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 $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday 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 on his plans to surgically dissect and reassemble the portfoloio, 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.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

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What does $6.9B buy these days in on­col­o­gy R&D? As­traZeneca has a land­mark an­swer

Given the way the FDA has been whisking through new drug approvals months ahead of their PDUFA date, AstraZeneca and their partners Daiichi Sankyo may not have to wait until Q2 of next year to get a green light on trastuzumab deruxtecan (DS-8201).

The pharma giant this morning played their ace in the hole, showing off why they were willing to commit to a $6.9 billion deal — with $1.35 billion in a cash upfront — to partner on the drug.

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Large advertisements for the drug Vivitrol decorate the walls of Grand Central Station on June 15, 2017 in New York City. (Photo: Andrew Lichtenstein via Getty)

FDA slaps down Alk­er­mes for mis­lead­ing Viv­it­rol ads — don't for­get vul­ner­a­bil­i­ty to opi­oid over­dose

The ads piqued interest as soon as they started appearing in 2016: at Grand Central Station, on the Red Line in Cambridge, and on a billboard off the New Jersey Turnpike. All showed a young person, generally with his or her arms crossed, and the question, “what is Vivitrol?”

Vivitrol’s maker, Alkermes, was in the midst of a marketing and lobbying campaign to promote the anti-opioid addiction drug — a campaign that would face significant backlash for tarnishing competitors despite little evidence for Vivitrol’s superiority.

FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.

Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.

Seat­tle Ge­net­ics de­tails pos­i­tive OS and PFS da­ta for tu­ca­tinib in breast can­cer

Seattle Genetics $SGEN is showing off more positive data around tucatinib, its pivotal-stage drug for HER2 positive breast cancer.

A month after hearing about solidly upbeat hazard ratios, we learned today that the estimated progression-free survival rate at one year was 33% in the tucatinib arm compared to 12% for patients taking trastuzumab and capecitabine alone.

Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.

Bat­tered, cash hun­gry In­tec feels the burn of No­var­tis re­jec­tion

It’s a case of some bad timing for Intec.

Just when a key trial testing the company’s Accordion drug delivery tech imploded in Parkinson’s disease, they handed Novartis data from a successful PK study of a custom Accordion pill engineered to deliver a Novartis compound to entice the Swiss drugmaker into signing a licensing agreement.

Novartis said thanks, but no thanks.

For the cash-strapped Israeli drug developer, the failure to clinch the deal marks a big blow. As of the third quarter, the company has $15.7 million in cash and equivalents, which HC Wainwright analysts estimate will keep the lights on into mid-2020.

Bris­tol-My­ers shows off a low-pro­file AML con­tender it gained from Cel­gene buy­out — and they’re tak­ing it straight to the FDA

Bristol-Myers Squibb reaped an enormous pipeline with its much-criticized $64 billion megadeal to buy Celgene. And it got a few hidden gems in the deal.

One of those gems was brought out for display on Tuesday, with a late-breaker at ASH on CC-486, which is now being prepped for regulatory filings at the FDA and elsewhere.

Celgene top-lined the positive results in a maintenance setting for acute myeloid leukemia a few months ago, but at ASH investigators pulled back the curtains on the all-important data they believe will give them an advantage in the commercial wars to come.

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De­sert­ed by Astel­las and Mer­ck, lit­tle Cor­re­vio still can't win over FDA pan­el con­cerned with its AFib drug's safe­ty

When the FDA spurned Astellas’ pitch for atrial fibrillation drug vernakalant in 2008, regulators made it abundantly clear that it wasn’t the efficacy they had a problem with — two Phase III trials had shown the drug successfully restored 52% of patients’ heartbeat from irregular to normal — but the cardio safety issues for a drug that was to compete with well established, low-risk options. One licensing deal, one clinical hold and several studies later, the chances of approval aren’t looking any better.