Juno us­es lethal neu­ro­tox lessons to guide Goldilocks for­mu­la for its next-gen CAR-T

WASH­ING­TON, DC — Neu­ro­tox­i­c­i­ty killed JCAR015 right along with 5 pa­tients in the lead piv­otal study, de­rail­ing Juno Ther­a­peu­tics $JUNO and al­low­ing first No­var­tis and then Gilead/Kite to surge way ahead with the first two ap­provals in the field. But Juno now plans to take what it’s learned from that lethal im­plo­sion and make over its next drug — JCAR017 — in­to what it promis­es will be a dra­mat­i­cal­ly im­proved drug that can leapfrog the lead­ers.

Mark Gilbert

Mark Gilbert, the chief med­ical of­fi­cer at Juno, ap­peared at the So­ci­ety for Im­munother­a­py of Can­cer (#SITC2017) meet­ing over the week­end to out­line where the biotech has reached in its in­ves­ti­ga­tion, and how it’s ap­ply­ing those lessons to make JCAR017 in­to the im­pres­sive ther­a­py that they’ve be­gun up­dat­ing along the way to a planned mar­ket­ing ap­pli­ca­tion.

“We al­ways thought it was mul­ti­ple things that were con­tribut­ing,” Gilbert told me in a one-on-one at SITC. “We just couldn’t iden­ti­fy them as well as we can to­day.”

That fail­ure led to one of the most dead­ly re­ac­tions tracked in the clin­ic in re­cent biotech times.

Ini­tial­ly, Juno halt­ed its study of JCAR015 af­ter a pair of deaths from brain swelling — cere­bral ede­ma — trig­gered a safe­ty alert, but al­most im­me­di­ate­ly got a green light from the FDA to get back in­to the clin­ic af­ter pin­ning the blame on flu­dara­bine, which is used to prep pa­tients for the per­son­al­ized cell ther­a­py.

Once dos­ing be­gan again, though, an­oth­er three pa­tients died in quick or­der, killed by the same neu­ro­tox­ic re­ac­tion to the ther­a­py and forc­ing Juno back to the draw­ing board to un­der­stand bet­ter what went wrong, and how to con­trol it in their next on­go­ing pro­gram for JCAR017.

“The ear­ly and rapid ex­pan­sion (of cells) we saw ap­pears to cor­re­late with high­er lev­els of IL-15,” a growth fac­tor for T cells, says Gilbert. “We now know that IL-15 was in­creased be­fore they ever got CAR-T cells.” And that was as­so­ci­at­ed with the com­bined use of flu­darib­ine and cy­clophos­phamide.

“We like to see CAR-T cell ex­pan­sion that peaks out 11, 12, 14 days,” he says, look­ing for a steady Goldilocks ap­proach to the ramp up — nei­ther too hot or too cold. “We see that in JCAR017 in TRAN­SCEND. In ROCK­ET that hap­pens in 7 days in some of these pa­tients. That ex­pan­sion is what we want to avoid.”

“As para­dox­i­cal as it sounds,” he adds, “the is­sue wasn’t so much flu­darib­ine as the two drugs to­geth­er. We’ve moved to a sub­stan­tial­ly less in­ten­sive lym­phode­ple­tion reg­i­men.”

But there’s more. Juno has been work­ing on de­liv­er­ing a more per­son­al­ized cell ther­a­py, look­ing to as­sign spe­cial lev­els of ther­a­py cal­i­brat­ed to a va­ri­ety of fac­tors, in­clud­ing the type of can­cer pa­tients have, their age, the lev­el of dis­ease bur­den a pa­tient has or the pres­ence of anti­gens.

“Dif­fer­ent dis­ease set­tings have risk of ear­ly ex­pan­sion,” he adds.

Juno — and some of the oth­er com­pa­nies in this area, in­clud­ing No­var­tis — al­so notes that there is an­i­mal da­ta to sug­gest that the 4-1BB cos­tim­u­la­to­ry do­main now in use could al­so play a role in the phar­ma­co­ki­net­ics, which is why mov­ing from CD28 on JCAR015 to 4-1BB in JCAR017 is be­ing watched close­ly. Ul­ti­mate­ly, that could al­so have a bear­ing on Gilead’s pi­o­neer­ing CAR-T Yescar­ta, which us­es CD28.

