In the first day of a two-day meeting, the FDA’s Cellular, Tissue and Gene Therapies advisory committee on Thursday gave a big thumbs up to bluebird bio’s potential gene therapy for the rare but fatal condition known as cerebral adrenoleukodystrophy (CALD) by a vote of 15-0, despite FDA safety concerns.
Following critical comments and safety questions from the FDA in its briefing documents, including a link between three cancer cases known as myelodysplastic syndrome (MDS) in those receiving the treatment, dubbed eli-cel, adcomm members dug through what transpired in each of the cases and called for continued monitoring.
But overall, committee members seemed to agree that evidence of eli-cel’s benefit is real, particularly for patients without a sibling or other matched donor. Questions related to bluebird’s other gene therapy for sickle cell, known as lovo-cel, also raised some safety concerns. But panelists voted overwhelmingly, 13-1, with one abstaining, against the idea that lovo-cel safety data are relevant to the safety assessment of eli-cel.
Adcomm panelist Stephanie Keller of Emory University and Children’s Healthcare of Atlanta noted a significant benefit for some patients who received the gene therapy and otherwise would’ve had to use a mismatched donor. She noted that the treatment at least gives these boys time, and without a treatment, they don’t have the time to wait for anything else.
Panelist John DiPersio, director of the Washington University Medical School’s center for gene and cellular immunotherapy, said that even though there are substantial risks, this is a worthwhile endeavor. He also mentioned that the FDA should have elaborated more on the quality of life for those in the trial, however.
Bluebird experts further explained how with a 10-20% early mortality rate in those diagnosed with CALD, even an event rate of MDS at about 5% still compares favorably. The five-year survival of a child with MDS is 75%, bluebird experts said during the panel.
The FDA does not have to listen to the advice of its advisory committees but it often does.
Agency reviewers also raised some serious concerns in presentations about the way in which the pivotal trial was conducted, questioning the established efficacy.
Shelby Elenburg of CBER’s Office of Tissues and Advanced Therapies explained how some untreated subjects in the pivotal trial’s control arm had symptoms at baseline, unlike those who received eli-cel in the trial, who did not have symptoms. This suggests eli-cel subjects were treated at an earlier point in their disease progression, which means the results may have been biased toward those on treatment, Elenburg said.
“While the results look impressive for eli-cel, during the review process, the FDA discovered several issues that led us to question the interpretability of these results,” Elenburg said. “The most pressing concern is comparability of populations. While the untreated population appeared clearly inferior to the primary efficacy endpoint… I remind you these subjects had very advanced symptomatic disease at baseline and it does not seem relevant to compare their 24 month outcome to the outcome of subjects with early, mostly asymptomatic disease who receive HSCT and eli-cel. ”
Other FDA reviewers noted the “high risk of hematologic malignancy with eli-cel” in the afternoon presentations, explaining how the current 4% rate of MDS incidence may increase.
“In addition to the three recognized cases of MDS, there are at least four other subjects with concern for impending MDS. Although the clinical significance is unclear, 98% of subjects in the eli-cel study population have vector integration sites in MECOM, a proto-oncogene, ”the FDA noted.
Panelists said MDS is a concern, but they sought to ensure very close and long-term monitoring from the FDA and bluebird for those on treatment if it is approved.
Adcomm panelist Nirali Shah of the National Cancer Institute said there isn’t a lot known about this form of MDS, and “it should be clear that at the present moment, we need to understand what level [of MDS] we are willing to accept overall ”given the course of CALD.
Bluebird’s senior medical director Jakob Sieker presented data in the morning showing how eli-cel compares favorably to no treatment, despite the FDA’s questions regarding the way in which bluebird ran its trials. Sieker also said eli-cel compared favorably with the standard of care, allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly when there was not a matched donor.
Despite the positive vote, how the FDA comes to its final decision still remains unknown.
OTAT director Wilson Bryan stressed at the outset of the meeting that a single arm study of limited duration can be extremely difficult to interpret. There is a tremendous unmet need, however, patients should not be subject to products that are ineffective, he said.
If bluebird does win an approval for eli-cel, it would also be rewarded with a priority review voucher, which is typically worth about $ 100 million.