A Study Evaluating the Safety and Efficacy of bb1111 in Severe 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 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).

Detailed Description
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Subject participation for this study will be 2 years post-transplant. 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 an additional 13 years for a total of 15 years post-drug product infusion.

Official Title
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A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe 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: Be ≥12 and ≤50 of age at time of consent. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g.,pain management plan) have experienced at least 4 severe VOEs in the 24 months prior to informed consent. For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a ≥ 24-hour hospital or Emergency Room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age). Have either experienced hydroxyurea (HU) failure at any point in the past or must have intolerance to HU (defined as patient being unable to continue to take HU per PI judgement). Have been treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on SCD history. Exclusion Criteria: Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV). Clinically significant and active bacterial, viral, fungal, or parasitic infection. Inadequate bone marrow function, as defined by an absolute neutrophil count of < 1000/µL (< 500/µL for subjects on HU treatment) or a platelet count < 100,000/µL. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler [≥200 cm/sec] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with radiologic evidence of silent infarction in the absence of any of the above criteria would still be eligible Advanced liver disease, defined as: Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value >3× the upper limit of normal (ULN), or Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of arising from liver disease, or Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up liver biopsy in subjects ≥18 years of age. In subjects <18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary. 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. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin. Prior receipt of an allogeneic transplant. Immediate family member with a known or suspected Familial Cancer Syndrome. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. Participation in another clinical study with an investigational drug within 30 days of Screening. Prior receipt of gene therapy. Patients needing curative anticoagulation therapy during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants are eligible). Unable to receive RBC transfusion.

Ages Eligible for Study
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Minimum Age: 12 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting | Genetic: bb1111<br>* bb1111 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 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution;|
| Experimental: Group B<br>Group B1: Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting Group B2: Plerixafor mobilization and apheresis will be used for collection of rescue cells and exploratory manufacturing development. Subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting | Genetic: bb1111<br>* bb1111 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 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution;|
| Experimental: Group C<br>Plerixafor mobilization and apheresis will be used for collection of rescue cells, and subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by plerixafor mobilization and apheresis transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting | Genetic: bb1111<br>* bb1111 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 lentiviral vector 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 | 6-24 months post-transplant | 
| Change in the annualized number of vaso-occlusive events (VOEs) in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent |  | Through Month 24 post-transplant | 
| Change in the annualized number of severe VOEs in the 24 months after drug product infusion as compared to the 24 months prior to informed consent |  | Through Month 24 post-transplant | 
| VOE-CR24 | Proportion of subject 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 a 75% reduction in annualized severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent | Through Month 24 post-transplant | 
| Proportion of subjects who meet the definition of Globin Response at Month 24 |  | Month 24 post-transplant | 
| Duration of Globin Response |  | 6-24 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 HbAT87Q 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 non-HbS percentage of non-transfused total Hb |  | Month 6, 12, 18, and 24 post-transplant | 
| Average and median of non-transfused total Hb over time |  | Through Month 24 post-transplant | 
| Average and median of HbS percentage of non-transfused total Hb over time |  | Through Month 24 post-transplant | 
| Average and median of HbAT87Q percentage of non-transfused total Hb over time |  | Through Month 24 post-transplant | 
| Average and median of non-HbS percentage of non-transfused total Hb over time |  | Through Month 24 post-transplant | 
| Change from baseline in hemolysis markers |  | Through Month 24 post-transplant | 
| Change from baseline in markers of iron stores |  | Through Month 24 post-transplant | 
| Change from baseline in annualized frequency and volume of packed red blood cell (pRBC) transfusions |  | 6 - 24 months post-transplant | 
| Change from baseline in markers of stress erythropoiesis |  | Through Month 24 post-transplant | 
| Change from baseline in renal function as measured by eGFR |  | Through Month 24 post-transplant | 
| Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF) |  | Through Month 24 post-transplant | 
| Change from baseline in cardiac-pulmonary function via pulmonary function tests |  | Through Month 24 post-transplant | 
| Change from baseline in meters walked during 6-minute walk test |  | Through Month 24 post-transplant | 
| Change from baseline in annualized VOE-related hospital admissions |  | From post-transplant hospital discharge to Month 24 post-transplant | 
| Change from baseline in annualized total days hospitalized |  | From post-transplant hospital discharge to Month 24 post-transplant | 
| Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System (PROMIS) |  | Month 3, 6, 12, 18, and 24 post-transplant |