John Leonard, Intellia CEO

Search­ing for CRISPR 2.0, In­tel­lia spends $45M cash on an un­known Berke­ley spin­out

Even as two of the first gen­er­a­tion of CRISPR com­pa­nies have shown pow­er­ful re­sults in the clin­ic, they’ve faced a grow­ing threat: new tech­nolo­gies such as base and prime edit­ing that can con­duct more ver­sa­tile and po­ten­tial­ly safer edit­ing.

In­tel­lia, which last year be­came the first com­pa­ny to show CRISPR can work di­rect­ly in pa­tients, is hop­ing that a lit­tle-known start­up can help it stay on the cut­ting edge. On Thurs­day it an­nounced a buy­out of a tiny and ef­fec­tive­ly un­known Berke­ley spin­out called Rewrite Ther­a­peu­tics for $45 mil­lion cash and $155 mil­lion in mile­stones that In­tel­lia claims can do a host of ge­net­ic ed­its cur­rent­ly lim­it­ed to prime edit­ing and a cou­ple oth­er tech­nolo­gies.

“At In­tel­lia, we have built the in­dus­try’s broad­est and deep­est genome edit­ing plat­form by stay­ing at the fore­front of new tech­niques, while al­so ex­tend­ing the ca­pa­bil­i­ties of CRISPR/Cas9 edit­ing to make pre­cise­ly tar­get­ed changes to DNA,” CEO John Leonard said in a state­ment. Rewrite of­fers In­tel­lia “new pos­si­bil­i­ties and the po­ten­tial to tar­get dis­eases be­yond those cur­rent­ly be­ing ex­plored in our pipeline.”

Shahram Seyedin-Noor, head of Civ­i­liza­tion Ven­tures — the VC that seed­ed Rewrite — claimed the com­pa­ny is a “kind of CRISPR 2.0,” the same moniker of­ten ap­plied to base and prime edit­ing but with po­ten­tial im­prove­ments on both.

That’s no small boast: Prime edit­ing caused a me­dia fren­zy when Har­vard pro­fes­sor David Liu and his post­doc An­drew An­za­lone pub­lished it in Oc­to­ber 2019. A hand­ful of blue-chip VCs poured $315 mil­lion in­to a new start­up fo­cused on turn­ing the tech in­to ther­a­pies.

Prime al­lowed re­searchers to ma­nip­u­late DNA in ways no oth­er sys­tem had: chang­ing any let­ter of DNA in­to any oth­er and mak­ing com­plex changes, such as large in­ser­tions and dele­tion.

It is al­so a com­plex and un­wieldy sys­tem, dif­fi­cult to work with and dif­fi­cult to fit in­side the vi­ral vec­tors some­times used to de­liv­er oth­er CRISPR sys­tems. (Al­though im­prove­ments are be­ing made.)

Shahram Seyedin-Noor

Seyedin-Noor claims Rewrite’s tech­nol­o­gy al­lows it to be snuck in­side a vi­ral vec­tor or lipid nanopar­ti­cle, al­though he didn’t elab­o­rate on how. His­tor­i­cal­ly, re­searchers have some­times fit CRISPR sys­tems in­to vi­ral vec­tors, by break­ing it apart and putting it in­to two dif­fer­ent vec­tors, but that tends to make the sys­tem less ef­fi­cient.

It can al­so, they say, work in non-di­vid­ing cells such as those in the ner­vous sys­tem, where Seyedin Noor said can be dif­fi­cult to get prime edit­ing to work.

“That’s pret­ty large,” said Seyedin-Noor. It “adds a whole area of ther­a­peu­tics that’s un­touched right now.”

Liu’s lab, how­ev­er, did show ef­fi­ca­cy in neu­rons in their orig­i­nal 2019 pa­per. In a Na­ture Gene Ther­a­py re­view of the field last year, two re­searchers, Ja­nine Schofield and Patrick T. Har­ri­son, not­ed prime edit­ing was par­tic­u­lar­ly im­por­tant be­cause it showed pre­cise ge­net­ic sub­sta­tions in non-di­vid­ing cells, “al­beit at low fre­quen­cy.”

And for now, Rewrite’s claims are just that. Un­like Prime, Rewrite Ther­a­peu­tics’ tech­nol­o­gy re­mains un­pub­lished.

Its founders, how­ev­er, have re­leased ear­li­er it­er­a­tions of the work, al­beit for an en­tire­ly dif­fer­ent ap­pli­ca­tion.

Shakked Halperin

In 2018, Rewrite co-founder and CEO Shakked Halperin and his then-ad­vi­sor David Schaf­fer pub­lished in Na­ture a CRISPR-based sys­tem that al­lowed re­searchers to tar­get a 750-let­ter stretch in the genome and in­tro­duce se­mi-ran­dom mu­ta­tions at that spot. At the time, though, they demon­strat­ed it not as a way to ed­it genes in pa­tients but to has­ten and re­fine di­rect­ed evo­lu­tion — a No­bel Prize-win­ning tech­nique for con­duct­ing ba­sic re­search and for de­sign­ing use­ful pro­teins.

In­tel­lia was qui­et about how it would use the tech­nol­o­gy, but they’ve long hint­ed at plans be­yond Cas9. Al­though their head­line-grab­bing amy­loi­do­sis tri­al last year and the rest of their list­ed pipeline us­es clas­sic Cas9, they’ve al­so be­gun de­sign­ing and pub­licly pre­sent­ing base ed­i­tors.

