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.”

The 20 un­der 40: In­side the next gen­er­a­tion of bio­phar­ma lead­ers

“Each generation needs a new music,” Francis Crick wrote in 1988, reflecting back on his landmark discovery. Crick was 35, then, in 1953, when he began working with a 23-year-old named James Watson, and 37 when the pair unveiled the double helix. Rosalind Franklin, whose diffraction work undergirded their metal model, was 32.

The model would become the score for a new era in biology, one devoted to cracking the basic structures turning inside life. Subsequent years would bring new conductors and new rhythms: Robert Swanson, 29 when he convinced a 39-year-old Herb Boyer to build a company off his work and call it Genentech; Phillip Sharp, 29 when he discovered RNA splicing and 34 when he co-founded Biogen; Frances Arnold, 36 when she pioneered directed evolution; Feng Zhang, 31 when he published his CRISPR paper.

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Chart-top­ping ven­ture cash? Strong deal flow? In the month Covid-19 ripped around the globe? Yup

It turns out that even sending everyone from the CEO to rank-and-file staffers home to work in the middle of a Category 5 pandemic wasn’t enough to put a crimp in the flow of venture cash into biopharma. And even dealmaking held its own against the howling winds of misfortune — largely because a group of savvy players was quick to adjust to the new reality.

Our deal expert Chris Dokomajilar ran the numbers for us on a month-to-month basis and found that not only was venture money flowing during the panicky month of March, but it was also hitting home in record sums compared to the last 26 months of deal flow.

Say what?

As you can see in the top chart below, Dokomajilar outlined how the industry racked up $2.41 billion in total for March, just barely ahead of one other topper during the heady days of August 2018.

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FDA Commissioner Stephen Hahn and President Donald Trump at a press briefing on March 19, 2020. (AP Images)

Biotech ex­ecs warn that the FDA is fum­bling their re­sponse to the Covid-19 open-door promise, de­lay­ing progress

A few days ago the FDA touted a procedure for Covid-19 meds that committed the agency to immediate action for developers, formalizing a high-speed response that’s been promised for weeks.

Bioregnum Opinion Column by John Carroll

Decisions that once required months would be measured in hours under the Coronavirus Treatment Acceleration Program. “In many cases” trial protocols could be hammered out in less than a single day. If you had a potential solution to the crisis, the appropriate staffer would be in touch “to get studies underway quickly.”

It would be the ultimate high-speed regulatory pathway from Phase I to approval. Red tape was banished.

But it’s clear that for some — and quite likely many — biopharma execs, the actual agency response has not measured up to the promise. Beyond the front ranks of advanced companies in the field, like Gilead, or for drugs endorsed by President Trump, it may not even come close.

“The first response is this form letter everyone gets,” says one biotech CEO who’s reached out to the FDA on Covid-19. And when you try to cut through that, the ball gets dropped as it is passed from top officials to the frontline staff actually charged with getting things done.

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GSK's Hal Bar­ron buys a $250M stake in George Scan­gos' Vir and makes a bee­line to the clin­ic with Covid-19 an­ti­bod­ies

GlaxoSmithKline is diving straight into the swirling waters of Covid-19 R&D work, and investing $250 million to grab a chunk of equity in one of the emerging stars in infectious disease research to make it official.

GSK put out word this morning that it is partnering with Vir Biotechnology $VIR, the infectious disease startup founded in the Bay Area by former Biogen CEO George Scangos. They’re planning a leap into Phase II studies for 2 preclinical antibody candidates — VIR-7831 and VIR-7832 — that have been engineered to target the SARS-CoV-2 spike protein.

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UP­DAT­ED: A small, ob­scure biotech just won big with their IPO. In this mar­ket. Are you kid­ding me?

How could a small, largely unknown biotech that emerged from stealth mode just months ago with early-stage cancer programs jump onto Wall Street in the middle of a Category 6 financial hurricane and sail through with a $165 million IPO?

And what does that mean for the rest of the industry waiting to see just how much damage global lockdowns will wreak on clinical development?

The biotech is a company called Zentalis. The crew there nabbed an $85 million crossover round late last year — notably waiting 5 years before waving the numbers around to attract attention, according to my read of a FierceBiotech story. Perceptive joined in, but the syndicate was not in general the kind of marquee affair that gets tongues wagging.

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Ready to de­clare a de­fin­i­tive come­back in two months, Im­munomedics stops PhI­II ear­ly, re­cruits new CEO

More than a year ago, hit by a surprise complete response letter from the FDA, Immunomedics bid its then-CEO, Michael Pehl, adieu and began a 15-month quest to resolve the manufacturing issues cited in the CRL and seek a new leader — all the while moving forward with a Phase III study on its lead drug for metastatic triple-negative breast cancer.

Today the biotech said their stars are finally aligning. Not only is Novartis Oncology vet Harout Semerjian coming on board as CEO to steer what they believe will be a smooth sail to a new PDUFA date in June, Immunomedics has also been informed that their late-stage trial can be stopped early due to “compelling evidence of efficacy.”

An­oth­er day, an­oth­er boat­load for biotech. Deer­field adds $840M to rush of ven­ture dol­lars

The biotech dollars just keep rolling in.

Even as the world economy faces an economic contraction unprecedented in nature, biotech venture capital firms are announcing huge new investment pots. The latest? Deerfield Management Co.

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Small mol­e­cules, bi­o­log­ics and now gene ther­a­pies: Ger­many's Evotec adds an­oth­er feath­er to its R&D cap

German drug discovery company Evotec — which has a thriving rolodex of biopharma partners such as Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda — is now venturing into gene therapies.

The company swallowed Seattle-based Just Biotherapeutics, a company focused on reducing the cost of manufacturing protein therapies last year. It is now setting up a dedicated R&D site for gene therapies in Austria, in an effort to achieve a “modality-agnostic” repertoire — small molecules, biologics and now gene therapies.

A pair of PhI­II fail­ures spells last rites for Men­lo’s once-promis­ing Mer­ck drug

Four months after an intercontinental merger, Menlo Therapeutics is counting yet another pair of trial failures — ones with significant consequences for the companies, their shareholders and the drug.

In two pivotal Phase III trials, Menlo’s lead drug serlopitant failed to treat pruritus associated with prurigo nodularis — basically itchiness from a particular skin disease that causes red lesions on a person’s arms or legs. Serlopitant has long been the company’s only drug and as recently as 2018, it looked promising enough to support a stock price of $37. In April of that year, a Phase II failure demolished the stock price overnight: $35 to $9. Other subsequent stumbles trickled the ticker down to just above $2.