For the first time in half a decade, the FDA will convene to address two therapies developed by bluebird bio that could have ripple effects across the industry regarding lentiviral vectors.
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For the first time in half a decade, the U.S. Food and Drug Administration’s Cell, Tissue and Gene Therapies Advisory Committee will convene to address two therapies developed by bluebird bio in back-to-back meetings that will draw the eyes of all companies developing lentiviral vectors as potential therapeutics for rare diseases.
For Cambridge, Mass.-based bluebird, the two-day meetings will be a huge moment in a watershed year for the beleaguered company that laid off nearly one-third of its employees in April. Not only will the advisory committee help shape the future for beti-cel and eli-cel, gene therapies that are already marketed in Europe, it could likely shape the future of the company that has been battered by financial woes. Like a spelunker carefully exploring a newly-discovered cave, the bluebird team, along with the scientists who make up the advisory committee, will be navigating new regulatory territory in gene therapy. The discussions set for June 9 and 10 will have ripple effects across the industry regarding other lentiviral vectors that could come before the regulatory committee.
Tuesday, the FDA posted briefing documents ahead of the advisory committee meetings. The PDUFA date for beti-cel is Aug. 19 and for eli-cel, which has a more complicated history, is set for Sept. 16. At issue is the concern of insertional oncogenesis, the potential cause of a malignant mutation, caused by the gene therapy.
Eli-cel, also known as elivaldogene autotemcel, will be the first bluebird program to be discussed by the advisory committee. Eli-cel was previously approved in Europe under the brand name Skysona. It was approved last year as a treatment for juvenile patients with early Cerebral Adrenoleukodystrophy (CALD), a serious neurological disorder caused by mutations in the ABCD1 gene. CALD typically develops in a juvenile around the age of 7. The rare, progressive, x-linked disorder is ultimately fatal but not before sending the patient into a vegetative state.
Eli-cel uses ex vivo transduction with the Lenti-D lentiviral vector (LVV) to add functional copies of the ABCD1 gene into a patient’s hematopoietic stem cells (hsc). The addition of the functional ABCD1 gene allows patients to produce the ALD protein, which is thought to facilitate the breakdown of very long-chain fatty acids, causing the breakdown of myelin, the protective sheath around nerve cells in the brain.
Throughout the course of its development, eli-cel has shown positive efficacy. But, at the same time, there have been some safety concerns, which the FDA advisory committee members will likely discuss in detail. The eli-cel study was hit with a clinical hold in 2021 over safety concerns after a patient treated with the gene therapy developed a rare form of cancer, myelodysplastic syndrome.
There are no FDA-approved therapies for CALD. The committee will have to weigh whether or not the efficacy of eli-cel outweighs the risks for these juvenile patients.
On day two, the advisory committee will assess beti-cel, which is being developed for the blood disorder beta-thalassemia. Beti-cel is marketed as Zynteglo in Europe. Beti-cel is one-time gene therapy to treat beta-thalassemia in patients who need regular transfusions of red blood cells. In Phase III trials of beti-cel, 89% of patients who could be evaluated achieved transfusion independence. With beti-cel, there have not been the same safety concerns seen with eli-cel.
In its briefing documents, the FDA noted that beti-cel has been free of insertional oncogenesis concerns but highlighted concerns that have been seen in other LVV candidates, including eli-cel. The FDA said considering the similarities between the two gene therapy candidates, the committee will have to carefully weigh the concerns. Also, the committee will be tasked with discussing whether or not it will recommend screening patients for potential germline and somatic mutations predisposed to hematologic malignancy prior to administration of beti-cel.
The advisory committee meetings this week will be closely monitored by companies across the globe as the bar will be set for LVV gene therapies.
