Aprea Therapeutics, Inc. Common stock Conference

Thank you, and welcome everyone to the pre-ESMO webinar. We want to get started by talking about the state of WEE1 inhibition in precision oncology. WEE1 inhibition is emerging as an approach to precision oncology driven by advances in biomarker-defined window. Today, I would like to welcome Dr. Alex Spira, Director of the Thoracic and Phase I Program at the Virginia Cancer Specialists Research Institute, Chief Scientific Officer at NEXT Oncology, and Clinical Assistant Professor at Johns Hopkins, a leader in early-stage oncology drug development. Dr. Alex Spira will share his clinical perspective on the evolving evidence supporting WEE1 inhibition and the unmet need of cancer patients and the potential impact of this therapeutic approach on patient outcomes. Next, Kevin DeGeeter, Managing Director in Equity Research at Ladenburg Thalmann & Co. Inc..

Kevin DeGeeter will provide insights into the broader investment landscape industry interests, as well as the clinical and commercial milestones that could shape the future development of WEE1 inhibition. Also joining us is Dr. Eugene Kennedy, Chief Medical Advisor of Aprea Therapeutics. Dr. Eugene Kennedy will discuss the specific rationale behind WEE1 inhibition, the importance of biomarker-driven patient selection, and Aprea Therapeutics' approach to developing selective targeted therapies for patients with biomarker-defined cancers. Let's go ahead and get started by talking about the biology, why WEE1 and the DNA damage response truly matter. To set the stage, let's start with the underlying biology, what the DNA damage response is, and why WEE1 has emerged as a compelling target in precision oncology. Dr. Spira, let's start with you. In accessible terms, what is the DNA damage response, and why has it become an attractive source of targets in oncology?

Thanks, Solomon. The easiest way I find to think about this is it's the quality control system of a cell. So every time a cell divides, it has to copy its DNA accurately. If you think about it, even if it's 99.999% accurate, cells replicate hundreds and hundreds and thousands and millions of times a day. Cancer cells are doing it even more. So if there are errors or damage, the cell has to recognize that damage and change it. These are enzymes that are built in, these DNA repair enzymes. So it has to repair it before it continues. Cancer cells are interesting because they have a lot of what we call genomic instability. They're replicating very rapidly, they have inherent defects, and they accumulate DNA damage and replication stress as they grow rapidly. But they also develop ways to survive that stress.

In many cases, they become unusually dependent on these repair pathways. It is a therapeutic opportunity. If we can identify the pathways a particular cancer cell depends on and disrupts them, you can push the cancer cell beyond its ability to recover. Because the cancer cells are replicating far more rapidly than normal cells, you can use this as a therapeutic intervention to take care of the cancer cells but allow the normal cells to grow. We have seen this before, right? This is what PARP inhibitors are. There are other therapies as well, but that is the best example to extrapolate this DNA damage response. WEE1 is also an important part of that strategy. The challenge is not to damage the cancer cells.

It is to identify these biologic vulnerabilities that can exploit this therapeutic ratio where the cancer cells require more than normal cells, and they are more susceptible to it than normal cells.

Dr. Kennedy, let us turn to you. What role does WEE1 play in the DNA damage response, and what makes it a compelling target for cancer therapeutics?

Thanks, Solomon. As Dr. Spira just said, WEE1 is basically one of the edit checks on copying DNA when cells divide as Dr. Spira described, right? These edit checks are designed to make sure things go in a reliable fashion. But, as we just heard, these cancer cells are divided even faster and probably with a little less control than normal cells, primarily because they contain mutations, right? With modern genetic screening, we can look for mutations in these edit checks that exist, so it makes the cells vulnerable. Then if we come through with a drug, like a WEE1 inhibitor, that knocks out an additional edit check, that can tip the cell over from reproducing in a functional way to sort of having a catastrophic collapse and failure when it tries to reproduce, right?

Why is this one particular—and there's multiple of these edit checks you could go after—why do we find that WEE1 is compelling? We benefit from the experience of others, because people have already gone after WEE1 as an approach to fighting cancer cells. Other companies have made some progress in this area, and they've shown that by going after WEE1, you can actually fight cancers and get tumors to shrink.

The challenge thus far has been able to do it with enough of the safety window, this therapeutic window that Dr. Spira was mentioning. Can you make one that's big enough? Can you make the room between shrinking tumors and causing patients to become sick large enough that physicians can actually use this drug for their patients in a reliable and relatively easy fashion? We think it's a great target because we know if you hit it will work, and we think that we can actually work on the toxicity in the future.

Mr. DeGeeter, from a market perspective, why has the WEE1 class captured so much investor and industry attention over the past several years?

Next, let's have a discussion on where the need is the greatest, patients who have not responded to existing therapies. With that said, with that biology in mind, let's turn to the patients and where WEE1 inhibition may offer the greatest benefit. In cancer patients who have not responded to existing therapies, Dr. Spira, where do WEE1 inhibitors hold the greatest potential? Do you envision using WEE1 inhibitors to overcome antibody drug conjugate resistance?