In stag­ger­ing set­back, tox­ic re­ac­tion kills Cel­lec­tis’ first CAR-T pa­tient, forc­ing tri­al halt

The FDA has forced Cel­lec­tis $CLLS to slam the brakes on two clin­i­cal tri­als of its off-the-shelf ver­sion of a CAR-T ther­a­py af­ter their first pa­tient was killed by a lethal­ly tox­ic re­ac­tion to treat­ment.

Ac­cord­ing to the biotech, which is based in Paris with R&D op­er­a­tions in New York, a 78-year-old pa­tient suf­fer­ing from blas­tic plas­ma­cy­toid den­drit­ic cell neo­plasm (BPD­CN) died eight days af­ter re­ceiv­ing the biotech’s first dose of the cell ther­a­py. He ex­pe­ri­enced a lethal re­ac­tion as cy­tokine re­lease syn­drome hit, along with a grade 4 case of cap­il­lary leak syn­drome. A sep­a­rate study which al­so treat­ed one pa­tient is un­der­way for acute myeloid leukemia.

The com­pa­ny’s stock was ham­mered by the bad news, drop­ping about 30% in pre-mar­ket trad­ing and shed­ding more than $400 mil­lion of its mar­ket cap.

Sig­nif­i­cant­ly, nei­ther of the first two pa­tients treat­ed with UCART123 ex­pe­ri­enced graft ver­sus host dis­ease, one of the chief fears in­volved in an al­lo­gene­ic ther­a­py that takes do­nat­ed pa­tient cells then adapts them in­to a ready-to-use ther­a­py, by­pass­ing a com­plex step re­quired by the first CAR-Ts.

The FDA ap­proved the first per­son­al­ized CAR-T from No­var­tis just days ago, and Kite is ex­pect­ed to get an OK of its own soon. But the move by the FDA to slap a hold on these off-the-shelf ther­a­pies rais­es a host of thorny ques­tions for Cel­lec­tis.

Juno $JUNO was al­so forced to halt a study of its lead CAR-T last year — one of the pi­o­neer­ing au­tol­o­gous ver­sions that ex­tracts pa­tient cells and then adapts them be­fore re­in­fus­ing them in­to pa­tients — af­ter pa­tients died from cere­bral ede­ma. Then in an as­ton­ish­ing­ly short pe­ri­od of just a few days, reg­u­la­tors agreed to let re­searchers pro­ceed with the piv­otal tri­al af­ter a ques­tion­able change-up in the pre­con­di­tion­ing reg­i­men used to pre­pare pa­tients for the cell ther­a­py. Al­most im­me­di­ate­ly af­ter treat­ment re­sumed, three more pa­tients died fol­lowed by a tri­al halt and the sub­se­quent de­ci­sion to scrap a drug Juno and the FDA clear­ly didn’t com­plete­ly un­der­stand.

An­dre Chouli­ka

Will that dead­ly mis­take by reg­u­la­tors force them to be ex­tra sen­si­tive to this quick and ear­ly death in the UCART123 stud­ies? Or will reg­u­la­tors be quick to green-light this new ther­a­py back in­to the study, con­fi­dent that years of treat­ing CRS — a com­mon re­ac­tion among pa­tients re­ceiv­ing CAR-T ther­a­py — can be man­aged?

Cel­lec­tis spelled out the down­ward spi­ral ex­pe­ri­enced by its first pa­tient.

About a week ago, Cel­lec­tis re­ports, the da­ta safe­ty mon­i­tor­ing board sug­gest­ed low­er­ing the dose — to 6.25×104 UCART123 cells per kilo­gram — in both stud­ies and cap­ping cy­clophos­phamide to a to­tal dose of 4g over three days. But the FDA fol­lowed up by de­mand­ing a halt to the BPD­CN study along with the sep­a­rate study on acute myeloid leukemia, which has al­so seen one pa­tient treat­ed. That pa­tient ex­pe­ri­enced a grade 3 case of CRS and a grade 4 case of cap­il­lary leak syn­drome — both of which re­solved with­in a few days.

Cap­il­lary leak syn­drome is a con­di­tion in which leaky blood ves­sels can cause a po­ten­tial­ly lethal drop in blood pres­sure.

