CEO Lex Rovner (64x Bio)

George Church backs a start­up so­lu­tion to the mas­sive gene ther­a­py man­u­fac­tur­ing bot­tle­neck

George Church and his grad­u­ate stu­dents have spent the last decade seed­ing star­tups on the ra­zor’s edge be­tween bi­ol­o­gy and sci­ence fic­tion: gene ther­a­py to pre­vent ag­ing, CRISPRed pigs that can be used to har­vest or­gans for trans­plant, and home kits to test your poop for healthy or un­healthy bac­te­ria. (OK, maybe they’re not all on that ra­zor’s edge.)

But now a new spin­out from the De­part­ment of Ge­net­ics’ sec­ond floor is tack­ling a far hum­bler prob­lem — one that ma­jor com­pa­ny af­ter ma­jor com­pa­ny has stum­bled over as they tried to get cures for rare dis­eases and oth­er gene ther­a­pies in­to the clin­ic and past reg­u­la­tors: How the hell do you build these?

There’s a lot hap­pen­ing for new ther­a­pies but not enough at­ten­tion around this prob­lem,” Lex Rovn­er, who was a post-doc at Church’s lab from 2015 to 2018, told End­points News. “And if we don’t fig­ure out how to fix this, many of these ther­a­pies won’t even reach pa­tients.”

This week, with Church and a cou­ple oth­er promi­nent sci­en­tists as co-founders, Rovn­er launched 64x Bio to tack­le one key part of the man­u­fac­tur­ing bot­tle­neck. They won’t be look­ing to retro­fit plants or build gene ther­a­py fac­to­ries, as Big Phar­ma and big biotech are now spend­ing bil­lions to do. In­stead, with $4.5 mil­lion in seed cash, they will try to en­gi­neer the in­di­vid­ual cells that churn out a crit­i­cal com­po­nent of the ther­a­pies.

George Church

The goal is to build cells that are fine-tuned to do noth­ing but spit out the vi­ral vec­tors that re­searchers and drug de­vel­op­ers use to shut­tle gene ther­a­pies in­to the body. Dif­fer­ent vec­tors have dif­fer­ent de­mands; 64x Bio will look to make ef­fi­cient cel­lu­lar fac­to­ries for each.

“While a few gen­er­al ways to in­crease vec­tor pro­duc­tion may ex­ist, each unique vec­tor serotype and pay­load pos­es a spe­cif­ic chal­lenge,” Church said in an emailed state­ment. “Our plat­form en­ables us to fine tune cus­tom so­lu­tions for these dis­tinct com­bi­na­tions that are par­tic­u­lar­ly hard to over­come.”

Be­fore join­ing Church’s lab, Rovn­er did her grad­u­ate work at Yale, where she stud­ied how to en­gi­neer bac­te­ria to pro­duce new kinds of pro­tein for drugs or oth­er pur­pos­es. And af­ter leav­ing Church’s lab in 2018, she ini­tial­ly set out to build a man­u­fac­tur­ing start­up with a broad fo­cus.

Yet as she spoke with hun­dreds of biotech ex­ec­u­tives on LinkedIn and in cof­fee shops around Cam­bridge, the same is­sue kept pop­ping up: They liked their gene ther­a­py tech­nol­o­gy in the lab but they didn’t know how to scale it up.

“Every­one kept say­ing the same thing,” Rovn­er said. “We ba­si­cal­ly re­al­ized there’s this huge prob­lem.”

The is­sue would soon make head­lines in in­dus­try pub­li­ca­tions: blue­bird de­lay­ing the launch of Zyn­te­glo, No­var­tis de­lay­ing the launch of Zol­gens­ma in the EU, Ax­o­vant de­lay­ing the start of their Parkin­son’s tri­al.

Part of the prob­lem, Rovn­er said, is that gene ther­a­pies are de­liv­ered on vi­ral vec­tors. You can build these vec­tors in mam­malian cell lines by feed­ing them a small cir­cu­lar strand of DNA called a plas­mid. The prob­lem is that mam­malian cells have, over bil­lions of years, evolved tools and de­fens­es pre­cise­ly to avoid mak­ing virus­es. (Lest the mam­mal they live in die of in­fec­tion).

