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.

Forge Bi­o­log­ics’ cGMP Com­pli­ant and Com­mer­cial­ly Vi­able Be­spoke Affin­i­ty Chro­matog­ra­phy Plat­form

Forge Biologics has developed a bespoke affinity chromatography platform approach that factors in unique vector combinations to streamline development timelines and assist our clients in efficiently entering the clinic. By leveraging our experience with natural and novel serotypes and transgene conformations, we are able to accelerate affinity chromatography development by nearly 3-fold. Many downstream purification models are serotype-dependent, demanding unique and time-consuming development strategies for each AAV gene therapy product1. With the increasing demand to propel AAV gene therapies to market, platform purification methods that support commercial-scale manufacturing of high-quality vectors with excellent safety and efficacy profiles are essential.

Feng Zhang (Susan Walsh/AP Images)

In search of new way to de­liv­er gene ed­i­tors, CRISPR pi­o­neer turns to mol­e­c­u­lar sy­ringes

Bug bacteria are ruthless.

Some soil bacteria have evolved tiny, but deadly injection systems that attach to insect cells, perforate them and release toxins inside — killing a bug in just a few days’ time. Scientists, on the other hand, want to leverage that system to deliver medicines.

In a paper published Wednesday in Nature, MIT CRISPR researcher Feng Zhang and his lab describe how they engineered these syringes made by bacteria to deliver potential therapies like toxins that kill cancer cells and gene editors. With the help of an AI program, they developed syringes that can load proteins of their choice and selectively target human cells.

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Luke Miels, GSK chief commercial officer

GSK picks up Scynex­is' FDA-ap­proved an­ti­fun­gal drug for $90M up­front

GSK is dishing out $90 million cash to add an antifungal drug to its commercial portfolio, in a deal spotlighting the pharma giant’s growing focus on infectious diseases.

The upfront will lock in an exclusive license to Scynexis’ Brexafemme, which was approved in 2021 to treat a yeast infection known as vulvovaginal candidiasis, except in China and certain other countries where Scynexis already out-licensed the drug.

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See­los Ther­a­peu­tics 'tem­porar­i­ly' stops study in rare neu­ro dis­or­der for busi­ness rea­sons

Microcap biotech Seelos Therapeutics is halting enrollment of its study in spinocerebellar ataxia type 3 (also known as Machado-Joseph disease) because of “financial considerations,” and in order to focus on other studies, the company said today, adding that the pause would be temporary.

The study will continue with the patients who have already enrolled, and the data from them will be used to decide whether to continue enrolling others in the future.

Alec­tor cuts 11% of work­force as it dou­bles down on late-stage neu­ro pro­grams part­nered with GSK, Ab­b­Vie

A month after revealing plans to concentrate on its late-stage immuno-neurology pipeline, Alector is trimming its headcount by 11%.

The layoffs will impact around 30 employees across the organization, the company disclosed in an SEC filing, adding that the plan will “better align the company’s resources” with the new strategy. With $712.9 million in cash, cash equivalents and investments as of the end of 2022, Alector believes the reserves will now get it through 2025.

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Mathai Mammen, FogPharma's next CEO

Math­ai Mam­men hands in J&J's R&D keys to lead Greg Ver­dine’s Fog­Phar­ma 

In the early 1990s, Mathai Mammen was a teaching assistant in Greg Verdine’s Science B46 course at Harvard. In June, the former R&D head at Johnson & Johnson will succeed Verdine as CEO, president and chair of FogPharma, the same month the seven-year-old biotech kickstarts its first clinical trial.

After leading R&D at one of the largest drugmakers in the world, taking the company through more than half a dozen drug approvals in the past few years, not to mention a Covid-19 vaccine race, Mammen departed J&J last month and will take the helm of a Cambridge, MA biotech attempting to go after what Verdine calls the “true emperor of all oncogenes” — beta-catenin.

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J&J bows out of RSV vac­cine race, end­ing PhI­II study and ced­ing to Pfiz­er, GSK

Johnson & Johnson announced Wednesday morning it is ending development of its adult RSV vaccine that was in the middle of a 27,200-patient trial, giving up a big slice of what’s expected to be the next multibillion-dollar pharma market.

The decision came down to the shifting RSV “competitive landscape,” a company spokesperson tells Endpoints News, adding the “breadth of options” was much different than when J&J first started its pivotal study. The spokesperson declined to comment on the Phase III data, saying only the shot is undergoing an “ongoing assessment.”

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No longer ‘dead or just hi­ber­nat­ing,’ drug­mak­ers re­turn to heart med­i­cines

In 2015, now-FDA Commissioner Robert Califf joined industry, academic and regulatory representatives in Washington to discuss why more drugs weren’t in development for cardiovascular diseases, the leading US cause of death and once a mainstay of pharmaceutical industry blockbusters.

The group pointed to many reasons. Clinical trials could take years and testing was expensive. Wide availability of generic drugs made the commercial prospects uncertain. Their paper title summed up the mood: “Cardiovascular Drug Development: Is it Dead or Just Hibernating?”

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Mihael Polymeropoulos, Vanda Pharmaceuticals CEO

Van­da wins court case against FDA over dis­clo­sure of CRL de­tails for sleep drug

DC District Court Judge Christopher Cooper today granted Vanda Pharma’s request to require the FDA to disclose more info on the complete response letter for its sleep disorder drug Hetlioz.

The melatonin receptor agonist is approved by the FDA to treat non-24-hour sleep-wake disorder, a circadian rhythm disorder. But in 2018 Vanda filed a supplemental application to market Hetlioz as a treatment for jet lag, which the FDA rejected in August 2019, with few details on what Vanda needed to correct course, according to the company.