Cel­lec­tis, ris­ing star Al­lo­gene de­sign an 'all-in-one' CAR con­struct with em­bed­ded safe­ty switch as the new part­ners an­gle for the clin­ic

When Arie Bellde­grun and David Chang bagged all of Pfiz­er’s off-the-shelf CAR-T ther­a­pies, they high­light­ed a col­lab­o­ra­tion pro­gram with Cel­lec­tis that po­ten­tial­ly puts Al­lo­gene Ther­a­peu­tics on a path to com­mer­cial­iza­tion. Two months lat­er, the French biotech is fol­low­ing up with a safer, next-gen­er­a­tion chimeric anti­gen re­cep­tor con­struct now po­si­tioned for the clin­ic.

Julien Val­ton

In a pa­per pub­lished in Sci­en­tif­ic Re­ports to­day, Cel­lec­tis re­ports an all-in-one CAR ar­chi­tec­ture that com­bines can­cer-killing po­ten­cy, a “sui­cide switch” for safe­ty, as well as pu­rifi­ca­tion and de­tec­tion ca­pac­i­ties. Dubbed Cu­biCAR, the mol­e­cule was shown to be “ef­fi­cient­ly and ro­bust­ly” de­plet­ed in the pres­ence of Rit­ux­an (rit­ux­imab) both in vit­ro and in vi­vo.

The idea of a sui­cide switch is, of course, not new. CAR-T is a liv­ing drug that could the­o­ret­i­cal­ly stay in­side pa­tients for years, and giv­en the well-known safe­ty con­cerns with CAR-T — such as cy­tokine re­lease syn­drome and neu­ro­tox­i­c­i­ty — an emer­gency switch has been tout­ed as a life­saver.

Cel­lec­tis’ big achieve­ment here, in­no­va­tion team leader Julien Val­ton tells me, is the in­te­gra­tion of both the safe­ty mech­a­nism and oth­er de­sir­able qual­i­ties in one mol­e­cule. That dis­tin­guish­es Cu­biCAR from most of the oth­er sui­cide switch­es in the clin­ic right now, which he says ex­press­es the CAR and the switch in sep­a­rate mol­e­cules — lead­ing to po­ten­tial im­bal­ance be­tween the two.

“Some­times, we have in­stances where the CAR is ex­pressed, and we couldn’t see the sui­cide switch,” he says.

Philippe Duchateau

Pfiz­er had been in­volved in the project since Cel­lec­tis came up with it three years ago, pro­vid­ing Val­ton’s team with a BC­MA-tar­get­ing CAR for mul­ti­ple myelo­ma. That prod­uct now be­longs to Al­lo­gene, which is work­ing with Cel­lec­tis to find clin­i­cal ap­pli­ca­tions for the con­struct. Mean­while, Cel­lec­tis is al­so putting the Cu­biCAR scaf­fold to use in their own CARs hit­ting the CD123, CD22 and oth­er anti­gens.

The part­ners now joins the likes of Bel­licum and Au­to­lus in pur­suit of bet­ter, safer cell ther­a­pies, first for blood can­cer and even­tu­al­ly — ide­al­ly — for sol­id tu­mors.

While Cu­biCAR’s sui­cide switch is ac­ti­vat­ed by an an­ti­body, oth­er com­pa­nies have opt­ed for the small mol­e­cule-me­di­at­ed ap­proach. One of them is Po­sei­da Ther­a­peu­tics, whose CEO Er­ic Os­tertag told C&EN that an­ti­body-me­di­at­ed switch­es can “take days to re­al­ly work.”

There’s no re­al way to mea­sure it un­til the drug is test­ed in hu­mans, but Val­ton tells me that “us­ing Cel­lec­tis’ ex­per­i­men­tal con­di­tions in vit­ro, it takes about 15 min­utes to de­plete the vast ma­jor­i­ty of Safe­guard CAR T-cells with clin­i­cal­ly rel­e­vant dose of [rit­ux­imab]. This ki­net­ic is on par with the da­ta ob­tained with ICas­pase9 and RQR8 sui­cide switch­es doc­u­ment­ed in the lit­er­a­ture.”

