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.

A new era of treat­ment: How bio­mark­ers are chang­ing the way we think about can­cer

AJ Patel was recovering from a complicated brain surgery when his oncologist burst into the hospital room yelling, “I’ve got some really great news for you!”

For two years, Patel had been going from doctor to doctor trying to diagnose his wheezing, only to be dealt the devastating news that he had stage IV lung cancer and only six months to live. And then they found the brain tumors.

“What are you talking about?” Patel asked. He had never seen an oncologist so happy.

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ProFound Therapeutics founding team

Flag­ship's lat­est biotech could turn some of the thou­sands of new pro­teins it dis­cov­ered in­to ther­a­pies — and it has $75M to start

Flagship Pioneering, the incubator of Moderna and dozens of other biotechs, says it has landed upon tens of thousands of previously undiscovered human proteins. The VC shop wants to potentially turn them into therapeutics.

Like other drug developers that have turned proteins into therapeutics (think insulin for diabetes), Flagship’s latest creation, ProFound Therapeutics, wants to tap into this new trove of proteins as part of its mission to treat indications ranging from rare diseases to cancer to immunological diseases.

Richard Silverman, Akava Therapeutics founder and Northwestern professor

This time around, Lyri­ca's in­ven­tor is de­vel­op­ing his North­west­ern dis­cov­er­ies at his own biotech

Richard Silverman was left in the dark for the last five years of clinical development of the drug he discovered. The Northwestern University professor found out about the first approval of Lyrica, in the last few days of 2004, like most other people: in the newspaper.

What became one of Pfizer’s top-selling meds, at $5 billion in 2017 global sales before losing patent protection in 2019, started slipping out of his hands when Northwestern licensed it out to Parke-Davis, one of two biotechs that showed interest in developing the drug in the pre-email days, when the university’s two-person tech transfer team had to ship out letters to garner industry appetite.

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Peter Thompson, Terremoto Biosciences interim CEO

For­mer Prin­cip­ia team looks to shake up co­va­lent small mol­e­cules again, this time at 'earthquake' scale

Terremoto Biosciences goes back a long ways, in a sense, to about a dozen years ago when Principia Biopharma was founded by UCSF professor Jack Taunton. Peter Thompson initially helmed the biotech.

The company helped expand covalent small molecule inhibitors beyond oncology and into autoimmune disease by targeting cystine. But that amino acid is uncommon in a lot of proteins, offering fewer drug targets than, say, lysine, which is present in most proteins of interest. So, over the years, Taunton went back to the drawing board to check out that second amino acid.

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David Ricks, Eli Lilly CEO (David Paul Morris/Bloomberg via Getty Images)

Eli Lil­ly set to in­vest $2.1B in home state man­u­fac­tur­ing boost

Eli Lilly is looking to expand its footprint in its home Hoosier State by making a major investment in manufacturing.

The pharma is investing $2.1 billion in two new manufacturing sites at Indiana’s LEAP Lebanon Innovation and Research District in Boone County, northwest of Lilly’s headquarters in Indianapolis.

The two new facilities will expand Lilly’s manufacturing network for active ingredients and new therapeutic modalities, including genetic medicines, according to a press release.

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Up­dat­ed: US sees spike in Paxlovid us­age as Mer­ck­'s mol­nupi­ravir and As­traZeneca's Evusheld are slow­er off the shelf

New data from HHS show that more than 162,000 courses of Pfizer’s Covid-19 antiviral Paxlovid were administered across the US over the past week, continuing a streak of increased usage of the pill, and signaling not only rising case numbers but more awareness of how to access it.

In comparison to this week, about 670,000 courses of the Pfizer pill have been administered across the first five months since Paxlovid has been on the US market, averaging about 33,000 courses administered per week in that time.

Pfiz­er and CD­MOs ramp up Paxlovid man­u­fac­tur­ing with Kala­ma­zoo plant ex­pan­sion lead­ing the way

As the Covid-19 pandemic continues to evolve, pharma companies and manufacturers are exploring how to step up production on antivirals.

Pfizer is planning to expand its Kalamazoo-area facility to increase manufacturing capabilities for the oral Covid-19 antiviral Paxlovid, according to a report from Michigan-based news site MLive. The expansion of the facility, which serves as Pfizer’s largest manufacturing location, is expected to create hundreds of “high-skilled” STEM jobs, MLive reported. No details about the project’s cost and timeline have been released, but according to MLive, Pfizer will announce the details of the expansion at some point in early June.

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FDA spells out the rules and re­stric­tions for states seek­ing to im­port drugs from Cana­da

The FDA is offering more of an explanation of the guardrails around its program that may soon allow states to import prescription drugs in some select circumstances from Canada, but only if such imports will result in significant cost reductions for consumers.

While the agency has yet to sign off on any of the 5 state plans in the works so far, and PhRMA’s suit to block the Trump-era rule allowing such imports is stalled, the new Q&A guidance spells out the various restrictions that states will have to abide by, potentially signaling that a state approval is coming.

Simba Gill, CEO of Evelo Biosciences

While down 87% YOY, Evelo gets Flag­ship and oth­ers to in­fuse new cap­i­tal for come­back hope

Just four years after Flagship spinout Evelo Biosciences went public in an IPO worth $85 million, the biotech has seen its share price tank from $13 a share this time last year (ultimately reaching a peak of over $17) to now under $1.50. And today, it looks like Flagship still thinks the fledging biotech, in a down market, is still worth something after initial pre-IPO backing from the likes of Google’s GV, Celgene, Mayo Clinic and Alexandria Venture.

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