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.

Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,000+ biopharma pros reading Endpoints daily — and it's free.

Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,000+ biopharma pros reading Endpoints daily — and it's free.

Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,000+ biopharma pros reading Endpoints daily — and it's free.

Novotech CRO Ex­pands Chi­na Team as Biotech De­mand for Clin­i­cal Tri­als In­creas­es up to 79%

An increase in demand of up to 79% for clinical trials in China has prompted Novotech the Asia-Pacific CRO to rapidly expand the China team, appointing expert local clinical executives to their Shanghai and Hong Kong offices. The company is planning to expand their team by 30% over the next quarter.

Novotech China has seen considerable demand recently which is borne out by research from GlobalData:
A global migration of clinical research is occurring from high-income countries to low and middle-income countries with emerging economies. Over the period 2017 to 2018, for example, the number of clinical trial sites opened by biotech companies in Asia-Pacific increased by 35% compared to 8% in the rest of the world, with growth as high as 79% in China.
Novotech CEO Dr John Moller said China offers the largest population in the world, rapid economic growth, and an increasing willingness by government to invest in research and development.
Novotech’s 23 years of experience working in the region means we are the ideal CRO partner for USA biotechs wanting to tap the research expertise and opportunities that China offers.
There are over 22,000 active investigators in Greater China, with about 5,000 investigators with experience on at least 3 studies (source GlobalData).

On a glob­al romp, Boehringer BD team picks up its third R&D al­liance for Ju­ly — this time fo­cused on IPF with $50M up­front

Boehringer Ingelheim’s BD team is on a global deal spree. The German pharma company just wrapped its third deal in 3 weeks, going back to Korea for its latest pipeline pact — this time focused on idiopathic pulmonary fibrosis.

They’re handing over $50 million to get their hands on BBT-877, an ATX inhibitor from Korea’s Bridge Biotherapeutics that was on display at a science conference in Dallas recently. There’s not a whole lot of data to evaluate the prospects here.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,000+ biopharma pros reading Endpoints daily — and it's free.

Servi­er scoots out of an­oth­er col­lab­o­ra­tion with Macro­Gen­ics, writ­ing off their $40M

Servier is walking out on a partnership with MacroGenics $MGNX — for the second time.

After the market closed on Wednesday MacroGenics put out word that Servier is severing a deal — inked close to 7 years ago — to collaborate on the development of flotetuzumab and other Dual-Affinity Re-Targeting (DART) drugs in its pipeline.

MacroGenics CEO Scott Koenig shrugged off the departure of Servier, which paid $20 million to kick off the alliance and $20 million to option flotetuzumab — putting a heavily back-ended $1 billion-plus in additional biobuck money on the table for the anti-CD123/CD3 bispecific and its companion therapies.

Den­mark's Gen­mab hits the jack­pot with $500M+ US IPO as small­er biotechs rake in a com­bined $147M

Danish drugmaker Genmab A/S is off to the races with perhaps one of the biggest biotech public listings in decades, having reaped over $500 million on the Nasdaq, as it positions itself as a bonafide player in antibody-based cancer therapies.

The company, which has long served as J&J’s $JNJ key partner on the blockbuster multiple myeloma therapy Darzalex, has asserted it has been looking to launch its own proprietary product — one it owns at least half of — by 2025.

FDA over­rides ad­comm opin­ions a fifth of the time, study finds — but why?

For drugmakers, FDA advisory panels are often an apprehended barometer of regulators’ final decisions. While the experts’ endorsement or criticism often translate directly to final outcomes, the FDA sometimes stun observers by diverging from recommendations.

A new paper out of Milbank Quarterly put a number on that trend by analyzing 376 voting meetings and subsequent actions from 2008 through 2015, confirming the general impression that regulators tend to agree with the adcomms most of the time — with discordances in only 22% of the cases.

UP­DAT­ED: With loom­ing ‘apoc­a­lypse of drug re­sis­tance,’ Mer­ck’s com­bi­na­tion an­tibi­ot­ic scores FDA ap­proval on two fronts

Merck — one of the last large biopharmaceuticals companies in the beleaguered field of antibiotic drug development — on Wednesday said the FDA had sanctioned the approval of its combination antibacterial for the treatment of complicated urinary tract and intra-abdominal infections.

To curb the rise of drug-resistant bacteria and maintain the efficacy of the therapy, Recarbrio (and other antibacterials) — the drug must be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible gram-negative bacteria, Merck $MRK said.

Endpoints News

Basic subscription required

Unlock this story instantly and join 55,000+ biopharma pros reading Endpoints daily — and it's free.