Seven pediatric patients who received Bluebird Bio's Skysona gene therapy for cerebral adrenoleukodystrophy (CALD) developed blood cancers, according to a study published in The New England Journal of Medicine. The findings raise concerns about the long-term safety of lentiviral vector-based gene therapies.
Details of the Study
Researchers analyzed data from 67 patients under 18 years of age who participated in Phase II and Phase III trials (ALD-102 and ALD-104) and a follow-up study (LTF-304). Six patients were diagnosed with myelodysplastic syndrome (MDS), and one with acute myeloid leukemia (AML), developing between 14 and 92 months after Skysona treatment. Six patients with MDS underwent stem cell transplantation, with one succumbing to graft-versus-host disease. The AML patient responded well to transplant. The study links these cancers to clonal vector insertions in genes such as KRAS, WT1, and CDKN2A.
Skysona and Cerebral Adrenoleukodystrophy (CALD)
Skysona (elivaldogene autotemcel) is a gene therapy designed to treat early cerebral adrenoleukodystrophy (CALD), a rare and fatal neurodegenerative disease primarily affecting boys. It delivers functional copies of the ABCD1 gene into hematopoietic stem cells, promoting the production of ALDP, a protein crucial for breaking down very long chain fatty acids. The FDA granted Skysona accelerated approval in September 2022 based on the Phase II/III Starbeam trial, which demonstrated major functional disability-free survival over 24 months.
Safety Warnings and Previous Holds
Skysona's label includes a boxed warning for hematologic malignancies, reflecting the risk of MDS. In August 2021, the FDA placed a clinical hold on the development program after a patient developed MDS. An FDA analysis and the NEJM publication suggest the malignancies are driven by the lentiviral vector integrating into proto-oncogenes.
Implications for Bluebird Bio
The emergence of these safety signals coincides with the recent launch of Bluebird's Lyfgenia, a gene therapy for sickle cell disease. While Lyfgenia uses a different lentiviral vector (LentiGlobin BB305), the findings underscore the need for continued vigilance regarding the long-term safety of gene therapies. Bluebird Bio has acknowledged these cases and emphasizes its commitment to providing physicians with up-to-date safety information. The company has faced financial challenges, including recent restructuring and workforce reductions.
Expert Analysis
According to GlobalData senior analyst Jasminemay Barcelon, insertional mutagenesis remains a significant concern with lentivirus-based gene therapies. While Skysona has shown efficacy in stabilizing neurological function in CALD patients, the risk of secondary malignancies poses ongoing challenges for reducing the risk of haematological malignancies.
