Cap­ping AAV dose? Tweak­ing gene ther­a­py tri­als? New an­i­mal mod­els? FDA pos­es far-reach­ing ques­tions for ex­perts

Is it time to set a lim­it for how high a dose gene ther­a­py de­vel­op­ers and in­ves­ti­ga­tors are al­lowed to give pa­tients in each tri­al?

That’s one of the ques­tions the FDA is pos­ing to its Cel­lu­lar, Tis­sue, and Gene Ther­a­pies Ad­vi­so­ry Com­mit­tee as ex­perts pre­pare for a two-day meet­ing next week. De­pend­ing on how the dis­cus­sion goes — and what the agency makes of it — the re­sults could com­plete­ly re­de­fine the rules for a ma­jor sec­tion of the boom­ing gene ther­a­py field: treat­ments that are de­liv­ered by ade­no-as­so­ci­at­ed virus vec­tors.

Com­ing in the shad­ow of pre­clin­i­cal red flags, safe­ty alerts, clin­i­cal holds and pa­tient deaths, the meet­ing is de­signed to go through any and all tox­i­c­i­ty risks re­lat­ed to AAV. And the FDA wants to get in­put on how it should deal with each of those is­sues, with reg­u­la­to­ry im­pli­ca­tions on every­thing from mouse stud­ies to clin­i­cal tri­als to man­u­fac­tur­ing stan­dards.

So high are the stakes that BIO, the biotech trade group, is ask­ing for more time to put to­geth­er a full re­sponse to the meet­ing, which is sched­uled for Sept. 2-3.

“The top­ics iden­ti­fied in the Fed­er­al Reg­is­ter No­tice are key top­ics of in­ter­est to Spon­sors,” reads a re­quest post­ed on­line. “Giv­en the im­por­tance of these top­ics, BIO re­spect­ful­ly re­quests a 60-day ex­ten­sion to the dock­et to al­low com­ment­ing af­ter con­clu­sion of the meet­ing. Ex­tend­ing the dead­line for com­ments to 60 days post-meet­ing will al­low stake­hold­ers to see the meet­ing ma­te­ri­als, hear the dis­cus­sion, and pro­vide sub­stan­tive com­ments to FDA for con­sid­er­a­tion.”

In a brief­ing doc­u­ment re­leased ahead of the meet­ing, the FDA kicks off by not­ing just how big the space has grown: Be­tween 2015 and 2020, CBER re­ceived 99 IND ap­pli­ca­tions for AAV-based gene ther­a­py can­di­dates, and of­fered ad­vice to an even larg­er group of drug­mak­ers in­ter­est­ed in start­ing a hu­man study.

Yet as the num­ber of tri­als bal­looned, so did re­ports of se­ri­ous side ef­fects. It quot­ed a re­cent analy­sis point­ing out that 35% of 149 AAV gene ther­a­py tri­als had treat­ment-emer­gent se­ri­ous ad­verse events, or TESAEs.

“These TESAEs in­clude he­pa­to­tox­i­c­i­ties, throm­bot­ic mi­croan­giopathies (TMA), and brain mag­net­ic res­o­nance imag­ing (MRI) find­ings of un­cer­tain sig­nif­i­cance with some TESAEs re­sult­ing in the death of study sub­jects,” reg­u­la­tors wrote. “Oth­er tox­i­c­i­ties have large­ly been re­port­ed with AAV vec­tor ad­min­is­tra­tion in an­i­mal stud­ies. These in­clude dor­sal root gan­glion (DRG) and pe­riph­er­al nerve tox­i­c­i­ties, which have pri­mar­i­ly been char­ac­ter­ized in non­hu­man pri­mates (NHP).”

Over five sec­tions of the doc­u­ment, the FDA ex­plored each of the safe­ty con­cerns in greater de­tail and posed a set of draft ques­tions to ad­dress them: Should an­i­mal stud­ies be con­duct­ed dif­fer­ent­ly, us­ing dif­fer­ent species, ages and mod­els? Fol­lowed up for longer? How can pa­tients be screened so that clin­i­cians know their risk for de­vel­op­ing, say, liv­er in­jury or neur­al dam­age? What kind of strate­gies can be de­ployed to mit­i­gate those risks? Would giv­ing oth­er drugs help?

Then there’s the ex­is­ten­tial ques­tion:

Con­sid­er­ing the risk of tox­i­c­i­ties ob­served in clin­i­cal tri­als with high dos­es of AAV vec­tors,

a. please dis­cuss whether an up­per lim­it should be set for the to­tal vec­tor genome dose per sub­ject.

b. giv­en that many AAV prod­ucts con­tain sig­nif­i­cant amounts of emp­ty cap­sids, please dis­cuss whether an up­per lim­it should be set on the to­tal cap­sid dose.

None of the con­cerns are new, to be sure. As ear­ly as 2018, gene ther­a­py pi­o­neer Jim Wil­son had sound­ed the alarm on high-dose AAV af­ter ob­serv­ing tox­ic re­ac­tions in mon­keys — in one of the many stud­ies quot­ed by the FDA. The field is still go­ing through a reck­on­ing in the af­ter­math of three pa­tient deaths in a tri­al by Au­dentes, and safe­ty is a con­stant talk­ing point for a grow­ing crew of next-gen­er­a­tion star­tups promis­ing to en­gi­neer their way out of the vec­tor prob­lems, as oth­ers pro­pose some­what more im­me­di­ate so­lu­tions.

While ac­knowl­edg­ing those ad­vances in en­gi­neer­ing, though, the FDA is clear­ly won­der­ing if there is some­thing in­trin­si­cal­ly dan­ger­ous with AAV vec­tors.

Mem­bers of the ad­vi­so­ry com­mit­tee have like­ly run in­to these is­sues one way or an­oth­er. Three of them — Roland Her­zog at In­di­ana Uni­ver­si­ty, Ken­neth Berns at the Uni­ver­si­ty of Flori­da and Charles Vite at the Uni­ver­si­ty of Penn­syl­va­nia — have de­clared con­flicts of in­ter­est, ei­ther due to grants or stock hold­ings in af­fect­ed com­pa­nies. All were grant­ed waivers to par­tic­i­pate in the pan­el.

Source: FDA

Click on the im­age to see the full-sized ver­sion

So­cial: AAV by Katery­na Kon/Shut­ter­stock

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

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