Daniel Grau, Avilar CEO

An RA-backed start­up 'AT­AC­s' a nov­el chal­lenge, look­ing to spur pro­tein degra­da­tion out­side the cell

Pro­tein degra­da­tion is one of the hot drug class­es of the fu­ture, but com­peti­tors are pil­ing in with the likes of C4, Arv­inas, Fron­tier Med­i­cines and Vi­vid­ion jostling for po­si­tion. A new start­up wants to ap­ply the lessons learned from degra­da­tion out­side the cell, and it now has the green­light from RA Cap­i­tal to steam ahead.

Avi­lar Ther­a­peu­tics launched Thurs­day with $60 mil­lion from found­ing in­vestor RA to chase a nov­el pro­tein degra­da­tion drug class the start­up is call­ing AT­ACs— short for “AS­G­PR Tar­get­ing Chimeras” — that looks to trash un­want­ed pro­teins cir­cu­lat­ing out­side the hu­man cell.

AT­ACs are the next in a line of acronymed degra­da­tion drugs, fol­low­ing the likes of PRO­TAC, LYTEC, AT­TEC and more. The big dif­fer­ence here is that Avi­lar’s plat­form looks to spur on pro­tein degra­da­tion in the ex­tra­cel­lu­lar en­vi­ron­ment, drag­ging tar­get­ed pro­teins to dis­pos­al sites on liv­er cells.

The idea be­hind AT­ACs start­ed from a sim­ple ques­tion in the halls at RA, CEO Dan Grau told End­points News: Pro­tein de­graders are great and grow­ing in­creas­ing­ly val­i­dat­ed in an­i­mals and hu­mans, but can we use the same mech­a­nism out­side the cell? That in­quiry led the Avi­lar team to the AS­G­PR re­cep­tor on the sur­faces of he­pa­to­cytes, a key tran­sit point for liv­er cells’ break­ing down en­doge­nous pro­teins.

By lever­ag­ing the liv­er’s nat­ur­al process­es, the team en­vi­sioned a drug class that could latch a vast range of pro­teins on­to those AS­G­PR re­cep­tors and kick­start degra­da­tion in the lyso­some. Such a drug, com­prised of one lig­and used to bind to a tar­get pro­tein and an­oth­er to bind to AS­G­PR, would act as an Uber to the shred­der for un­want­ed pro­teins in the blood, a mech­a­nism that could have a broad range of ap­pli­ca­tions across ther­a­peu­tic ar­eas.

“What was im­por­tant ear­ly on was the iden­ti­fi­ca­tion ear­ly on of an op­por­tu­ni­ty to de­sign small mol­e­cule lig­ands to AS­G­PR that could per­form bet­ter than his­tor­i­cal chemistries or per­form bet­ter than the way na­ture is do­ing it it­self,” Grau said. “The way we like to think about it is on the one hand we’re har­ness­ing a nat­ur­al process while al­so im­prov­ing on na­ture it­self.”

The prob­lem, Grau said, is that there was a lot of bi­o­log­i­cal and chem­i­cal ground­work still un­known be­tween con­ceiv­ing of such a project and re­al­iz­ing it. The idea be­hind AT­AC came up in ear­ly 2020 and was mov­ing quick­ly, but Grau, who came on board in May, said the com­pa­ny most­ly had to start from scratch to build its tech plat­form while al­so run­ning at full speed.

Effie Toz­zo

First, the team dove in­to the chem­istry of high-affin­i­ty AS­G­PR bind­ing, cre­at­ing a li­brary of lig­ands it could use to ef­fec­tive­ly bind to that re­cep­tor. Then, Avi­lar turned its at­ten­tion to de­vel­op­ing a mod­u­lar plat­form for AT­ACs — ef­fec­tive­ly swap­ping out lig­ands with dif­fer­ent binders to tar­get a wider range of pro­teins — and cre­at­ing math­e­mat­i­cal mod­els to best pre­dict the PK and PD ef­fects of the drugs.

