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.

Com­mu­ni­cat­ing the val­ue of pre­ci­sion med­i­cine

By Natasha Cowan, Content Marketing Manager at Blue Latitude Health.
Many stakeholders are confused by novel precision medicines, including patients and healthcare professionals. So, how can industry help them to navigate this complexity?

Precision medicine represents a new paradigm in healthcare. It embodies the shift from treating many patients with the same therapy, to having the tools to identify the best treatment for every patient.

Spe­cial re­port: Twen­ty ex­tra­or­di­nary women in bio­phar­ma R&D who worked their way to the top

What differentiates a woman leader in biopharma R&D from a man?

Not much, except there are fewer of them in senior posts. Data suggest women are not more risk-averse, family-oriented or less confident than their male counterparts — indeed the differences between the two sexes are negligible. But a glance at the top R&D positions in Big Pharma leaves little doubt that upward migration in the executive ranks of biopharma R&D is tough.

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The lat­est Cin­derel­la sto­ry in on­col­o­gy ends with a sud­den rout as up­dat­ed da­ta dis­play spooks in­vestors

NextCure’s turn as the Cinderella of cancer-focused biotechs was short-lived.
Just a few days after its shares $NXTC zoomed up more than 250% on some very early stage results in a SITC abstract, a more complete analysis over the weekend spiked the hype and left investors in high dudgeon as the stock price collapsed back towards earth Monday.
The focus at NextCure is centered on NC318, an antibody that is intended to shut down the immunosuppressive Siglec-15 — or S-15 — target. After adding a small group of patients to the readout, investigators circled 2 clinical responses, a complete and partial response, along with 4 stable disease cases in non-small cell lung cancer.

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Te­va spin­out rais­es $85M in IPO; No­var­tis beefs up gener­ics unit with $440M deal

→ After Teva spinout 89bio recently announced that its IPO was being held up, the company is back in the game offering 5,304,687 shares at a price of $16 per share. The company has raised $84.9 million IPO in gross proceeds and will be listed under the ticker symbol $ETNB. BofA Securities, SVB Leerink and RBC Capital Markets are the joint book-running managers for the offering. Oppenheimer & Co is the co-manager for the offering.
→ Looking to amp up its presence in Japan’s hospitals, Novartis has struck a deal to buy out Aspen’s portfolio of generics in the world’s third largest healthcare market. The pharma giant is paying $440 million for Aspen’s Japanese subsidiary.
→ Novartis said tropifexor, a non-bile acid FXR agonist, has scored on several key biomarkers of NASH in a Phase IIb trial, including reductions in hepatic fat, alanine aminotransferase and body weight compared to a placebo at 12 weeks.

Break­through sta­tus and promise of a speedy re­view ar­rives for Op­di­vo/Yer­voy com­bi­na­tion as Bris­tol-My­ers bites at Bay­er

Its frontline and single-agent aspirations have been set back, but Bristol-Myers Squibb just took a big step forward in its efforts to apply its checkpoint inhibitor Opdivo to liver cancer. The FDA has granted breakthrough status and priority review to a combination, second-line treatment.

The designation is for Opdivo (nivolumab) in combination with Yervoy (ipilimumab),  for treating advanced hepatocellular carcinoma (HCC), the most common form of liver cancer. The PD-L1 drug was already approved as a single-agent, second-line treatment for HCC. A PDUFA date was set for March 10, 2020 — just 4 months from now.

Third time un­lucky: Lipocine's lat­est quest to mar­ket their oral testos­terone drug snubbed again by FDA

Lipocine’s latest attempt at securing approval for its oral testosterone drug has fizzled yet again.

The Utah-based drug developer on Monday said the FDA has spurned its marketing application, indicating that some efficacy data on the drug, Tlando, was not up to scratch to treat male hypogonadism, a condition characterized by low production of the hormone testosterone, which is responsible for maintaining muscle bulk, bone growth, and sexual function.

UP­DAT­ED: De­cry­ing 'ar­bi­trary and capri­cious' ac­tion, Re­genxBio sues FDA over clin­i­cal holds on gene ther­a­py

When RegenxBio disclosed that the FDA had placed a partial clinical hold on one of its lead gene therapies, execs outlined several customary next steps: continuing assessment and monitoring, delaying a related IND filing, and working with the FDA to address the matter.

As it turned out, they were planning something much less mundane. Two days after announcing the hold in its Q3 update, RegenxBio filed a lawsuit seeking to set it aside, the FDA Law Blog noted.

Roche's SMA chal­lenge to Bio­gen's Spin­raza fran­chise looms larg­er with piv­otal win

Roche has just landed a crucial advance in scoring a come-from-behind win on the spinal muscular atrophy field, giving Novartis and Biogen a run for their money.

The update was brief, but Roche said risdiplam hit the primary endpoint in the placebo-controlled pivotal SUNFISH trial, meeting the threshold for change from baseline in the Motor Function Measure 32 (MFM-32) scale after one year of treatment. The results, which is the second, confirmatory portion of a two-part study, involved 180 patients with type 2 or 3 spinal muscular atrophy between 2 and 25 years old.

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Roche steers Gazy­va in­to a new PhI­II pro­gram af­ter com­bo shows promise in lu­pus nephri­tis study

Roche is working on putting together a late-stage study for its monoclonal antibody Gazyva in patients with severe kidney disease associated with lupus after a combination approach helped patients in a mid-stage study.

The 125-patient NOBILITY trial evaluated Gazyva, combined with standard-of-care treatment mycophenolate mofetil or mycophenolic acid and corticosteroids, versus standard treatment alone. The combo met the main goal of inducing a statistically superior complete renal response (CRR) of 40% at week 76, versus 18% in patients given standard treatment, Roche said.