GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - APREA THERAPEUTICS INC

So welcome everyone to this next session. My name is Paul Jang. I'm one of the biotech analysts 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. So maybe for those in the audience who might be newer to the story, could you give us a quick introduction to Apreia 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 targeting, by synthetic lethality, targeting the DNA damage and response pathway. And synthetic lethalty, the concept of synthetic letھality is matching the drug with the disease. So 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, so then let's go through some of the key programs in your pipeline. So maybe starting with the WE-1 inhibitor, APRO 1051. So 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 sort of widen the therapeutic window yes and that takes us back to when we first started the program so we did look at the other we want inhibitors and we identified liabilities associated with their molecule that makes it makes the therapeutic index typically window very narrow and the two that we identified are one is selectivity with the PLK families. And the second is the PK properties. So what we did, we chemically worked very long and designed a molecule that is selective for V1, so still inhibiting V1 but not inhibiting as much any of the PLK1, 2, or 3 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. So, what kind of on target, or I guess toxins are you avoiding by being more selective for V1 as opposed to PLK1 for instance? It's eventually we're probably going to see neutropenia so neutropinia is probably on target but it's the therapeutic window right because when you have when you co-inhibit V1 and PLK one and we have it in our deck we're showing that the PLK inhibition takes away from the V1 activity so you have to dose higher and by dosing higher you're introducing um more toxicity and then on top of it when you have a short half-life um and c-max then that's also associated with the with toxicity so you are widening the therapeutic window by allowing the the we are apr 1051 to inhibit v1 more so than the other kinases okay um okay and then so you know v1 is sort of relevant for the the cyclin e amplified sort of therapeutic area and especially ovarian cancer and there are others that are in this space so how do you see other updates in this field as impacting your therapy or perhaps um you know where do you See 1051 fitting in So, I think that the interest in the WI-1 is benefit for the field and for prayer. And as, I mean, WI 1 has been clinically validated, right? So, you can shrink tumors by inhibiting WI1. 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? And I believe that APR 1051 is positioned to answer these questions. Okay, so then maybe going to the clinical data, so I think this past year you showed some activity for 1051 in some heavily pre-treated patients. So can you sort of summarize the update from earlier this year, and what are the key takeaways that have left you more encouraged on the program? So yeah, so referring to ASCO, and ASCO was really, we laid out the foundation. We showed that APR1051 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. And we also showed nice tolerability. Patients are able to tolerate 1051 very nicely. Okay. Then, as 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 Optimist. 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. Okay. And I guess, what are the dose levels that you're sort of honing in on right now? It's hard to tell because it's still dose escalation, but we will know, we should be able to know in the next quarter or two. Okay. And then so I know some of the responses that you showed so far have common patients with specific alterations. So what have you learned about how to identify which patients are the most likely to benefit from treatment? We're still learning. We're learning and we're also going to enroll exactly in E overexpressing PROC, we're going enroll 50 also a usc total of 50 for these two um we have fbxw7 we have colorectal care vasp 53 so we're still learning and we're Still dosing and this phase of the development we should have up to 100 patients maybe even higher and that's when we're going to be focusing on the response here before we move to the expansion okay and how do you think about I guess what threshold for responses would be considered to be encouraging so you know if you have a drug that is showing a 30% or then you have a drug right so the benchmark has been pretty established ideally you want to show activity and nice tolerability and so that's what we'll be focusing on and and then identifying the patient that respond and get the most benefit and it's not showing side effects, I think that's what we're striving for. Okay. So then you're going to have an update at the upcoming triple meeting in Barcelona. So I guess without getting ahead of the data, what should we expect in terms of the update? I mean, the base is safety. We're going expand on the safety. We're going to see additional patients that are being enrolled. We increased the number of sites from three to nine, and we're getting more sites active and enrolling more patients. We're gonna show PK from the higher doses. We're also gonna share PD biomarker because we're taking a skin biopsy. So we're gonna target engagement there for the study, for the ongoing phase one. Okay. Maybe honing in on safety, so what kind of threshold for specific tox profiles such as neutropenia are you trying to stay within? Is there a range that you think is acceptable versus a little bit more challenging? So