Plus, Val­ton says, Cu­biCAR is al­so eas­i­ly de­tect­ed and pu­ri­fied — mean­ing the ac­tive el­e­ments can be ef­fi­cient­ly ex­tract­ed — by the an­ti­body QBEND10.

“Not on­ly is the Cu­biCAR ar­chi­tec­ture an in­te­grat­ed, com­pact safe­guard al­low­ing for the fast and ef­fi­cient de­ple­tion of CAR T-cells, it is al­so com­pat­i­ble with mul­ti­ple scFvs that are de­signed against dif­fer­ent tar­gets, which gives it the unique po­ten­tial to make CAR T-cell im­munother­a­pies safer,” says Cel­lec­tis CSO Philippe Duchateau in a state­ment.

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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Aca­dia is mak­ing the best of it, but their lat­est PhI­II Nu­plazid study is a bust

Acadia’s late-stage program to widen the commercial prospects for Nuplazid has hit a wall. The biotech reported that their Phase III ENHANCE trial flat failed. And while they $ACAD did their best to cherry pick positive data wherever they can be found, this is a clear setback for the biotech.

With close to 400 patients enrolled, researchers said the drug flunked the primary endpoint as an adjunctive therapy for patients with an inadequate response to antipsychotic therapy. The p-value was an ugly 0.0940 on the Positive and Negative Syndrome Scale, which the company called out as a positive trend.

Their shares slid 12% on the news, good for a $426 million hit on a $3.7 billion market cap at close.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

Now in its third year, the nonprofit created a new set of standards with Yale School of Medicine and Stanford Law School to evaluate the track record on trial registration, results reporting, publication and data-sharing practice.

Busy Gilead crew throws strug­gling biotech a life­line, with some cash up­front and hun­dreds of mil­lions in biobucks for HIV deal

Durect $DRRX got a badly needed shot in the arm Monday morning as Gilead’s busy BD team lined up access to its extended-release platform tech for HIV and hepatitis B.

Gilead, a leader in the HIV sector, is paying a modest $25 million in cash for the right to jump on the platform at Durect, which has been using its technology to come up with an extended-release version of bupivacaine. The FDA rejected that in 2014, but Durect has been working on a comeback.

In­tec blitzed by PhI­II flop as lead pro­gram fails to beat Mer­ck­'s stan­dard com­bo for Parkin­son’s

Intec Pharma’s $NTEC lead drug slammed into a brick wall Monday morning. The small-cap Israeli biotech reported that its lead program — coming off a platform designed to produce a safer, more effective oral drug for Parkinson’s — failed the Phase III at the primary endpoint.

Researchers at Intec, which has already seen its share price collapse over the past few months, says that its Accordion Pill-Carbidopa/Levodopa failed to prove superior to Sinemet in reducing daily ‘off’ time. 

Cel­gene racks up third Ote­zla ap­proval, heat­ing up talks about who Bris­tol-My­ers will sell to

Whoever is taking Otezla off Bristol-Myers Squibb’s hands will have one more revenue stream to boast.

The drug — a rising star in Celgene’s pipeline that generated global sales of $1.6 billion last year — is now OK’d to treat oral ulcers associated with Behçet’s disease, a common symptom for a rare inflammatory disorder. This marks the third FDA approval for the PDE4 inhibitor since 2014, when it was greenlighted for plaque psoriasis and psoriatic arthritis.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Vlad Coric (Biohaven)

In an­oth­er dis­ap­point­ment for in­vestors, FDA slaps down Bio­haven’s re­vised ver­sion of an old ALS drug

Biohaven is at risk of making a habit of disappointing its investors.

Late Friday the biotech $BHVN reported that the FDA had rejected its application for riluzole, an old drug that they had made over into a sublingual formulation that dissolves under the tongue. According to Biohaven, the FDA had a problem with the active ingredient used in a bioequivalence study back in 2017, which they got from the Canadian drugmaker Apotex.

Apotex, though, has been a disaster ground. The manufacturer voluntarily yanked the ANDAs on 31 drugs — in late 2017 — after the FDA came across serious manufacturing deficiencies at their plants in India. A few days ago, the FDA made it official.

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