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

Genetix Biotherapeutics Inc.7 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Beta-Thalassemia Major Sickle Cell Disease

Interventions

LentiGlobin BB305 Drug ProductDRUG

LentiGlobin BB305 Drug Product was administered by intravenous (IV) infusion.

Eligibility

Sex: ALLMin age: 5 YearsMax age: 35 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Be between 5 and 35 years of age, inclusive. 2. 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). 3. Be eligible for allogeneic hematopoietic stem cell transplant (HSCT) based on institutional medical guidelines, but without a matched related donor. 4. Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol. 5. 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: 6. 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. 7. 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. 8. 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: 1. 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. 2. Clinically significant, active bacterial, viral, fungal, or parasitic infection. 3. Contraindication to anesthesia for bone marrow harvesting. 4. Any prior or current malignancy, myeloproliferative or immunodeficiency disorder. 5. A white blood cell (WBC) count \<3×10\^9/L and/or platelet count \<120×10\^9/L. 6. 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.

Locations (1)

Unnamed facility

Paris, France

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: From time of drug product infusion through Month 24