Two more pa­tients die as Juno’s lead CAR-T turns lethal again; tri­al halt­ed

Juno CEO Hans Bish­op

Juno’s lead CAR-T drug is killing more pa­tients, and this time it may have reached the end of the clin­i­cal road.

Four months af­ter the biotech was forced to scram­ble to save the pro­gram in the wake of three pa­tient deaths, Juno says that two more pa­tients have died of cere­bral ede­ma out of on­ly 12 more pa­tients treat­ed in the study.

Juno has vol­un­tar­i­ly put the study back on clin­i­cal hold and in­formed reg­u­la­tors at the FDA, who may not be so quick to al­low this study to re­sume this time around.

Juno’s stock $JUNO im­me­di­ate­ly cratered af­ter trad­ing was re­sumed, plung­ing 45%.

In­ves­ti­ga­tors have been treat­ing adult pa­tients with re­lapsed or re­frac­to­ry B cell acute lym­phoblas­tic leukemia in the “ROCK­ET” tri­al. “The clin­i­cal hold was ini­ti­at­ed af­ter two pa­tients suf­fered cere­bral ede­ma ear­li­er this week,” Juno said in a state­ment. “One pa­tient died and as of last night the oth­er is not ex­pect­ed to re­cov­er.”

Juno is now con­sid­er­ing its “op­tions.”

In a call with an­a­lysts, Juno ex­ecs said that one of those op­tions is drop­ping the JCAR015 tri­al and mov­ing on to JCAR017 and oth­er drugs in the pipeline, which would put them even fur­ther be­hind.

In Ju­ly, the com­pa­ny firm­ly pinned the first deaths on flu­dara­bine, a drug used to con­di­tion pa­tients in this and many oth­er stud­ies. Pulling flu from the treat­ment reg­i­men, they in­sist­ed, would pre­vent fur­ther deaths.

That did not hap­pen. And to­day Juno’s team was forced to deal with a sim­ple ques­tion: “Do we know what’s re­al­ly go­ing on?”

CMO Mark Gilbert han­dled that ques­tion gin­ger­ly, not­ing that the com­pa­ny con­tin­ues to learn more about CAR-T over time.  These new cas­es oc­curred very re­cent­ly, he adds. And cere­bral ede­mas have been as­so­ci­at­ed with a num­ber of CAR-Ts.

“I do think we un­der­stand that there’s a strong cor­re­la­tion of rapid ex­pan­sion of CAR-T cells seem to cor­re­late di­rect­ly on cere­bral ede­ma,” he added. “That’s the big fo­cus for us.”

I queried the FDA on its de­ci­sion to quick­ly green-light the re­sump­tion of the tri­al back in Ju­ly and whether they were go­ing to re­in­sti­tute the hold, but in a lengthy re­sponse a spokesper­son didn’t an­swer my ques­tions, or even re­fer to Juno, JCAR015 or cere­bral ede­ma.

While no de­ci­sion on JCAR015’s fu­ture has been made at Juno, ex­ecs quick­ly fo­cused on JCAR017 as its next lead pro­gram to turn to.

“We’ve not seen any se­vere cas­es of se­vere CRS” with JCAR017, said Juno CEO Hans Bish­op on the call. There was al­so a low­er neu­ro­tox­i­c­i­ty rate and no treat­ment-re­lat­ed mor­tal­i­ties. “We’re en­cour­aged by the safe­ty and ef­fi­ca­cy pro­file of JCAR017.”

Back in Ju­ly the FDA took on­ly a few days to re­spond pos­i­tive­ly to Juno’s plan to re­sume the study, drop­ping the use of flu­dara­bine, which is com­mon­ly used to prep pa­tients for these cell ther­a­pies. The com­pa­ny pinned the first three deaths from cere­bral ede­mas — along with a fourth in a sep­a­rate study — on its mix of JCAR015 and the com­bo that was used to im­prove its chances of suc­cess.

This new set­back will force the FDA to re­view its own role in get­ting the pro­gram restart­ed af­ter just a few days of re­view — a rare oc­cur­rence at the agency which stunned a num­ber of ob­servers at the time.

While the last hold was brief, it held se­ri­ous con­se­quences for Juno, throw­ing it off track and push­ing any new drug ap­pli­ca­tion back to 2018. That gave the edge to Kite, which has so far re­port­ed no un­usu­al ad­verse events re­lat­ed to its use of flu­dara­bine. Kite now ex­pects to com­plete its first ap­pli­ca­tion in Q1 2017, and No­var­tis is al­so shoot­ing for a 2017 fil­ing for its ri­val CAR-T.

These drugs work by ex­tract­ing T cells from pa­tients and then equip­ping them with chimeric anti­gen re­cep­tors, which then ze­ro in on can­cer cells. This first gen­er­a­tion of CAR-Ts, which is like­ly to be eclipsed by ear­ly-stage ef­forts, has been known to trig­ger harsh side ef­fects. But reg­u­la­tors have been will­ing to put up with the added risk for tri­als that in­volve very sick vol­un­teers.