There are ge­net­ic mu­ta­tions that can turn off some of the in­ter­nal de­fens­es and un­leash a cell’s abil­i­ty to pro­duce virus, but they’re rare and hard to find. Oth­er plat­forms, Rovn­er said, try to find these mu­ta­tions by us­ing CRISPR to knock out genes in dif­fer­ent cells and then screen­ing each of them in­di­vid­u­al­ly, a process that can re­quire hun­dreds of thou­sands of dif­fer­ent 100-well plates, with each well con­tain­ing a dif­fer­ent group of mu­tant cells.

“It’s just not prac­ti­cal, and so these plat­forms nev­er find the cells,” Rovn­er said.

64x Bio will try to find them by build­ing a li­brary of mil­lions of mu­tant mam­malian cells and then us­ing a mol­e­c­u­lar “bar­cod­ing” tech­nique to screen those cells in a sin­gle pool. The tech­nique, Rovn­er said, lets them trace how much vec­tor any giv­en cell pro­duces, al­low­ing re­searchers to quick­ly iden­ti­fy su­per-pro­duc­ing cells and their mu­ta­tions.

The tech­nol­o­gy was de­vel­oped par­tial­ly in-house but draws from IP at Har­vard and the Wyss In­sti­tute. Har­vard’s Pam Sil­ver and Wyss’s Jef­frey Way are co-founders.

The com­pa­ny is now based in So­Ma in San Fran­cis­co. With the seed cash from Fifty Years, Refac­tor and First Round Cap­i­tal, Rovn­er is re­cruit­ing and look­ing to raise a Se­ries A soon. They’re in talks with phar­ma and biotech part­ners, while they try to val­i­date the first pre­clin­i­cal and clin­i­cal ap­pli­ca­tions.

Gene ther­a­py is one fo­cus, but Rovn­er said the plat­form works for any­thing that in­volves vi­ral vec­tor, in­clud­ing vac­cines and on­colyt­ic virus­es. You just have to find the right mu­ta­tion.

“It’s the rare cell you’re look­ing for,” she said.

Scoop: Google’s GV spear­heads the Spot­light syn­di­cate — back­ing an up­start biotech aimed at ‘de­moc­ra­tiz­ing’ gene edit­ing

CRISPR had no sooner started to shake the very foundations of drug development before its limitations began to loom large. Gene editing could change the world — if only you could get around the hurdles that threatened to trip up every program.

So it’s only natural to see CRISPR 2.0 taking shape before the pioneers can get the lead therapies through development. And who better than Google’s GV venture arm to take the lead spot in a small syndicate backing some scientists with their own unique twist on a solution?

Robert Clarke (Kinaset)

Ki­naset launch­es with $40M and a JAK in­hibitor from Vec­tura's old pipeline

Kinaset Therapeutics is joining the search for a better severe asthma treatment, picking up where Vectura left off when it decided to clear house last year.

UK-based Vectura — which took a big hit when its most advanced candidate flopped in a Phase III asthma trial back in 2018 — recently shifted to a CDMO model, offloading all of its R&D programs. Robert Clarke, who’s worked on inhalable therapeutics for 21-plus years, had close contacts at the company and took a look at what they were offering. After doing some research, he was attracted by VR475, a pan-JAK inhibitor.

Biogen CEO Michel Vounatsos (via Getty Images)

With ad­u­canum­ab caught on a cliff, Bio­gen’s Michel Vounatsos bets bil­lions on an­oth­er high-risk neu­ro play

With its FDA pitch on the Alzheimer’s drug aducanumab hanging perilously close to disaster, Biogen is rolling the dice on a $3.1 billion deal that brings in commercial rights to one of the other spotlight neuro drugs in late-stage development — after it already failed its first Phase III.

The big biotech has turned to Sage Therapeutics for its latest deal, close to a year after the crushing failure of Sage-217, now dubbed zuranolone, in the MOUNTAIN study.

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Pascal Soriot (Getty)

As­traZeneca CEO So­ri­ot plans new study to test that con­tro­ver­sial 90% ef­fi­ca­cy fig­ure, wait­ing for US da­ta be­fore go­ing to FDA

Pascal Soriot spent the long Thanksgiving weekend digging AstraZeneca out of a hole, promising to put an end to the questions around its interim Phase III vaccine data by conducting a new study while going to regulators with a large part of what it already has.

