Aprea Therapeutics Guggenheim 3rd Annual Healthcare Innovation Conference

analyst with Guggenheim, and I'm very pleased to welcome our next presenting company, Aprea Therapeutics, and with us today is Oren Gilad, President and CEO. Oren, thank you for joining us.

Thank you for the invitation.

All right. Maybe for those in the audience who might be newer to the story, could you give us a quick introduction to Aprea and your focus on synthetic lethality and the DNA damage response pathway?

Happy to do so. At Aprea, we can't wait to cure cancer, and we do it, as you said, by synthetic lethality, targeting the DNA damage and response pathway. Synthetic lethality, the concept of synthetic lethality is matching the drug with the disease. What it means is that cancer that have specific genetic mutation plus our drug should lead to cancer cell death. Normal cell that doesn't carry that mutation plus a drug should stay alive, and that genetic mutation is the biomarker that makes patient eligible for study.

Okay. Let's go through some of the key programs in your pipeline. Maybe starting with the WEE1 inhibitor, APR-1051. This is obviously a well-validated target, but there are some liabilities from the earlier generations, and you've designed the therapy from the ground up. Can you talk about the differentiation for 1051 from the class, and why do you think that it can widen the therapeutic window?

Yes, and that takes us back to when we first started the program. We did look at the other WEE1 inhibitors, and we identified liabilities associated with their molecule that makes the therapeutic index, therapeutic window very narrow. The two that we identified are, one is selectivity with the PLK families, and the second is the PK properties. What we did, we chemically worked very long and designed a molecule that is selective for WEE1, so still inhibiting WEE1, but not inhibiting as much any of the PLK1, two, or three families, and also having a very long and prolonged PK, so you don't have the Cmax-related tox, and it seems like we achieved both.

What kind of on-target, or I guess, toxes are you avoiding by being more selective for WEE1 as opposed to PLK1, for instance?

Eventually, we're probably going to see neutropenia. Neutropenia is probably on target, but it's the therapeutic window, right? Because when you co-inhibit WEE1 and PLK1, and we have it in our deck, we're showing that the PLK inhibition takes away from the WEE1 activity. You have to dose higher, and by dosing higher, you're introducing more toxicity. On top of it, when you have a short half-life and Cmax, then that's also associated with toxicity. You are widening the therapeutic window by allowing the APR-1051 to inhibit WEE1 more so than the other kinases.

Okay. Okay. WEE1 is relevant for the cyclin E-amplified therapeutic area, especially ovarian cancer, and there are others that are in this space. How do you see other updates in this field as impacting your therapy, or perhaps, where do you see 1051 fitting in?

I think that the increased interest in the WEE1 is benefit for the field and for Aprea. As, I mean, WEE1 has been clinically validated, right? You can shrink tumors by inhibiting WEE1, but the question is, can you do it in a safer way, right? Which patient population is going to respond the most to the therapy, and how do you optimize tolerability with efficacy? I believe that APR-1051 is positioned to answer these questions.

Okay. Maybe going to the clinical data. I think this past year, you showed some activity for 1051 in some heavily pretreated patients. Can you summarize the update from earlier this year, and what are the key takeaways that have left you more encouraged on the program?

Yeah, referring to ASCO was really, we laid out the foundation. We showed that APR-1051 has activity. We also showed for the first time the PK properties, and you see a nice long and prolonged PK profile with half-life of about 17 hours. We also showed nice tolerability. Patients are able to tolerate 1051 very nicely.

Okay. Then, I guess with the data you have on hand, how are you thinking about the dose selection as you look towards additional enrollment or later stages of development?

The program is subject to Project Optimus. The study is still ongoing, and we are going to follow the guide by the FDA and pick the two doses as we move on to the expansion.