FDA lets bluebird resume trials for sickle cell gene therapy after cancer scare, but big questions linger over field
Bluebird bio announced that the FDA has lifted its holds on clinical trials for their gene therapies for sickle disease and beta-thalassemia, ending a 4-month saga that began after the biotech reported that two patients had come down with cancer and a cancer-like condition.
Regulators were concerned that the cases may have been triggered by the virus bluebird uses to deliver a healthy gene for hemoglobin into patients with rare blood disorders, as had happened in a 2004 gene therapy trial that relied on a similar virus. Bluebird largely allayed those concerns in March, when they released a genetic analysis showing that the virus didn’t interfere with the patient’s DNA in a way likely to trigger cancer, but experts say the cases have broadly raised concerns about the risks any of the more than half dozen of sickle disease gene therapies now in clinical development may pose.
Akshay Sharma, a pediatric bone marrow specialist at St. Jude, said doctors already knew people with sickle cell disease are at greater risk of developing leukemia. But the cases highlighted how any form of genetic manipulation — including the CRISPR-based approaches Vertex, Novartis, Beam and others are pursuing — could exacerbate that predisposition.
“We definitely need more research to understand exactly what is this predisposition, and once we know it, only then will we satisfactorily answer this question: Is it safe or not?” Sharma, who has served as an investigator on gene therapy trials, told Endpoints News. “And I think the answer may be in the middle. Perhaps these genetic therapies are safe for most patients, but some patients are at greater risk.”
For bluebird, the hold was another in a series of setbacks the Cambridge biotech has faced in the years since they first showed data from a handful of patients suggesting that their gene therapy can be a functional cure for sickle cell disease. Unable to prove to the FDA they could manufacture their product safely at scale, they’ve repeatedly pushed back the date for filing for approval.
Most recently, they pushed their timeline into late 2022, although that was before the FDA hold came down. The delays have allowed Vertex and CRISPR Therapeutics to catch up with a gene editing approach that entered the clinic five years later. The two now believe they will be first-to-market with a sickle cell cure, which could provide a major commercial advantage.
In February, bluebird announced that a sickle cell patient who received their gene therapy five years prior was diagnosed with acute myeloid leukemia. A second, they said, had been diagnosed with a suspected case of myelodysplastic syndrome, a cancer-like disease that occurs in the bone marrow. They later said the latter case was in fact a misdiagnosed case of transfusion-dependent anemia.
Although bluebird’s analysis showed that the virus bluebird uses — a re-engineered form of HIV, called a lentivirus — didn’t interfere with genes known to cause cancer, Sharma said the therapy could have elevated the patients’ risks in other ways. It could have made more subtle genetic alterations, or the chemotherapy “conditioning” regiment patients prior to the therapy could have made them more susceptible.
After a patient who received bluebird’s therapy was diagnosed with myelodysplastic syndrome in 2018, the company attributed it to the chemotherapy.
Recent studies, Sharma noted, have linked the risk of leukemia after a transplant to specific genetic mutations. Researchers need to develop methods of screening for patients who have that mutation and potentially other mutations that could put them at greater risk and quantify precisely how high that risk is. They will also need ways of minimizing those risks, such as by developing safer alternatives to chemotherapy — a task companies such as Magenta and Jasper Therapeutics are now working on.
He emphasized that it would not be a problem just for bluebird but to any of the nearly dozen attempts to cure sickle cell disease now at or near the clinic.
“If somebody has a predisposition,” he said, “any type of genetic alteration or exposure to chemotherapy could accelerate that and lead to leukemia.”