Eikon Therapeutics, Inc. Common Stock Status update

Thanks so much, Imogen. Good morning, everyone, and really thank Imogen for the kind invitation. Great honor to be here with Roger. My name's Tim Yap. I'm at MD Anderson Cancer Center. Been here for 10 years. Before that, I was at The Institute of Cancer Research and The Royal Marsden Hospital for about 12 years, where I've had a big interest in synthetic lethality, been involved with the development of many first-generation PARP inhibitors, and then, of course, now the new generation PARP-1 selective agents and also many other DDR agents. Also, I guess, Werner helicase that we'll be covering as well. Wonderful to be here, and thanks so much for the invitation.

Thank you, Imogen. Thanks very much for making this possible. It's a great privilege to be here with Tim Yap. He's modest, but he is a towering figure in clinical research, and it's a privilege to be here with him. I'm a physician scientist. I worked for many years studying signal transduction in hematopoietic populations when I was a professor at the University of Washington in Seattle. Moved to Merck to try to apply some of those lessons to drug discovery. Had a brief, well, 12 years at Amgen, taking a small, little company called Amgen and turning it into a great big giant company called Amgen, which I then retired from. Had no intention of doing that kind of job again, but was recruited back to Merck to lead research and development there again, and did that for a number of years.

My focus has been quite broad in the treatment of infectious disease and malignancy and also metabolic disease. But I have focused quite a lot on methods to improve cancer treatment, and in particular, the introduction of checkpoint inhibitors. We did that at Merck. When I say we, I mean everybody at Merck. I was just there to applaud. But we did that in a quite robust way, and I think really it transformed cancer care. That led me to think about how to proceed still further in this area, and it was at that point that I began working with the company that became Eikon. The premise of Eikon is that we can use super-resolution microscopy to visualize individual proteins in living cells. In doing so, we can develop novel methods for screening for active pharmaceutical ingredients that would alter the behavior of proteins.

It turns out that all drugs change protein motion. In fact, that's largely how they work. That wasn't something that we knew about before we got started with this. It took quite a long time for us to build the instruments necessary to apply super-resolution microscopy fruitfully to drug discovery. But we have now, for some years, reached that point and have been able to use our platform to introduce what we think are going to be important new medicines into the therapeutic armamentarium. We'll talk about one of those, EIK1005, which is a Werner helicase inhibitor, perhaps towards the end of the period today. But in the meantime, we also were able to use our tools fruitfully to look at some areas in DNA damage repair, particularly, because that's an especially good area for us to apply our tools to.

We were able to identify some very, very selective PARP1 inhibitors. One of the things that my colleagues and I had done when we were at Merck is we had worked together with the group at AstraZeneca to develop olaparib, which is the leading dual PARP inhibitor. Tim knows that drug very well and has used that very effectively. We felt that it was possible to find drugs that could have similar therapeutic efficacy but a superior safety profile, particularly with respect to hematologic toxicity, which frankly is limiting for the dual PARP inhibitors. We were able to identify two very good series of molecules from a small company in China called Impact.

We partnered with them and have developed 1003 and 1004, a brain-penetrant one, 1004, which Tim has been working with, I think at MD Anderson, and then a non-brain penetrant one, 1003, which is somewhat further along, but both of them are making good progress in the clinic. We're optimistic that they will turn out to be meaningful improvements for patient care, and that's, I think, much of what we're going to talk about today.

Yeah. All right. Let's start off with a tough question, huh? It's never easy to explain synthetic lethality without some slides, but I'll have a go. Essentially, if you think about two genes, X and Y, essentially if both genes are working and viable, you essentially get a viable, functioning cell with no issues. If you have an issue with one of them, loss of function of one of them, the cell still lives and there are no issues. But if you actually have an impact or a non-functioning X and Y gene, that is when the cell will undergo apoptosis and cell death, essentially. An easier way to think about things is to think about synthetic lethality as a table with four different legs, each leg representing a DNA repair pathway, and that could be base excision repair pathway, which is controlled by PARP.

PARP stands for poly ADP-ribose polymerase. There are several different members of the PARP family, but really it's PARP-1 and 2 that are relevant to what we're all discussing from a pharmacological perspective. If we go back to that table, one leg represents base excision repair that's controlled by PARP. Another leg could be homologous recombination, which is the error-free way of repairing DNA double-strand breaks, and that's something controlled by, for example, BRCA, the BRCA genes, BRCA1, BRCA2. If you think about how this applies to the clinic, how does this table apply to patients? We know that there are patients with BRCA1, BRCA2 alterations. This could be inherited. For example, Angelina Jolie has a BRCA1 mutation. These patients, we know are at great risk of developing different cancers. That includes breast, ovarian, prostate, pancreatic cancers, and also other malignancies as well.

If we're dealing with an individual who has a high-risk, penetrant, germline BRCA1 or 2 mutation, they have a non-functioning homologous recombination pathway. In other words, their table is standing on 3 legs rather than the 4 legs. If you think about that 3-legged table and you come in with, say, a pharmacological inhibitor of, say, PARP, you can actually block that other leg that controls base excision repair pathway. If you administer a PARP inhibitor to a patient who has a BRCA mutation plus a cancer, that's going to lead to the taking out, if you like, of that third leg. That table's not going to stand on 2 legs, and that table's going to collapse. In other words, that tumor cell is going to undergo apoptosis and cell death because you're taking out that third leg.

If you think about the normal cells in these germline carriers, they have a functioning homologous recombination. Their BRCA gene is functioning, and so that table is still standing in the normal cells with 3 legs without any issues, versus the tumor cells, which will collapse and die and undergo apoptosis because you're taking out the third leg. It is that difference between the cancer cells and the impact that you can have with a PARP inhibitor in those individuals that will lead to that whole synthetic lethality and the real personalized medicine, if you like, to kill the cancer cells without necessarily impacting the normal cells. I hope that Yeah summarizes things like That's great.