Dafna Bar-Sagi (Sasha Nialla, NYU Langone Health)

How pan­cre­at­ic RAS tu­mors pro­tect them­selves. Re­searchers point to a new pro­tein — and maybe a new treat­ment

A cou­ple years back, some car­dio­vas­cu­lar spe­cial­ists at Boston’s Brigham and Women’s Hos­pi­tal stum­bled across a sur­pris­ing re­sult.

No­var­tis had tasked them with car­ry­ing out the long-range Phase III tri­al for canakinum­ab, an ex­per­i­men­tal an­ti-in­flam­ma­to­ry drug the com­pa­ny was try­ing to mar­ket for car­dio­vas­cu­lar dis­ease. The main re­sults were mixed — mod­est re­duc­tions in fa­tal car­dio­vas­cu­lar events, clear side ef­fects — but an ad­di­tion­al, ex­plorato­ry analy­sis, turned heads over in on­col­o­gy: Across 10,061 pa­tients, those who had re­ceived canakinum­ab were less like­ly to de­vel­op lung can­cer; 33% less like­ly for the high­est dosage.

“The haz­ard ra­tio was strik­ing,” Kwok-Kin Wong, a lung can­cer spe­cial­ist at NYU’s Gross­man School of Med­i­cine told End­points News, re­fer­ring to the 33% fig­ure and an even high­er num­ber for a dif­fer­ent sub­group.

Kwok-Kin Wong

The ques­tion: Why?

New re­search pub­lished to­day in Can­cer Re­search, from one of the ear­li­est RAS-mu­tant pan­cre­at­ic can­cer re­searchers, may give a peak in­to that ques­tion, while of­fer­ing the po­ten­tial to open up one of the most in­tractable can­cers to the lat­est wave of tar­get­ed ther­a­pies.

A team led by NYU’s Daf­na Bar-Sa­gi dis­cov­ered that RAS-pos­i­tive pan­cre­at­ic can­cer cells emit an im­mune-sig­nal­ing pro­tein called in­ter­leukin-1β – al­so the pro­tein that canakinum­ab, the No­var­tis drug, in­hibits. That pro­tein turns down the im­mune sys­tem near the tu­mor in a va­ri­ety of ways, they found, most no­tably by help­ing build more col­la­gen fibers that es­sen­tial­ly guard the can­cer from T cells that would or­di­nar­i­ly try to in­vade and kill it.

“It’s a wall the tu­mor build around it­self, and does not al­low the im­mune sys­tem in,” Bar-Sa­gi told End­points.

These walls, she said, ac­count­ed not on­ly for the tu­mor’s abil­i­ty to elude the body’s nat­ur­al im­mune sys­tem, but al­so the all-but-com­plete fail­ure of the im­mune-un­leash­ing PD-1 check­point ther­a­pies in pan­cre­at­ic can­cer.

“The PD-1 check­point ther­a­py won’t have an ef­fect if the [im­mune] cell can’t get in­to the tu­mor,” she said. Her pa­per test­ed if an an­ti-in­ter­leukin drug like canakinum­ab could be used in com­bi­na­tion with a PD-1 drug, the for­mer clear­ing the way for the lat­ter, find­ing a 32% re­duc­tion in mice. (No­var­tis did not fund the study but did pro­vide the in­ter­leukin and check­point drugs).

Gre­go­ry L Beat­ty

Gre­go­ry Beat­ty, an as­sis­tant pro­fes­sor of im­munol­o­gy at the Uni­ver­si­ty of Penn­syl­va­nia School of Med­i­cine who was not in­volved with the study, said the study was “ex­cit­ing and ap­plic­a­ble to not on­ly pan­creas can­cer but po­ten­tial­ly oth­er ma­lig­nan­cies.”

“Ap­proach­es to over­come im­mune re­sis­tance in pan­creas can­cer are of ut­most im­por­tance and IL-1b is a nov­el tar­get,” Beat­ty said via email.

