Surprisingly, FDA adcomm unanimously votes in favor of bluebird gene therapy for rare diseases, despite safety concerns – Endpoints News

On the first day of a two-day meeting, the FDA’s Cell, 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 information documents, including a link between three cancer cases known as myelodysplastic syndrome (MDS) in those who received the treatment, dubbed eli-cel, adcomm members investigated what happened in each case and required continuous monitoring.

But overall, committee members seemed to agree that the evidence of benefit from eli-cel is real, particularly for patients without a sibling or other compatible donor. Questions related to the bluebird’s other sickle cell gene therapy, known as lovo-cel, have also raised some safety concerns. But panelists voted overwhelmingly, 13-1, with one abstention, against the idea that lovo-cel safety data is 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 would otherwise have to use a mismatched donor. She noted that treatment at least buys these boys time, and without treatment they don’t have time to wait for anything else.

Panelist John DiPersio, director of the Center for Gene and Cell Immunotherapy at Washington University Medical School, said that while there are substantial risks, this is a worthwhile effort. He also mentioned that the FDA should have elaborated more on quality of life for those in the trial, however.

Bluebird experts further explained how, with an early death rate of 10-20% in those diagnosed with CALD, even an MDS event rate of around 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 need to listen to the advice of its advisory committees, but it usually does.

Agency reviewers also raised some serious concerns in presentations about the way the pivotal study was conducted, questioning the established effectiveness.

Shelby Elenburg of the CBER Office of Tissues and Advanced Therapies explained how some untreated subjects in the control arm of the main study had symptoms at baseline, unlike those who received eli-cel in the study, who had no symptoms. This suggests that individuals with eli-cel were treated at an earlier point in disease progression, meaning the results may have been biased towards those on treatment, Elenburg said.

“While the results seem impressive for eli-cel, during the review process the FDA discovered several issues that led us to question the interpretability of these results,” said Elenburg. “The most pressing concern is the comparability of populations. Although the untreated population appears to be clearly inferior on the primary efficacy endpoint…I remind you that these subjects had very advanced symptomatic disease at baseline and it does not seem relevant to compare their 24-month outcome with the outcome of subjects with early, mostly asymptomatic, disease , which 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% MDS incidence rate may increase.

“In addition to the three recognized cases of MDS, there are at least four other matters of imminent MDS concern. Although the clinical significance is unclear, 98% of subjects in the eli-cel study population have vector integration sites in MECOM, a proto-oncogene,” noted the FDA.

Panelists said MDS is a concern, but they sought to ensure very close, long-term monitoring by the FDA and bluebird for those on treatment, if approved.

Adcomm panelist Nirali Shah of the National Cancer Institute said that not much is known about this form of MDS and “it should be clear that at the moment we need to understand what level of MDS it is. [of MDS] we are willing to accept globally” given the course of CALD.

Bluebird’s senior medical director, Jakob Sieker, presented data this morning showing how eli-cel compares favorably to no treatment, despite questions from the FDA about the way bluebird performed its tests. Sieker also said that eli-cel compares favorably with the standard of care, allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly when there was no matched donor.

Despite the upvote, it remains to be seen how the FDA arrives at its final decision.

OTAT Director Wilson Bryan emphasized at the beginning 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 subjected to products that are ineffective, he said.

If bluebird gets an approval for eli-cel, he will also be rewarded with a priority review voucher, which is typically worth around $100 million.

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