In the ab­sence of any sim­ple ex­pla­na­tion, in­vestors like Biren Amin at Jef­feries spec­u­lat­ed on caus­es and de­fects. His note:

We think there is a chance that CRS events could be mit­i­gat­ed up­on low­er­ing the dose of UCART123 be­yond the DSMB rec­om­men­da­tion and treat­ing CRS symp­toms more ag­gres­sive­ly, al­though ul­ti­mate­ly we look to more in­for­ma­tion. These events may be par­tial­ly due to the UCART123 cells be­ing from a healthy donor but, giv­en the dearth of da­ta, we think CLLS needs to ap­proach through a more holis­tic ap­proach and utliliz­ing key re­search on safe­ty from au­tol­o­gous CAR-T tri­als over the last 3-4 years. How­ev­er, we be­lieve the Grd 3 in­fec­tion (po­ten­tial­ly a re­sult of a neu­tropenic state) and Grd 4 CLS events have the po­ten­tial to be tar­get spe­cif­ic. For the lat­ter, we note that sAEs in­volv­ing CLS has been re­port­ed for Stem­line’s (STML, NC) CD123-di­rect­ed SL-401 ther­a­peu­tic. It’s un­clear if CLLS al­so re­quired pa­tients in their stud­ies to have nor­mal ejec­tion frac­tions and cer­tain pre-spec­i­fied al­bu­min lev­els at time of study en­try.

Cel­lec­tis will get ham­mered by in­vestors to­day, par­tic­u­lar­ly as the en­thu­si­asm for all things CAR-T seen in the past few days has swelled every­one’s stock price. Cel­lec­tis shares have soared past the $32 mark. The safe­ty is­sue will chal­lenge CEO An­dré Chouli­ka, a fierce and un­abashed pro­po­nent of all things Cel­lec­tis.

“Cel­lec­tis is the first com­pa­ny do­ing CAR-T,” he told me dur­ing an in­ter­view at AS­CO two years ago. “We are the first gene edit­ing com­pa­ny in the world,” dat­ing back to 1999. “There was no gene edit­ing be­fore us; we are the lead­ers.”

To­day, Cel­lec­tis and Chouli­ka will be lead­ing a charge to re­solve their biggest chal­lenge to date. It won’t be easy.

Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,100+ biopharma pros reading Endpoints daily — and it's free.

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.”

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,100+ biopharma pros reading Endpoints daily — and it's free.

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.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,100+ biopharma pros reading Endpoints daily — and it's free.

Chas­ing Roche's ag­ing block­buster fran­chise, Am­gen/Al­ler­gan roll out Avastin, Her­ceptin knock­offs at dis­count

Let the long battle for biosimilars in the cancer space begin.

Amgen has launched its Avastin and Herceptin copycats — licensed from the predecessors of Allergan — almost two years after the FDA had stamped its approval on Mvasi (bevacizumab-awwb) and three months after the Kanjinti OK (trastuzumab-anns). While the biotech had been fielding biosimilars in Europe, this marks their first foray in the US — and the first oncology biosimilars in the country.

Seer adds ex-FDA chief Mark Mc­Clel­lan to the board; Her­cules Cap­i­tal makes it of­fi­cial for new CEO Scott Bluestein

→ On the same day it announced a $17.5 million Series C, life sciences and health data company Seer unveiled that it had lured former FDA commissioner and ex-CMS administrator Mark McClellan on to its board. “Mark’s deep understanding of the health care ecosystem and visionary insights on policy reform will be crucial in informing our thinking as we work to bring our liquid biopsy and life sciences products to market,” said Seer chief and founder Omid Farokhzad in a statement.

Daniel O'Day

No­var­tis hands off 3 pre­clin­i­cal pro­grams to the an­tivi­ral R&D mas­ters at Gilead

Gilead CEO Daniel O’Day’s new task hunting up a CSO for the company isn’t stopping the industry’s dominant antiviral player from doing pipeline deals.

The big biotech today snapped up 3 preclinical antiviral programs from pharma giant Novartis, with drugs promising to treat human rhinovirus, influenza and herpes viruses. We don’t know what the upfront is, but the back end has $291 million in milestones baked in.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,100+ biopharma pros reading Endpoints daily — and it's free.

On a glob­al romp, Boehringer BD team picks up its third R&D al­liance for Ju­ly — this time fo­cused on IPF with $50M up­front

Boehringer Ingelheim’s BD team is on a global deal spree. The German pharma company just wrapped its third deal in 3 weeks, going back to Korea for its latest pipeline pact — this time focused on idiopathic pulmonary fibrosis.

They’re handing over $50 million to get their hands on BBT-877, an ATX inhibitor from Korea’s Bridge Biotherapeutics that was on display at a science conference in Dallas recently. There’s not a whole lot of data to evaluate the prospects here.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,100+ biopharma pros reading Endpoints daily — and it's free.

Servi­er scoots out of an­oth­er col­lab­o­ra­tion with Macro­Gen­ics, writ­ing off their $40M

Servier is walking out on a partnership with MacroGenics $MGNX — for the second time.

After the market closed on Wednesday MacroGenics put out word that Servier is severing a deal — inked close to 7 years ago — to collaborate on the development of flotetuzumab and other Dual-Affinity Re-Targeting (DART) drugs in its pipeline.

MacroGenics CEO Scott Koenig shrugged off the departure of Servier, which paid $20 million to kick off the alliance and $20 million to option flotetuzumab — putting a heavily back-ended $1 billion-plus in additional biobuck money on the table for the anti-CD123/CD3 bispecific and its companion therapies.