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.

Dan Skovronsky, Eli Lilly CSO

UP­DAT­ED: An­a­lysts are quick to pan Eli Lil­ly's puz­zling first cut of pos­i­tive clin­i­cal da­ta for its Covid-19 an­ti­body

Eli Lilly spotlighted a success for one of 3 doses of their closely-watched Covid-19 antibody drug Wednesday morning. But analysts quickly highlighted some obvious anomalies that could come back to haunt the pharma giant as it looks for an emergency use authorization to launch marketing efforts.

The pharma giant reported that LY-CoV555, developed in collaboration with AbCellera, significantly reduced the rate of hospitalization among patients who were treated with the antibody. The drug arm of the study had a 1.7% hospitalization rate, compared to 6% in the control group, marking a 72% drop in risk.

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#ES­MO20: Alk­er­mes of­fers their first snap­shot of a ben­e­fit for their next-gen IL-2 drug. But why did 1 pa­tient starve to death?

Everyone in the cancer R&D arena is looking to build new franchises around better drugs and combos. And one busy pocket of that space is centered entirely on creating an IL-2 drug that can be as effective as the original without the toxicity that damned it to the sidelines.

Alkermes $ALKS formally tossed its hat into the ring of contenders at virtual ESMO today, highlighting the first glimpse of efficacy for their candidate, ALKS 4230, as both a monotherapy as well as in combination with Merck’s Keytruda.

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Albert Bourla (Photo by Steven Ferdman/Getty Images)

Pfiz­er match­es Mod­er­na with their full Covid-19 tri­al blue­print — As­traZeneca says it will un­veil its pro­to­col 'short­ly'

Yesterday, after sustained public pressure as Moderna released its Phase III Covid-19 trial blueprint, Pfizer released its own full trial design for their vaccine trials. The move was designed to boost transparency and shore up public trust in the vaccines, but it also revealed differences in how the two companies are approaching the much-watched studies while failing to satisfy the demands of the fiercest advocates for transparency.

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Stronger to­geth­er? Boehringer and Mi­rati team to put first KRAS-KRAS com­bo in the clin­ic

Researchers are still waiting to see how much any of the vaunted KRAS drugs now in the clinic can, after decades of preclinical research and some early human studies, help patients. But while they do, two of the leading developers will look to see whether a KRAS-KRAS combo might pose a better shot than any KRAS alone.

Boehringer Ingelheim and Mirati have signed a collaboration to combine Mirati’s closely-watched lead KRAS inhibitor, MRTX849, in a clinical trial with the pan-KRAS blocker that Boehringer has quietly developed with high expectations behind their flashier contenders.

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#ES­MO20: Re­gen­eron, Sanofi eye an­oth­er first for their PD-1 con­tender Lib­tayo with promis­ing da­ta for on­col­o­gy niche

Regeneron and Sanofi took another step forward in the long march towards a greatly expanded market for their late-bloomer PD-1 checkpoint Libtayo.

The two occasional allies posted an objective response rate of 31% for Libtayo among 84 patients suffering from advanced cases of basal cell carcinoma at virtual ESMO. That spotlights progress for 26 patients, 5 of whom had a complete response. The data also reflect a boost in the number of responses seen from the last cut of the numbers.

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Albert Bourla, Pfizer CEO (Steven Ferdman/Getty Images)

Pfiz­er ex­ecs con­fi­dent­ly tap their top 10 block­busters-to-be. But what are the chances of sur­viv­ing PhI­II, let alone hit­ting these big peak sales es­ti­mates?

Pfizer’s top executive team doesn’t lack for confidence.

Where many Big Pharmas would be reluctant to put a peak sales figure on their late-stage drugs, Pfizer CEO Albert Bourla has shrugged off the usual diffidence to outline where the pharma giant expects to get $15 billion-plus.

The list, outlined this week during their investor presentations, is topped by 3 drugs in the $3 billion-plus peak sales category. They are:

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Christian Itin, Autolus CEO (Autolus)

#ES­MO20: Au­to­lus pro­vides glimpse of next-gen­er­a­tion CAR-T pro­gram, show­ing ear­ly pos­i­tive safe­ty da­ta

CAR-T therapies were hailed as a breakthrough when Novartis received the first FDA approval for Kymriah back in 2017. Though highly effective at treating certain types of blood cancers, CAR-Ts are also associated with severe and potentially deadly side effects, including lethal instances of cytokine release syndrome.

With this in mind, Autolus Therapeutics is looking to take a crack at a safer CAR-T and presented Phase II cohort data for its AUTO3 program at virtual ESMO 2020. The data showed that, among the 35 patients in the cohort being treated for r/r diffuse large B cell lymphoma, there were no instances of Grade 3 or higher CRS. Eight individuals saw Grade 1 inflammation while another four patients reached Grade 2.

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Sean Bo­hen's break from bio­phar­ma is over. The ex-As­traZeneca CMO has re­tired his Big Phar­ma jer­sey and is now — hap­pi­ly — run­ning a lit­tle biotech

The last I had heard about Sean Bohen, he had stepped out of his high-profile job as chief medical officer at AstraZeneca at the beginning of 2019 as CEO Pascal Soriot triggered a broad-ranging R&D shakeup. And then, earlier this week, I got a chance to catch up.

It turns out that Bohen decided at the time that he would not just jump into a new job in the booming biopharma business. As an oncologist, he had worked on the big programs at AstraZeneca, and before that he was at Genentech. That was good for a ticket to just about anyplace in the big biopharma world. But he felt it was time to stop and think things through.

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Covid-19 roundup: UP­DAT­ED: Amid calls for trans­paren­cy, Mod­er­na re­leas­es full PhI­II pro­to­col; As­traZeneca tri­al halt thought to be 'con­firmed trans­verse myelitis,' per CNN

Prominent scientists, public health experts and industry critics have been calling for more transparency from vaccine makers, including the release of the companies’ Phase III trial protocols. On Thursday, Moderna became the first major developer to do so.

“It is usually not what industry does,” CEO Stéphane Bancel told Endpoints News in an interview in advance of their R&D day today. “But given the need there is for the scientific community and the medical community and the media to understand how the vaccine is being developed, to make sure people are confident in the safety of the process, in the governance with scientific independence in the medical world and the like, we’re dropping tomorrow the full protocol. It is unredacted.”

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