The European Medicines Agency (EMA) was notified by a gene therapy firm that the company has suspended marketing of its beta thalassemia treatment Zynteglo (betibeglogene autotemcel, bluebird bio) as a precautionary measure.
 
In a press release, the agency related that bluebird bio’s actions came after a recipient of the related bb1111 gene therapy for sickle cell disease developed acute myeloid leukemia (AML). Another bb1111 recipient has also developed myelodysplastic syndrome (MDS), according to bluebird bio.
 
All clinical trials of bb1111 for sickle cell disease are temporarily suspended per trial protocols as the Suspected Unexpected Serious Adverse Reaction (SUSAR) cases are investigated; the lentiviral vector therapy has both Phase 1/2 and Phase 3 trials ongoing.
 
“Cancer caused by this type of treatment (insertional oncogenesis) was already identified as a potential risk with Zynteglo, so patients who receive the medicine are followed up and monitored in a registry,” noted EMA in its announcement.
 
The reported case of AML occurred more than 5 years after the patient received the proprietary LentiGlobin gene therapy. The two patients reporting malignancies were in separate arms of bb1111’s development program; the individual diagnosed with MDS received lentiviral therapy developed via “a refined manufacturing process designed to increase vector copy number (VCN) and further protocol refinements made to improve engraftment potential of gene-modified stem cells,” according to bluebird bio’s announcement. This group also received plerixafor mobilization and then was engrafted with hematopoietic stem cells from peripheral blood, rather than the bone marrow harvest process used with the other two study arms, including the individual diagnosed with AML.
 
Zynteglo received conditional marketing authorization in the EU in May 2019 for transfusion-dependent patients with beta thalassemia 12 years and older with certain genotypes who do not have a human leukocyte antigen-matched donor; currently, Germany is the only country in the EU where Zynteglo is marketed. The treatment is also authorized in the United Kingdom.
 
The firm reported in November 2020 that its plans for a biological license application (BLA) submission to the US Food and Drug Administration (FDA) were being pushed back to 2022 as FDA and bluebird bio worked out details of demonstrating drug product comparability; pandemic-associated issues contributed to delays as well.
 
“EMA is liaising closely with the company and experts within the regulatory network, and will now examine the evidence at EU level and decide on any relevant regulatory action for Zynteglo or any similar medicines under evaluation,” wrote the regulator, noting that no other currently authorized products use this lentiviral vector, “so no direct implications are foreseen for other licensed medicines.”
 
EMA