AstraZeneca and its partners at Oxford had initially touted high-level results from two studies conducted in the UK and Brazil as positive. But the enthusiasm was soon shadowed by confusion as observers probed into how the highest, 90% efficacy was seen in a dosing regimen given to a small group of volunteers due to an error. Among a larger cohort given the intended shots, the vaccine was only 62% effective, a rate that would’ve been respectable had Pfizer/BioNTech and Moderna not posted efficacy rates of 94%, 95% for their mRNA candidates. And many weren’t sure what to make of the average 70% number that AstraZeneca ran in headlines.

Stephané Bancel (Endpoints at JPM20)

Mod­er­na cal­i­brates fi­nal Covid-19 vac­cine ef­fi­ca­cy at 94.1% — and to­day it's gun­ning for the EUA

Nearly a year ago, as the coronavirus emerged in China, the NIH and four major companies bet on an unproven genetic technology as the best tool for developing a vaccine to stem the outbreak. Today, a second such vaccine is heading to the FDA.

Moderna said Monday that they will request an emergency use authorization from the FDA after a final analysis showed their mRNA vaccine was 94.1% effective at preventing symptomatic Covid-19. The data confirm the results from an interim analysis and matches efficacy Pfizer and BioNTech showed in a Phase III study, setting the biotech up to potentially nab one of the first two Covid-19 vaccine OKs.

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Bob Nelsen (Photo by Michael Kovac/Getty Images)

Bob Nelsen rais­es $800M and re­cruits a star-stud­ded board to build the 'Fox­con­n' of biotech

Bob Nelsen spent his pandemic spring in his Seattle home, talking on the phone with Luciana Borio, the scientist who used to run pandemic preparedness on the National Security Council, and fuming with her about the dire state of American manufacturing.

Companies were rushing to develop vaccines and antibodies for the new virus, but even if they succeeded, there was no immediate supply chain or infrastructure to mass-produce them in a way that could make a dent in the outbreak.

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Jason Kelly, Ginkgo Bioworks CEO (Kyle Grillot/Bloomberg via Getty Images)

Af­ter Ko­dak de­ba­cle, US lends $1.1B to a syn­thet­ic bi­ol­o­gy com­pa­ny and their big Covid-19, mR­NA plans

In mid-August, as Kodak’s $765 million government-backed push into drug manufacturing slowly fell apart in national headlines, Ginkgo Bioworks CEO Jason Kelly got a message from his company’s government liaison: HHS wanted to know if they, too, might want a loan.

The government’s decision to lend Kodak three quarters of a billion dollars raised eyebrows because Kodak had never made drugs before. But Ginkgo, while not a manufacturing company, had spent the last decade refining new ways to produce materials inside cells and building automated facilities across Boston.

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Feng Tian, Ambrx CEO (Ambrx)

Af­ter 5 qui­et years, a for­mer Scripps spin­out rais­es $200M and an­nounces plans to try again at an IPO

The first time San Diego biotech Ambrx tried to go public in 2014, they failed and the company’s board switched to a radically different strategy: They sold themselves for an undisclosed amount to a syndicate of Chinese investors and pharma companies.

Now, after 5 quiet years, that syndicate has raised a mountain of cash and indicated they’ll soon make another bid to go public.

Earlier this month, Ambrx raised $200 million in what they billed as a crossover round financed by Fidelity, BlackRock, Cormorant Asset Management, HBM Healthcare Investments, Invus, Adage Capital Partners and Suvretta Capital Management. It’s the largest amount they’ve ever raised and, according to Crunchbase figures, more than doubles the total amount of VC capital collected since their launch 17 years ago.

The ad­u­canum­ab co­nun­drum: The PhI­II failed a clear reg­u­la­to­ry stan­dard, but no one is cer­tain what that means any­more at the FDA

Eighteen days ago, virtually all of the outside experts on an FDA adcomm got together to mug the agency’s Billy Dunn and the Biogen team when they presented their upbeat assessment on aducanumab. But here we are, more than 2 weeks later, and the ongoing debate over that Alzheimer’s drug’s fate continues unabated.

Instead of simply ruling out any chance of an approval, the logical conclusion based on what we heard during that session, a series of questionable approvals that preceded the controversy over the agency’s recent EUA decisions has come back to haunt the FDA, where the power of precedent is leaving an opening some experts believe can still be exploited by the big biotech.

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