George Church (Mary Altaffer/AP Images)

George Church and an en­tre­pre­neur­ial post­doc join the hunt for AAV 2.0 with a new vec­tor-cloak­ing tech­nol­o­gy

About five years ago, George Church and his new post­doc, Ying Kai Chan, sat hunched over a lap­top in the ge­net­ics pi­o­neer’s Har­vard of­fice and stared in be­wil­der­ment at an old pa­per.

The pa­per doc­u­ment­ed ear­ly tri­als for Gly­bera, the first and at the time on­ly gene ther­a­py ap­proved any­where on the plan­et. Less than three dozen pa­tients ever re­ceived it, but in the years be­fore Lux­tur­na and Zol­gens­ma, it gave re­searchers an ex­am­ple they could point to for gene ther­a­py ac­tu­al­ly work­ing.

Chan and Church, though, were shocked to see that re­searchers run­ning clin­i­cal tri­als had giv­en pa­tients a bat­tery of high dose im­muno­sup­pres­sive drugs of­ten re­served for or­gan trans­plants, names like my­cophe­no­lic acid and cy­closporine. And when they biop­sied pa­tients’ mus­cles, they were filled with T cells, sug­gest­ing an im­mune re­sponse in ac­tion.

The re­sults were par­tic­u­lar­ly sur­pris­ing be­cause Gly­bera used the vi­ral vec­tor AAV, a de­liv­ery sys­tem that had led to a resur­gence in gene ther­a­py pre­cise­ly be­cause it was com­mon­ly be­lieved to evade the im­mune over­re­ac­tion that doomed the field in the 90s.

Ying Kai Chan

“There are so many peo­ple work­ing on gene ther­a­py now and even when you tell them, oh, ‘Did you know cy­closporin was used? Did you know all these things were used?’ Peo­ple are like, ‘Huh, what?” Chan told End­points News. “Gly­bera was the poster child, but it seems peo­ple didn’t ap­pre­ci­ate how much im­muno­sup­pres­sion was re­quired.”

Chan trained as a vi­ral im­mu­nol­o­gist and he came in­to the Church lab with an in­tu­ition that vi­ral vec­tors, those hol­lowed out and souped up gene taxis, were still virus­es and still treat­ed by the body as such. Grad­u­al­ly, the field has come around to his view. Mul­ti­ple mon­key stud­ies showed that high dos­es of AAV could be tox­ic for cer­tain neu­rons, re­sults that com­pa­nies have re­luc­tant­ly ac­cept­ed. And last year, three deaths in a high-dose tri­al height­ened AAV safe­ty con­cerns, even if those have yet to be linked con­clu­sive­ly to an im­muno­log­ic re­ac­tion.

Mean­while, Chan has been work­ing on new meth­ods of cloak­ing AAV to make it safer and re­duce the need for im­muno­sup­pres­sants. This week, he, Church, and a larg­er team at the Wyss In­sti­tute pub­lished the work in Sci­ence Trans­la­tion­al Med­i­cine, show­ing how weav­ing spe­cif­ic strands of hu­man DNA in­to the vec­tor can neu­tral­ize one of the body’s key de­fens­es against for­eign in­vaders.

“It was very much in­spired by na­ture,” Chan said.

One of the first ways gene ther­a­py pi­o­neer Jim Wil­son showed the body could re­act to AAV was through a set of sen­tinels called toll-like re­cep­tors. These sen­tinels pro­vide one of the im­mune sys­tem’s first lay­ers of de­fense, sound­ing an alarm if they de­tect any­thing that ap­pears for­eign. That means, though, that nor­mal cells need a way of telling the re­cep­tors they’re safe — an en­cryp­tion key that on­ly hu­man cells know.

That en­cryp­tion key is en­cod­ed in a few strands of DNA on the ends of telom­eres, those pa­per­clip-shaped strands at the end of chro­mo­somes that are some­times im­pli­cat­ed in ag­ing. Chan in­cor­po­rat­ed those strands in­to the DNA of an AAV2 vec­tor, the serotype used in Lux­tur­na. When the vec­tor is in­ject­ed, the strands should bind to the toll-like re­cep­tors through­out the body and tell the re­cep­tors not to sound any alarm.

When the team in­ject­ed it in­to the mus­cles, liv­er and eye of pig and mouse mod­els, it trig­gered a marked­ly re­duced im­mune re­ac­tion than a tra­di­tion­al vec­tor, Chan re­port­ed in STM.

