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.

Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

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Deborah Dunsire, Lundbeck CEO

Af­ter a 5-year re­peat PhI­II so­journ, Lund­beck and Ot­su­ka say they're fi­nal­ly ready to pur­sue OK to use Rex­ul­ti against Alzheimer's ag­i­ta­tion

Five years after Lundbeck and their longtime collaborators at Otsuka turned up a mixed set of Phase III data for Rexulti as a treatment for Alzheimer’s dementia-related agitation, they’ve come through with a new pivotal trial success they believe will finally put them on the road to an approval at the FDA. And if they’re right, some analysts believe they’re a short step away from adding more than $500 million in annual sales for the drug, already approved in depression and schizophrenia.

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Chris Anzalone, Arrowhead CEO

Take­da, Ar­row­head spot­light da­ta from small tri­al show­ing RNAi works in a rare liv­er con­di­tion

Almost two years after Takeda wagered $300 million cash to partner with Arrowhead on an RNAi therapy for a rare disease, the companies are spelling out Phase II data that they believe put them one step closer to their big dreams.

In a small, open label study involving only 16 patients who had liver disease associated with alpha-1 antitrypsin deficiency (AATD), Arrowhead’s candidate — fazirsiran, previously ARO-AAT — spurred substantial reductions in accumulated mutant AAT protein in the liver, a hallmark of the condition. Investigators also tracked improvements in symptoms, with seven out of 12 who received the high, 200 mg dose seeing regression of liver fibrosis.

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Alex­ion puts €65M for­ward to strength­en its po­si­tion on the Emer­ald Isle

Ireland has been on a roll in 2022, with several large pharma companies announcing multimillion-euro projects. Now AstraZeneca’s rare disease outfit Alexion is looking to get in on the action.

Alexion on Friday announced a €65 million ($68.8 million) investment in new and enhanced capabilities across two sites in the country, including at College Park in the Dublin suburb of Blanchardstown and the Monksland Industrial Park in the central Irish town of Athlone, according to the Industrial Development Agency of Ireland.

State bat­tles over mifepri­s­tone ac­cess could tie the FDA to any post-Roe cross­roads

As more than a dozen states are now readying so-called “trigger” laws to kick into effect immediate abortion bans following the overturning of Roe v. Wade on Friday, these laws, in the works for more than a decade in some states, will likely kick off even more legal battles as states seek to restrict the use of prescription drug-based abortions.

Since Friday’s SCOTUS opinion to overturn Americans’ constitutional right to an abortion after almost 50 years, reproductive rights lawyers at Planned Parenthood and other organizations have already challenged these trigger laws in Utah and Louisiana. According to the Guttmacher Institute, other states with trigger laws that could take effect include Arkansas, Idaho, Kentucky, Mississippi, Missouri, North Dakota, Oklahoma, South Dakota, Tennessee, Texas, and Wyoming.

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A Mer­ck part­ner is sucked in­to the fi­nan­cial quag­mire as key lender calls in a note

Another biotech standing on shaky financial legs has fallen victim to the bears.

Merck partner 4D Pharma has reported that a key lender, Oxford Finance, shoved the UK company into administration after calling in a $14 million loan they couldn’t immediately make good on. Trading in their stock was halted with a market cap that had fallen to a mere £30 million.

“Despite the very difficult prevailing market conditions,” 4D reported on Friday, the biotech had been making progress on finding some new financing and turned to Oxford with an alternative late on Thursday and then again Friday morning.

Members of the G7 from left to right: Prime Minister of Italy Mario Draghi, European Commission President Ursula von der Leyen, President Joe Biden, German Chancellor Olaf Scholz, British Prime Minister Boris Johnson, Canadian Prime Minister Justin Trudeau, Prime Minister of Japan Fumio Kishida, French President Emmanuel Macron and European Council President Charles Michel (AP Photo/Susan Walsh)

Biden and G7 na­tions of­fer funds for vac­cine and med­ical prod­uct man­u­fac­tur­ing project in Sene­gal

Amidst recently broader vaccine manufacturing initiatives from the EU and European companies, the G7 summit in the mountains of Bavaria has brought about some positive news for closing vaccine and medical product manufacturing gaps around the globe.

According to a statement from the White House, the G7 leaders have formally launched the partnership for global infrastructure, PGII. The effort will aim to mobilize hundreds of billions of dollars to deliver infrastructure projects in several sectors including the medical and pharmaceutical manufacturing space.

Fed­er­al judge de­nies Bris­tol My­er­s' at­tempt to avoid Cel­gene share­hold­er law­suit

Some Celgene shareholders aren’t happy with how Bristol Myers Squibb’s takeover went down.

On Friday, a New York federal judge ruled that they have a case against the pharma giant, denying a request to dismiss allegations that it purposely slow-rolled Breyanzi’s approval to avoid paying out $6.4 billion in contingent value rights (CVR).

When Bristol Myers put down $74 billion to scoop up Celgene back in 2019, liso-cel — the CAR-T lymphoma treatment now marketed as Breyanzi — was supposedly one of the centerpieces of the deal. After going back and forth on negotiations for about six months, BMS put $6.4 billion into a CVR agreement that required an FDA approval for Zeposia, Breyanzi and Abecma, each by an established date.

David Hung, Nuvation Bio president and CEO (Nuvation Bio)

FDA places par­tial clin­i­cal hold on David Hung biotech af­ter cer­tain can­cer pa­tients ex­pe­ri­ence eye in­flam­ma­tion

Two and a half years after setting out on another foray into oncology R&D, a biotech headed by David Hung — of Medivation fame — has run into its first setback.

San Francisco-based Nuvation Bio announced early Monday the FDA placed a partial clinical hold on a Phase I dose-escalation study of NUV-422, its CDK inhibitor program for certain types of solid tumors. The trial began enrolling patients in December 2020, and, according to Nuvation, researchers were in the middle of exploring dose escalation and defining the maximum dose tolerable in patients.