The side effects of bluebird bio’s gene therapy Skysona (elivaldogene autotemcel) have been thrust back into the spotlight after new data shows seven children who took part in its clinical studies went on to develop a type of blood cancer.
The findings, from a study published in The New England Journal of Medicine (NEJM)yesterday (9 October), show that seven out of 67 patients under 18 years of age who took part in a Phase II and Phase III trial for Skysona developed haematologic cancers. The patients received the one-time autologous hematopoietic stem cell-based gene therapy as a treatment for early cerebral adrenoleukodystrophy (CALD) – a rare and fatal neurodegenerative disease.
Researchers at Boston Children’s Hospital analysed blood and bone marrow samples from patients in the clinical studies ALD-102 (NCT01896102) and ALD-104 (NCT03852498), along with an ongoing follow-up study called LTF-304. The researchers found one patient with haematological cancer from ALD-102, whilst six came from the ALD-104 study. Myelodysplastic syndrome (MDS) accounted for six of the cases, whilst one patient had acute myeloid leukaemia (AML).
“The well-being of patients with CALD treated with Skysona, or who are considering gene therapy following a diagnosis of CALD, is our top priority,” a spokesperson for bluebird bio told Pharmaceutical Technology.
“We recognise that families of children diagnosed with CALD face urgent treatment decisions, and bluebird is committed to ensuring that treating physicians have access to the most up-to-date safety information to support informed decision-making,” the spokesperson added.
Occurrences of blood cancer ranged from 14 months after therapy to around 7.5 years following Skysona treatment. The observed cases of haematologic malignancy appear to be driven by integration of Skysona’s lentiviral vector into a proto-oncogene, as per an FDA analysis document during the therapy’s approval, and the NEJM publication’s authors.
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Other therapies in bluebird bio’s portfolio use different lentiviral vectors. The sickle cell disease treatment Lyfgenia (lovo-cel), for example, uses LentiGlobin BB305.
The risk of secondary malignancies is a known one with gene therapies using such vectors, says GlobalData senior analyst of oncology and haematology Jasminemay Barcelon. She explains, “Insertional mutagenesis, leading to the activation of proto-oncogenes or disruption of tumour suppressor genes, remains a significant concern in lentivirus-based gene therapies, alongside the risks of acute inflammation and genotoxic events.”
Whilst one patient who developed MDS died, four remain cancer-free and without recurrence of CALD whilst the most recently diagnosed individual is awaiting treatment. The patient who developed AML is alive following a stem cell transplant.
“These safety issues are expected to persist among practitioners and patients, posing ongoing challenges in reducing the risk of haematological malignancies,” Barcelon added.
All the cases have been communicated to investigators, an independent data monitoring committee, and the FDA upon being reported to bluebird. Three of the seven haematological malignancies had already occurred when the FDA drew up a regulatory action document for the therapy in 2022.
Whilst the NEJM publication does not outline any new safety risks – the gene therapy’s cancer link already being known and included on the label as a boxed warning – it is the most complete and up-to-date assessment of the treatment’s safety figures.
Skysona is the first and only gene therapy approved in the US and EU to treat early CALD, greenlit in the regions in 2021 and 2022 respectively. The treatment became the most expensive FDA-approved medicine at the time, with a list price of $3.5m.
Skysona is an efficacious option for those with CALD, which primarily affects boys due to its X chromosome-linked nature. In the ALD-102 study, neurological function scores were stable in 30 of the 32 patients, with 26 having no major functional disabilities. Overall survival was 94% after two years, according to a separate paper published in NEJM on the same day as the blood cancer analysis.
Bluebird bio has grappled with weak financial performance, with its gene therapy portfolio struggling to turn a profit. Last month, the company launched a restructuring that involved cutting 25% of its workforce. The sale of priority review vouchers has helped bring quick cash in, but the biotech stated in August that it expects to fund its operations into the second quarter of 2025.
Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.
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