bluebird seeks gene therapy trial restart after cancer scare

bluebird bio is to ask regulators to restart clinical studies of its LentiGlobin for sickle cell disease, after an investigation concluded that a case of acute myeloid leukaemia (AML) was "very unlikely" to be caused by the gene therapy.

Known as Zynteglo in Europe where it is approved to treat the rare blood disorder beta-thalassemia, the gene therapy has been given the all-clear by bluebird’s scientists after reviewing the case of AML that emerged in a trial of the drug in sickle cell disease.

If regulators such as the FDA accept the findings it will also leave bluebird free to continue negotiations with NICE over funding in England and Wales to treat beta thalassemia after an initial rejection.

The US biotech said the suspected serious adverse reaction reported in the phase 1/2 study of LentiGlobin gene therapy for sickle cell disease was unlikely to be related to the virus vector used in the therapy, used to deliver the genetic material to the body.

Cancer is a perennial fear for therapies that involve altering DNA in cells, because of the risk that the viruses used to deliver genes into patient cells could inadvertently lodge in the wrong place on a chromosome, triggering a mutation or disrupting a mechanism that guards against a cell becoming cancerous.

Philip Gregory, chief scientific officer at bluebird, said the latest analysis showed that the integration site of the vector was in a gene called VAMP4.

bluebird bio's Philip Gregory

VAMP4 has no known association with development of AML or with processes such as cellular proliferation or genome stability that could be linked with cancer.

He added: “We have seen no significant gene misregulation attributable to the insertion event.

“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 beta-thalassemia and sickle cell disease programs.”

Laboratory analyses showed that the patient who developed AML had significant chromosomal abnormalities and mutations in the RUNX1 and PTPN11 genes typically associated with the development of the disease.

Findings suggested that the BB305 LVV vector was present in the AML blast cells, but there was not sufficient information to determine causality.

Vector insertion in the AML cells from this patient took place in the VAMP4 gene, or vesicle-associated membrane protein 4 – but the gene itself has no known role in the development of AML or with any cellular process related to cancer.

Insertion into the VAMP4 gene has had no impact on gene expression or gene regulation nor caused any disruption of nearby genes, bluebird added.

Shares in bluebird ticked up following the announcement.