CAR-T has al­ways been a high-risk, high-re­ward kind of ther­a­py, re­served ini­tial­ly for some very sick pa­tients. Cel­lec­tis, with its off-the-shelf ap­proach, has just come out of its own two-month clin­i­cal hold. As the ther­a­pies be­come more main­stream, that risk has to be bet­ter con­trolled, with the com­pa­nies that are best at man­u­fac­tur­ing and de­liv­ery look­ing for a dom­i­nant mar­ket share.

Juno may have been bad­ly de­layed. But it’s still in the big­ger race now un­der­way.

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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Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

This is the second biotech buyout pact today, marking a brisk tempo of M&A deals in the lead-up to the big JP Morgan gathering in mid-January. It’s no surprise the acquisitions are both for cancer drugs, where Sanofi will try to make its mark while Merck beefs up a stellar oncology franchise. And bolt-ons are all the rage at the major pharma players, which you could also see in Novartis’ recent $9.7 billion MedCo buyout.

ArQule — which comes out on top after their original lead drug foundered in Phase III — highlighted early data on ‘531 at EHA from a group of 6 chronic lymphocytic leukemia patients who got the 65 mg dose. Four of them experienced a partial response — a big advance for a company that failed with earlier attempts.

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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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Am­gen puts its foot down in shiny new South San Fran­cis­co hub as it re­or­ga­nizes R&D ops

Amgen has signed up to be AbbVie’s neighbor in South San Francisco as it moves into a nine-story R&D facility in the booming biotech hub.

The arrangement gives Amgen 240,000 square feet of space on the Gateway of Pacific Campus, just a few minutes drive from its current digs at Oyster Point. The new hub will open in 2022 and house the big biotech’s Bay Area employees working on cardiometabolic, inflammation and oncology research.

Ab­b­Vie, Scripps ex­pand part­ner­ship, for­ti­fy fo­cus on can­cer drugs

Scripps and AbbVie go way back. Research conducted in the lab of Scripps scientist Richard Lerner led to the discovery of Humira. The antibody, approved by the FDA in 2002 and sold by AbbVie, went on to become the world’s bestselling treatment. In 2018, the drugmaker and the non-profit organization signed a pact focused on developing cancer treatments — and now, the scope of that partnership has broadened to encompass a range of diseases, including immunological and neurological conditions.

South Ko­rea jails 3 Sam­sung ex­ecs for de­stroy­ing ev­i­dence in Bi­o­Log­ics probe

Three Samsung executives in Korea are going to jail.

The convictions came in what prosecutors had billed as “biggest crime of evidence destruction in the history of South Korea”: a case of alleged corporate intrigue that was thrown open when investigators found what was hidden beneath the floor of a Samsung BioLogics plant. Eight employees in total were found guilty of evidence tampering and the three executives were each sentenced to up to two years in prison.

Nick Plugis, Avak Kahvejian, Cristina Rondinone, Milind Kamkolkar and Chad Nusbaum. (Cellarity)

Cel­lar­i­ty, Flag­ship's $50M bet on net­work bi­ol­o­gy, mar­ries ma­chine learn­ing and sin­gle-cell tech for drug dis­cov­ery

Cellarity started with a simple — but far from easy — idea that Avak Kahvejian and his team were floating around at Flagship Pioneering: to digitally encode a cell.

As he and his senior associate Nick Plugis dug deeper into the concept, they found that most of the models others have developed take a bottom-up approach, where they assemble the molecules inside cells and the connections between them from scratch. What if they opt for a top-down approach, aided by single-cell transcriptomics and machine learning, to gauge the behavior of the entire cellular network?

Sanofi’s big week in­cludes a promis­ing PhI­II for an or­phan dis­ease drug, with plans for a pitch to the FDA

The biopharma R&D food chain is paying off with a plan at Sanofi to pitch regulators on a new drug for an orphan disease called cold agglutinin disease.

The pharma giant ushered out a statement Tuesday morning — after it spelled out plans to radically restructure the company, abandoning cardio and diabetes research altogether — saying that their C1s inhibitor sutimlimab had cleared the pivotal study.