The re­sults add to a suite of new tech­nolo­gies emerg­ing out of labs across the coun­try to com­bat AAV im­muno­genic­i­ty. Wil­son’s lab has of­fered a way of us­ing mi­croR­NAs — short strands that min­i­mize ex­pres­sion of a par­tic­u­lar­ly gene in a giv­en cell — to mit­i­gate the neur­al ef­fects. And Dyno Ther­a­peu­tics, a Church lab spin­out, us­es en­gi­neer­ing and ma­chine learn­ing to come up with whol­ly new vec­tors, with the hopes of find­ing some that can avoid the im­mune sys­tem.

Chan has now helped launch a new com­pa­ny, team­ing with ARCH and a cou­ple oth­er VCs to form Al­ly Ther­a­peu­tics, a still-in-stealth biotech that tries to min­i­mize the im­muno­genic­i­ty of vi­ral vec­tors.

Still, he ac­knowl­edges that he had hoped for more sweep­ing re­sults than he ul­ti­mate­ly had. Al­though his tech­nol­o­gy suc­cess­ful­ly tamped down the im­mune re­sponse in pigs and mice, the re­sults were less pro­found in mon­keys.

Chan’s team in­ject­ed the vec­tor in­to non-hu­man pri­mates’ eyes, a part of the body where much of the im­mune sys­tem can’t en­ter and, con­se­quent­ly, toll-like re­cep­tors are acute­ly im­por­tant. They saw im­proved safe­ty when they ad­min­is­tered be­neath the reti­na, but in­ject­ing it di­rect­ly in­to the vit­re­al jel­ly at the cen­ter of the eye still trig­gered sig­nif­i­cant in­flam­ma­tion. In­trav­it­re­al in­jec­tion is im­por­tant for tack­ling sev­er­al con­di­tions and for more broad­ly mak­ing oc­u­lar gene ther­a­pies safer and eas­i­er to de­liv­er, as on­ly eye sur­geons can ad­min­is­ter sub-reti­nal­ly.

The new pa­per, though, is just ver­sion 1.0 of the ap­proach, Chan said, and they’ve come up with sig­nif­i­cant im­prove­ments since.

More broad­ly, the field has a long way to go. An­i­mal mod­els, for ex­am­ple, are still poor pre­dic­tors of the im­mune re­sponse in hu­mans, mak­ing trans­la­tion dif­fi­cult and putting big holes in safe­ty tests. A vec­tor that ap­pears im­mune-silent in mon­keys could still trig­ger re­ac­tions in hu­mans and vice ver­sa. Al­though their role in an­i­mals is well-doc­u­ment­ed, it’s still not clear how great a role toll-like re­cep­tors play in the hu­man re­sponse to AAV.

Still, Chan says they ac­com­plished what they set out to do: They im­proved the vec­tor and, in the process, helped the field wake up to an is­sue that for years went over­looked.

“There are still chal­lenges,” Chan said. “What we re­al­ly want­ed to ac­com­plish was to raise aware­ness, as well as come up with a promis­ing so­lu­tion. I would say we made progress on both fronts.”

The top 100 bio­phar­ma VCs, Bob Brad­way places $2B bet in can­cer, gene edit­ing pi­o­neer's new big idea, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Before diving in, we had some news to share: Endpoints is launching a premium weekly report focusing on all things regulatory. Coverage will be led by our new senior editor, Zachary Brennan, who joins us from POLITICO. Arsalan Arif has more details in his Publisher’s Note.

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Robert Bradway (Photographer: Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Am­gen snaps up can­cer drug play­er Five Prime, adding PhI­II-ready FGFR2b drug in $2B M&A play

Amgen is making a long-awaited move on the M&A side, buying South San Francisco-based Five Prime $FPRX for close to $2 billion and adding a slate of new cancer drugs to the pipeline.

Amgen is paying $38 a share, putting the deal value at $1.9 billion. The stock closed at $21.26 last night, giving investors a 78% premium.

The jewel in the crown of this deal is bemarituzumab, which Amgen describes as a first-in-class, Phase III-ready anti-FGFR2b antibody. Amgen was drawn to the bargaining table by Five Prime’s mid-stage data on gastric cancer, satisfied by PFS and OS data helping to validate FGFR2b as a target. Amgen researchers will now expand on the R&D program in other epithelial cancers, including lung, breast, ovarian and other cancers.

