Hack­ing in­to macrophage at­tack cir­cuits, Stan­ford sci­en­tists pitch a bet­ter ear­ly-warn­ing alert sys­tem for tu­mors

Af­ter years of fine tun­ing ways to en­list the im­mune sys­tem in the fight against can­cer, im­munother­a­py has tak­en the field by storm, with a No­bel prize and a pair of block­buster check­point drugs to boast. But can im­mune cells help in an even broad­er ef­fort — flag­ging ma­lig­nant tu­mors be­fore they are de­tectable by tra­di­tion­al in­stru­ments?

Push­ing the thresh­old of can­cer di­ag­noses to ear­li­er and ear­li­er stages of the dis­ease is one of the Holy Grails in on­col­o­gy, in­spir­ing mul­ti­mil­lion-dol­lar in­vest­ments in­to star­tups like Grail. This week, a team from Stan­ford has chipped in with their own pitch and some mouse da­ta to show for it.

Pi­o­neer­ing a new de­f­i­n­i­tion of the con­cept “im­mun­odi­ag­notics,” San­jiv “Sam” Gamb­hir of Stan­ford’s Ca­nary Cen­ter for Ear­ly De­tec­tion re­pur­posed macrophages to re­port the pres­ence of dis­ease or dam­aged cells, achiev­ing de­tec­tion of tu­mors as small as 4 mil­lime­ters in di­am­e­ter, out­per­form­ing “some of the most ad­vanced ear­ly tu­mor de­tec­tion meth­ods out there.”


Im­age: San­jiv “Sam” Gamb­hir. Steve Fisch, STAN­FORD

His tech­nique, re­port­ed in Na­ture Biotech­nol­o­gy, makes use of macrophages’ in­nate abil­i­ty to find (and eat) mal­func­tion­ing or dead cells. That’s sim­ple; the big chal­lenge is to hack the process in a way such that these im­mune cells emit a de­tectable sig­nal be­fore they be­gin to feast.

To do that, Gamb­hir’s team tagged a mol­e­c­u­lar mark­er to a gene pro­mot­er that awak­ens and ac­ti­vates the gene di­rect­ing the macrophage on­slaught in the pres­ence of a tu­mor.

“The mol­e­c­u­lar mark­er is called Gaus­sia lu­ciferase, and un­der cer­tain chem­i­cal cir­cum­stances, it glows,” Gamb­hir said in a state­ment. “So the idea is, we pick a gene that turns on when a macrophage sens­es a tu­mor cell, we link that gene’s pro­mot­er to Gaus­sia lucer­iferase and fi­nal­ly, we in­te­grate it in­to the macrophages.”

Macrophages have been a key im­mune cell type of in­ter­est, at­tract­ing a num­ber of biotechs to re­move the “don’t eat me” sig­nal that tu­mors of­ten de­ploy to pre­vent an at­tack.

There are, of course, lim­i­ta­tions with the method. For one, macrophages don’t just re­spond to can­cer­ous tar­gets, so a “hit” on this test rep­re­sents a call for oth­er, con­fir­ma­to­ry tests rather than a de­fin­i­tive di­ag­no­sis. But the ap­proach, which in­volves cre­at­ing a syn­thet­ic bio­mark­er, is a ma­jor de­par­ture from the tra­di­tion­al prac­tice, which re­lies on iden­ti­fy­ing bio­mark­ers in the body.

The syn­thet­ic na­ture of this tech­nique means the strat­e­gy can be ap­plied to mul­ti­ple in­stru­ments and im­mune cells — all pos­si­bil­i­ties that Gamb­hir is ex­plor­ing with his start­up, Ear­li.

Mov­ing for­ward, Gamb­hir plans to test the method in oth­er types of can­cers and an­i­mal mod­els, while re­fin­ing the tech­nique to home in on just tu­mor cells, not cells with oth­er types of dam­age.

John Hood [file photo]

UP­DATE: Cel­gene and the sci­en­tist who cham­pi­oned fe­dra­tinib's rise from Sanofi's R&D grave­yard win FDA OK

Six years after Sanofi gave it up for dead, the FDA has approved the myelofibrosis drug fedratinib, now owned by Celgene.

The drug will be sold as Inrebic, and will soon land in the portfolio at Bristol-Myers Squibb, which is finalizing a deal to acquire Celgene.

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UP­DAT­ED: AveX­is sci­en­tif­ic founder was axed — and No­var­tis names a new CSO in wake of an ethics scan­dal

Now at the center of a storm of controversy over its decision to keep its knowledge of manipulated data hidden from regulators during an FDA review, Novartis CEO Vas Narasimhan has found a longtime veteran in the ranks to head the scientific work underway at AveXis, where the incident occurred. And the scientific founder has hit the exit.

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Ab­b­Vie gets its FDA OK for JAK in­hibitor upadac­i­tinib, but don’t look for this one to hit ex­ecs’ lofty ex­pec­ta­tions

Another big drug approval came through on Friday afternoon as the FDA OK’d AbbVie’s upadacitinib — an oral JAK1 inhibitor that is hitting the rheumatoid arthritis market with a black box warning of serious malignancies, infections and thrombosis reflecting fears associated with the class.

