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.

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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Michel Vounatsos, Getty Images

UP­DAT­ED: Stay tuned: Bio­gen’s num­bers are great — it’s their wor­ri­some fu­ture that leaves an­a­lysts skit­tish

Biogen came out with an upbeat assessment of their Q2 numbers today, discounting the arrival of a key rival for its blockbuster Spinraza franchise. But the top execs remain grimly determined to not say much anything new about the sore points that have dragged down its stock, including the future of its big investment in Alzheimer’s or how it plans to invest the considerable cash that the big biotech continues to reap.

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Why wait? Cel­gene re­struc­tures a big Jounce pact — ze­ro­ing in on new I/O path­way with $530M deal and bump­ing ICOS

Celgene’s business team isn’t waiting for the big merger with Bristol-Myers Squibb to go through before syncing its strategy with the new mother ship.

Tuesday evening the big biotech unveiled a $530 million deal — $50 million in upfront cash — to amend their alliance with Jounce Therapeutics $JNCE to gain worldwide rights to JTX-8064, an antibody that targets the LILRB2 receptor on macrophages. Their old, $2.6 billion deal is being scrapped, leaving Jounce with a pipeline that includes the lead drug, the ICOS-targeting vopratelimab.

PACT Phar­ma says it's per­fect­ed the tech to se­lect neoanti­gens for per­son­al­ized ther­a­py — now on­to the clin­ic

At PACT Pharma, the lofty goal to unleash a “tsunami” of T cells personalized for each patient has hinged on the ability to correctly identify the neoantigens that form something of a fingerprint for each tumor, and extract the small group of T cells primed to attack the cancer. It still has a long way to go testing a treatment in humans, but the biotech says it has nailed that highly technical piece of the process.

UP­DAT­ED: My­ovan­t's uter­ine fi­broid drug looks com­pet­i­tive in PhI­II — but can they van­quish mighty Ab­b­Vie?

Vivek Ramaswamy’s Myovant $MYOV has closely matched its positive first round of Phase III data for their uterine fibroid drug relugolix, setting up a head-to-head rivalry with pharma giant AbbVie as the little biotech steers to the market with a planned filing in Q4.

Here’s how Myovant plans to prevail over the AbbVie $ABBV empire.

In the study, 71.2% of women receiving once-daily relugolix combination therapy achieved the clinical response they were looking for, compared to only 14.7% in the control arm. The data comfortably reflected the same outcomes in the first Phase III — 73.4% of women receiving once-daily oral relugolix combination therapy achieved the responder criteria compared with 18.9% of women receiving placebo — which will reassure regulators that they are getting the carefully randomized data that qualifies for the FDA’s gold standard for success.

Lit­tle Mar­i­nus sees its shares eclipsed as the Sage ri­val fails to com­pare on PPD in PhII

The executive team at Sage $SAGE have skirted another potential pitfall on its way to racking up a big future for its depression drug Zulresso.

Little Marinus Pharmaceuticals $MRNS had sought to challenge the Sage drug with an IV formulation — followed by an oral version — of ganaxolone for postpartum depression. But researchers say their Phase II study failed to positively differentiate itself from a placebo at 28 days — leaving them to hold up “clinically meaningful” data within the first day of administration compared to the control arm.

Roche cuts loose Tam­i­flu OTC rights, hand­ing Sanofi the keys as the phar­ma gi­ant dou­bles down on Xofluza

Roche set out to make a better flu medicine than Tamiflu as that franchise was headed to a generic showdown. Now they’ll see just how well Xofluza stacks up against the mainstay drug after handing off over-the-counter rights in the US to Sanofi.

Sanofi $SNY says it will now step in to negotiate a deal with the FDA to steer Tamiflu into the OTC market, a role that could well involve new studies to ease passage of the drug out of doctor’s hands and into the consumer end of the market. And the French pharma giant will have first dibs over “selected” OTC markets around the world as they push ahead.

Aca­dia is mak­ing the best of it, but their lat­est PhI­II Nu­plazid study is a bust

Acadia’s late-stage program to widen the commercial prospects for Nuplazid has hit a wall. The biotech reported that their Phase III ENHANCE trial flat failed. And while they $ACAD did their best to cherry pick positive data wherever they can be found, this is a clear setback for the biotech.

With close to 400 patients enrolled, researchers said the drug flunked the primary endpoint as an adjunctive therapy for patients with an inadequate response to antipsychotic therapy. The p-value was an ugly 0.0940 on the Positive and Negative Syndrome Scale, which the company called out as a positive trend.

Their shares slid 12% on the news, good for a $426 million hit on a $3.7 billion market cap at close.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

Now in its third year, the nonprofit created a new set of standards with Yale School of Medicine and Stanford Law School to evaluate the track record on trial registration, results reporting, publication and data-sharing practice.