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. 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.
