David Liu, Liu Group

David Liu un­veils newest ad­vance­ment in CRISPR tech: Prime edit­ing

The re­searcher be­hind base-edit­ing is out with what some sci­en­tists are hail­ing as the biggest ad­vance­ment in CRISPR tech­nol­o­gy since that 2016 break­through: “prime edit­ing.” The new mol­e­c­u­lar gad­get is ca­pa­ble of eras­ing any base pair and sten­cil­ing in an­oth­er and cut­ting or adding long seg­ments of DNA with­out break­ing both strands of the he­lix.

Luke Dow Dow Lab

David Liu, base edit­ing pi­o­neer and founder of Beam Ther­a­peu­tics, pub­lished the find­ings in Na­ture along­side An­drew An­za­lone. They es­ti­mat­ed that the break­through “in prin­ci­ple” puts 89% of hu­man dis­eases in purview — al­though ex­perts cau­tioned that hu­man ther­a­pies were a long way off.

“This is a big ad­vance,” Luke Dow, a Cor­nell can­cer re­searcher who was not in­volved in the study,  told End­points News. “The ev­i­dence in this case for cor­rect­ing those dis­ease al­le­les is the first step and that’s a long way off from the last step.”

To piv­ot the tech in­to ther­a­peu­tic ap­pli­ca­tions, Liu al­so launched Prime Med­i­cine with the back­ing of Arch Ven­ture Part­ners, GV, New­path Part­ners and F-Prime.  That could spell trou­ble for Beam, which filed for a $100 mil­lion in Sep­tem­ber and may now see some of their sci­ence out­paced, al­though the prime edit­ing tech has been sub­li­censed to Beam for some fields.

The ear­ly CRISPR tech­nol­o­gy, for all its her­ald­ed pre­ci­sion, was some­thing of a blunt force ob­ject. It tears open DNA, cre­at­ing what are called dou­ble-strand breaks, and then leaves the DNA to patch it­self back up, by knit­ting the two strands to­geth­er, tak­ing ran­dom nu­cleotides from with­in the cell to fill the gap or splic­ing in patch­es of DNA sup­plied by sci­en­tists. It’s of­ten loathe to do the lat­ter, a ma­jor ob­sta­cle in ap­ply­ing CRISPR to dis­eases that re­quire not on­ly re­mov­ing faulty genes but putting in the right ones. Even when it does, it can of­ten cause off-tar­get ef­fects.

Liu made a ma­jor break­through in 2016 when he in­tro­duced base edit­ing – the abil­i­ty to di­rect­ly rewrite the nu­cleotides that make up DNA’s 4-let­ter al­pha­bet. News cov­er­age talked about the po­ten­tial to cure dis­eases such as sick­le cell, caused by a sin­gle nu­cleotide in the gene for he­mo­glo­bin.

The prob­lem was Liu’s first dis­cov­ery –and Beam Ther­a­peu­tics, the com­pa­ny he launched around it – had ma­jor dif­fi­cul­ty at­tack­ing sick­le cell, be­cause that first gad­get could on­ly make four switch­es: C-to-T, T-to-C, A-to-G, and G-to-A. A sick­le cell treat­ment would re­quire switch­ing T to A on the right gene.

In yes­ter­day’s Na­ture pa­per, Liu and his coau­thors switched T to A. They al­so switched every oth­er of the 12 pos­si­bil­i­ties.

“It doesn’t im­prove on base-edit­ing,” Dow said.  “The orig­i­nal base edit­ing tool the Liu lab de­scribed a few years ago with a few mod­i­fi­ca­tions be­came very ef­fi­cient. What this does is open up a lot of dif­fer­ent types of mu­ta­tions that weren’t avail­able pre­vi­ous­ly.

Liu de­scribed the new tech as a “search-and-re­place” tool – es­sen­tial­ly con­trol F for the hu­man genome. That’s prob­a­bly over­selling where the tech is to­day – Dow said they on­ly test­ed it on four hu­man cell types, leav­ing ques­tions on how it will fare in the rest – but it gets at the po­ten­tial. In ad­di­tion to sick­le cell, re­searchers spliced out the 4-let­ter se­quence that caus­es Tay-Sachs. Over­all, they made 175 ed­its in mouse and hu­man mod­els.

The au­thors re­port­ed be­ing able to do 44 in­ser­tions and said more was pos­si­ble. They al­so were able to ed­it in non-di­vid­ing such as neu­rons and liv­er cells.

Rather than break­ing the cell DNA on both sides and pro­vid­ing an­oth­er piece of DNA for the cell to in­cor­po­rate, the new tech­nol­o­gy breaks on­ly one strand and us­es RNA to sup­ply the nu­cleotides. By not caus­ing dou­ble-strand breaks, it lim­its off-tar­get ef­fects on oth­er parts of the genome – one of the big­ger risks of CRISPR tech­nol­o­gy.

UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

In what could be an early shot in the battle against drugmakers that whiff on confirmatory studies to support accelerated approvals, the FDA ordered Bristol Myers Squibb late last year to give up Opdivo’s approval in SCLC. Now, Merck is next on the firing line — are we seeing the FDA buckling down on post-marketing offenders?

Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Paul Sekhri

The next big biotech su­per­star? Paul Sekhri has some thoughts on that

It occasionally occurs to Paul Sekhri that if they pull this off, his company will be on the front page of the New York Times and a lead story in just about every major news outlet on the planet. He tries not to dwell on it, though.