Kwok-Kin Wong — who was not in­volved with the study but works at the same in­sti­tu­tion — said the find­ings were im­por­tant for a range of can­cers, in­clud­ing by of­fer­ing a mech­a­nism for the 2017 find­ings in lung can­cer. Lung can­cer spe­cial­ists could look for the same process.

“This pa­per will spur a lot of in­ter­est,” Wong said, not­ing many com­pa­nies al­ready have an in­ter­leukin an­ti­body and a PD-1 on hand. “There’s a lot of ther­a­peu­tic im­pli­ca­tions.”

Bar-Sa­gi was one of the ear­li­est re­searchers in­to RAS mu­ta­tions. She joined James Feramis­co’s Cold Spring Har­bor Lab as a post­doc in 1986, short­ly af­ter the onco­gene was first dis­cov­ered, and quick­ly co-au­thored in Sci­ence one of the first pa­pers sug­gest­ing how the RAS gives rise to tu­mors.

Over the years, though, no one ful­ly iden­ti­fied in­ter­leukin-1β in the tu­mors, even as un­der­stand­ing of RAS pro­gressed to a point at which drug de­vel­op­ers could bring tar­get­ed ther­a­pies in­to the clin­ic.

The rea­son for this was sim­ple, Bar-Sa­gi said, and it has ma­jor im­pli­ca­tions for any fu­ture re­search: The pro­tein doesn’t show up in tu­mor cell cul­tures.

Build­ing off of re­search at her lab, Wash­ing­ton Uni­ver­si­ty of St. Louis and else­where, Bar-Sa­gi de­vised a way of test­ing it in vi­vo. They dis­cov­ered that the tu­mor re­lies on a pre­vi­ous­ly undis­cov­ered lig­and bind­ing to its TLR4 re­cep­tors. By giv­ing an­tibi­otics to clear bac­te­ria in some mice, they found that a warped mi­cro­bio­me may pro­mote the bind­ing, con­tribut­ing to the de­vel­op­ment of can­cer.

On­ly once they in­sert­ed the lig­and in­to cell cul­tures, the cells be­gan pro­duc­ing in­ter­leukin-1β . And when they gave RAS-pos­i­tive mice a com­bi­na­tion of a PD-1 and an in­ter­leukin-1β an­ti­body, they found a 32% re­duc­tion in tu­mors.

Bar-Sa­gi said it’s a break­through that con­tin­ues to point to the im­por­tance of not just the tu­mor but al­so the tu­mor’s ef­fect on the mi­cro-en­vi­ron­ment around it and the im­mune sys­tem there. But to ex­plore that, she said, re­searchers will have to turn away from Petri dish­es and find new meth­ods of study­ing tu­mors — pan­cre­at­ic, lung or oth­er­wise — as they ex­ist with­in the body.

“Many of these ef­fects are not go­ing to be rec­og­nized or will be very hard to study us­ing the con­ven­tion­al study meth­ods,” Bar-Sa­gi said. “And that’s def­i­nite­ly a shift.”

Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Nick Galakatos, Blackstone global head of life sciences

Nick Galakatos and the Black­stone team now have a record $4.6B to in­vest in bio­phar­ma, with a big fo­cus on push­ing com­pa­nies over the top

Nick Galakatos and his team at Blackstone Life Sciences have seen their biggest opportunities swell up in mostly established players who don’t have all the money they need to accomplish everything on the to-do list. And right now, with the industry booming, that’s a long list with some hefty needs.

The Blackstone team has neatly tied up the largest private fund ever raised in life sciences for making big dreams come true in biopharma. Late Thursday, Blackstone put out word that they had closed their highly anticipated fund with the projected $4.6 billion all in.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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Gilead boasts of pos­i­tive remde­sivir da­ta on mor­tal­i­ty — but their analy­sis pro­vokes the skep­tics

Gilead is surging again off data that suggest its antiviral remdesivir might improve survival.

