Add one fa­tal flaw to Jiankui He's litany of mis­takes in CRISPR ba­by de­ba­cle

Sci­en­tists the world over have found plen­ty of rea­sons to con­demn their Chi­nese col­league Jiankui He’s ex­per­i­ment with the world’s first CRISPR ba­bies late 2018: The al­leged med­ical need to con­fer HIV im­mu­ni­ty was un­found­ed, the con­sent process seemed du­bi­ous, the ac­tu­al gene edit­ing ap­peared spot­ty, just to name a few. But a new re­search pa­per may have un­cov­ered the most stag­ger­ing of them all.

Two re­searchers at UC Berke­ley has found that the ge­net­ic mu­ta­tion He at­tempt­ed to mim­ic in twins Lu­lu and Nana — known as CCR5-∆32 — is as­so­ci­at­ed with a high­er risk of pre­ma­ture death.

It’s been wide­ly re­port­ed that the mu­ta­tion, which in ef­fect knocked out the CCR5 gene, had al­ready been shown to ren­der peo­ple more sus­cep­ti­ble to the West Nile virus and more like­ly to suf­fer se­ri­ous com­pli­ca­tions, in­clud­ing death, from in­fluen­za. But the over­all ef­fect on mor­tal­i­ty has yet to be es­tab­lished.

By comb­ing through geno­type and death reg­is­ter de­tails of 410,000 in­di­vid­u­als UK Biobank, Berke­ley pro­fes­sor Ras­mus Nielsen and his post­doc Xinzhu Wei found a 21% in­crease in all-cause mor­tal­i­ty rate among peo­ple with two copies of the ∆32 mu­ta­tion, in which 32 base pairs are omit­ted from the gene.

Wei and Nielsen are quick to warn against over­in­ter­pret­ing their find­ings, not least be­cause they on­ly an­a­lyzed genomes of UK vol­un­teers, and they don’t nec­es­sar­i­ly trans­late to East Asians as “the ef­fect of the mu­ta­tion de­pends on the ge­net­ic back­ground and the en­vi­ron­ments,” Wei wrote to Na­tion­al Ge­o­graph­ic.

That said, a sim­i­lar point was al­so made with re­gards to the stud­ies that He cit­ed to jus­ti­fy in­tro­duc­ing the mu­ta­tion in the ba­bies in the first place. Signs that CCR5-∆32 had pro­tec­tive ef­fects against HIV, nat­u­ral­ly ob­served in Eu­ro­pean pop­u­la­tions, spurred him to en­gi­neer their trait in­to the em­bryos that even­tu­al­ly grew in­to twin ba­by girls.

No­tably, He didn’t ex­act­ly recre­ate the ∆32 mu­ta­tion in ei­ther em­bryo. Based on the slides he pre­sent­ed at a con­fer­ence in Hong Kong, Both in­fants ap­peared to still car­ry nor­mal copies of the CCR5 gene, and where the gene edit­ing did work it re­sult­ed in very dif­fer­ent mu­ta­tions whose ef­fects have nev­er been stud­ied.

Nonethe­less, these new find­ings once again lay bare the knowl­edge gap on the con­se­quences — good and bad — of gene vari­a­tions and, thus, the dan­gers of ap­ply­ing gene edit­ing tools on hu­man cells, es­pe­cial­ly when the al­ter­ations can be passed on­to fu­ture gen­er­a­tions as in the case of an em­bryo.

He him­self ex­pressed sec­ond thoughts about his ex­per­i­ment in an email ex­change with Stan­ford Uni­ver­si­ty bioethi­cist William Hurl­but, STAT’s Sharon Be­g­ley re­port­ed.

“I have been think­ing,” He wrote, “I rec­og­nize I pushed too quick­ly in­to a first-of-kind clin­i­cal study with­out the nec­es­sary open di­a­log with reg­u­la­tors, the sci­en­tif­ic com­mu­ni­ty, and the pub­lic.”

As gov­ern­ments and ex­perts rush to pro­pose new reg­u­la­tions on the bound­aries of gene edit­ing, with new stud­ies such as this, the world is fi­nal­ly hav­ing the con­ver­sa­tion that He — now com­plete­ly side­lined and close­ly mon­i­tored by Chi­nese au­thor­i­ties — didn’t have.