Fi­nal­ly, and per­haps most promis­ing giv­en the wide range of po­ten­tial ther­a­peu­tic ap­pli­ca­tions for a plat­form like this, Avi­lar cre­at­ed a pro­teome map­ping sys­tem that would give it a grow­ing un­der­stand­ing of how ex­tra­cel­lu­lar pro­teins func­tion and how the body’s nat­ur­al degra­da­tion process works; a guide­post, if you will, for the path to clin­i­cal de­vel­op­ment.

Now, with its tech ready for show­time, Avi­lar is work­ing on con­struct­ing a pipeline as Grau looks to build a team of ex­perts around him. He took the first shot this week, hir­ing on Effie Toz­zo, a vet­er­an of Mer­ck, Roche and Astel­las, as the com­pa­ny’s first CSO.

On the pipeline front, Grau was mum, but he did say the first pro­gram would be close­ly watched as it could po­ten­tial­ly of­fer proof-of-mech­a­nism for the com­pa­ny’s en­tire plat­form.

“When we go in­to our first clin­i­cal tri­al … in that con­text, we will be mea­sur­ing the lev­els of pro­tein we wish to de­grade and will be able to show the lev­els of degra­da­tion of that pro­tein,” Grau said. “This pro­vides a very ear­ly proof of mech­a­nism and an ac­cel­er­a­tion of val­ue, but what’s nice is that it’s go­ing to be true for every AT­AC pro­gram.”

So, with no dead­line set, it’s all eyes on that first hu­man study. But there may be even more in the works over at Avi­lar: Grau not­ed the com­pa­ny is work­ing on “ad­di­tion­al tech­nolo­gies” in ex­tra­cel­lu­lar degra­da­tion that could add even more meat on the bone here.

Stay tuned.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

The slate of products we’re offering here at Endpoints is continuing to grow, and it’s not just limited to editorial. If you haven’t, do visit your reader profile to see if there are any other weekly newsletters you’re interested in — as each comes with its own exclusive content. And don’t miss the publisher’s note from Arsalan Arif on Endpoints Studio, our latest avenue for advertising on Endpoints.

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Radek Spisek, Sotio CEO (Cellestia)

A qui­et Czech biotech bags $315M to dri­ve its blos­som­ing can­cer pipeline through the clin­ic

In the rather insular world of biotech, most innovation inevitably comes from a cluster of R&D hubs — Cambridge, San Francisco, etc. But sometimes success stories sprout from rocky soil, which is most certainly the case with Prague-based Sotio Biotech and its suddenly jam-packed pipeline of cancer drugs.

After years in quiet development, Sotio now has $315 million in new funds to play with from parent company PPF Group, an investment group founded in the Czech Republic, as the biotech looks to advance its growing pipeline through early- and mid-stage trials.

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In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Lisa Deschamps, AviadoBio CEO

Ex-No­var­tis busi­ness head hops over to a gene ther­a­py start­up — and she's reeled in $80M for a dash to the clin­ic

Neurologist and King’s College London professor Christopher Shaw has been researching neurodegenerative diseases like ALS and collaborating with drugmakers for the last 25 years in the hopes of pushing new therapies forward. But unfortunately, none of those efforts have come anywhere close to fruition.

“So, you know, after 20 years in the game, I said, ‘Let’s try and do it ourselves,’” he told Endpoints News. 

Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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Biospec­i­men M&A: Dis­cov­ery ac­quires Al­bert Li's he­pa­to­cyte project; PhI­II tri­al on Bay­er's Nube­qa reached pri­ma­ry end­point

Discovery Life Sciences has acquired what claims to be the Maryland-based host of the world’s largest hepatocyte inventory, known as IVAL, to help researchers select more effective and safer drug candidates in the future.

The combined companies will now serve a wider range of drug research and development scientists, according to Albert Li, who founded IVAL in 2004 and is set to join the Discovery leadership team as the CSO of pharmacology and toxicology.