Johns Hop­kins spin­out spot­lights a show­case an­i­mal test for an­ti­body-lig­and I/O traps — match­ing check­points with a rein on Tregs

With the block­buster pop­u­lar­i­ty of PD-1/L1 check­points chang­ing the way tu­mors are treat­ed around the world, the spot­light in re­search has shift­ed away from the suc­cess­ful though lim­it­ed and some­what crude first gen­er­a­tion of these ther­a­pies to new ways to amp up their ef­fi­ca­cy and dura­bil­i­ty.

One of the key hur­dles, in­ves­ti­ga­tors have found, is the gen­er­a­tion of reg­u­la­to­ry T cells — Tregs — that sup­press the im­mune re­sponse to can­cer cells. And now a re­search team at Johns Hop­kins led by At­ul Be­di, a prac­tic­ing on­col­o­gist and as­so­ciate pro­fes­sor at Johns Hop­kins Uni­ver­si­ty School of Med­i­cine, say they have de­vel­oped an an­ti­body/lig­and with a bi­fur­cat­ed war­head that can do a bet­ter job on the check­point side while blunt­ing the Tregs that both pre­vent ef­fi­ca­cy as well as help trig­ger a grad­ual loss of po­ten­cy, lead­ing to re­cur­rence.

Work­ing with soft­ware from the AI/ma­chine learn­ing spe­cial­ists at Bal­ti­more-based In­sil­i­co Med­i­cine, re­searchers were able to do a sig­nif­i­cant amount of path­way ex­plo­ration. They found that ac­ti­va­tion of the trans­form­ing growth fac­tor-β (TGFβ) path­way was linked to the pres­ence of the FOXP3 bio­mark­er, spot­light­ing its link to Tregs. So the re­search team un­der Be­di cre­at­ed a Y-trap: fus­ing a CT­LA-4 an­ti­body as well as a PD-1 with a “TGFβ trap” de­signed to turn off, redi­rect and delete Tregs.

“This Y-trap not on­ly dis­ables CT­LA-4 func­tion, but dis­rupts the TGFβ feed­back loop that is nec­es­sary for in­duc­tion and main­te­nance of Tregs in the tu­mor,” says Be­di, who li­censed the tech through Johns Hop­kins to a start­up called Y-Trap, Inc, which he man­ages with San Fran­cis­co-based CEO So­nia Bhan­ot.

This first project is still very much at the pre­clin­i­cal phase, with re­searchers work­ing with mouse mod­els of can­cer. And longterm suc­cess with mouse mod­els of can­cer is rare. But the use of AI com­bined with bet­ter drug de­sign has de­liv­ered what the re­searchers vow is a su­pe­ri­or an­ti­body-lig­and con­struct, with an­i­mal da­ta to back up its claim that the Y-traps are able to sur­pass ate­zo (Roche’s PD-L1 Tecen­triq) and avelum­ab (Baven­cio from Pfiz­er and Mer­ck KGaA) with a promise to be able to break out of the 1 in 5 or so ra­tio on ef­fi­ca­cy with a bet­ter prog­no­sis for dura­bil­i­ty. And they’re fo­cused ini­tial­ly on can­cers where there’s a known re­sis­tance to check­point ther­a­pies.

Be­di ex­plained to me that his work on Y-traps has been evolv­ing for the past 6 years. Boot­strap­ping the work with grants from the NIH as well as re­gion­al groups, he says he’s brought in a seed round from pri­vate in­vestors and built the frame­work for an ad­vanced pre­clin­i­cal plat­form com­pa­ny with a new tech­nol­o­gy that can branch out in­to a va­ri­ety of dif­fer­ent fields, in­clud­ing in­fec­tious dis­eases, where the im­mune sys­tem plays a key role. And he has a full set of I/O Y-trap pro­grams that can be brought to­geth­er to at­tack dif­fer­ent hur­dles — like cell ex­haus­tion — fac­ing the first gen­er­a­tion of check­points, get­ting straight in­to the tu­mor mi­croen­vi­ron­ment.

With AI and ma­chine learn­ing, says Be­di, you can feed in da­ta on re­spons­es “that gives you clues as to which Y-traps are best to ad­dress them.” Go fur­ther down the road, he says, and even­tu­al­ly you’ll be able to per­son­al­ize these Y-trap con­structs to in­di­vid­ual pa­tients, rather than just cer­tain sub­groups based on key bio­mark­ers.

