Rare Daily Staff

Despite concerns that Bluebird bio’s gene therapy eli-cel may cause cancer, the U.S. Food and Drug Administration’s (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) unanimously supported approval of eli-cel for the treatment of early active cerebral adrenoleukodystrophy in patients less than 18 years of age who do not have an available and willing human leukocyte antigen (HLA)-matched sibling hematopoietic stem cell (HSC) donor.

On the question “Do the benefits of eli-cel outweigh the risks, for the treatment of any sub-population of children with early active cerebral adrenoleukodystrophy (CALD)?” the Advisory Committee voted 15 (yes) to 0 (no).

Cerebral adrenoleukodystrophy (CALD) is a rare, progressive, neurodegenerative disease that primarily affects young boys and causes behavioral, cognitive, and neurological deficits. Nearly half of patients who do not receive treatment die within five years of symptom onset. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the only effective treatment option but is associated with serious potential complications and mortality that increase in patients without a matched sibling donor. If approved, eli-cel will be the first approved gene therapy to address the underlying genetic cause of disease for patients living with CALD in the United States, offering the more than 70 percent of patients diagnosed with CALD who do not have a matched sibling donor an alternative to allo-HSCT.

“For decades, the CALD community has fought for the opportunity to stave off the rapid, irreversible decline associated with this devastating disease,” said Andrew Obenshain, CEO of Bluebird bio. “Today we are one step closer to delivering a potentially lifesaving therapy for CALD. We are grateful to the families, clinicians, and committee members who participated in today’s advisory committee discussion and remain committed to working with the FDA as it completes its review of the eli-cel Biologics License Application.”

The committee’s recommendation is based on the Biologics License Application (BLA) currently under priority review by the FDA with a PDUFA goal date set for September 16, 2022. The BLA for eli-cel is supported by efficacy and safety data from the completed phase 2/3 Starbeam study of 32 patients. Additionally, the BLA contains data for 35 patients dosed in the phase 3 ALD-104 study. In clinical studies, patients treated with eli-cel were more likely to achieve both overall and event-free survival than allo-HSCT patients without a matched sibling donor, with the clearest benefit for patients without a matched donor of any type.

The eli-cel clinical program was placed on a clinical hold following a Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome (MDS) in August 2021. Consistent with this known risk, two additional cases of MDS have subsequently been reported. All patients who received eli-cel in the clinical program continue to be closely monitored, per study protocols.

The Advisory Committee also discussed the overall safety of lentiviral vector (LVV) gene therapies, concluding in a 13 to 1 vote that the safety data from lovo-cel for sickle cell disease is not relevant to the review of eli-cel. In addition to granting eli-cel BLA priority review, the FDA previously granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation. bluebird bio is eligible to receive a priority review voucher upon potential approval of eli-cel.

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 own hematopoietic stem cells (HSCs). The addition of the functional ABCD1 gene allows patients to produce the ALD protein (ALDP), which is thought to facilitate the breakdown of very long-chain fatty acids (VLCFAs). The expression of ALDP and effect of eli-cel is expected to be life-long. The goal of treatment with eli-cel is to stop the progression of CALD and, consequently, preserve as much neurological function as possible, including the preservation of motor function and communication ability. Importantly, with eli-cel, there is no need for donor HSCs from another person.

Bluebird bio’s clinical development program for eli-cel includes the completed pivotal phase 2/3 Starbeam study (ALD-102) and the ongoing phase 3 ALD-104 study, which has completed enrollment and treatment of all patients. Additionally, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-304) for patients who have received eli-cel for CALD and completed two years of follow-up in ALD-102 or ALD-104. Enrollment into studies of eli-cel is currently on hold with the FDA and follow-up of all patients continues, per protocol.

In ALD-102, 90.6 percent (29/32) of patients met the primary endpoint of Major Functional Disabilities (MFD)-free survival at 24 months. As previously reported, two patients withdrew from study ALD-102 at investigator discretion, and one additional subject experienced rapid disease progression early after treatment, resulting in MFDs and subsequent death. All patients who completed ALD-102 enrolled in the long-term follow-up study. The median duration of follow-up is approximately four years.

Adverse reactions attributed to eli-cel observed in clinical trials include myelodysplastic syndrome, viral cystitis, pancytopenia, and nausea and vomiting. There have been no reports of graft-versus-host-disease, graft failure or rejection, transplant-related mortality, or replication competent lentivirus in the 67 patients who received eli-cel in clinical studies.

Photo: Andrew Obenshain, CEO of Bluebird bio

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