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, 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.
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.
Okay. 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.
Yeah.
We will know, we should be able to know in the next quarter or two.
Okay. I know some of the responses that you showed so far have common patients with specific alterations.
What have you learned about how to identify which patients are the most likely to benefit from treatment?
We are still learning. We are still learning, and we are also going to enroll cyclin E overexpressing PROC. We are going to enroll 50, also USC, total of 50 for these two. We have FBXW7, we have colorectal cancer TP53. So we are still learning, and we are still dosing, and this phase of the development, we should have up to 100 patients, maybe even higher, and we are going to be focusing on the response here before we move to the expansion.
Okay. How do you think about, I guess, what threshold for responses would be considered to be encouraging?
If you have a drug that is showing a 30% ORR, then you have a drug, right? The benchmark has been pretty established. Ideally, you want to show activity and nice tolerability. That's what we'll be focusing on, 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. You're going to have an update at the upcoming Triple Meeting in Barcelona. 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 to expand on the safety. You'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 going to show PK from the higher doses. We're also going to share PD biomarker because we're taking a skin biopsy, so we're going to show a target engagement there for the study, for the ongoing phase I.
Okay. Maybe honing in on safety. What kind of, I guess, 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?
When you look at our first responders, we see disease stabilization. It started to see at 70 mg per day. The 150 mg showed the first PR and really did not have much tox associated with it. At the 220 mg, we had a confirmed PR, so we are going to also update on that patient as well. The widening of the therapeutic window is what is going to determine if this is a good drug or not.
Okay. At the upcoming meeting, how should we think about, I guess, the efficacy data? Will you have some or majority of patients with, sort of, two scans to get confirmed responses, and what is the read on durability that we might be able to see?
Yeah, because the patient being scanned every two months, and we just increased the number of sites, so we are not going to have lots of long-term data on these patients. We will have higher numbers. We will have data from the first scan. So we are going to show as much as we can up to the data cutoff.
Got it. Okay. Then taking a longer-term view about development strategy. 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? I mean, 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 going to 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 I dose escalation into more focused dose expansion. That's something that we will let the data drive the decision, because right now, we're mentioning PPP2R1A, FBXW7, USC, cyclin E, overexpressing PROC, which the IHC is going to come live soon. That's what we're not going to show. We're not going to have data to show on these patients yet, but they're going to get enrolled soon.
We are in the process of finalizing the agreement with one of the leading pharma that can carry that as companion diagnostic through registration. So we're going to shift from wide into more narrow, and hopefully then we're going to see durability and efficacy in this patient population. That also can be hopefully providing the path for accelerated approval.
Okay. Speaking of expansions, as you mentioned, you are expanding the trial in patients with uterine serous carcinoma and cyclin E expressing platinum-resistant ovarian cancer. 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 Zentalis is focusing on this specific patient population. There's definitely need for that, and you don't have to be the first new one in class in order to generate value for the asset. It should work there, and as I mentioned, we're going to start enrolling these patients soon based on the IHC that we are going to implement.
Okay. Can you remind me what's the target enrollment numbers for these indication expansions?
For the USC and the cyclin E overexpressing PROC, we're looking at minimum of 50 patients. Look at it as a midi phase II building within the phase I dose escalation, because by then we should know the response rate.
That's right. Okay. All right. Beyond, I guess, monotherapy, you're also adding some combo arms with standard of care therapies for head and neck cancer and colorectal cancer. 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. We have collaborating with a group at MD Anderson, and they did a lot of preclinical work showing that the combination of our WEE1 inhibitor, APR-1051, plus cisplatin in a model that is resistant to both is showing very strong synergy. 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. The patient, the PROC, USC, the PPP2R1A, FBXW7, they're going to stay on the monotherapy. It's the preclinical data and the data that is going to lead the decision of which one's going to be on combination, which patient going to be on combination, and which going to stay on monotherapy.
Okay. 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. 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. Enrollment has not been an issue for us. As I mentioned, the next phase of development, the expansion, is going to be more focused. After we identify the patient that likely to respond, they're going to be the one that we're going to be focusing on in the expansion.
