I'm Marc Frahm from the biotech team here at TD Cowen. I'm joined by my colleague, Tara Bancroft. We're really excited to have the next session here, a panel discussion of a handful of companies here on gynecologic cancers. We're really happy to be joined by CEO of Acrivon, Peter Blume-Jensen, Chief Medical Officer of Cullinan Oncology, Jeff Jones, Chief Medical Officer of Repare Therapeutics, Maria Koehler, CEO of Sutro, William Newell, and a return—well, a frequent guest in our prior lives at the conference, but now becoming a frequent guest, or hopefully becoming a frequent guest, as the CEO of Zentalis, Kim Blackwell. So welcome back again. So we're gonna start off the discussion with some general topics that hopefully cut across all of these companies and, and just kind of over the gynecologic cancer space and some of the issues they're all facing together. And then we will use the latter part of the discussion to dive into some specific company-specific questions, more of a round-robin fashion. But maybe to start off with, people have... Kim, if you wanna give kind of the treatment landscape in ovarian and endometrial cancers, kind of how it's changed in the recent years, and, and how does that change your ability to benchmark early results as you continue to get your, your, your data from different combinations or monotherapy? And we'll then we'll kind of pass this around the panel a bit. Sure. I guess you picked me 'cause I'm in the middle. But, so, you know, the treatment landscape for ovarian cancer has significantly changed, and this is kind of a fun fact, in a good way, I think, is that when many of us were working on the PARP inhibitors in 2010, 2012, platinum-resistant ovarian cancer was considered an orphan disease, meaning the prevalence affected less than 200,000 women in the United States. Today, it's estimated that platinum-resistant ovarian cancer prevalence would be about 340,000-350,000 women. So the treatment landscape has changed based on the need of women facing platinum-resistant ovarian cancer, and last year, we saw the approval of the ImmunoGen Elahere ADC, and I was really struck when Katie Moore on the ASCO podium said, basically, this is the first drug approved for platinum-resistant ovarian cancer in over a decade. So that was a long way of saying platinum-resistant ovarian cancer treatment landscape is changing because the need has significantly increased, in part because of earlier diagnosis, better management of these patients in the platinum-sensitive or earlier line setting. And I think that's given drug developers, including my own company, Zentalis, an opportunity to think very keenly about what is platinum-resistant ovarian cancer. What is the standard of care? Which right now, for one-third of patients, it's Elahere, but for the rest of them, it's simply been chemo in a patient population where the, the tumors have already progressed, having received multiple lines of active chemotherapy. So we're keenly intent on developing drugs for this space, including our lead asset, a WEE1 inhibitor known as azenosertib. Maria, you know, you're evaluating a handful of different combinations that have been run in the last, you know, year or two, but they, they have some of this evolving landscape happening, you know, as they're running. How are you addressing this in your, in your trials? So I agree with everything what Kim said. We are just looking a little differently at this, because platinum resistant is a very old term, as Kim said, like, long time. We are looking more from a biology-driven, division. Platinum resistant is because they got platinum, and then they are resistant, and eventually, they will get second platinum, and they will become resistant, and then this, this whole field is getting more muddy. So we are looking at, specifically isolating the, let's say, CCNE-amplified patients that we know have a very different prognosis. They have very different reaction to treatment. They do sometimes respond to platinum. However, they progress much faster. They do not respond to, PARP inhibitors as well. The field currently in ovarian cancer is going towards typing of the patients, hopefully more frequently, into the homologous recombination-deficient, homologous recombination proficient, and further to the BRCA and other. So how we are looking at it with our compounds is we are trying to prove that just like in lung cancer or breast cancer, Herceptin and EGFR, et cetera, when you have a drug for this specific subset, you can then position it regardless of the line of therapy. So I think we are looking forward to change the landscape in a different way. And, Peter, with you, you know, maybe you're more into Phase II and, you know, potentially kind of a somewhat seamless design towards registrational. You know, how has this kind of changing landscape been impacted in your discussions with the FDA? Well, our company is centered around our Acrivon Predictive Precision Proteomics platform. We have a phospho-proteomics platform that drives everything we are doing, and it has a number of deliverables, one of which is these drug-tailored patient responder identification tests. We have deployed one such for our lead asset, ACR-368, a CHK1, partial CHK2 inhibitor that's selective. ... and has proven single-agent activity towards a registrational intent trial for monotherapy. So we are kind of already buying into that whole concept that Kim and Maria so eloquently described, which is that there's a huge unmet need here, and we are moving more and more towards targeted therapies. I think there's actually space for a lot of different mechanisms, and we are just trying to really tailor our therapies and also identify the patients that are truly vulnerable to that CHK1, CHK2 inhibition we have in our lead asset. So I think it's just consistent with