February 18, 2021
Bluebird Bio’s suspension of trials of its sickle cell gene therapy LentiGlobin has put the vector used to make it in the spotlight.
The US biotech announced the temporary suspension of two LentiGlobin trials – specifically HGB 206 NCT02140554 and HGB 210 NCT04293185 – this week.
It said the measure was prompted by reports a patient in group A of the Phase I/II HGB-206 study treated with the therapy five years ago had developed acute myeloid leukemia (AML).
Image: iStock/Marta Ortiz
Bluebird also said a case of myelodysplastic syndrome (MDS) in a patient from Group C of the HGB-206 trial reported last week is under investigation.
CEO Nick Leschly said told analysts “We have made the decision to voluntarily and temporarily place a clinical hold on the ongoing Phase I/II HGB 206 and Phase III HGB 210 study of Lentiglobin for sickle cell.
“In both studies the BB305 lentiviral vector is used to manufacture the drug product used to treat patients and we are working to determine whether this specific vector played a potential role in these events.”
In addition, Bluebird has stopped selling Zynteglo (betibeglogene autotemcel) – its gene therapy for transfusion-dependent β-thalassemia – in the EU and UK because it is also made using the BB305 vector.
The BB305 is a replication defective, self-inactivating vector that uses erythroid-specific globin gene regulatory elements. The technology is used to introduce functioning genes into cells.
In Zynteglo, for example, the vectors are filled with a sequence encoding the HBB gene – which is defective in thalassemia – into the patient’s blood-producing hematopoietic stem cells (HSC).
What role, if any, BB305 played in the two cases remains to be seen.
Leschly told analysts there are multiple potential causes that are not related to the vector, citing spontaneous mutation, genetic abnormalities or the underlying genetics of the sickle cell disease itself.
However, vector-related causes are being considered. Bluebird is looking at a process called “insertional oncogenesis,” which is when malignancies occur after genetic material is introduced into cellular DNA.
Leschly said “Lentiglobin uses a self-inactivating lentiviral vector with a lineage specific promoter that has been specifically designed to minimize the risk of insertional oncogenesis.”
He added that while “no evidence of insertional oncogenesis related to lentiviral vector based hemopoietic stem cell gene therapy has been reported in any indication thus far, this remains an area of inquiry.”
“For the MDS case we do not yet know if the tumor cells are carrying a vector sequence. For the AML case we have been able to detect vector in these cells, but do not yet have sufficient information to determine causality.
“Specifically, if the BB305 integration event is a contributor to the disease or simply a passenger to a cell that has acquired a malignant phenotype via means that remain to be determined.”
The AML case is not the first malignancy reported in the HGB 206 study.
In 2018, Bluebird reported a patient in Group A of the 206 study who received LentiGlobin three years prior in had developed myelodysplasia syndrome.
At the time the firm made clear the vector was not involved, writing “analysis of the patient’s cells showed no evidence of vector mediated insertional oncogenesis.
It also said “the independent data monitoring committees, along with the treating physician, agreed the SAE was unlikely related to LentiGlobin gene therapy.”
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