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.

Was nev­er con­vinced about flu­dara­bine be­ing at fault for ear­li­er JCAR15 prob­lems. If these events are w/o then they have big prob­lems here

— Sal­ly Church 🏴󠁧󠁢󠁥󠁮󠁧󠁿 (@Mav­er­ick­NY) No­vem­ber 23, 2016

The FDA on Tuesday released a warning letter sent earlier this month to the Mason, OH-based site of Procter & Gamble Manufactura, raising questions about the list of ingredients on the label and in the electronic filing.

The warning says that for P&G’s over-the-counter Vicks Nyquil Severe Hot Remedy Cold and Flu Plus Congestion, there’s a “mismatched” list of active ingredients between the labeling and the electronic listing file. The listing file for the active ingredients did not match the active ingredients in the electronic file.

The Federal Trade Commission has gotten involved in a patent feud over Supernus’ Parkinson’s drug Apokyn, a case the agency said may have ‘‘significant implications” for patients who rely on the drug.

Sage Chemical won the first generic approval for its Apokyn formulation (also known as apomorphine hydrochloride injection) back in 2022. The non-ergoline dopamine agonist is approved to treat Parkinson’s symptoms during “off episodes,” such as difficulty moving, tremors and intense cramping. However, regulators specified that the approval pertained to the generic drug cartridges only, not the injector pen required for administration.