Bluebird Bio has lifted the voluntary suspension on products containing its Zynteglo gene therapy after the EMA concluded the beta thalassemia therapy’s benefits outweigh its risks.

The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) published its findings last week, concluding that there is “no evidence” Zynteglo causes a blood cancer known as acute myeloid leukaemia (AML).

The EMA wrote “The PRAC reviewed two cases of AML in patients treated with an investigational medicine, bb1111 [also known as LentiGlobin] in a clinical trial for sickle cell disease.

Image: iStock/Aycan

“Although there have been no reports of AML with Zynteglo, both medicines use the same viral vector and there was a concern that the vector may be implicated in the development of the cancer, insertional oncogenesis.”

A company spokesperson welcomed the EMA finding, telling us “The review found that the viral vector was unlikely to be the cause of the two cases of acute myeloid leukaemia (AML) reported.

“In one of the patients, the viral vector was not present in the cancer cells, and in the other patient it was present at a site (VAMP4) that does not appear to be involved in cancer development.

He added that, “No cases of hematologic malignancy have been reported in any patient who has received treatment with Zynteglo.”

Blood cancers

Bluebird voluntarily suspended Zynteglo sales in February after initial reports suggested two patients involved in bb1111 studies developed blood cancer.

The spokesman told us “The first patient was part of Group A of HGB-206 and had been diagnosed with myelodysplastic syndrome (MDS) in 2018, approximately three years after receiving conditioning chemotherapy in preparation for treatment with LentiGlobin for SCD. Sadly, this patient passed away due to relapsed acute myeloid leukemia (AML) in July 2020.”

“An analysis of the patient’s cells showed no evidence of vector mediated insertional oncogenes. The development of MDS was unlikely related to LentiGlobin for SCD as determined by the independent data monitoring committee and the primary investigator treating the patient.

He added that, “The patient’s MDS was attributed to the use of busulfan, the conditioning chemotherapy agent in used in LentiGlobin for SCD studies. Treatment with LentiGlobin for SCD, like other gene therapies and standard bone marrow transplantation, requires chemotherapy agents to remove old stem cells from the bone marrow. Busulfan is in standard chemotherapy regimens for conditioning.”

The spokesman also told us “The case of MDS reported in February in a patient from Group C of the Phase 1/2 HGB-206 study of LentiGlobin gene therapy for SCD was further assessed following the review of results from additional tests. The treating investigator concluded it was not a case of MDS and revised the diagnosis to transfusion-dependent anemia.

“bluebird bio continues to work with the treating investigator to determine the potential cause of this patient’s anemia.”

Manufacturing

The spokesman told us that no changes have been made to the Zynteglo manufacturing process as a result of the suspension.

In contrast, the manufacturing process for bb1111 has been modified.

He told us “During the development of LentiGlobin for SCD bluebird bio made changes to the manufacturing process and the way it collected hematopoietic stem cells from patients. The conditioning agent used in bluebird bio’s studies remains busulfan, though the dosing regimen was changed to improve myeloablation.”