AACR: Bay Area biotech bets on an­ti­bod­ies armed with im­muno-stim­u­lant to fight check­point-re­sis­tant can­cers

The sci­en­tist be­hind the first prostate can­cer vac­cine Provenge — once cel­e­brat­ed as a his­toric break­through, but now a fad­ing star — has de­vised a type of armed an­ti­body — loaded with an im­muno-stim­u­lant rather than a cy­to­tox­ic pay­load — to fight can­cers re­sis­tant to the army of ex­ist­ing check­point in­hibitors.

Ed En­gle­man

The re­searcher, Stan­ford’s Ed En­gle­man, has built on his re­search in­to den­drit­ic cells — which are con­sid­ered ‘sen­tinels’ of the im­mune sys­tem as they are re­spon­si­ble for in­duc­ing im­mune T-cell re­spons­es — to de­vel­op this Im­mune-Stim­u­lat­ing An­ti­body Con­ju­gate (ISAC) tech­nol­o­gy, which was un­veiled by ex­clu­sive li­censee Bolt Bio­ther­a­peu­tics at the Amer­i­can As­so­ci­a­tion for Can­cer Re­search (AACR) Con­fer­ence on Mon­day.

“What Bolt has come up with is to wake up den­drit­ic cells with­in the (tu­mor) mi­croen­vi­ron­ment, and we were able to do this in a tar­get­ed way,” said David Dor­nan, se­nior VP of re­search, in an in­ter­view with End­points News ahead of the con­fer­ence.

Many pa­tients are re­frac­to­ry to check­point in­hibitors be­cause there are a num­ber of im­muno­sup­pres­sive fac­tors present in their tu­mor mi­croen­vi­ron­ment, and so re­searchers have been try­ing to har­ness dif­fer­ent mol­e­cules to stim­u­late the im­mune sys­tem, one of which are toll-like re­cep­tor (TLR) ag­o­nists — spe­cial­ized pro­teins that ini­ti­ate an im­mune re­sponse to for­eign pathogens or, in this case, can­cer cells.

David Dor­nan

But the chal­lenge of de­liv­er­ing these ad­ju­vants is that they must be de­liv­ered in­tra­tu­moral­ly, be­cause if they were ad­min­is­tered sys­tem­i­cal­ly — say oral­ly or in­tra­venous­ly — they can be­come tox­ic as im­mune cells across the body are ac­ti­vat­ed and the im­pact is not tar­get­ed, Dor­nan em­pha­sized.

Bolt’s ISAC tech­nol­o­gy is there­fore tar­get­ed — it con­ju­gates an ad­ju­vant on to a tu­mor tar­get­ing an­ti­body in or­der to de­liv­er this im­mune ag­o­nist di­rect­ly to the tu­mor.

Grant Yone­hi­ro

This is a log­i­cal evo­lu­tion — orig­i­nal­ly, re­searchers were tar­get­ing the tu­mor with chemother­a­peu­tics or an­ti­body drug con­ju­gates, then came the check­point in­hibitors that were de­signed to prime the im­mune sys­tem to at­tack the tu­mor, Bolt’s chief op­er­at­ing of­fi­cer Grant Yone­hi­ro said. “We do both, we’re tar­get­ing the tu­mor with our an­ti­body, but we’re al­so turn­ing on the im­mune sys­tem in the tu­mor.”

But it’s still ear­ly days. Bolt has so far con­duct­ed pre­clin­i­cal stud­ies.

The da­ta sug­gest that the tech can “rein­vig­o­rate the im­mune sys­tem to an ex­tent that if the can­cer came back you have a reper­toire of T-cells that can find, start pro­lif­er­at­ing and then start to kill the can­cer cells,” Dor­nan said.

“We see pro­found tu­mor shrink­age in pre­clin­i­cal mod­els, we see im­muno­log­i­cal mem­o­ry — the abil­i­ty for once when you clear a tu­mor, that if the can­cer comes back — if we give the mouse the can­cer cells, we don’t have re-ad­min­is­ter any ther­a­py — the mouse’s T-cells rec­og­nize the tu­mor and erad­i­cate it. We’ve done these mod­els in can­cers that are large­ly re­frac­to­ry to stan­dard-of-care ther­a­pies.”

With the ad­di­tion of a cy­to­tox­ic pay­load, the du­ra­tion of re­sponse is the main hur­dle — but adding on an im­muno-stim­u­lant can cir­cum­vent that, the ex­ec­u­tives un­der­scored. Bolt’s pre­clin­i­cal da­ta has shown that the ISAC ap­proach is arm­ing the body with a reper­toire of T-cells that even if the can­cer tries to mu­tate around it, the pa­tient has a fight­ing chance.

Bolt has sev­er­al pro­grams in its ar­se­nal, and its lead pro­gram is like­ly go­ing to be de­vel­oped for use in breast can­cer, gas­tric can­cer and blad­der can­cer, Dor­nan said.

The 30-em­ploy­ee Bay Area com­pa­ny has raised $72 mil­lion so far, and hopes to be in the clin­ic by 2020. An IPO is al­so on the cards. “We’re still a lit­tle ear­ly for that, but we think there’s a lot of po­ten­tial for an IPO down the line,” Yone­hi­ro said.

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.