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.

Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In early 2021, Bluebird Bio was forced to suspend clinical trials of its gene therapy for sickle cell disease after two patients in the trial developed cancer. As company scientists rushed to assess whether there was any causal link between the therapy and the cancer cases, Bluebird’s stock value plummeted – as did those of multiple other biopharma companies developing similar therapies.

While investigations concluded that the gene therapy was unlikely to have caused cancer, investors and the public may be more skittish regarding the safety of gene and cell therapies after this episode. This recent example highlights how delicate the fields of cell and gene therapy remain today, even as they show great promise.

Sen. Patty Murray (D-WA) (Graeme Sloan/Sipa USA/Sipa via AP Images)

Sen­a­tors to NIH: Do more to pro­tect US bio­med­ical re­search from for­eign in­flu­ence

Although Thursday’s Senate health committee hearing was focused on how foreign countries and adversaries might be trying to steal or negatively influence biomedical research in the US, the only country mentioned by the senators and expert witnesses was China.

Committee chair Patty Murray (D-WA) made clear in her opening remarks that the US cannot “let the few instances of bad actors” overshadow the hard work of the many immigrant researchers in the US, many of which have won Nobel prizes for their work. But she also said, “There is more the NIH can be doing here.”

Covid-19 man­u­fac­tur­ing roundup: Mary­land looks to grow biotech ca­pac­i­ty with $400M check; Rus­sia lands sec­ond Sput­nik V part­ner this week

A Maryland real estate project has added three new biotech-focused manufacturing and research buildings to an office park to keep up with demand created by the pandemic, the Washington Business Journal reported.

The Milestone Business Park — located off of I-270 in Germantown, MD — will see the new buildings and a total of 532,000 square feet as the campus rebrands to Milestone Innovation Park.

Law pro­fes­sors call for FDA to dis­close all safe­ty and ef­fi­ca­cy da­ta for drugs

Back in early 2018 when Scott Gottlieb led the FDA, there was a moment when the agency seemed poised to release redacted complete response letters and other previously undisclosed data. But that initiative never gained steam.

Now, a growing chorus of researchers are finding that a dearth of public data on clinical trials and pharmaceuticals means industry and the FDA cannot be held accountable, two law professors from Yale and New York University write in an article published Wednesday in the California Law Review.

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

As fears mount over J&J and As­traZeneca, No­vavax en­ters a shaky spot­light

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax.

In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line.

FDA of­fers scathing re­view of Emer­gent plan­t's san­i­tary con­di­tions, em­ploy­ee train­ing af­ter halt­ing pro­duc­tion

The FDA wrapped up its inspection of Emergent’s troubled vaccine manufacturing plant in Baltimore on Tuesday, after halting production there on Monday. By Wednesday morning, the agency already released a series of scathing observations on the cross contamination, sanitary issues and lack of staff training that caused the contract manufacturer to dispose of millions of AstraZeneca and J&J vaccine doses.

Brad Bolzon (Versant)

Ver­sant pulls the wraps off of near­ly $1B in 3 new funds out to build the next fleet of biotech star­tups. And this new gen­er­a­tion is built for speed

Brad Bolzon has an apology to offer by way of introducing a set of 3 new funds that together pack a $950 million wallop in new biotech creation and growth.

“I want to apologize,” says the Versant chairman and managing partner, laughing a little in the intro, “that we don’t have anything fancy or flashy to tell you about our new fund. Same team, around the same amount of capital, same investment strategy. If it ain’t broke, don’t fix it.”

But then there’s the flip side, where everything has changed. Or at least speeded into a relative blur. Here’s Bolzon:

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Jenny Rooke (Genoa Ventures)

Ear­ly Zymer­gen in­vestor Jen­ny Rooke re­flects on 'chimeras' in biotech, what it takes to spot a $500M gem

When Jenny Rooke first heard of Zymergen back in 2014, she knew she was looking at something different and exciting. The Emeryville, CA biotech held the promise of blending biology and technology to solve a huge unmet need for cost-effective chemicals — of all things — and a stellar founding team to boot.

But back then, West Coast venture capitalists didn’t see in Zymergen the one thing they were looking for in a winning biotech: therapeutic potential. Rooke, however, saw an opportunity and made her bets. Seven years later, that bet is paying off in a big way.

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Saurabh Saha at Endpoints News' #BIO19

On the heels of $250M launch, Centes­sa barges ahead with an IPO to fu­el its 10-in-1 Medicxi pipeline

Francesco De Rubertis made no secret of IPO plans for Centessa, his 10-in-1 legacy play. Barely two months later, the S-1 is in.

The hot-off-the-press filing depicts the same grand vision that the longtime VC touted when he did the rounds in February: Take the asset-centric mindset that he’s been preaching at Medicxi over the years, and roll up a bunch of biotech upstarts, with unrelated risk profiles, into 1 pharma company that can carry on the development at scale.