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.

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus — chop­ping di­a­betes, car­dio and slash­ing $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners on his plans to surgically dissect and reassemble the portfoloio, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

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What does $6.9B buy these days in on­col­o­gy R&D? As­traZeneca has a land­mark an­swer

Given the way the FDA has been whisking through new drug approvals months ahead of their PDUFA date, AstraZeneca and their partners Daiichi Sankyo may not have to wait until Q2 of next year to get a green light on trastuzumab deruxtecan (DS-8201).

The pharma giant this morning played their ace in the hole, showing off why they were willing to commit to a $6.9 billion deal — with $1.35 billion in a cash upfront — to partner on the drug.

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Large advertisements for the drug Vivitrol decorate the walls of Grand Central Station on June 15, 2017 in New York City. (Photo: Andrew Lichtenstein via Getty)

FDA slaps down Alk­er­mes for mis­lead­ing Viv­it­rol ads — don't for­get vul­ner­a­bil­i­ty to opi­oid over­dose

The ads piqued interest as soon as they started appearing in 2016: at Grand Central Station, on the Red Line in Cambridge, and on a billboard off the New Jersey Turnpike. All showed a young person, generally with his or her arms crossed, and the question, “what is Vivitrol?”

Vivitrol’s maker, Alkermes, was in the midst of a marketing and lobbying campaign to promote the anti-opioid addiction drug — a campaign that would face significant backlash for tarnishing competitors despite little evidence for Vivitrol’s superiority.

Paul Hudson, Sanofi

Paul Hud­son promis­es a bright new fu­ture at Sanofi, kick­ing loose me-too drugs and fo­cus­ing on land­mark ad­vances. But can he de­liv­er?

Paul Hudson was on a mission Tuesday morning as he stood up to address Sanofi’s new R&D and business strategy.

Still fresh into the job, the new CEO set out to convince his audience — including the legions of nervous staffers inevitably devoting much of their day to listening in — that the pharma giant is shedding the layers of bureaucracy that had held them back from making progress in the past, dropping the duds in the pipeline and reprioritizing a more narrow set of experimental drugs that were promised as first-in-class or best-in-class.  The company, he added, is now positioned to “go after other opportunities” that could offer a transformational approach to treating its core diseases.

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FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.

Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.

Seat­tle Ge­net­ics de­tails pos­i­tive OS and PFS da­ta for tu­ca­tinib in breast can­cer

Seattle Genetics $SGEN is showing off more positive data around tucatinib, its pivotal-stage drug for HER2 positive breast cancer.

A month after hearing about solidly upbeat hazard ratios, we learned today that the estimated progression-free survival rate at one year was 33% in the tucatinib arm compared to 12% for patients taking trastuzumab and capecitabine alone.

Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.

Bat­tered, cash hun­gry In­tec feels the burn of No­var­tis re­jec­tion

It’s a case of some bad timing for Intec.

Just when a key trial testing the company’s Accordion drug delivery tech imploded in Parkinson’s disease, they handed Novartis data from a successful PK study of a custom Accordion pill engineered to deliver a Novartis compound to entice the Swiss drugmaker into signing a licensing agreement.

Novartis said thanks, but no thanks.

For the cash-strapped Israeli drug developer, the failure to clinch the deal marks a big blow. As of the third quarter, the company has $15.7 million in cash and equivalents, which HC Wainwright analysts estimate will keep the lights on into mid-2020.

Bris­tol-My­ers shows off a low-pro­file AML con­tender it gained from Cel­gene buy­out — and they’re tak­ing it straight to the FDA

Bristol-Myers Squibb reaped an enormous pipeline with its much-criticized $64 billion megadeal to buy Celgene. And it got a few hidden gems in the deal.

One of those gems was brought out for display on Tuesday, with a late-breaker at ASH on CC-486, which is now being prepped for regulatory filings at the FDA and elsewhere.

Celgene top-lined the positive results in a maintenance setting for acute myeloid leukemia a few months ago, but at ASH investigators pulled back the curtains on the all-important data they believe will give them an advantage in the commercial wars to come.

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