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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

Mirati’s adagrasib, dosed solo or in combination with chemotherapy cetuximab, showed response rates grater than sotorasib solo  and as part of combination study in a similar patient population also revealed this week at #ESMO21. Mirati’s data were presented as part of a cohort update from the Phase II KRYSTAL-1 study testing adagrasib in a range of solid tumors harboring the KRAS-G12C mutation.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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The best of the rest: High­lights from the be­low-the-fold pre­sen­ta­tions at #ES­MO21

This year’s ESMO Congress has had a major focus on Big Pharma drugs — most notably candidates from Merck and AstraZeneca — but there have also been updates from smaller biotechs with data looking to challenge the big-name drugmakers.

Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

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Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.