No word yet on how they’ll use those, ei­ther.

The ar­ti­cle has been up­dat­ed to clar­i­fy lan­guage on dif­fer­ence be­tween rewrite’s tech­nol­o­gy and prime edit­ing. 

Image courtesy of The Janssen Pharmaceutical Companies of Johnson & Johnson.

Pro­tect­ing the glob­al phar­ma­ceu­ti­cal in­no­va­tion ecosys­tem – what’s at stake?

We are living in a new era of healthcare that is rapidly advancing progress impacting patient outcomes and experiences. We’ve seen a remarkable pace of transformational innovation, applied research, and advanced clinical development over the last decade.

Despite this tremendous progress, there is much more work to be done, and patients are counting on us – now more than ever – to continue that momentum. At the heart of our industry is a focus on developing and delivering medicines for some of the world’s most challenging diseases, including those that have few or no effective treatments today.

Rich Horgan (R) with his late brother, Terry

Rich Hor­gan spear­head­ed a gene ther­a­py for his broth­er. The tri­al end­ed in tragedy, but the work con­tin­ues for more pa­tients

Rich Horgan’s quest to create a custom gene therapy for his brother, Terry, ended in tragedy. But Horgan doesn’t believe it’s the end of the story.

Terry, a 27-year-old patient with Duchenne muscular dystrophy, died last October just eight days after receiving the therapy in a clinical trial in which he was the only participant. The case raised questions about the safety of certain gene therapies and what would happen to other drug programs under a nonprofit that Horgan created, called Cure Rare Disease.

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End­points 20(+2) un­der 40, 2023; Bio­phar­ma's high­est-paid CEOs; N-of-1 CRISPR sto­ry goes on af­ter tragedy; 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.

We will be off Monday in observance of Memorial Day — and when we get back, it will be a straight march to ASCO, BIO and more. Enjoy the (long) weekend!

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Bio­phar­ma's 20 high­est-paid CEOs of 2022, each bring­ing in $20M+ pay­days

Even in a down year for much of the biopharma market, 20 CEOs brought in pay packages valued at more than $20 million, an Endpoints News analysis found.

Endpoints collected data on more than 350 CEO compensation packages, covering a wide range of pharma, biotech, and life sciences companies. All told, the 20 largest earners made over $725 million in 2022 — an average package of $36.4 million. Three brought in paydays over $50 million, and one CEO broke the $100 million mark.

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Mi­rati’s drug sitra­va­tinib flops PhI­II in com­bo with Op­di­vo for cer­tain lung can­cer

Mirati Therapeutics’ path to a second drug approval will likely have to wait. The San Diego biotech company said Wednesday that its investigational lung cancer drug failed a Phase III trial testing it in combination with Bristol Myers Squibb’s Opdivo.

The drug, sitravatinib, and Opdivo weren’t better than the chemo drug docetaxel at keeping patients alive, Mirati said in a press release. The spectrum-selective kinase inhibitor missed the primary goal of overall survival in patients with second- or third-line advanced non-squamous, non-small cell lung cancer.

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The 20(+2) un­der 40: Your guide to the next gen­er­a­tion of biotech lead­ers

This year’s list of 20 biotech leaders under the age of 40 includes a huge range of ambitions. Some of our honorees are planning to create the next big drug giant. Others are pushing the bounds of AI. One is working to revolutionize TB testing. All are compelling talents who are still young in age, but already far along in achievement.

And, as in years past, we went over. The 20 are actually 22 because of two double profiles that reflect how important teamwork is in the industry. As one of our honorees, Joe Illingworth of DJS Antibodies, told me in our interview, “It takes a village to raise a biotech.”

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FDA ap­proves Lex­i­con’s heart-fail­ure drug af­ter de­feat in di­a­betes

The FDA on Friday approved Lexicon’s heart failure drug sotagliflozin following a string of setbacks for the pharma company, including an FDA rejection in diabetes and the loss of a development deal with Sanofi.

The dual SGLT1 and SGLT2 inhibitor will be marketed as Inpefa and is a once-daily tablet. It’s been approved to reduce the risk of cardiovascular death and heart failure-related hospitalization or urgent visits in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. The label spans the range of left ventricular ejection fraction, including preserved ejection fraction and reduced ejection fraction, as well as patients with or without diabetes, Lexicon said Friday.

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FDA de­lays Sarep­ta's Duchenne gene ther­a­py de­ci­sion by a month

The FDA delayed its decision whether to grant accelerated approval to Sarepta Therapeutics’ gene therapy for Duchenne muscular dystrophy, pushing it back about one month to June 22.

Sarepta announced the delay in a news release on Wednesday morning, saying the FDA needs “modest additional time to complete the review, including final label negotiations and post-marketing commitment discussions.”

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Eu­ro­pean Com­mis­sion to re­ceive few­er Pfiz­er-BioN­Tech vac­cine dos­es un­der amend­ed con­tract

The European Commission has made a few changes to its vaccine contract with Pfizer and BioNTech, reducing the dose volume while extending the delivery timeline to cope with “evolving public health needs.”

The Commission previously struck a contract in May 2021 for 900 million doses, with the option to purchase another 900 million. Of those, 450 million were expected to be delivered in 2023, though an amendment now calls for fewer doses. While neither the Commission nor Pfizer and BioNTech have revealed an exact amount, an unnamed source told Reuters that the amendment reduces the remaining expected doses by about a third.

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