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

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Jason Foster, Ori Biotech CEO

UK up­start rais­es $100M in bid to dig­i­tize and stan­dard­ize cell and gene ther­a­py man­u­fac­tur­ing

There’s a giant need for cell and gene therapy manufacturing options going forward, as companies move to invest massively into that space. Ori Biotech is the latest, as the UK-based biotech announced it has secured more than $100 million in its oversubscribed Series B funding round Tuesday.

Novalis LifeSciences led the round. The Boston-based company is led by chairman Marijn Dekkers and partner Paul Meister, who built Thermo Fisher Scientific. Dekkers went on to become the CEO of Bayer, and is currently also the chairman at Ginkgo Bioworks.