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.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; and more

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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Lisa Deschamps, AviadoBio CEO

Ex-No­var­tis busi­ness head hops over to a gene ther­a­py start­up — and she's reeled in $80M for a dash to the clin­ic

Neurologist and King’s College London professor Christopher Shaw has been researching neurodegenerative diseases like ALS and collaborating with drugmakers for the last 25 years in the hopes of pushing new therapies forward. But unfortunately, none of those efforts have come anywhere close to fruition.

“So, you know, after 20 years in the game, I said, ‘Let’s try and do it ourselves,’” he told Endpoints News. 

Vas Narasimhan, Novartis CEO (Thibault Camus/Pool via AP Images)

With gener­ic com­pe­ti­tion heat­ing up, Vas Narasimhan out­lines No­var­tis' growth plans at R&D day

Thursday marks Novartis’ annual R&D day, and with it comes CEO Vas Narasimhan’s attempt to spotlight the company’s pipeline strategy and emerging stars.

The biggest question entering Thursday’s presentation dealt with how the big biopharma will make up revenues from upcoming generic competition — Novartis says within the next five years, generics will eat away roughly $9 billion in sales. To offset this, Narasimhan outlined a strategy for 4% growth or higher until 2026, focusing on six key medicines he believes will see multibillion dollar profits during this time.

In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Reshma Kewalramani, Vertex CEO (Vertex via YouTube)

Bat­tling a line­up of skep­tics, Ver­tex claims an­oth­er ear­ly clin­i­cal win — this time in kid­ney dis­ease

Vertex claimed its second early-stage win of the fall Wednesday, announcing positive results in a small study on a genetically defined form of kidney disease.

The 16-patient, Phase II trial focused on patients with focal segmental glomerulosclerosis, a rare disease where kidneys are unable to filter blood properly. Over 13 weeks on an experimental pill, the level of protein in the patients’ urine fell by an average of 47.6%.

Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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