Bluebird Says Case of AML Unlikely Related to Gene Therapy Vector

Rare Daily Staff

Bluebird Bio said based on the analyses completed to date, it is very unlikely the case of acute myeloid leukemia reported in its phase 1/2 LentiGlobin gene therapy HGB-206 for sickle cell disease was related to the lentiviral vector used and it is asking regulators to let it resume clinical studies.

The U.S. Food and Drug Administration 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 β-thalassemia.

An Article 20 referral procedure was triggered by the European Commission and will be conducted by the European Medicines Agency. The EMA’s Pharmacovigilance Risk Assessment Committee will begin the process of reviewing the benefit/risk of Zynteglo for the treatment of transfusion-dependent β-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 while the review is ongoing.

No cases of hematologic malignancy have been reported in any patient who has received treatment with Zynteglo for transfusion-dependent β-thalassemia, however because it is also manufactured using the same BB305 LVV used in LentiGlobin for sickle cell disease, the company decided to temporarily suspend marketing of Zynteglo while the AML case is assessed.

Bluebird Bio reported on February 25 that 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, the company has consulted with independent academic experts in lentiviral vector gene therapy. Bluebird Bio also 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.

The company said 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 looked to see 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, the company said it 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 β-thalassemia.

“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,” said Philip Gregory, chief scientific officer, Bluebird Bio. “We have shared with the FDA that we believe these results support lifting the clinical holds on our β-thalassemia and sickle cell disease programs.”

A second suspected unexpected serious adverse reaction of myelodysplastic syndrome 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.