The new data come from an analysis Gilead conducted comparing the death rate and recovery time of patients in one of its remdesivir trials to a group of 800 patients “with similar baseline characteristics and disease severity” who received only standard-of-care around the same time. The result, they said, suggested that patients who received remdesivir had a 62% better chance at surviving than those who did not.

Andrew Kruegel, Kures president and co-founder (Columbia Tech Ventures via Vimeo)

Af­ter psilo­cy­bin and ke­t­a­mine, a new biotech comes along de­vel­op­ing a drug Scott Got­tlieb fought

Andrew Kruegel was six years into his chemistry work at Columbia University, when, one day in August 2016, he learned he might have only 30 days before the government made him destroy his research.

Kruegel had been studying kratom, a leaf long used in Southeast Asia as a stimulant or for pain. It had opioid-like properties, he found, but seemed to offer pain relief without the addictive potential or respiratory side effects of traditional opioids — a riddle that might help illuminate how human opioid receptors work.

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The home run count: The $100M+ mega-round boom in biotech in­spired a $7.3B feed­ing fren­zy — so far this year

Over the last 6 months there’s been a blizzard of money piling up drifts of the green stuff through the biotech landscape. And the forecast calls for more cash windfalls ahead.

Even as a global pandemic has killed more than half a million people, blighted economies and divided nations over the proper response, it’s also helped ignite an unprecedented burst of big-time investing. And not just in Covid-19 deals, as we’ve looked at before.

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Atul Deshpande, Harbour BioMed chief strategy officer & head, US operations (Harbour BioMed)

An­oth­er biotech IPO set-up? Multi­na­tion­al biotech leaps from round to round, scoop­ing up cash at a blis­ter­ing pace

A short four months after announcing a $75 million haul in Series B+ fundraising, the multinational biotech Harbour BioMed pulled in another round of investments and eclipsed the nine-digit mark in the process.

Harbour completed its Series C financing, the company announced Thursday morning, raising $102.8 million and bringing its total investment sum to over $300 million since its founding in late 2016. The biotech plans to use the money to transition early-stage candidates from the discovery phase, fund candidates already in the clinic, and prep late-stage candidates for commercialization.

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Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

A new study points to $6.5B in pub­lic sup­port build­ing the sci­en­tif­ic foun­da­tion of Gilead­'s remde­sivir. Should that be re­flect­ed in the price?

By drug R&D standards, Gilead’s move to repurpose remdesivir for Covid-19 and grab an emergency use authorization was a remarkably easy, low-cost layup that required modest efficacy and a clean safety profile from just a small group of patients.

The drug OK also arrived after Gilead had paid much of the freight on getting it positioned to move fast.

In a study by Fred Ledley, director of the Center for Integration of Science and Industry at Bentley University in Waltham, MA, researchers concluded that the NIH had invested only $46.5 million in the research devoted to the drug ahead of the pandemic, a small sum compared to the more than $1 billion Gilead expected to spend getting it out this year, all on top of what it had already cost in R&D expenses.

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Hal Barron, GSK

Win or lose on the mar­ket­ing OK, the FDA just gunned down GSK’s bright hopes for their BC­MA ther­a­py

The FDA’s ODAC — the Oncologic Drugs Advisory Committee — has a well-known bias in favor of adding new cancer drugs to the market, even if efficacy is at best marginal and serious safety issues demand careful management.

Doctors want as many arrows in their quiver as they can get. And when patients are dying after failing multiple drugs, why not give it a go one more time?

GlaxoSmithKline, though, is about to test out how their new BCMA antibody drug conjugate belantamab mafodotin can do after being mauled in an in-house FDA review, ahead of the Tuesday expert panel discussion. Even if the agency goes ahead with an expected green light, this drug will likely be constrained to a small niche — icing any plans they may have for making waves in oncology anytime soon.

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