disease (SCD). The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).

Official Title
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A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the BB305 Lentiviral Vector in Subjects With Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Genetic: bb1111


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of SCD, with either βS/βS, βS/β0, or βS/β+ genotype. Be ≥2 and ≤50 years of age at time of consent. Weigh a minimum of 6 kg. Have a Karnofsky performance status of ≥60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age). Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history. In the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 protocol-defined VOEs in the 24 months prior to informed consent. Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment). Female and male subjects of childbearing potential agree to use 1 method of highly effective contraception from Screening to at least 6 months after drug product infusion. Provision of written informed consent for this study by subject, or as applicable, subject's parent(s)/legal guardian(s). Exclusion Criteria: Subjects for whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically appropriate per PI judgment and a willing, human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available. Severe cerebral vasculopathy, defined by any history of overt ischemic or hemorrhagic stroke, a history of abnormal transcranial Doppler (TCD) or TCD imaging (TCDI) for subjects ≤ 16 years of age (e.g. TCD velocity >200 cm/sec) requiring ongoing chronic transfusions, a Screening TCD or TCDI velocity > 200 cm/sec (central read), a Screening MRA showing > 50% stenosis or occlusion in the circle of Willis (central read), or a Screening MRA showing the presence of Moyamoya (central read). Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotropic virus-1 (HTLV-1), active syphilis. Clinically significant, active bacterial, viral, fungal, or parasitic infection Advanced liver disease, such as clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy) liver iron concentration ≥15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L. Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients. Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment Unable to receive pRBC transfusion. Prior receipt of an allogeneic transplant. Prior receipt of gene therapy. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin. Immediate family member with a known or suspected Familial Cancer Syndrome. Female subject is breastfeeding, pregnant or will attempt to become pregnant from Screening to at least 6 months after drug product infusion. Any other condition that would render the subject ineligible for HSCT. Participation in another clinical study with an investigational drug within 30 days of screening. Presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) per Investigator's judgment. Presence of genetic mutations that result in the inactivation of 2 or more α-globin genes

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 50 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: bb1111<br>Subjects will receive treatment with a single dose of Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis, transduced with BB305 lentiviral vector (LVV) encoding the human beta-A-T87Q globin gene. Plerixafor mobilization and apheresis will also be used for collection of rescue cells. | Genetic: bb1111<br>* Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.<br>* Other names: autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 LVV encoding the βA-T87Q-globin gene, suspended in cryopreservation solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VOE-CR | Proportion of subjects achieving complete resolution of VOEs between 6 months and 18 months after drug product infusion | 6-18 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| sVOE-CR | Proportion of subjects achieving complete resolution of severe vaso-occlusive events, between 6 months and 18 months after drug product infusion | 6-18 months post-transplant | 
| Proportion of subjects achieving Globin Response | Globin Response, defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion: Weighted average HbAT87Q percentage of non-transfused total Hb* ≥30% AND Weighted average non-transfused total Hb* increase of ≥3 g/dL compared to baseline total Hb* OR weighted average non-transfused total Hb* ≥10 g/dL non-transfused total Hb is the total g/dL of HbS + HbF + HbA2 + HbAT87Q | 6-24 months post-transplant | 
| Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent |  | 1-24 months post-transplant | 
| Change in the annualized number of severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. |  | 1-24 months post-transplant | 
| VOE-CR24 | Proportion of subjects achieving complete resolution of VOEs between 6 months and 24 months after drug product infusion | 6-24 months post-transplant | 
| sVOE-CR24 | Proportion of subjects achieving complete resolution of severe VOEs between 6 months and 24 months after drug product infusion | 6-24 months post-transplant | 
| sVOE-75 | Proportion of subjects achieving at least a 75% reduction in annualized severe VOEs in the 24 months after drug product administration compared to the 24 months prior to Informed Consent. | 1-24 months post-transplant | 
| Weighted average non-transfused total Hb |  | Month 6, 12, 18 and 24 post-transplant | 
| Weighted average HbS percentage of non-transfused total Hb |  | Month 6, 12, 18 and 24 post-transplant | 
| Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% |  | Month 6, 12, 18 and 24 post-transplant | 
| Weighted average HbAT87Q percentage of non-transfused total Hb |  | Month 6, 12, 18 and 24 post-transplant | 
| Weighted average non-HbS percentage of non-transfused total Hb |  | Month 6, 12, 18 and 24 post-transplant | 
| Average and median of non-transfused total Hb |  | 1-24 months post-transplant | 
| Average and median of HbS percentage of non-transfused total Hb |  | 1-24 months post-transplant | 
| Average and median of HbAT87Q percentage of non-transfused total Hb |  | 1-24 months post-transplant | 
| Average and median of non-HbS percentage of non-transfused total Hb |  | 1-24 months post-transplant | 
| Change from baseline in absolute reticulocyte count |  | 1-24 months post-transplant | 
| Change from baseline in percent reticulocytes |  | 1-24 months post-transplant | 
| Change from baseline in percent erythrocytes |  | 1-24 months post-transplant | 
| Change from baseline in total bilirubin |  | 1-24 months post-transplant | 
| Change from baseline in haptoglobin |  | 1-24 months post-transplant | 
| Change from baseline in lactate dehydrogenase |  | 1-24 months post-transplant | 
| Change from baseline in ferritin |  | 1-24 months post-transplant | 
| Change from baseline in liver iron content |  | 1-24 months post-transplant | 
| Change from baseline in cardiac iron content (if assessed at baseline) |  | 1-24 months post-transplant | 
| Change from baseline in erythropoietin |  | 1-24 months post-transplant | 
| Change from baseline in serum transferrin receptor |  | 1 - 24 months post-transplant | 
| Change from baseline in annualized frequency of packed red blood cell (pRBC) transfusions |  | 6-24 months post-transplant | 
| Change from baseline in annualized volume of pRBC transfusions |  | 6-24 months post-transplant | 
| Change from baseline in TCD velocity at Month 12 and Month 24 (for subjects ≤ 16 years old at Informed Consent) |  | Month 12 and Month 24 post-transplant | 
| Change from baseline in meters walked during the 6-minute walk test |  | 1 - 24 months post-transplant | 
| Change from baseline in annualized number of SCD-related hospital admissions |  | 1 - 24 months post-transplant | 
| Change from baseline in annualized number of total days hospitalized |  | 1 - 24 months post-transplant | 
| Change from baseline in patient-reported quality of life, as measured by PROMIS-57 Version 2.1 for subjects ≥ 18 years of age and PROMIS Pediatric Profile/Parent Proxy Profile 49 Version 2.0 for subjects < 18 years of age |  | 1 - 24 months post-transplant |