Advisers to the Food and Drug Administration voted unanimously in favor of approving an investigational gene therapy from Bluebird Bio on Thursday, concluding that its benefits for children with a rare and deadly disorder outweigh a demonstrable risk of causing cancer.
The FDA’s independent advisers voted 15-0 to recommend Bluebird’s eli-cel, a one-time treatment for cerebral adrenoleukodystrophy, a genetic neurological disorder that affects young boys. The agency, which has promised to make a final decision on eli-cel by Sept. 16, is not required to follow the advice of its advisory committees.
“This treatment isn’t a cure, but it at least gives these boys time until hopefully one day we can come up with something better for them,” said Stephanie Keller, a professor of pediatrics at Emory University and a member of the advisory committee.
Thursday’s panel is part of a two-day meeting on Bluebird’s products. On Friday, the same committee will consider a Bluebird gene therapy for the rare blood disorder beta-thalassemia. The FDA’s final actions on each is of existential importance to Bluebird, a one-time trailblazer in gene therapy that has recently cut deep into its business and has only enough cash to last until next year.
The vote in favor of eli-cel followed a full day of discussion and debate on Bluebird’s supporting data, which FDA scientists described as compelling but vexingly difficult to interpret. Three patients in Bluebird’s trial developed cancer as a result of treatment, casting doubt on whether eli-cel’s benefits warranted such a risk. The company methodically defended its gene therapy as a needed option for patients and their families, and, in an emotional public comment period, parents affected by the disease implored the FDA to approve Bluebird’s medicine.
“The moral injury of not having this lifesaving option available to families can neither be overlooked nor overstated,” said Kirsten Finn, whose son was diagnosed with adrenoleukodystrophy at age 4. “The right to refuse treatment will always be there. Parents must have the right, with full understanding of all the risks involved, to choose.”
Without treatment, children with cerebral adrenoleukodystrophy, or CALD, gradually lose their ability to see, hear, and walk, and most die in the second decade of life. The most common treatment is a bone-marrow transplant, which can be dramatically effective when the donor is a sibling. But for the roughly 90% of boys with CALD who don’t have a sibling with matching marrow cells, relying on non-familial donors can lead to graft-versus-host disease, a sometimes severe side effect in which the transplanted cells attack healthy tissue. And every day spent waiting on a viable donor increases the risk of progression.
“This is a disease where time equals brain,” said Bradford Zakes, whose son, Ethan, died of CALD at age 10. “There’s simply no other way to put it.”
Treatment with eli-cel involves taking a patient’s own stem cells, using a modified virus to deliver a correct copy of the mutated gene that causes CALD, and then reinfusing them. In clinical trials enrolling 67 patients, Bluebird’s therapy met its primary goal, keeping 91% of CALD patients alive and free of major disability two years after treatment. Eli-cel’s efficacy was similar to that of bone-marrow transplants from a matched sibling, and it outperformed unmatched transplants, which had a two-year disability-free survival rate of about 75%.
The question facing the FDA’s advisers was whether that benefit compensates for an undeniable risk of cancer. The three cases in eli-cel’s clinical trial appeared to arise from Bluebird’s modified virus. And while just 4% of boys in Bluebird’s study developed malignancies, that number is likely to go up the longer patients are followed, said Leah Crisafi, a clinical reviewer at the FDA’s gene therapy division.
Panelist John DiPersio, an oncologist at Washington University School of Medicine, said the FDA should closely monitor patients treated with eli-cel to better understand its ties to cancer. But despite the safety concerns, the quality-of-life difference between getting a one-time gene therapy and the years of disruptive treatment often required to manage graft-versus-host disease makes Bluebird’s product an approvable medicine, he said.
“Even though there are substantial risks for this population, I’m convinced by what I saw that this is probably a worthwhile endeavor for those high-risk patients,” DiPersio said.
As for Bluebird’s business, even if eli-cel wins approval, it’s unlikely to be a major revenue driver. Citing CALD’s rarity, the company said it expects to treat about 10 patients a year. The beta-thalassemia therapy, called beti-cel, has greater commercial potential, but analysts believe it could be quickly displaced by next-generation therapies, including a potentially curative medicine that uses CRISPR genome-editing.
Thanks to an FDA incentive program, winning approval for both gene therapies could provide some much-needed short-term cash for Bluebird. CALD and beta-thalassemia qualify as neglected diseases under FDA policy, and companies that successfully develop new medicines receive a priority-review voucher, a tradeable asset that entitles its holder to an expedited FDA review. Such vouchers have recently sold for upward of $100 million each, money Bluebird could use to extend its cash runway.