Bluebird Falls! 7 Children Develop Blood Cancer After Receiving Bluebird Bio's Gene Therapy

Bluebird Bio, once a gene therapy unicorn with a market value peaking at $30 billion, now sees its valuation drop below $1 billion, just 0.5% of its former peak.

The latest trigger stems from a study published on Wednesday in The New England Journal of Medicine. Out of 67 children receiving Bluebird Bio's gene therapy, Skysona, in clinical trials, seven eventually developed blood cancer. This means that since June 2022, four additional patients have been diagnosed with blood cancer.

Skysona, developed by Bluebird Bio, is a drug designed to treat early-stage cerebral adrenoleukodystrophy (CALD). In the past, three patients in Skysona's clinical trials developed Myelodysplastic Syndrome (MDS), which is believed to have been caused by the lentiviral vector used by Bluebird to deliver a functional ABCD1 gene into the human genome. Skysona's label already contains a warning stating that the gene therapy could activate oncogenes, potentially leading to blood cancer. Concerns about the three cancer cases led the FDA to hold an external advisory hearing before approving the Skysona therapy.

In June 2022, at the FDA advisory committee meeting, experts unanimously voted in favor of Skysona, finding the evidence for its efficacy in treating CALD convincing and believing that the benefits outweighed the risks. In September 2022, the FDA granted accelerated approval for Skysona (also known as eli-cel) to slow the progression of neurodegenerative decline in boys aged 4 to 17 with early active cerebral adrenoleukodystrophy.

The primary paper from The New England Journal of Medicine reveals that among the 67 patients treated with Skysona, seven developed blood cancers after treatment. Six of these seven cases were diagnosed as Myelodysplastic Syndrome (MDS), a rare neurodegenerative disease, occurring between 14 and 92 months after Skysona treatment. The seventh child was diagnosed with Acute Myeloid Leukemia (AML) 57 months post-treatment. Following this, six patients underwent stem cell transplants, with one dying from suspected graft-versus-host disease. The seventh patient is awaiting a stem cell transplant.

Researchers suggest the new cases of blood cancer are related to clonal vector insertions into cancer-related genes and the accumulation of somatic mutations at certain hotspots of interest, including KRAS, WT1, and CDKN2A. 

While lentiviral vector therapies can occasionally trigger cancer, Skysona therapy seems to carry a higher risk, which may be linked to the design of the lentiviral vector used. The Skysona vector design includes a viral promoter intended to boost gene expression. However, one potential risk of such promoters is the induction of cancer.

Bluebird Bio is also marketing two other gene therapies: one called Zynteglo, used to treat severe beta-thalassemia, and another called Lyfgenia, designed to treat sickle cell disease. These two therapies use different lentiviral vectors with different promoters. 

On December 8, 2023, the FDA approved Lyfgenia, a gene therapy for patients aged 12 and older with a history of vaso-occlusive events due to sickle cell disease. This gene therapy uses a lentiviral vector to genetically modify hematopoietic stem cells, enabling them to produce a derived hemoglobin, HbAT87Q, which functions similarly to normal adult hemoglobin to reduce the formation of sickled cells and alleviate symptoms.

In Lyfgenia’s trials, one patient developed leukemia, though researchers determined it was unlikely to have been caused by the treatment. Sickle cell patients are inherently at higher risk of leukemia.

As of this year, 41 patients have initiated treatment with one of Bluebird’s three therapies, with the company expecting approximately 40 additional patients to begin treatment in the fourth quarter. Adoption of these therapies is critical for Bluebird, which has been struggling with ongoing financial challenges over the past two years. According to a statement from Bluebird Bio on September 24, the company will cut 25% of its workforce as part of a restructuring plan aimed at optimizing its cash structure, targeting a 20% reduction in cash burn, and helping the company achieve cash flow breakeven in the second half of 2025.