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

The DCT-OS: A Tech­nol­o­gy-first Op­er­at­ing Sys­tem - En­abling Clin­i­cal Tri­als

As technology-enabled clinical research becomes the new normal, an integrated decentralized clinical trial operating system can ensure quality, deliver consistency and improve the patient experience.

The increasing availability of COVID-19 vaccines has many of us looking forward to a time when everyday things return to a state of normal. Schools and teachers are returning to classrooms, offices and small businesses are reopening, and there’s a palpable sense of optimism that the often-awkward adjustments we’ve all made personally and professionally in the last year are behind us, never to return. In the world of clinical research, however, some pandemic-necessitated adjustments are proving to be more than emergency stopgap measures to ensure trial continuity — and numerous decentralized clinical trial (DCT) tools and methodologies employed within the last year are likely here to stay as part of biopharma’s new normal.

'Chang­ing the whole game of drug dis­cov­ery': Leg­endary R&D vet Roger Perl­mut­ter leaps back in­to work as a biotech CEO

Roger Perlmutter needs no introduction to anyone remotely involved in biopharma. As the R&D chief first at Amgen and then Merck, he’s built a stellar reputation and a prolific career steering new drugs toward the market for everything from cancer to infectious diseases.

But for years, he’s also held a less known title: science partner at The Column Group, where he’s regularly consulted about the various ideas the VCs had for new startups.

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UP­DAT­ED: Pfiz­er hits the brakes on their piv­otal tri­al for a BC­MA/CD3 bis­pe­cif­ic on safe­ty con­cerns while FDA road­block is hold­ing up Duchenne MD PhI­II

Pfizer’s ambitious plan to take a Phase II study of its BCMA CD3-targeted bispecific antibody elranatamab (PF-06863135) and run it through to an accelerated approval has derailed.

The pharma giant said in a release this morning that they have halted enrollment for their MagnetisMM-3 study after researchers tracked three cases of peripheral neuropathy in the ongoing Phase I. They are now sharing info with the FDA as they explore the red safety flag.

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FDA ex­tends re­search agree­ment with MIT-li­censed or­gan-on-chip sys­tems

The FDA on Wednesday extended its four-year agreement with CN Bio, a developer of single- and multi-organ-on-chip systems used for drug discovery, for another three years.

CN Bio said the scope of the research performed by the FDA’s Center for Drug Evaluation and Research has expanded to include the exploration of the company’s lung-on-a-chip system to help with the agency’s evaluation of inhaled drugs, in addition to the agency’s work on its liver model.

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In quest to meet user fee goals, FDA’s per­for­mance con­tin­ues down­ward trend

A recent update to the FDA’s running tally of how it’s meeting its user fee-related performance goals during the pandemic shows an agency that is not out of the woods yet.

The latest numbers reveal that for a second straight quarter in 2021, the FDA has met its user fee goal dates for 93% of original new drug applications, which compares with 94% and 98% for the previous two quarters in 2020, respectively.

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Andrew Radin, Aria Pharmaceuticals CEO (Aria)

An­drew Radin or­ches­trates his AI dis­cov­ery plat­for­m's piv­ot to R&D with a har­mo­nious name change and eyes on the clin­ic

Andrew Radin was a straight A student. So when he stopped turning in assignments in Nigam Shah’s class at Stanford University, the professor knew something was up.

“If you don’t hand in assignments, you’re gonna fail,” Radin recalls Shah saying one day after class. “Everything alright at home?”

Little did Shah know that a project Radin did for another class had piqued the interest of Andreessen Horowitz’s Vijay Pande, who also taught at the university. As a biomedical informatics student, Radin was looking at how technology could be used to comb through large swaths of data and find drug-target matches — and Pande offered him the first investment from his new $200 million biotech fund to turn the platform into a company.

Cynthia Butitta (L) and Joe Jimenez

Is that an­oth­er IPO in the mak­ing? Ex-No­var­tis CEO Joe Jimenez and a lead Kite play­er take up new posts at an off-the-shelf ri­val to 2 pi­o­neer­ing drugs

Right on the heels of taking on a $160 million crossover round in a likely leap to Nasdaq, Century Therapeutics CEO Lalo Flores is now pushing ahead with the high-profile ex-Novartis chief Joe Jimenez as chairman.

Jimenez’s greatest fame at Novartis was earned for one of its weakest products, as their pioneering personalized CAR-T Kymriah won the honors for the first such drug to make it to the market. Now a host of players, including Century, are barreling in behind the frontrunners with allogeneic rivals that can be created for off-the-shelf use.

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Joe Wiley, Amryt CEO

A biotech with a yen for pricey rare dis­ease drugs — and bar­gain base­ment shop­ping — adopts an­oth­er or­phan in lat­est M&A pact

After making it through a long, painful haul to get past a CRL and on to an FDA approval last summer, little Chiasma has found a buyer.

Amryt $AMYT, a company known for its appetite for acquiring expensive drugs for rare diseases at bargain prices, snagged Chiasma and its acromegaly drug Mycapssa (octreotide) capsules in an all-stock deal — with an exchange of 0.396 shares of Amryt for every share of Chiasma.

Ngozi Okonjo-Iweala, Director general of WTO (AP Photo/Keystone/Alessandro Della Bella)

Opin­ion: Waiv­ing Covid-19 vac­cine IP could save lives, but where is the man­u­fac­tur­ing ca­pac­i­ty?

Droves of House Democrats in Washington and members of the European Parliament have now glommed onto a major push by India and South Africa at the WTO to abolish all IP around Covid-19 vaccines.

At first blush, waiving this IP sounds like an easy win: More Covid-19 vaccines made locally for more people means more lives saved. Simple enough, especially as low-income countries have received just a tiny fraction of the world’s vaccine allotment so far.