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.”

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Deborah Dunsire

The fourth CGRP mi­graine drug is here. Time for Lund­beck to prove it's worth $2B

They may be late, but Lundbeck is now officially in the game for preventing migraine with CGRP drugs.

The FDA has OK’d eptinezumab, the prize in Lundbeck’s $2 billion acquisition of Alder. Like rival offerings from Amgen/Novartis, Eli Lilly and Teva, the antibody blocks the calcitonin gene-related peptide, which is believed to dilate blood vessels in the brain and cause pain.

It will now be sold as Vyepti. The company has yet to announce a price. Amgen and Novartis had set the wholesale acquisition cost of their pioneering Aimovig at $6,900 for a year’s supply before raising it slightly this year; Lilly and Teva had followed suit with Emgality and Ajovy.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Special report

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

Click on the image to see the full-sized version

The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.

Jim Scholefield via PR Newswire

Mer­ck los­es its chief dig­i­tal of­fi­cer, spot­light­ing tal­ent hunt for the hottest ti­tle in Big Phar­ma

Over the last few years we’ve seen the chief digital officer title become one of the hottest commodities in Big Pharma as global organizations hunt the best talent to sharpen the cutting edge of their tech platforms.

But Merck just discovered how hard it may be to keep them focused on pharma.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,900+ biopharma pros reading Endpoints daily — and it's free.