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.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; 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.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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David Kirn, 4D Molecular Therapeutics CEO (via website)

FDA places hold on 4D Mol­e­c­u­lar’s Fab­ry gene ther­a­py

4D Molecular Therapeutics quietly tucked an FDA clinical hold on its Fabry gene therapy into an SEC filing.

Meanwhile, the biotech issued a press release the same day after the closing bell on Thursday touting an IND for another asset, in diabetic macular edema.

The California biotech had paused enrollment of patients in its two trials of the Fabry gene therapy (4D-310) last month after three patients experienced kidney issues, all of which were resolved within four weeks. At the time, 4DMT said it would wait until the second half of this year to look at 12-month clinical data on six patients in the Phase I/II trials, one in the US and one in Taiwan and Australia.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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Uğur Şahin, BioNTech CEO (Andreas Arnold/picture-alliance/dpa/AP Images)

BioN­Tech opens new plas­mid DNA man­u­fac­tur­ing fa­cil­i­ty in Ger­many

German mRNA player BioNTech opened the doors to a new manufacturing facility on Thursday, this one just about 75 miles north of its headquarters in Mainz, Germany.

BioNTech announced on Thursday that it has completed the construction of its first plasmid DNA manufacturing facility in Marburg, Germany. The facility will produce materials for mRNA-based vaccines and therapies along with cell therapies.

Te­va drops out of in­dus­try trade group PhRMA

Following in AbbVie’s footsteps, Teva confirmed on Friday that it’s dropping out of the industry trade group Pharmaceutical Research and Manufacturers of America (PhRMA).

Teva didn’t give a reason for its decision to leave, saying only in a statement to Endpoints News that it annually reviews “effectiveness and value of engagements, consultants and memberships to ensure our investments are properly seated.”

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Sanofi CFO Jean-Baptiste de Chatillon (L) and CEO Paul Hudson (Romuald Meigneux/Sipa via AP Images)

Sanofi sees downtick in flu sales as it preps for launch of RSV an­ti­body

Sanofi expects its RSV antibody jointly developed with AstraZeneca will be available next season, executive VP of vaccines Thomas Triomphe announced on the company’s quarterly call.

Beyfortus, also known as nirsevimab, was approved in the EU back in November and is currently under FDA review with an expected decision coming in the third quarter of this year. The news comes as the FDA plans to hold advisory committee meetings over the next couple months to review RSV vaccines from Pfizer and GSK.