- Bluebird bio has stopped two clinical studies of its gene therapy for sickle cell disease after one participant developed leukemia and researchers reported another has a cancer-like disease of the bone marrow.
- A patient treated five years ago as part of the first group enrolled in a Phase 1/2 study of Bluebird's study was recently diagnosed with acute myeloid leukemia, Bluebird said Tuesday. Another study participant, who was enrolled in a later group of that trial, is reported to have developed myledoysplastic syndrome, the second such case to occur in testing of the gene therapy since 2018. Bluebird is investigating to determine the cause.
- The news from Bluebird comes about two months after an unexpected cancer diagnosis in a gene therapy trial run by UniQure, renewing old safety concerns that had chilled research in the field years ago. Bluebird said it will work with regulators in the U.S. and Europe to complete its investigation. In the meantime, however, the company has stopped sales of its only approved product, Zynteglo, a similar gene therapy that's authorized in Europe and the U.K. for beta thalassemia.
The possibility gene-based treatments could spur development of rare cancers has shadowed gene therapy researchers for decades. In the early 2000s, several children with a rare immune condition developed leukemia between three and six years after receiving an experimental gene therapy in a small study.
The children's diagnosis added to other, unrelated safety concerns spurred by the 1999 death of a U.S. teenager treated in a gene therapy trial, and resulted in a broader reevaluation by researchers of their approach.
Since then, scientists began using different tools — thought to be safer and less likely to cause cancer — to make their gene-based treatments. Over the past several years, gene therapy research has rapidly accelerated, with hundreds of new studies launched and two landmark approvals in the U.S.
Bluebird's been at the forefront of that development boom, although clinical delays and manufacturing setbacks have hurt its progress. The cases of leukemia and myelodysplastic syndrome reported Tuesday could have a more lasting impact on the company's research, although both are still being assessed to determine whether gene therapy was the cause.
"I would like to caution everyone up front to resist the temptation to draw premature conclusions and let the rapidly emerging data lead the way," said Nick Leschly, Bluebird's CEO, on a Tuesday conference call.
Bluebird's treatment, called LentiGlobin, is created from stem cells extracted from each patient. The cells are engineered in a laboratory using a type of virus called a lentivirus, which delivers a functional copy of the gene that's mutated in sickle cell. Lentiviruses integrate, or merge, with the genome of the target cells, which are reinfused into the body to produce anti-sickling hemoglobin.
That "viral vector," known as BB305, is the focus of Bluebird, which said it's evaluating whether there's any relationship between BB305 and the study volunteer's acute myeloid leukemia. Viral vectors are the first suspect for cancer cases involving gene therapy, because their interaction with cell genomes carries a risk of triggering unwanted mutations. Lentiviruses are considered safer than the retroviruses previously used in early gene therapies.
Acute myeloid leukemia and myleodysplastic syndrome, or MDS, can also be the result of the chemotherapy treatment used to prepare patients for an infusion of gene-corrected stem cells. The earlier MDS case was determined by an independent data monitoring committee to be unlikely related to LentiGlobin.
On Tuesday's call, Bluebird offered several possible explanations, noting the possibility of a spontaneous genetic mutation as well as the higher rate of blood cancers in patients with sickle cell.
Leschly also acknowledged the vector could be to blame, however. Bluebird has detected sequences of the vector in cancerous cells of the patient with AML. But it's unclear whether the vector is a contributor to the disease or a "passenger to a cell that has acquired a malignant phenotype," Leschly said. The cancerous cells, for instance, have a mutation commonly associated with AML.
"This question," he added, "is at the heart of our research effort that is ongoing."
Bluebird is trying to determine where the vector integrated into the cell's genome, aiming to assess proximity to the genes that triggered the patient's cancer. The company will also examine whether the vector influenced gene expression, said chief scientific officer Phillip Gregory.
Leschly expects to complete the investigation in "weeks" and hopes the outcome won't impact planned regulatory filings for LentiGlobin.
There have been no cases of blood cancers developing in patients treated in the EU or the U.K. with Zynteglo, which is made similarly to LentiGlobin.
But "because it is also manufactured using the same BB305 lentiviral vector used in LentiGlobin gene therapy for [sickle cell disease] the company has decided to temporarily suspend marketing of Zynteglo while the AML case is assessed," Bluebird said in its Tuesday statement.
Whether or not LentiGlobin is ultimately determined to have caused either the AML or MDS case, their occurrence so soon after the cancer diagnosis in UniQure's gene therapy trial could raise fresh concerns among scientists and regulators about the risks of gene therapy.
Bluebird shares fell 32% Tuesday morning, to roughly $31 apiece, the stock's lowest price since 2014.