that and also with the developments generally in gynecologic cancers towards targeted therapies and more patient stratification, originally next-gen sequencing, and now with new approaches that are even higher resolution and more activity, functional based. So- Thanks. Bill, you're in a little bit of a different situation because you, yeah, you're kinda trying to more directly take on some of the drugs that are now launching, right? Just can you talk through some of the nuances there of you know, proving out the platform and how you do that, as you know, we're learning more about the drug as it launches. Absolutely. Thank you for having me here today. Our lead asset is a drug called Luvelta. It's a folate receptor alpha-targeted antibody drug conjugate. It goes after the same target that Elahere goes after. We know Elahere and folate receptor alpha are validated because of the approvals that they've received and the tremendous benefit that they've conferred on a third of the women who have platinum-resistant ovarian cancer. That's an important step forward, as we've already talked about here, for women with this terrible disease. The fact of the matter is, though, that about 75, 70% of women are not benefited by Elahere, and so there's a need for new therapies, and everyone up here is working to address new therapies for patients. For us, we've started our pivotal trial. The first part of it is thanks to Project Optimus, where we are closing in on finishing the last patients to help us select the dose. We actually think the two doses we're studying are both going to be robust registration doses, but Project Optimus requires us to do this little initial work. We'll talk more about Project Optimus and regulatory environment later on in this panel, by the way. But then the second piece of it is really a two-part study that allows us to go after an accelerated approval in an unmet need patient population. So to your question, if you are not of the highest expressor and eligible for Elahere, then you are an unmet patient, unmet need patient, and that's the patient group that we will look at. Through the earlier work that we've done, we've come to conclude that the tumor proportion score is the most appropriate benchmark for us to select our patients. A tumor proportion score is calculated using the same immunohistochemistry assay that ImmunoGen uses. Instead, though, of requiring intensity, we just count the number of cells that stain positive at all. Our data suggests that if you stain positive at a rate of 25% or higher, then you're going to have a reasonable chance of benefiting from our drug Luvelta. So what we'll be doing is looking at the unmet need population, but also in the same study, continuing on beyond the unmet need patient population, looking at PFS and OS, and ultimately having that opportunity for full approval both in the United States and Europe. So we're mindful of the patients who are being treated by Elahere, and they're frankly being treated predominantly in the United States today, because there are not that many studies going on with Elahere ex U.S., and it's certainly not on label ex U.S. or even reimbursed at that point. So we're going to do a global study. We are in the midst of it. We had 30 sites open in five countries at the end of last year, and we're gonna have 140. So we'll get the full range of patients, but we believe we have the opportunity to treat eight in 10 women who are platinum resistant, not just three in 10. Jeff, you are doing some work in ovarian, but also, you know, a little bit more prominent in endometrial right now. You can feel free to add something on the ovarian part of this discussion, but, you know, any nuances you'd kind of put out there more on the endometrial side and how to think about the evolving landscape there, where it's also changing with different drugs? Yeah, I'd say, you know, the most remarkable development in endometrial cancer has been identification of the really important role of PD-1, which I think is unique among most gynecologic malignancies. PD-1 initially approved as monotherapy in patients with mismatch repair deficient or MSI high disease, and then subsequently in combination with VEGF-TKIs in patients who were mismatch repair proficient. But the recent data in the frontline suggests that the broader group of patients, regardless of the molecular subtype, can benefit when PD-1 is added to traditional platinum doublet chemotherapy, where both a clinically and statistically significant improvement in progression-free survival has been identified. And we know just in the past two weeks that Merck has filed for a broad label in endometrial cancer. So that really opens up an entirely new, a new patient population with an evolving unmet need. So with patients expected to receive a PD-1-directed therapy as part of their initial episode of care, there's a huge unmet need for patients now entering into the second line, where prior, PD-1 or a PD-1 combination was their first best choice.... There's no data yet to suggest that retreatment with PD-1 or any PD-1 combination can salvage a patient who's failed PD-1 chemo in the frontline. And there, as Kim was suggesting in platinum-resistant ovarian, many patients now will receive single-agent chemotherapy with an expectation of no better than an overall response of about 15%. Unfortunately, durable for less than six months. So, I think there are still opportunities to address the patient population in post-PD-1, and as in many other malignancies, I think there is also great interest to understand whether PD-1 can be reutilized in subsequent lines of therapy in perhaps a novel combination. And at Cullinan, we're exploring both, our anti-MICA, MICB antibody, CLN-619, in patients both, after PD-1, prior treatment, as well as, in combination with PD-1 in a broader