when you look at our first responders, we see the destabilization, it started to see at 70 per day. The 150 showed the first PR and really didn't have much talks associated with it. At the 220, we had a confirmed PR, so we're going to also update on that patient as well. So the widening of the therapeutic window is what's going to determine if this is a good drug or not. Okay. And then at the upcoming meeting, how should we think about, I guess, the efficacy data? Will you have some or majority patients with two scans to get confirmed responses? And what's the read on durability that we might be able to see? Yeah, because the patient's being scanned every two months, and we just increased the number of sites. So we're not going to have lots of long-term data on these patients. We will have higher numbers. We will not have data from the first scan. So we're going to show as much as we can up to the data cutoff. Got it. Okay. Then maybe taking a longer-term view about development strategy. So can you talk a little bit about the biomarker strategy that you're planning to implement and how that may or may not be refined as you continue to advance in the development? Yeah. Biomarker is the fundamental of what we do, right? It's something that patient, it's going to make or break the study. That's where we're going to see, hopefully, the activity. So we're gonna keep enrolling, and some of the patients are going to be moved to combination, some still on monotherapy. Our goal is to shift from a wide phase one dose escalation into more focused dose expansion. And, you know, that's something that we will be, let the data drive the decision because right now, you now, we're mentioning PPP2R1A, FBXW7, USC, cycling E, overexpressing PROC, which the IHC is going to come live soon. That's what we're now going to show. We're not going to have data to show on these patients yet, but they're going to get enrolled soon. process of finalizing the agreement with one of the leading pharma that can carry that as companion diagnostic through registration so we're gonna shift from wide into more narrow and hopefully then we're going to see durability and efficacy in this patient population that's also can be hopefully providing the path for accelerated approval okay um so then speaking Speaking of expansions, as you mentioned, you are expanding the trial in patients with uterine serous carcinoma and then cyclin E expressing platinum resistant ovarian cancer. So I guess first, what's the rationale for prioritizing these indications for expansion? Biology is the rationale. But if you look at historically Merck, AstraZeneca, and Zentalis, they're very reputable companies that have been spending lots of time, and then Zentalis is focusing on this specific patient population so there's definitely you know need for that and you don't have to be the first we want in class in order to generate value for the asset so it should work there and as I mentioned we're now we're going to start in running this patient soon based on the IHC that we are going to implement okay and can you remind me what's the target enrollment numbers for these indication expansions? For the USC and the 2nd E over-excessing PROC, we're looking at minimum of 50 patients. So look at it as the midi phase 2 building within the phase 1 dose escalation, because by then we should know the response rate. That's right, okay. All right, then beyond, I guess, monotherapy, you're also adding some combo arms with standard of care therapies for head and neck cancer and colorectal cancer so can you talk about the strategy here and how you're deciding which patients might be better served by monotherapy as opposed to combos yeah and we have collaborating with the group at MD Anderson and they did a lot of preclinical work showing that the combination of our we want inhibitor APR 1051 plus is platinum in the model that is resistant to both is showing very strong synergy so the biology is there and the patient that we're going to be putting on combination are these patients the patients that are resistant to both and the patients the Proct, USC, the PPP2R1AF, BXW7 they're going stay on the monotherapy so it's the preclinical data and the data is going to lead the decision of which one is going to be on combination, which patient is going to be on a combination, and which is going to stay on a monotherapy. OK. So then for the study, you've sort of expanded your site footprint recently to accelerate the enrollment. And I think you've mentioned completing dose escalation and backfill at some point next year. So how is the enrollment tracking? What does the path to the next phase of development look like? We're very happy with the enrollment At any given time, we have about eight patients in screening. We're calculating about one patient per site per month. So enrollment has not been an issue for us. And as I mentioned, the next phase of development, the expansion, is going to be more focused. After we identify the patient that's likely to respond, they're going to the one that we're going to be focusing on in the expansion okay so then maybe there's a lot of questions that still have to be answered obviously but how broadly do you think of the size of the total opportunity for a we one inhibitor both as a monotherapy and a biomarker selected sort of segments as well as perhaps in combinations across other tumor types if we look at PARP inhibitors right which is in our field. Olaparib on its own annual says it's over three billion dollars. WE-1 has a different mechanism of action. WE1 can be worked as a monotherapy but also a combination. So