Parabilis Medicines, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Of course. I appreciate it.

Yeah, thanks for that question. The company was founded by a Harvard professor called Greg Verdine, who was the same professor behind Warp Drive that got folded into Revolution Medicines, that's the basis of their product now, and Warp Drive and other companies as well. The problem he had been thinking about for a long time is one of drug ability, undruggability. Most proteins inside cells lack small molecule binding pockets. Pockets are required for any kind of small molecule or version of a small molecule we have today, from degraders to covalents to anything. So what to do then? Because 80% or so of proteins inside cells lack these, and yet the genetics and phenotypic screening efforts that abound in the industry now, they often point to one of those 80% as causes of various diseases. So if that's a cause, you're kind of out of luck.

The principle that he pushed then was, well, nature enables helical peptides to sit inside membranes, and perhaps that will allow us to put a protein, effectively a peptide, into a cell and function like an antibody might, that binds flat epitopes. Need for pockets is unnecessary, was his hypothesis. What he did with that was evolve a peptide platform that we call now the Helicon platform, that is comprised of stabilizing entities that hold this peptide as a helix, as an alpha helix, so it is constrained to be that way. Once it is constrained, you can go kind of crazy on the side chains. You can use whatever side chains you want. You do not have to stay within the 20 canonical amino acids.

We use now over 2,000 different amino acids, so it is an astronomical diversity of peptides that we can create, and what we found subsequent to the founding is through creation of very large data sets, how to predict compositions that both enter cells and engage proteins that are otherwise undruggable. That is the fundamental problem that we have solved.

I think very much so. It should provide great confidence that this platform is not only validated biologically, not only validated through non-clinical tox studies, but now clinically, that this molecule that you are putting into the human is able to go and find its target that is inside a cell, so therefore get into a cell and adhere to it and engage it and keep it from having function and adequately dealing with side effects and kinetics and manufacturing and all the things that need to be true to get to that point. We feel really good about the validity of the platform as illustrated through zolucatetide.

Yeah. That is the question. First of all, why beta-catenin? Why was it tackled in the first place? It has been on the table forever. Not forever, but since 1990 when Bert Vogelstein first described it and its relationship to cancer. It was recognized alongside P53 and MYC as major elements of why a cancer is a cancer. You want to be able to do something about those proteins, and right now it is only beta-catenin through Parabilis where that has been possible. So why have we been able to do that? Why has it been difficult in the first place? Beta-catenin interacts with a key transcription factor, the family of them called TCFs, and it is that interaction that the Broad, DepMap, and other ways of pointing to causality points right at that node. That node is undruggable. It lacks a pocket.

It is a flat protein interacting with another flat protein. There is nothing there for a molecule to bind to. It has been therefore very challenging. It has actually been impossible. It is actually interesting anecdote is that both J&J and Merck, when I ran research at Merck and R&D at J&J, we tried very hard to drug that node, and I feel like I have personal experience failing twice on that. That was a not fun experience. It also provides some personal motivation and satisfaction for me.

That's the right way to look at it.