group of patients. And we look forward to sharing those results next year. Okay, so, you know, there are drugs like, like Bill mentioned, with Luvelta, that—you know what you're targeting and going after, and it satisfies that unmet need. But then there are other instances like, you know, gynecological cancers are unique because they have this maintenance setting. And I especially want to hear from Kim on this, considering your recent update. But how do you approach the choice between selecting an active line in disease versus the maintenance setting and why? Yeah, sure. So I'll start, just so we're all starting on the same page. I mean, my perspective is maintenance in the ovarian is not too dissimilar to adjuvant for many other solid tumors. So I think there's, that's a source of a little bit of confusion, where we use in the ovarian space, maintenance, but in every other disease, you've optimally surgerized, I think that's the word, the patient, removed as much tumor as possible, shrunk it as much with systemic therapy. It's basically the same thing as what we're trying to accomplish in the first-line maintenance setting. And as we've seen with many solid tumors, drugs that have monotherapy activity in heavily pretreated disease, where you're not having to layer it on top of multiple things and then try to tease out what's really helping the patient. When you see monotherapy activity, whether it be an ADC or a small molecule inhibitor, it makes a lot of sense to move it into an earlier line of setting because that is where patients derive the longest amount of benefit from drugs that work. So, you know, we've recently said, well, we saw monotherapy activity in a small phase I, heavily pretreated ovarian setting of 31%, confirmed objective response and a durability of over 6 months. It made a lot of sense as a drug developer and a company to say, if we're shrinking established, heavily pretreated tumors, that it would also benefit women who are in the potentially curable. Although in ovarian, that's a very small population in maintenance, unfortunately for these women. But to move the drug into an earlier line of setting with a clear standard to beat, which in HRP, which is patients who are really, for all practical purposes, no longer eligible for the benefits of maintenance PARP. These are the non-BRCA patients. You have drugs that work in the platinum resistant, moving them up as a monotherapy and layering it on top of a standard that's now almost 15 years old, single-agent bev, which is what we had 15 years ago. So layering drugs that are active in the heavily pretreated, layering it on top of a clear standard of care in what we'll call the adjuvant, I'm using air quotes, which is also known as the maintenance setting, makes a lot of sense in the ovarian cancer space. Okay. And, Bill, since I called you out, it's not to say that it was an easy decision to go with the target population that you did, but how would you approach this kind of decision-making process? Yeah, it's interesting. That decision was really made about four years ago, right? Yeah. Yeah. Yeah. When you start your journey to treat patients, you have a sense of what the current landscape is and maybe a vision of what it's gonna be by the time you get to the end of the road, and of course, the landscape almost always changes. I think, for us, it's important to be able to demonstrate a robust single-agent activity over chemotherapy so that we do have a broad label. We thought, though, as to the future of Luvelta, and we really do agree that the future of Luvelta is going earlier line as well. And so we've done a study where we combined Luvelta with bevacizumab and reported out that data. And what we find is, irrespective of folate receptor alpha status, you can get a 35% response rate, using Luvelta in combination with bevacizumab. If you actually—and that's all comers, regardless of expression level. If you look at patients who express greater than 25% or greater tumor proportion score of the antigen, that number goes to 50%. So what we're hoping we're gonna be able to do, as we broaden out this study and get more patients enrolled in it, what we're hoping we're gonna be able to do is say: "We don't actually need to test in the future for folate receptor alpha status, and you can move to earlier lines of therapy and combine with bevacizumab." And that would be, I think, a game-changer in terms of broadening out the opportunity for women to benefit at earlier stages of their disease progression. ... We're getting. Looks like you wanna comment on this. I was gonna say, like, you wanna say something. Well, you know, I think that the maintenance setting, because this is the main question, is a very interesting setting, and as Kim said, it's like adjuvant treatment. What we learned—I worked in breast cancer for a very long time. What we learned is that to get the adjuvant therapy or to get the maintenance, the drugs need to be planned for very long time, which is a good thing, but they also need to be extremely safe. Because even for Arimidex in adjuvant setting, that is supposed to be given for five years, the women are discontinuing after two years because of some bone pain, et cetera. People, because they know that the tumor is sort of not there, because you are just maintaining something, it's very different psychology than treating patients with an active tumor. So the safety for maintenance or the safety for adjuvant is of paramount experience, and this is what the PARPs learned as well, because, you know, you do maintain this PARP, but this continuation rate is amazing. But it is definitely a fantastic strategy for positioning a drug, especially a drug that you cannot use in just as you are doing in treatment setting, because you have to combine with something or with chemo, which you can or cannot