bluebird bio provides updated findings from reported case of AML in LentiGlobin for sickle cell disease gene therapy program.

bluebird bio, Inc. announced that based on the analyses completed to date, it is very unlikely the Suspected Unexpected Serious Adverse Reaction (SUSAR) of acute myeloid leukemia (AML) reported in its Phase 1/II (HGB-206) study of LentiGlobin gene therapy for sickle cell disease (SCD) (bb1111) was related to the BB305 lentiviral vector (LVV). “In addition to our earlier findings of several well-known genetic mutations and gross chromosomal abnormalities commonly observed in AML in this patient, our latest analyses identified the integration site for the vector within a gene called VAMP4. VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability. Moreover, we see no significant gene misregulation attributable to the insertion event,” said Philip Gregory, chief scientific officer, bluebird bio. “In totality, the data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case and we have shared with the FDA that we believe these results support lifting the clinical holds on our ?-thalassemia and sickle cell disease programs.” As reported by bluebird bio on February 25, 2021, laboratory analyses showed that this patient had significant chromosomal abnormalities and mutations in genes typically associated with the development of AML. Specifically, mutations in the RUNX1 and PTPN11 genes have been detected in the leukemic cells of this patient. Preliminary findings suggested that the BB305 LVV vector was present in the AML blast cells, but there was not sufficient information to determine causality. Since then, and with the advice of several independent leading academic experts in lentiviral vector gene therapy, bluebird bio has performed additional scientific assessments to determine where in the genome the LVV insertion occurred, and if this integration was responsible for any change in gene regulation or gene expression nearby. Multiple independent analyses have confirmed that vector insertion in the AML cells from this patient took place in the VAMP4 gene, or vesicle-associated membrane protein 4. VAMP4 itself has no known role in the development of AML or with any cellular process related to cancer. bluebird bio also assessed if there was any disruption to normal gene regulation or gene expression in and around the site of vector insertion. Based on completed analyses, the insertion into the VAMP4 gene has had no impact on gene expression or gene regulation nor caused any disruption of nearby genes. Based on the available results to date, bluebird bio believes that the case of AML is very unlikely related to the BB305 LVV. Given this, the company has initiated engagement with regulators to begin the process of resuming clinical studies for sickle cell disease and ?-thalassemia. A second SUSAR of myelodysplastic syndrome (MDS) in a patient from Group C of HGB-206 was reported in early February and is currently being investigated to determine if the clinical findings meet the criteria to be classified as a case of MDS and, if so, if LentiGlobin for SCD had any role. The MDS diagnosis was based on prolonged anemia following LentiGlobin for SCD infusion coupled with the observation of trisomy 8 in a small percentage of the patient’s bone marrow cells. However, no blasts or dysplastic cells were seen in an examination of the patient’s bone marrow, and while trisomy 8 is associated with myeloid malignancies, this finding is not sufficient for a diagnosis of MDS in the absence of blasts or dysplastic cells. Regulatory Status : The FDA has placed a clinical hold on the HGB-206 and HGB-210 studies of LentiGlobin for SCD and the HGB-207 and HGB-212 studies of betibeglogene autotemcel for ?-thalassemia. The company is in dialogue with the FDA in order to resume all clinical studies currently on clinical hold.An Article 20 referral procedure was triggered by the European Commission (EC) and will be conducted by the European Medicines Agency (EMA). The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) will begin the process of reviewing the benefit/risk of Zynteglo (betibeglogene autotemcel) for the treatment of transfusion-dependent ?-thalassemia, during its March 8 – 11 session. The committee will determine whether any additional pharmacovigilance measures are necessary. The EMA has paused the renewal procedure for Zynteglo's conditional marketing authorization (CMA) while the PRAC review is ongoing. No cases of hematologic malignancy have been reported in any patient who has received treatment with betibeglogene autotemcel for transfusion-dependent ?-thalassemia, however because it is also manufactured using the same BB305 LVV used in LentiGlobin for SCD, the company decided to temporarily suspend marketing of Zynteglo while the AML case is assessed.