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An FDA advisory panel recommended the agency approve elivaldogene autotemcel (eli-cel), an investigational gene therapy, for select children with cerebral adrenoleukodystrophy (ALD), arguing that the benefits outweigh the risks, which include the possibility of malignancy.

By a vote of 15-0 on Thursday, members of the Cellular, Tissue, and Gene Therapies Advisory Committee agreed that eli-cel is best indicated for childhood ALD patients without an available and willing human leukocyte antigen (HLA)-matched sibling hematopoietic stem cell transplant (HSCT) donor.

And patients treated with eli-cel should be closely monitored due to the elevated risk of developing myelodysplastic syndromes (MDS), the advisers urged.

But that cancer risk "would be much more relevant in a population where there were other potential treatments," said panelist Stephanie Keller, MD, of Emory University in Atlanta, who noted that as treatment options are limited in this subset, families may be more likely to tolerate the risks.

Childhood cerebral ALD is a neurologically debilitating form of ALD (about a third of all cases) and generally occurs in young boys. It is characterized by an inflammatory process that destroys the myelin, causing relentless progressive deterioration.

"This is such a devastating disorder," Keller said. While not a cure, the proposed gene therapy "at least gives these boys time until we can come up with something better."

HSCT can slow or stop cerebral ALD progression, improve survival, and sometimes improve functional outcomes if performed early in the disease state. But compared to children with related donors, those with mismatched unrelated donors run greater risks of graft failure, graft-versus-host disease (GVHD), and mortality.

"These are the realities of unrelated donor transplantation," said Christine Duncan, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center, who spoke on behalf of Bluebird Bio, eli-cel's developer.

"These are not academic considerations," she said. "I transplanted a boy with cerebral ALD three times in the same hospitalization – the second and third performed in the ICU due to graft failure. He survived to hospital discharge and died a year later."

"And I stood next to a mother and father of a patient as they watched their son die after suffering a myocardial infarction at age 9 directly as a result of [GVHD]," Duncan continued. "That was not academic for any of us."

Panelist John DiPersio, MD, PhD, of Washington University School of Medicine in St. Louis, noted that while toxicity associated with transplant has improved, many patients continue to have persistent problems with GVHD.

"There is nothing better than the quality of life of an autologous transplant patient, and there often is nothing worse than the quality of life for an [allogeneic transplant] recipient," he said.

This "suggests to me that even though there are substantial risks for this population, I'm convinced ... that this is a worthwhile endeavor for these high-risk patients," DiPersio said.

The pivotal trial supporting eli-cel -- -- included boys with active early cerebral ALD and met its primary efficacy endpoint, demonstrating improvement in major functional disability (MFD)-free survival at 2 years. At that time point, 29 of the 32 patients, or 90.6% (95% CI 75.0-98.0), were alive and free of MFDs, and this met prespecified criteria for success. While FDA staff cited concerns over the MFD-free survival benchmark used to determine success in ALD-102 (lower bound CI of 50%) -- arguing that it was based on data from populations not comparable to the trial population -- panelists were not swayed enough to prevent the unanimous vote endorsing eli-cel.

An exploratory analysis indicated that event-free survival at 2 years with the gene therapy was comparable to HSCT with a matched unrelated donor and superior to HSCT with a mismatched donor (90% and 43%, respectively), suggesting that "the most clinical benefit of eli-cel was within the HLA unmatched donors group," said panelist Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.

But several committee members also emphasized the therapy should be available to the unrelated matched donor patients at the discretion of the physician, family, and patient.

Benefits vs Risk

The success of eli-cel came at a cost. Three of 67 children treated with eli-cel (32 patients in ALD-102, and an additional 35 in the ongoing phase III study) developed MDS, with all three requiring transplant to treat the blood malignancy.

"The FDA is concerned that with more time to follow subjects, more will be diagnosed with cancer," said Leah Crisafi, MD, a clinical reviewer at the agency.

"There are a number of subjects who are currently being closely watched due to concerns that they may be developing a hematologic malignancy," said Crisafi. "And it is concerning that nearly all subjects who have received eli-cel have integration into the proto-oncogene MECOM, which is implicated in two of the three cancer cases diagnosed so far."

MDS remains a concern, said panelist Nirali Shah, MD, of the National Cancer Institute in Bethesda, Maryland, but the benefit of eli-cel "outweighs the risk at the present moment."

"Given that transplant is the only curative therapy for MDS, the question I end up being left with is, What is the threshold at which the MDS incidence would be considered not acceptable?" she said.

While the FDA is not required to follow the advice of its advisory committees, it usually does.

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