It will be sold as Rinvoq — at a wholesale price of $59,000 a year — and will likely soon face competition from a drug that AbbVie once controlled, and spurned. Reuters reports that a 4-week supply of Humira, by comparison, is $5,174, adding up to about $67,000 a year.

The top 10 fran­chise drugs in bio­phar­ma his­to­ry will earn a to­tal of $1.4T (tril­lion) by 2024 — what does that tell us?

Just in case you were looking for more evidence of just how important Amgen’s patent win on Enbrel is for the company and its investors, EvaluatePharma has come up with a forward-looking consensus estimate on what the list of top 10 drugs will look like in 2024.

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UP­DAT­ED: Sci­en­tist-CEO ac­cused of im­prop­er­ly us­ing con­fi­den­tial in­fo from uni­corn Alec­tor

The executive team at Alector $ALEC has a bone to pick with scientific co-founder Asa Abeliovich. Their latest quarterly rundown has this brief note buried inside:

On June 18, 2019, we initiated a confidential arbitration proceeding against Dr. Asa Abeliovich, our former consulting co-founder, related to alleged breaches of his consulting agreement and the improper use of our confidential information that he learned during the course of rendering services to us as our consulting Chief Scientific Officer/Chief Innovation Officer. We are in the early stage of this arbitration proceeding and are unable to assess or provide any assurances regarding its possible outcome.

There’s no explicit word in the filing on what kind of confidential info was involved, but the proceeding got started 2 days ahead of Abeliovich’s IPO.

Abeliovich, formerly a tenured associate professor at Columbia, is a top scientist in the field of neurodegeneration, which is where Alector is targeted. More recently, he’s also helped start up Prevail Therapeutics as the CEO, which raised $125 million in an IPO. And there he’s planning on working on new gene therapies that target genetically defined subpopulations of Parkinson’s disease. Followup programs target Gaucher disease, frontotemporal dementia and synucleinopathies.

But this time Abeliovich is the CEO rather than a founding scientist. And some of their pipeline overlaps with Alector’s.

Abeliovich and Prevail, though, aren’t taking this one lying down.

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Chi­na has be­come a CEO-lev­el pri­or­i­ty for multi­na­tion­al phar­ma­ceu­ti­cal com­pa­nies: the trend and the im­pli­ca­tions

After a “hot” period of rapid growth between 2009 and 2012, and a relatively “cooler” period of slower growth from 2013 to 2015, China has once again become a top-of-mind priority for the CEOs of most large, multinational pharmaceutical companies.

At the International Pharma Forum, hosted in March in Beijing by the R&D Based Pharmaceutical Association Committee (RDPAC) and the Pharmaceutical Research and Manufacturers of America (PhRMA), no fewer than seven CEOs of major multinational pharmaceutical firms participated, including GSK, Eli Lilly, LEO Pharma, Merck KGaA, Pfizer, Sanofi and UCB. A few days earlier, the CEOs of several other large multinationals attended the China Development Forum, an annual business forum hosted by the research arm of China’s State Council. It’s hard to imagine any other country, except the US, having such drawing power at CEO level.

As dis­as­ter struck, Ab­b­Vie’s Rick Gon­za­lez swooped in on Al­ler­gan with an of­fer Brent Saun­ders couldn’t say no to

Early March was a no good, awful, terrible time for Allergan CEO Brent Saunders. His big lead drug had imploded in a Phase III disaster and activists were after his hide — or at least his chairman’s title — as the stock price continued a steady droop that had eviscerated share value for investors.

But it was a perfect time for AbbVie CEO Rick Gonzalez to pick up the phone and ask Saunders if he’d like to consider a “strategic” deal.

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As­traZeneca's jug­ger­naut PARP play­er Lyn­parza scoops up an­oth­er dom­i­nant win in PhI­II as the FDA adds a 'break­through' for Calquence

AstraZeneca’s oncology R&D group under José Baselga keeps churning out hits.

Wednesday morning the pharma giant and their partners at Merck parted the curtains on a successful readout for their Phase III PAOLA-1 study, demonstrating statistically significant improvement in progression-free survival for women with ovarian cancer in a first-line maintenance setting who added their PARP Lynparza to Avastin. This is their second late-stage success in ovarian cancer, which will help stave off rivals like GSK.

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ICER blasts FDA, PTC and Sarep­ta for high prices on DMD drugs Em­flaza, Ex­ondys 51

ICER has some strong words for PTC, Sarepta and the FDA as the US drug price watchdog concludes that as currently priced, their respective new treatments for Duchenne muscular dystrophy are decidedly not cost-effective.

The final report — which cements the conclusions of a draft issued in May — incorporates the opinion of a panel of 17 experts ICER convened in a public meeting last month. It also based its analysis of Emflaza (deflazacort) and Exondys 51 (eteplirsen) on updated annual costs of $81,400 and over $1 million, respectively, after citing “incorrect” lower numbers in the initial calculations.