combine. So the alternative strategy to having chemo is to have what we have is the same response rate that we demonstrated with our combination. However, the safety is dramatically improved and does not have the chemotherapy-like toxicity or does not have the myelotoxicity or diarrhea, et cetera. Our toxicity is limited to anemia, that we are now trying to decrease substantially. I think that the patients in 2024 want a specific and safe treatment. That's our rule of choosing drugs for development. Just with your drug, a bit more of a, you know, as an IO mechanism, and it obviously hasn't been done so much in this exact setting, but in general, those drugs have really shown in the more adjuvant-like settings. Just how are you approaching this as you kind of think out longer-term planning? Yeah, I mean, as a, as a small company early in the development of a novel mechanism of action, I'd say, many of the endpoints that are relevant for maintenance and adjuvant, clinical trials that are time to event, progression-free survival, overall survival endpoints, are not the ones that are generally, most practical for initial development. As Kim was suggesting, I think we are still at a point where we are very interested to identify drugs that have robust monotherapy activity, and then looking quickly for ways to move them up to either add to or replace existing components of combination regimens. Earlier in lines of therapy, either as part of an induction regimen or as maintenance, as ways of improving outcomes, because we know leading with your best in oncology has always resulted in better outcomes. There's been talk from the time I was training, but we need to save something for relapse, and most of the accumulated data suggests that leading with your best usually results in the best outcomes for patients. So I think for us, we're still looking for opportunities to identify patient populations and/or combinations in which the activity is sufficiently robust to merit further development. And I'll go back to you know, another point that's made. You know, I ultimately think most patients are indifferent to the mechanism of action. They're interested in drugs that work and that allow them to maintain their health. And so whether it's as part of primary treatment regimen or in maintenance in particular, drugs with modest side effect profiles are the ones that are most amenable for longer-term administration, particularly in the maintenance setting. I think that's something that we'll hope to eventually show for our drug azenosertib, but still early days for us. Peter, we will change topic a little bit to selection strategies, since that's really kind of the core of the company, right? It is. Okay, how do you approach this, and what do you view as kind of best practices as you develop an ideal patient selection strategy? Well, it has to be very science-based. It has to be mechanism of action driven, and you need to have robust blinded data to show that it works in simple scientific terms. In our case, we are trying to take a very differentiated approach, trying to overcome the limitations we've seen for a lot of very effective drug target classes, like cell cycle inhibitors and DNA damage response pathway inhibitors, that at least some of us are focused on here. And trying to kind of identify the individual patient context, where you have sensitivity. And in developing that, we are not taking the approach that is used with genetics or transcriptomics or even proteomics. We're not looking at-... train-test approaches and looking at correlation, we are taking a functional mechanism-based approach, where we then, after generating, an OncoSignature, which is functionally orthogonal biomarkers that combined inform about the sensitivity to a drug, we can actually do prospective studies to validate it. And that enable us to share that confidential data with FDA and get clearance for our approach, which is a novel approach. But you have to be completely rigorous with your scientific approach to that and really include also pass the species barrier and also include human tissues when human cancer tissues, when available. I did wanna mention just a comment on the earlier discussion, because I do think it's interesting. I totally agree with moving up to more treatment-naive tumors when you can and get your mechanism a better chance to work in a more treatment-naive patient. But also, again, mechanism of action is also important there. And especially for DDR inhibitors, you can argue that it's a balance with DNA damage as well, you know, that they often work better when you're more need for DNA repair, which is often in more heavily pretreated tumors. And I think it's always good to move up front when you can, and that's a tendency. And confirmatory trials, which are now required more and more in for accelerated approvals, obviously, drivers there. But PARP inhibitors, they are pulling out of data lines despite kind of some ADEs, right? But I think, as a community working towards better treatments for cancer patients, I think, there's so much opportunity where we see more and more niched approaches, and that leans into that whole patient stratification method. I think that's just where it's moving forward for everything we are doing. Yeah. Can I go back to something that that Maria and Kim were talking about before that I thought was interesting? So it should be a relatively easy concept, but the way that you referred to it made me think that we should probably touch on it. How do you define platinum-resistant versus platinum-sensitive? And can a drug that works in resistant also work in sensitive? Kim, first. So, to take your second question? Yeah. Yes. So we use single-agent paclitaxel in the platinum-resistant setting, but we also use it in combination with carboplatin in the platinum-sensitive