Okay. 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 WEE1 inhibitor, both as a monotherapy and a biomarker-selected sort of segment, 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 sales is over $3 billion. WEE1 has a different mechanism of action. WEE1 can be worked as a monotherapy, but also in combination. 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 WEE1 is involved from G1 to S, from G2 to M, it can be combined with chemo, it can be combined with IO, it can be combined with ADCs for different patient population. The market is pretty large.
Okay. Then again, obviously a lot of steps to go along the way, but how quickly could you potentially think about approaching the FDA to talk about a registration study and initiating a trial?
We always have that in mind, right? If we can get accelerated approval based on the phase II, we will definitely go to the FDA and have a conversation with them about the registration.
Okay. Okay. So then beyond APR-1051, you also have a broader pipeline, including the ATR inhibitor, ATRN-119. Can you sort of remind us of the rationale for this target and the asset and sort of where you are in development?
Yeah. WEE1 is G1 to S, G2 to M. ATR is replication fork instability in S phase, and ATR was developed first. It is a macrocyclic 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, DNA-PK, the other PIKK families within the ATR. We did complete dose escalation. The activity was not as satisfying, so we shifted to a combination. There, what we are looking for, we are looking for, and we did make a statement on that, we publicly disclosed that we are looking for combination, and we are going to look for collaboration with academic institutions. Hopefully, this year we will announce one collaboration and the others that we are working on. We are putting some BD efforts towards finding collaboration for the ATR program, but it is going to be combination.
What kind of combinations are in focus?
Looking combination because combination with radiation, combination with chemotherapy, everything that cause the double-strand breaks or DNA damage, and then the ATR inhibition prevent the cell from correcting the damage. That is the synergy, that the synthetic lethality that we are looking for.
Okay. Okay. In the earlier pipeline as well, you have talked about revisiting the p53 program, for instance, as well as some other preclinical assets. I guess, can you discuss what is most in focus right now and how they fit into your broader pipeline strategy?
The DYRK1, that is preclinical. It is a novel target that we have developed based on data that we generated in our labs. That is still in lead optimization. The p53, that is the legacy of Aprea. It had a successful phase II, went to phase III, came short. What we are 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 are some PIs that are excited about it. That one, we just do some internal work to see how we can bring it back to the clinic.
Got it. Okay. Then maybe just pulling back at your entire pipeline, including APR-1051. What are the next major milestones that we could expect? Obviously, we have Triple coming out very soon, but looking into 2027 perhaps, what are the major inflection points that you would expect?
Yeah. The focus is the WEE1. That has been also the focus of our financing that we did at the end of March. The capital allocation goes to the WEE1. Between now and H1 of next year, we are going to complete the dose escalation. We are going to have the 50 patients that we mentioned, the USC, cyclin E overexpressing PROC. It is an open label, right? So we see the data as it comes. Inflection points are going to be looking for the safety, 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 the emergence of ADCs, how do you see a biomarker-selected strategy and this mechanism being positioned in that landscape as you look forward?
I'm cautiously optimistic. I think combination makes sense. I think that the patient can benefit from combination. I think as what we started with, that the growing interest in this indication, the growing interest in WEE1, should benefit a patient. I'm looking forward to a potential combination for that patient population.
Okay. Are there any, I guess, lateral updates from WEE1 competitors or cyclin E more broadly that you think would have implications for your development strategy in the next few months as well?
I mean, right now, we're waiting for Zentalis to come up with their data. The other companies that have WEE1, PKMYT1, dual inhibitors, we believe in selectivity. We spend a lot of time identifying a selective molecule as opposed to dual inhibitor. We did that with all of our programs, because if you want to combine, you want to find the ratio that combination works the best as opposed to have a fixed ratio that you don't have control over it. We're looking at the field, and good news is good news for everybody. But we'll see. I think Zentalis should come out with their data in Q1 of next year or first half of next year.
Okay. Maybe lastly, can you remind us of your current cash runway?
Q1 2028. 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. With that, we can-