Im­age: Jiankui He in No­vem­ber 2018. KIN CHE­UNG for AP PHO­TO

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus -- chop­ping di­a­betes, car­dio and slash­ing costs in com­pa­ny-wide re­org

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy reveal tomorrow with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

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Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

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Left top to right: Mark Timney, Alex Denner, Vas Narasimhan. (The Medicines Company, Getty, AP/Endpoints News)

In a play-by-play of the $9.7B Med­Co buy­out, No­var­tis ad­mits it over­paid while of­fer­ing a huge wind­fall to ex­ecs

A month into his tenure at The Medicines Company, new CEO Mark Timney reached out to then-Novartis pharma chief Paul Hudson: Any interest in a partnership?

No, Hudson told him. Not now, at least.

Ten months later, Hudson had left to run Sanofi and Novartis CEO Vas Narasimhan was paying $9.7 billion for the one-drug biotech – the largest in the string of acquisitions Narasimhan has signed since his 2017 appointment.

The deal was the product of an activist investor and his controversial partner working through nearly a year of cat-and-mouse negotiations to secure a deal with Big Pharma’s most expansionist executive. It represented a huge bet in a cardiovascular field that already saw two major busts in recent years and brought massive returns for two of the industry’s most eye-raising names.

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Paul Hudson. Sanofi

New Sanofi CEO Hud­son adds next-gen can­cer drug tech to the R&D quest, buy­ing Syn­thorx for $2.5B

When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

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Game on: Re­gen­eron's BC­MA bis­pe­cif­ic makes clin­i­cal da­ta de­but, kick­ing off mul­ti­ple myelo­ma matchup with Bris­tol-My­ers

As J&J attempts to jostle past Bristol-Myers Squibb and bluebird for a landmark approval of its anti-BCMA CAR-T — and while GlaxoSmithKline maps a quick path to the FDA riding on its own BCMA-targeting antibody-drug conjugates — the bispecifics are arriving on the scene to stake a claim for a market that could cross $10 billion per year.

The main rivalry in multiple myeloma is shaping up to be one between Regeneron and Bristol-Myers, which picked up a bispecific antibody to BCMA through its recently closed $74 billion takeover of Celgene. Both presented promising first-in-human data at the ASH 2019 meeting.

FDA lifts hold on Abeon­a's but­ter­fly dis­ease ther­a­py, paving way for piv­otal study

It’s been a difficult few years for gene and cell therapy startup Abeona Therapeutics. Its newly crowned chief Carsten Thiel was forced out last year following accusations of unspecified “personal misconduct,” and this September, the FDA imposed a clinical hold on its therapy for a form of “butterfly” disease. But things are beginning to perk up. On Monday, the company said the regulator had lifted its hold and the experimental therapy is now set to be evaluated in a late-stage study.

Roche faces an­oth­er de­lay in strug­gle to nav­i­gate Spark deal past reg­u­la­tors — but this one is very short

Roche today issued the latest in a long string of delays of its $4.3 billion buyout of Philadelphia-based Spark Therapeutics. The delay comes as little surprise — it is their 10th in as many months — as their most recent delay was scheduled to expire before a key regulatory deadline.

But it is notable for its length: 6 days.

Previous extensions had moved the goalposts by about 3 weeks to a month, with the latest on November 22 expiring tomorrow. The new delay sets a deadline for next Monday, December 16, the same day by which the UK Competition and Markets Authority has to give its initial ruling on the deal. And they already reportedly have lined up an OK from the FTC staff – although that’s only one level of a multi-step process.

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KalVis­ta's di­a­bet­ic mac­u­lar ede­ma da­ta falls short — will Mer­ck walk away?

Merck’s 2017 bet on KalVista Pharmaceuticals may have soured, after the UK/US-based biotech’s lead drug failed a mid-stage study in patients with diabetic macular edema (DME).

Two doses of the intravitreal injection, KVD001, were tested against a placebo in a 129-patient trial. Patients who continued to experience significant inflammation and diminished visual acuity, despite anti-VEGF therapy, were recruited to the trial. Typically patients with DME — the most frequent cause of vision loss related to diabetes — are treated with anti-VEGF therapies such as Regeneron’s flagship Eylea or Roche’s Avastin and Lucentis.