“I just want to be laser-focused on getting to that point,” Sekhri says, before acknowledging, “Yes, it absolutely crossed my mind.”

Sekhri, a longtime biopharma executive with tenures at Sanofi and Novartis, is now entering year three as CEO of eGenesis, the biotech that George Church protégé Luhan Yang founded to genetically alter pigs so that they can be used for organ transplants. He led them through one megaround and has just closed another, raising $125 million from 17 different investors to push the first-ever (humanized) pig to human transplants into the clinic.

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Amit Munshi, Arena

One of Are­na's top drugs flops in a PhI­Ib study for IBS pain. But re­searchers tease out a pos­si­ble path for­ward as CEO ex­plores 's­trate­gic op­tion­s'

Four years ago, when Arena CEO Amit Munshi cut its ties to a troubled weight drug and doubled down on the pipeline, a cannabinoid receptor 2 agonist figured prominently in the biotech’s future. On Tuesday evening, however, Munshi’s high hopes for the drug took a nasty hit after it failed a Phase IIb study for patients with irritable bowel syndrome pain.

Put through a randomized pace with 273 patients, researchers said it flat failed the primary endpoint among the large group with abdominal pain. But they quickly went on to highlight subgroup data, always a tricky and controversial ploy, where they spotlighted a positive p value for patients with moderate to severe pain who received the high dose of the drug — one of 3 provided in the study.

Bob Nelsen (Photo by Michael Kovac/Getty Images)

With stars aligned and cash in re­serve, Bob Nelsen's Re­silience plans a makeover at 2 new fa­cil­i­ty ad­di­tions to its drug man­u­fac­tur­ing up­start

Bob Nelsen’s new, state-of-the-art drug manufacturing initiative is taking shape.

Just 3 months after gathering $800 million of launch money, a dream team board and a plan to shake up a field where he found too many bottlenecks and inefficiencies for the era of Covid-19, Resilience has snapped up a pair of facilities now in line for a retooling.

The company has acquired a 310,000-square-foot plant in Boston from Sanofi along with a 136,000-square-foot plant in Ontario to add to a network which CEO Rahul Singhvi says is just getting started on building his company’s operations up. The Sanofi deal comes with a contract to continue manufacturing one of its drugs.

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CEO Marco Taglietti (Scynexis)

'N­ev­er been more ur­gent:' Scynex­is looks to tack­le su­per­bug cri­sis with late-stage read­out for an­ti­fun­gal hope­ful

As the superbug crisis heats up around the world, Scynexis says it has new data from two interim analyses that prove its antifungal has the potential to treat a broad range of infections.

“The need for new anti-infectives capable of fighting the most resistant pathogens has never been more urgent as we confront the ongoing COVID-19 global pandemic,” CEO Marco Taglietti said in a statement.

A spot­light schiz­o­phre­nia drug in Neu­ro­crine's $2B Take­da deal flunks its first ma­jor test. But it's not giv­ing up yet

When Takeda spun out a pipeline of experimental psychiatry drugs to Neurocrine in a $2 billion deal amid a post-merger shakeout, R&D chief Andy Plump described the therapies as “very interesting but still difficult.”

On Tuesday, we got some idea of how difficult.

San Diego-based Neurocrine revealed that one of the three spotlight clinical programs they’d acquired failed the primary endpoint in a Phase II trial for schizophrenia, registering a negative outcome on the change from baseline in the positive and negative syndrome scale/negative symptom factor score (PANSS NSFS).

Af­ter bail­ing on Covid-19 vac­cines, Mer­ck will team up with J&J to pro­duce its shot as part of un­usu­al Big Phar­ma pact

Merck took a big gamble when it opted to jump into the Covid-19 vaccine race late, and made an equally momentous decision to back out in late January. Now, looking to chip in on the effort, Merck reportedly agreed to team up with one of the companies that has already crossed the finish line.

President Joe Biden on Tuesday is expected to announce a partnership between drugmakers Merck and Johnson & Johnson to jointly produce J&J’s recombinant protein Covid-19 vaccine that received the FDA’s emergency use authorization Saturday, the Washington Post reported.

Ab­b­Vie tees up a biotech buy­out af­ter siz­ing up their Parkin­son's drug spun out of Ke­van Shokat's lab

AbbVie has teed up a small but intriguing biotech buyout after looking over the preclinical work it’s been doing in Parkinson’s disease.

The company is called Mitokinin, a Bay Area biotech spun out of the lab of UCSF’s Kevan Shokat, whose scientific explorations have formed the academic basis of a slew of startups in the biotech hub. One of Shokat’s PhD students in the lab, Nicholas Hertz, co-founded Mitokinin using their lab work on PINK1 suggesting that amping up its activity could play an important role in regulating the mitochondrial dysfunction contributing to Parkinson’s disease pathogenesis and progression.

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Fi­bro­Gen shares skid low­er as a sur­prise ad­comm rais­es risks on roxa OK

FibroGen will likely have to delay its US rollout for roxadustat once again.

In an unexpected move, the FDA is convening its Cardiovascular and Renal Drugs Advisory Committee to review the NDA in an advisory committee meeting. The date is yet to be confirmed.

Just a few weeks ago, SVB Leerink analyst Geoffrey Porges predicted that the roxa approval could come ahead of the PDUFA date on March 20 — effusive despite already being let down once by the FDA’s extension of its review back in December. AstraZeneca, which is partnered with FibroGen on the chronic kidney disease-related anemia drug, disclosed regulators had requested further clarifying analyses of clinical data.