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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; and more

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.

EQRx chairman Alexis Borisy and CEO Melanie Nallichieri

EQRx, CStone un­furl full lung can­cer da­ta for PD-L1 drug in what the part­ners are call­ing a first

As a self-stylized drug pricing disruptor, EQRx has high hopes for its lead PD-(L)1 to offer proof of concept for the entire business model. After touting a win back in May, the biotech is back with full data in lung cancer that could back up an approval.

Patients dosed with EQRx and CStone Pharmaceuticals’ sugemalimab posted median progression-free survival of 9 months compared with 5.8 months for patients given placebo (p=0.0026), according to full data from the Phase III GEMSTONE-301 study in Stage III non-small cell lung cancer set to be presented at this weekend’s #ESMO21.

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As­traZeneca touts Imfinzi im­munother­a­py com­bos for lung can­cer in push to dri­ve PD-L1 drug up­take

Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an Innate’s anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.