In surprise, FDA adcomm votes unanimously in favor of bluebird's gene therapy for rare disease even with safety concerns

In surprise, FDA adcomm votes unanimously in favor of bluebird’s gene therapy for rare disease even with safety concerns

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 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 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, 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 on 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 present mo­ment, we need to un­der­stand what lev­el [of MDS] we’re 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 wasn’t 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 are typ­i­cal­ly worth about $100 mil­lion.

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