FDA Advisory Committee Endorses Gene Therapy for Neurogenerative Disease

If approved, elivaldogene autotemcel will be the first gene therapy to address the underlying genetic cause of cerebral adrenoleukodystrophy, a rare disease that affects young boys.

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted in support of approval of Bluebird Bio’s elivaldogene autotemcel (eli-cel). Committee members unanimously voted yes on the question of whether the benefits of the gene therapy outweigh the risks for treating early active cerebral adrenoleukodystrophy (CALD).

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 patients may not have a matched donor.

The biologic license application for eli-cel is currently under priority review by the FDA with a PDUFA goal date set for Sept. 16, 2022. The BLA is supported by data from the phase 2/3 Starbeam study (ALD-102) of 32 patients. Additionally, the BLA contains data for 35 patients in a separate 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.

Eli-cel uses the Lenti-D lentiviral vector (LVV)—HIV type 1 cells that have had their genetic information removed—to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells. 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. The expression of ALD protein and effect of eli-cel is expected to be life-long.

In materials released by the FDA ahead of the meeting, regulators expressed concern about several patients who developed myelodysplastic syndrome, a blood cancer. In August 2021, the studies had been put on clinical hold because of this. Initially one patient, and then later two additional patients, had developed myelodysplastic syndrome. These patients continue to be monitored, according to the company.

“I feel strongly that this should be an option for patients with matched unrelated donors because of the risk graft-vs-host disease in this patient population,” committee member Bernard Fox, Jr., Ph.D. said after the vote. “But I would be very aggressive at looking at the mechanisms of action and why some patients are getting myelodysplastic syndrome. I would support aggressive monitoring of these children.

Fox is chief, laboratory of molecular and tumor immunology, at Providence Portland Medical Center in Portland, Ore.

Lisa Butterfield, Ph.D., chair of the advisory committee, suggested risk monitoring with in-depth molecular analysis including integration type sequencing and clinical monitoring to catch any myelodysplastic syndrome early when it is easier to treat. Butterfield is vice president of research and development at Parker Institute for Cancer Immunotherapy and adjunct professor of microbiology and immunology at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

In ALD-102, 29 of the 32 patients met the primary endpoint of major functional disabilities (MFD)-free survival at 24 months. Two patients withdrew from ALD-102 at investigator discretion, and one additional subject experienced rapid disease progression and subsequent death.

Other adverse reactions attributed to eli-cel observed in clinical trials include 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 and are being followed in clinical studies