Even FDA's Peter Marks is worried about the commercial viability of gene and cell therapies

Even FDA’s Peter Marks is worried about the commercial viability of gene and cell therapies

When blue­bird bio’s gene ther­a­py to treat be­ta tha­lassemia won Eu­ro­pean ap­proval in 2019, the near­ly $2 mil­lion per pa­tient price tag for the po­ten­tial cure seemed like a sur­mount­able hur­dle.

Fast for­ward two years lat­er, and blue­bird has with­drawn Zyn­te­glo, the be­ta thal drug, along with the rest of its gene ther­a­py port­fo­lio from Eu­rope, which the com­pa­ny said is gen­er­al­ly un­will­ing to pay a fair price for the treat­ment.

In Ger­many, the on­ly coun­try for which blue­bird dis­closed de­tails, au­thor­i­ties of­fered $790,000 for the one-time treat­ment, with the pay­out mov­ing to $950,000 if the ther­a­py is still work­ing af­ter five years. That’s rough­ly in line with the $900,000 price tag Wall Street an­a­lysts ex­pect­ed blue­bird to put on the ther­a­py pri­or to launch. But blue­bird want­ed $1.8 mil­lion paid over 5 years, with pay­outs con­di­tioned on a pa­tient’s re­sponse.

This and oth­er ex­am­ples (see Gly­bera) have raised ques­tions about the vi­a­bil­i­ty of the gene and cell ther­a­py space, par­tic­u­lar­ly as it’s able to tar­get small­er and small­er groups of pa­tients.

Pe­ter Marks, di­rec­tor of the cen­ter at FDA that reg­u­lates these ther­a­pies, ad­dressed this is­sue of fi­nan­cial vi­a­bil­i­ty head on at a con­fer­ence on Tues­day morn­ing, par­tic­u­lar­ly as it re­lates to in­di­ca­tions where there may on­ly be sev­er­al dozen pa­tients world­wide.

The prob­lem is spon­sors are see­ing this group of on­ly 20 to 40 pa­tients per year for one ther­a­py as com­mer­cial­ly non­vi­able, Marks ex­plained. If there was bet­ter man­u­fac­tur­ing of small­er batch­es of AAV vec­tors for gene ther­a­pies, for ex­am­ple, he said, there might be a way to put to­geth­er a port­fo­lio of these small­er-pop­u­la­tion prod­ucts that would then be vi­able.

While it’s un­ortho­dox for any se­nior FDA of­fi­cial to ad­dress the com­mer­cial vi­a­bil­i­ty of any med­ical prod­ucts, and the FDA re­cent­ly ad­dressed some of the safe­ty ques­tion marks around gene and cell ther­a­pies, Marks specif­i­cal­ly ad­dressed these small­er groups of gene ther­a­pies, not­ing, “We’re all a lit­tle gun-shy when we see pro­grams be­ing dropped, and that means we have to find a way for­ward to re­store con­fi­dence for these small­er pop­u­la­tions.”

Part of the path for­ward in­cludes fig­ur­ing out how to price these ex­pen­sive and ex­pen­sive-to-make ther­a­pies, he said.

“Re­im­burse­ment is the 800 pound go­ril­la in the room,” Marks told the crowd vir­tu­al­ly on Tues­day at the AS­GCT’s 25th an­nu­al meet­ing in Wash­ing­ton, DC, not­ing that some of the ac­cel­er­at­ed ap­provals “make peo­ple shud­der be­cause of con­cerns” about pric­ing and risk-shar­ing mod­els.

“Once there are 5 to 8 gene ther­a­pies, things will work them­selves out,” Marks added, of­fer­ing the ex­am­ple of No­var­tis’ spinal mus­cu­lar at­ro­phy gene ther­a­py Zol­gens­ma as a case where:

the val­ue propo­si­tion is so over­whelm­ing, it’s hard to think of not to cov­er that. But for oth­ers, where it’s not a life or death is­sue, it will be more chal­leng­ing and will be sim­i­lar to what our Eu­ro­pean col­leagues see. How that gets re­solved will com­plete­ly af­fect how many peo­ple go in­to this field to de­vel­op ther­a­pies.

He al­so sug­gest­ed a much more in­ter­na­tion­al­ly har­mo­nized ap­proach for reg­u­lat­ing these gene ther­a­pies for small­er, rare dis­ease pa­tient groups, which might have dozens of pa­tients glob­al­ly.

Marks sug­gest­ed a way to move to a more com­mon ap­pli­ca­tion process glob­al­ly, not­ing, “Maybe we won’t get some of the pre­clin­i­cal in­fo we do care about, but can live with­out, and in turn, pa­tients get ac­cess in home coun­tries with­out hav­ing to trav­el” to gain ac­cess to these ther­a­pies. “We have to give se­ri­ous con­sid­er­a­tion to these prod­ucts. If it’s de­signed to 10-20 per 100 mil­lion peo­ple, any one coun­try won’t have enough pa­tients to sus­tain com­mer­cial­iza­tion,” he said.

Marks pre­vi­ous­ly penned an NE­JM ed­i­to­r­i­al on these in­di­vid­u­al­ized treat­ments and how to reg­u­late them in 2019.

On ques­tions re­lat­ed to ac­cel­er­at­ed ap­proval re­forms, which have been in the news as Con­gress at­tempts to tack sev­er­al of these re­forms on­to must-pass FDA user fee leg­is­la­tion, Marks said there’s a need for the AA path­way in the cell and gene ther­a­py space. Some neu­rode­gen­er­a­tive dis­eases, for in­stance, he said, “If we take away the abil­i­ty to use sur­ro­gate end­points, we would have a lot of trou­ble see­ing these prod­ucts de­vel­oped.”

But he did ac­knowl­edge that the ac­cel­er­at­ed ap­proval path­way “has been used like an off-ramp” lead­ing to prob­lems in the past.

“Sur­pris­es are not need­ed here in the gene ther­a­py field. The idea here is agree­ing up­front on the sur­ro­gate, there’s less a chance for sur­pris­es. What we will be do­ing is mov­ing these dis­cus­sions up­front,” Marks said.

In re­sponse to a ques­tion from the au­di­ence on what the timetable might look like for get­ting back to tele­con­fer­enc­ing be­tween CBER and spon­sors, Marks ac­knowl­edged the staff short­ages and that this “is not an op­ti­mal sit­u­a­tion. Even pri­or to the pan­dem­ic, we were un­der­staffed. My key for 2022 is a re­cov­ery theme — my hope is that as we ease in­to the next cal­en­dar year, more ro­bust ex­changes with the agency oc­cur, in­clud­ing tele­con­fer­ences.”

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