I think the market is pretty large that it should be but again it's going to be for the patient that would benefit from it But given the mechanism of action, given that V1 is involved from G1 to S, from G2 to M, it can be combined with chemo, it can been combined with IO, it can be combine with ADCs for different patient population. The market is pretty large. Okay. And then again, obviously a lot of steps to go along the way. But how quickly could you potentially, you know, think about approaching the FDA to talk about a registration study and initiating a trial? So we always have that in mind, right? And if we can get accelerated approval based on the phase two, we will definitely go to the FDA and have a conversation with them about the registration. Okay. So then beyond 1051, you also have a broader pipeline, including the ATR inhibitor, ATRN119. So can you sort of remind us of the rationale for this target and the asset and sort of where you are in development? Yeah. So, we want is G12S, G22M, ATR is replication fork instability in S phase, and ATR was developed first, it's a microcyclic ATR, similar story in the specificity, because with ATR we wanted to build a molecule that is specific for ATR and not also inhibiting ATM, mTOR, DNAPK, the other PIKK families within the ATR. So we did complete dose escalation. The activity was not as satisfying, so we shifted to a combination. So there, what we're looking for, we're looking for and we did make a statement on that, we publicly disclosed what we were looking for, combination, and we're going to look for collaboration with academic institutions. So hopefully, you know, this year we'll announce one collaboration and the others that we're working on. putting some BD efforts towards finding collaboration for the ATR program, but it's going to be combination. What kind of combinations are in focus? Looking combination because combination with radiation, combination with chemotherapy, everything that caused the double-strand breaks or DNA damage, and then the ATAR inhibition prevents the cell from correcting the damage. So that's the synergy, that the synthetic lethality that we're looking for. Okay. And then in the earlier pipeline as well, you've talked about revisiting the P53 program, for instance, as well as some other preclinical assets. So I guess, can you discuss what is most in focus right now and how they fit into your broader pipeline strategy? So the DERC one, that's preclinkal. It's a novel target that we have developed based on data that we generated in our labs. and that's still in lead optimization and the p53 that's the legacy of prayer it had a successful phase two went to phase three came short so what we're doing is that we are looking to identify patients that did benefit from this molecule because patients still reaching out to us looking for the drug there's some pis that are excited about it so that one and we just do some internal work to see how we can bring it back to the clinic okay and then maybe just pulling back at your entire pipeline including 1051 so what are the next major milestones that we could expect obviously we have triple coming out very soon but you know looking into 2027 perhaps what are the major inflection points that you would expect yeah so the focus is that the we won that's been also the focus of our financing that we did at the end of March the capital allocation goes to the we won between now and h1 of next year we're going to complete the dose escalation we're gonna have the 50 patients that we mentioned the USC talking the over expressing proc and so we should be and it's an open label right so we see the data as it comes inflection points are going to be looking for the safety and looking for activity and completion of the dose escalation portion of the study preparing for the expansion okay speaking of platinum resistant ovarian cancer just given the evolution of the space and sort of the emergence of ADC's how do you see a biomarker selected strategy and this mechanism being positioned in that landscape as you sort of look forward? I'm cautiously optimistic. I think combination makes sense. I think that the patient can benefit from combination and I think as we what we started with that the growing interest in this indication the growing interesting we won should benefit a patient so I'm looking forward to a potential combination for that patient population. Okay and are there any I guess lateral updates from we won competitors or in cycling e more broadly that you think would have implications for your development strategy in the next few months as well um i mean right now we're looking uh we're waiting for zentalis to come up with their data the other companies that have we want picking week one dual inhibitors we believe in selectivity we spend a lot of time identifying a selective molecule as opposed to do an inhibitor we did that with all of our programs because if you want to combine you want find the ratio that combination works the best as opposed to have a fixed ratio that we don't have control over it so we're looking at the field and good news is good news for everybody but we'll see I think zentai should come out with their data out in Q1 of next year or first half of next year. Okay and then maybe lastly can you remind us of your current cash runway? Q1 28. That's the cash runway and between now and then we're going to complete the dose escalation portion of the study so it's all baked into that. Okay fantastic. So I think with that we can wrap it up but thank you so much Oren for joining us and appreciate everyone anyone else tuning in. Thank you.