Late Fri­day ap­proval; Trio of biotechs wind down; Stem cell pi­o­neer finds new fron­tier; Biotech icon to re­tire; and more

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Pfiz­er lays off em­ploy­ees at Cal­i­for­nia and Con­necti­cut sites

Pfizer has laid off employees at its La Jolla, CA, and Groton, CT sites, according to multiple LinkedIn posts from former employees.

The Big Pharma confirmed to Endpoints News it has let go of some employees, but a spokesperson declined to specify how many workers were impacted and the exact locations affected. Earlier this month, the drug developer had confirmed to Endpoints it was sharpening its focus and doing away with some early research on areas such as rare disease, oncology and gene therapies.

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Jake Van Naarden, Loxo@Lilly CEO

Lil­ly en­ters ripe BTK field with quick FDA nod in man­tle cell lym­phoma

Eli Lilly has succeeded in its attempt to get the first non-covalent version of Bruton’s tyrosine kinase, or BTK, inhibitors to market, pushing it past rival Merck.

The FDA gave an accelerated nod to Lilly’s daily oral med, to be sold as Jaypirca, for patients with relapsed or refractory mantle cell lymphoma.

The agency’s green light, disclosed by the Indianapolis Big Pharma on Friday afternoon, catapults Lilly into a field dominated by covalent BTK inhibitors, which includes AbbVie and Johnson & Johnson’s Imbruvica, AstraZeneca’s Calquence and BeiGene’s Brukinsa.

No­var­tis' ap­proved sick­le cell dis­ease drug fails to beat place­bo in PhI­II

Novartis’ sickle cell drug, approved in 2019 and branded as Adakveo, has failed an ongoing Phase III, according to preliminary results.

The Swiss pharma giant unveiled early data from the ongoing STAND Phase III study on Friday, saying that crizanlizumab showed no statistically significant difference between the drug at two different dose levels compared to placebo in annualized rates of vaso-occlusive crises that lead to a healthcare visit over the first year since being randomized into the trial.

Filip Dubovsky, Novavax CMO

No­vavax gets ready to take an­oth­er shot at Covid vac­cine mar­ket with next sea­son plans

While mRNA took center stage at yesterday’s FDA vaccine advisory committee meeting, Novavax announced its plans to deliver an updated protein-based vaccine based on new guidance.

Vaccines and Related Biological Products Advisory Committee (VRBPAC) members voted unanimously in favor of “harmonizing” Covid vaccine compositions, meaning all future vaccine recipients would receive a bivalent vaccine, regardless of whether they’ve gotten their primary series.

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FDA ap­proves an­oth­er in­di­ca­tion for Keytru­da, this time in the ad­ju­vant NSCLC set­ting

Merck’s blockbuster cancer treatment Keytruda has been handed another indication by the FDA.

The US regulator announced on Thursday that it has approved Keytruda to serve as an adjuvant treatment for non-small cell lung cancer (NSCLC), which is its fifth indication in NSCLC and 34th indication overall.

According to a Merck release, the approval is based on data from a Phase III trial, dubbed Keynote-091, which measured disease-free survival in patients who received chemotherapy following surgery. The data from Merck displayed that Keytruda cut down on the risk of disease recurrence or death by 27% versus placebo.

Ying Huang, Legend CEO

J&J, Leg­end say Carvyk­ti beat stan­dard ther­a­py in ear­li­er-line blood can­cer

J&J and Legend Biotech’s next step in turning their CAR-T therapy Carvykti into a potential megablockbuster has succeeded, the companies said Friday.

Carvykti achieved the primary endpoint — progression-free survival — in an open-label Phase III study testing the treatment in second- to fourth-line multiple myeloma patients. The CARTITUDE-4 trial, for which there aren’t any hard data yet, represents the biggest development for Carvykti’s ability to compete with Bristol Myers Squibb’s Abecma since its approval last February.

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A 13-year-old Dutch biotech is going through a liquidation process after an unexpected end to its Phase III trial testing whether its combination of two monoclonal antibodies was superior to Incyte’s Jakafi.

Xenikos had hoped to prove its investigational therapy, named T-Guard, was better than Jakafi at garnering a complete response in patients experiencing life-threatening complications in which new cells from a hematopoietic stem cell transplant begin to fight the body. Jakafi was approved for the indication, steroid-refractory acute graft-versus-host disease, in May 2019.

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Eliot Forster, F-star CEO (Rachel Kiki for Endpoints News)

F-star gets down to the wire with $161M sale to Chi­nese buy­er as na­tion­al se­cu­ri­ty con­cerns linger

With the clock ticking on F-star Therapeutics’ takeover by a Chinese buyer, the companies are still scrambling to remove a hold on the deal from the US government’s Committee on Foreign Investment in the United States.

F-star and invoX Pharma said they are “actively negotiating” with CFIUS “about the terms of a mitigation agreement to address CFIUS’s concerns regarding potential national security risks posed by the transaction.”

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