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David Liu (Casey Atkins Photography courtesy Broad Institute)

David Liu has a new big idea: pro­teome edit­ing. It could one day shred tau, RAS and some of the worst dis­ease-caus­ing pro­teins

Before David Liu became famous for inventing new forms of gene editing, he was known around academia in part for a more obscure innovation: a Rube Goldberg-esque system that uses bacteria-infecting viruses to take one protein and turn it into another.

Since 2011, Liu’s lab has used the system, called PACE, to dream up fantastical new proteins: DNA base editors far more powerful than the original; more versatile forms of the gene editor Cas9; insecticides that kill insecticide-resistant bugs; enzymes that slide synthetic amino acids into living organisms. But they struggled throughout to master one of the most common and powerful proteins in the biological world: proteases, a set of Swiss army knife enzymes that cut, cleave or shred other proteins in everything from viruses to humans.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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In the lat­est big in­vest­ment in gene ther­a­py man­u­fac­tur­ing, Bio­gen com­mits $200M to a ma­jor new fa­cil­i­ty in NC

You’d be forgiven for thinking that the only R&D effort of any consequence at Biogen belongs to aducanumab, its controversial Alzheimer’s drug. But behind the uproar around that drug, the big biotech has a full scale pipeline in play that includes a growing focus on developing gene therapies.

Now Biogen plans to build up the kind of manufacturing muscle that will give it an advantage in gaining FDA approvals — where CMC is always key — and then marketing them around the world.

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Bruce Cozadd, Jazz CEO (Jazz Pharmaceuticals)

Jazz CEO Bruce Cozadd cam­paigned for 6 months to buy GW Phar­ma. A 90% pre­mi­um sealed the deal — along with $17.6M in ‘re­ten­tion’ in­cen­tives

Jazz CEO Bruce Cozadd didn’t beat around the bush.

In his first video meeting with GW Pharma chief Justin Gover last July 8, he offered to pay $172 a share to get the company, which had beaten the odds in getting its remarkable cannabinoid drug Epidiolex across the regulatory finish line for epilepsy. GW’s stock closed at $129 that day.

Cozadd had already done his homework on the financing to make sure he could swing it the way he wanted. He just needed to do some due diligence before making the non-binding bid firm.

UP­DAT­ED: Not 3 weeks af­ter tak­ing Hu­ma­cyte pub­lic, Ra­jiv Shuk­la launch­es an­oth­er blank check com­pa­ny

One of biotech’s earliest SPAC investors is back with another blank-check company, less than a month after his last effort announced its intent to merge.

Rajiv Shukla is intending to take a third lucky winner public with Alpha Healthcare Acquisition III, filing to go public Thursday with a $150 million raise penciled in. The move comes just a couple of weeks after Shukla’s second SPAC said it would jump to Nasdaq in tandem with Laura Niklason’s Humacyte in a $255 million new investment.

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Paul Hudson, Getty Images

How does Paul Hud­son's $13.5M comp pack­age stack up against oth­er CEOs? He's in the 'first quar­tile'

Paul Hudson arrived at Sanofi like a hurricane, chopping off duds in the pipeline, shaking up the C-suite, striking big M&A deals and jumping into the Covid-19 vaccine race — all in an attempt to reboot a pharma giant notorious for its setbacks.

Now, we’re getting a look at what the CEO brought home in his first year on the job.

When all is said and done, Hudson will have made about $6.7 million in 2020, about $2.5 million of which has already been paid. The bigger figure includes a $2.3 million bonus that’s subject to approval at an April meeting, and another $1.8 million in variable compensation that has yet to be paid.

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Ab­b­Vie of­floads UK site for $119M in sale to Chi­nese cell and gene ther­a­py play­er Phar­maron

With its Allergan buyout now long in the books, AbbVie has been taking a hard look at its suddenly expansive global ops to find space for a deal. Now, working with a Chinese cell and gene therapy player hungry for more elbow room abroad, AbbVie has taken one UK facility off its books.

AbbVie has offloaded its Liverpool manufacturing site as part of a $118.7 million sale to Chinese cell and gene therapy player Pharmaron, which is pitching the purchase as the next step in its global expansion plans, the companies said last week.