A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease

Study Overview
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Brief Summary
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This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to participants with either transfusion dependent beta-thalassemia (TDT) or sickle cell disease (SCD).

Official Title
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A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the β-Hemoglobinopathies (Sickle Cell Anemia and β-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral β-A-T87Q Globin Vector (LentiGlobin BB305 Drug Product)

Conditions
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Beta-Thalassemia Major, Sickle Cell Disease

Intervention / Treatment
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* Drug: LentiGlobin BB305 Drug Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between 5 and 35 years of age, inclusive. Have severe SCD or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs). Be eligible for allogeneic hematopoietic stem cell transplant (HSCT) based on institutional medical guidelines, but without a matched related donor. Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol. Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history. Participants with severe SCD also must: Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated. Have 1 or more of the following poor prognostic risk factors: Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program). Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions). Stroke without any severe cognitive disability. Osteonecrosis of 2 or more joints. Anti-erythrocyte alloimmunization (>2 antibodies). Presence of sickle cell cardiomyopathy documented by Doppler echocardiography. Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever [>38.5°C], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Participants with a chronic oxygen saturation <90% (excluding periods of SCD crisis) or carbon monoxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study. Participants with severe SCD and cerebral vasculopathy (defined by overt stroke; abnormal transcranial Doppler [> 170 cm/sec]; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease) may be enrolled only with approval by the Comite de Surveillance after review of safety and efficacy data from >or= 2 SCD participants without cerebral vasculopathy treated with LentiGlobin BB305 Drug Product Exclusion Criteria: Availability of a willing 10 /10 matched human leukocyte antigen (HLA) identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comite de Surveillance following a review of the case. Clinically significant, active bacterial, viral, fungal, or parasitic infection. Contraindication to anesthesia for bone marrow harvesting. Any prior or current malignancy, myeloproliferative or immunodeficiency disorder. A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L. History of major organ damage including: Liver disease, with transaminase levels >3× upper limit of normal. This observation will not be exclusionary if a liver biopsy shows no evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis. Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy. Heart disease, with a left ventricular ejection fraction <25%. Kidney disease with a calculated creatinine clearance <30% normal value. Severe iron overload, which in the opinion of the physician is grounds for exclusion. A cardiac T2* <10 ms by magnetic resonance imaging (MRI). Evidence of clinically significant pulmonary hypertension requiring medical intervention.

Ages Eligible for Study
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Minimum Age: 5 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: LentiGlobin BB305 Drug Product<br>Following myeloablative conditioning with IV busulfan for 4 consecutive days (dose may be adjusted as per protocol) and subsequent daily monitoring of busulfan levels for confirmation of adequate washout, a single dose cluster of differentiation (CD) 34+ cells/kg LentiGlobin BB305 Drug Product was administered to participants by IV infusion. | Drug: LentiGlobin BB305 Drug Product<br>* LentiGlobin BB305 Drug Product was administered by intravenous (IV) infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treated Participants With Successful Neutrophil and Platelet Engraftment | Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) > or = 0.5 × 10^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (<) 0.5 × 10^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for participants with TDT and values > or =50 × 10^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements. | From time of drug product infusion through Month 24 | 
| Time to Successful Neutrophil and Platelet Engraftment | Neutrophil engraftment was defined as the first of ANC > or = 0.5 × 10^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value < 0.5 × 10^9/L). Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for participants with TDT and values > or =50 × 10^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements. | From time of drug product infusion through Month 24 | 
| Incidence of Transplant Related Mortality | This was the safety outcome measure related to mortality. Transplant related mortality was defined as any death occurring in the study post drug product infusion deemed related to the transplant by the investigator. | From screening through 365 days post-transplant | 
| Number of Participants With Overall Survival (OS) Events | Overall survival was defined as time from date of LentiGlobin BB305 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive. Number of participants with OS events were reported. | From time of drug product infusion through Month 24 | 
| Percentage of Participants With Vector-Derived Replication-Competent Lentivirus (RCL) | Blood samples were analyzed for detection of RCL using RCL co-culture assay. | From time of drug product infusion through Month 24 | 
| Number of Treated Participants With Greater Than (>) 30 Percent (%) Contribution of an Individual Clone As Per Integration Site Analysis (ISA) | Clonal dominance was defined as an ISA result greater than (>) 90% of the total insertion sites (IS) at any time and a vector copy number (VCN) > or =0.3, or an initial ISA result of > 30% of the total IS with a VCN > or =0.3 followed by a result > 30% and less than or equal to (< or =) 90% at first repeat and a result > 50% at second repeat. | From time of drug product infusion through Month 24 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study. This definition includes inter-current illnesses or injuries, and exacerbation of pre-existing conditions. An SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed previously. The number of participants with AEs and SAEs were evaluated. | From date of Informed Consent signing up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Treated Participants With Transfusion-Dependent β-Thalassemia (TDT) Who Achieved Transfusion Independence (TI) | TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. | From time of drug product infusion through Month 24 | 
| Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) | TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. | From time of drug product infusion through Month 24 | 
| Duration of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) | TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This outcome measure reports the duration of TI and was evaluated in the TDT Transplant Population (TP) that reached TI. | From time of drug product infusion through Month 24 | 
| Time From LentiGlobin BB305 Drug Product Infusion to Last Packed Red Blood Cells (pRBC) Transfusion Prior to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) | TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This endpoint reports the time from infusion to the last pRBC transfusion prior to achieving TI. | From time of drug product infusion through Month 24 | 
| Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) | TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This outcome measure reports the time from infusion to achievement of TI. | From time of drug product infusion through Month 24 | 
| Weighted Average Nadir Hemoglobin (Hb) in Participants With Transfusion-Dependent β-Thalassemia (TDT) | Weighted average Hb nadir was defined as an average area under the curve where the Hb closest but within 3 days prior to a transfusion was used as the Hb nadir. Hb values on the day of the transfusion were considered for nadir calculations. | From 6 months post-drug product infusion through Month 24 | 
| Percentage Change From Baseline in Annualized Packed Red Blood Cell (pRBC) Transfusion Volume | Percent change from baseline in the average annual transfusion volume from 6 months post-drug product infusion through last visit were reported. | Baseline, From 6 months post-drug product infusion through Month 24 | 
| Percentage Change From Baseline in Annualized Number of Packed Red Blood Cell (pRBC) Transfusions | Percentage change from baseline in annualized number of pRBC transfusions from 6 months post-drug product infusion through last visit were reported. | Baseline, From 6 months post-drug product infusion through Month 24 | 
| Number of Participants With Vaso-Occlusive Crisis (VOC) and/or Acute Chest Syndrome (ACS) Events Post Drug Product Infusion in Sickle Cell Disease Participants | Number of VOCs, ACS, and vaso-occlusive events (VOEs; which included both VOC and ACS) through 24 months after drug product infusion. | From time of drug product infusion through Month 24 | 
| Therapeutic Globin Expression Measured by Hb Containing β^A -T87Q Globin (HbA^T87Q) in Peripheral Blood | Therapeutic globin expression was measured by HbA^T87Q in peripheral blood and the ratio of alpha(α)- globin to all beta (β)-like-globins. The relative amount of each globin produced by a participant (including βA^A-T87Q globin) was determined in peripheral blood throughout the study. | From time of drug product infusion through Month 24 | 
| Vector Copy Number (VCN) in Peripheral Blood | LentiGlobin BB305 lentiviral vector (LVV) transduction efficiency was measured by VCN. The presence of vector sequences in the genomic DNA of cells is detected using quantitative polymerase chain reaction (qPCR), and results were expressed as VCN. | From time of drug product infusion through Month 24 |