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.

Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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Joseph Kim, Inovio CEO (Andrew Harnik, AP Images)

Pos­i­tive Covid-19 vac­cine da­ta? New mouse study? OWS in­clu­sion? Yep, but some­how, the usu­al tid­bits from In­ovio back­fire

You don’t go more than 40 years in biotech without ever getting a product to market unless you can learn the art of writing a promotional press release. And Inovio captures the prize in baiting the hook.

Tuesday morning Inovio, which has been struggling to get its Covid-19 vaccine lined up for mass manufacturing, put out a release that touched on virtually every hot button in pandemic PR.

There was, first and foremost, an interim snapshot of efficacy from their Phase I program for INO-4800.

Jan van de Winkel, Genmab CEO

Seat­tle Ge­net­ics, Gen­mab turn on TV for a high­light reel in cer­vi­cal can­cer — but a ri­val biotech promis­es a bet­ter show

Seattle Genetics $SGEN and their partners at Genmab $GMAB polished up some positive Phase II numbers for their antibody drug conjugate tisotumab vedotin — you can call it TV — for recurrent cervical cancer. And while they mapped out a shortcut to a potential quick approval, the big challenge for this team is being presented by a rival biotech which muscled its way into the spotlight for the same indication a year ago.

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Dan Gold, MEI Pharma CEO

De­vel­op­ment part­ners at MEI, Helsinn dump a high-risk PhI­II AML study af­ter con­clud­ing it would fail sur­vival goal

Four years after Switzerland’s Helsinn put $25 million of cash on the table for an upfront and near-term milestone to take MEI Pharma’s drug pracinostat into a long-running Phase III trial for acute myeloid leukemia, the partners are walking away from a clinical pileup.

The drug — an HDAC inhibitor — failed to pass muster during a futility analysis, as researchers concluded that pracinostat combined with azacitidine wasn’t going to outperform the control group in the pivotal.