Alex Zha­voronkov

“My aim in this field is ag­ing re­search,” notes Alex Zha­voronkov, the CEO at In­sil­i­co Med­i­cine, “look­ing at new ways to make the im­mune sys­tem look younger; im­mune senes­cence, wak­ing up the im­mune sys­tem.”

Last sum­mer In­sil­i­co part­nered with Glax­o­SmithK­line on their maid­en ef­fort on AI and ma­chine learn­ing in drug de­vel­op­ment. And Zha­voronkov has been backed by UK bil­lion­aire Jim Mel­lon, who helped found the start­up Ju­ve­nes­cence, which is mak­ing ag­ing re­search its cen­tral fo­cus, at a time most of the play­ers in R&D are just get­ting their feet wet with this tech­nol­o­gy.

The next step at Y-Traps Inc is to move past the seed fund­ing and raise a ven­ture round to cre­ate a full-fledged plat­form biotech that can move to file an IND and then start hu­man stud­ies in I/O, where the tech­nol­o­gy can ad­dress the most ob­vi­ous chal­lenges well rec­og­nized in the field. Then they can start branch­ing out, ex­plor­ing in­dus­try part­ner­ships to lever­age more work in the field.

That all fits with a key trend in on­col­o­gy re­search. As a tsuna­mi of check­points promis­es to com­modi­tize the first gen­er­a­tion of check­points, the em­pha­sis now is on the next-gen in­no­va­tions that can main­tain a prod­uct’s unique sta­tus. And Be­di is bet­ting that Y-traps can play a big role in that.

We’ll keep you post­ed on that.


Il­lus­tra­tion: In­sil­i­co Med­i­cine

Chas­ing Roche's ag­ing block­buster fran­chise, Am­gen/Al­ler­gan roll out Avastin, Her­ceptin knock­offs at dis­count

Let the long battle for biosimilars in the cancer space begin.

Amgen has launched its Avastin and Herceptin copycats — licensed from the predecessors of Allergan — almost two years after the FDA had stamped its approval on Mvasi (bevacizumab-awwb) and three months after the Kanjinti OK (trastuzumab-anns). While the biotech had been fielding biosimilars in Europe, this marks their first foray in the US — and the first oncology biosimilars in the country.

Seer adds ex-FDA chief Mark Mc­Clel­lan to the board; Her­cules Cap­i­tal makes it of­fi­cial for new CEO Scott Bluestein

→ On the same day it announced a $17.5 million Series C, life sciences and health data company Seer unveiled that it had lured former FDA commissioner and ex-CMS administrator Mark McClellan on to its board. “Mark’s deep understanding of the health care ecosystem and visionary insights on policy reform will be crucial in informing our thinking as we work to bring our liquid biopsy and life sciences products to market,” said Seer chief and founder Omid Farokhzad in a statement.

Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Daniel O'Day

No­var­tis hands off 3 pre­clin­i­cal pro­grams to the an­tivi­ral R&D mas­ters at Gilead

Gilead CEO Daniel O’Day’s new task hunting up a CSO for the company isn’t stopping the industry’s dominant antiviral player from doing pipeline deals.

The big biotech today snapped up 3 preclinical antiviral programs from pharma giant Novartis, with drugs promising to treat human rhinovirus, influenza and herpes viruses. We don’t know what the upfront is, but the back end has $291 million in milestones baked in.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

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On a glob­al romp, Boehringer BD team picks up its third R&D al­liance for Ju­ly — this time fo­cused on IPF with $50M up­front

Boehringer Ingelheim’s BD team is on a global deal spree. The German pharma company just wrapped its third deal in 3 weeks, going back to Korea for its latest pipeline pact — this time focused on idiopathic pulmonary fibrosis.

They’re handing over $50 million to get their hands on BBT-877, an ATX inhibitor from Korea’s Bridge Biotherapeutics that was on display at a science conference in Dallas recently. There’s not a whole lot of data to evaluate the prospects here.

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Servi­er scoots out of an­oth­er col­lab­o­ra­tion with Macro­Gen­ics, writ­ing off their $40M

Servier is walking out on a partnership with MacroGenics $MGNX — for the second time.

After the market closed on Wednesday MacroGenics put out word that Servier is severing a deal — inked close to 7 years ago — to collaborate on the development of flotetuzumab and other Dual-Affinity Re-Targeting (DART) drugs in its pipeline.

MacroGenics CEO Scott Koenig shrugged off the departure of Servier, which paid $20 million to kick off the alliance and $20 million to option flotetuzumab — putting a heavily back-ended $1 billion-plus in additional biobuck money on the table for the anti-CD123/CD3 bispecific and its companion therapies.