setting. And, you know, a lot of women are receiving single-agent paclitaxel. This is off real-world data sets, like as their last treatment prior to death, and they still respond to it. So I'm 100% in agreement that it, it is an archaic term that was created out of necessity in order to design trials for large cooperative groups long before precision medicine was on the scene. So I applaud everyone on this panel because we're all taking it, what I call an enrichment strategy, which is: Are these patients that really will benefit from our drug, as opposed to you've gotten 12 cycles of paclitaxel and carboplatin, and your cancer came back more quickly without any attention to burden of disease, prior responses? I could go on and on forever. We do need to bring precision medicine into the ovarian cancer space. So I think we're all trying to strike that balance as leaders of companies, figuring out how we enrich for the patient population and at the same time straddling our PIs, our investigators, and the regulatory kind of oversight as to how drugs have been historically developed. And so I don't know you-- I know- Yeah. You've been in this space for a long time, too. Yeah. So I have basically nothing to add. I think that this is an archaic concept. We are trying to-- So what we are doing now is we are opening a trial, in everybody gets platinum carboplatin, because that's the first-line treatment. And then some patients have decrease in CA-125, and some don't. Most do. Those who don't are very suspicious for platinum resistance, and these patients get then rucaparib, which is the agent that will hopefully take care of the CCNE amplification. So this is a surrogate, and we are going to get the proof of concept in a very early line, because if we believe that the CCNE amplified patients in first line are there, should they really get platinum if they are platinum resistant? And when do you identify the patients with platinum resistant, you really have to do it early. And the optimal scenario would be to screen everybody with NGS, but that's not going to happen. So we have to use some sort of surrogates. And all this, well, just like Kim said, all these divisions of platinum resistance or even in lung cancer, adenocarcinoma versus non-adenocarcinoma, squamous versus non-squamous, all these are very archaic terms. And we are using them because we have no other choice, and it is easy for our investigators. But really, what should happen eventually, that everybody should get either DNA or protein testing up front, but this is like distant future, but this is where it all should go if we really progress in precision oncology. And FDA will be very happy with that because it'll be easy ask for them. So if I could add a couple of other thoughts in addition. I think, there is no question that if patients who are platinum resistant respond, then platinum-sensitive patients will respond. Yeah. We certainly see that. ... in the patient populations, because we did earlier studies that had mixed with platinum sensitive and platinum resistant. I think the real challenge, and you've alluded to it, but I want to be firm on it, is the regulatory environment is not where we are from a scientific environment as yet. It's very clear that FDA is not as forward-thinking in terms of their regulatory strategy as many of the companies up here on this panel are in terms of how best to treat patients. It's a sad reality, and so, you know, the challenge will be not only to prove that your drug works in the setting that you're studied it in, but persuading FDA to change their archaic thinking about how disease is classified. They're even going backwards. I touched a little bit more earlier on accelerated approval, and that used to be a pathway that was easily available to smaller companies because you could establish that you actually have an approvable agent with a small single-arm patient study, and then use that data set not only to get accelerated approval, but also start a confirmatory trial, which is going to be many more patients and it is much more expensive. That regulatory standard has now changed, and it is not going back. You have to have your confirmatory study ongoing and almost fully enrolled in order to be eligible to receive an accelerated approval. That is not friendly to the development of novel agents for cancer patients, and let's just be plain about that. We were forced to do a two-trial study with one trial, where the first set of patients that we will be selecting will file for accelerated approval on, and that same study continues to allow us to have, in effect, a confirmatory trial with a larger patient set, so that we satisfy the FDA requirements for accelerated approval. That is a much more expensive trial for us to do than the original strategy would have been. And so the challenge here is not only developing the drug, but bringing the regulators along with you in this journey, and they're not as friendly as they have been. So how will you collectively change their minds? Well, I'll- Is it possible? I'll start. Yeah. You develop drugs that work- Yeah ... and have a highly favorable therapeutic index. I actually remain a little bit more optimistic about regulatory interactions. If you have a drug that has a clear population that meets a certain bar, and you're aggressive about your confirmatory study that compares your drug with the standard of care, I think that that still remains a very valid pathway. And I'll leave my comments at that. Again, I think everyone on this panel is developing drugs that we want to have the highest therapeutic index, and if you do that, there is still a path towards single arm with a confirmatory study, as long as you know exactly what patients derive the highest amount of benefit from your drug. I'd agree, and I think it does depend on somewhat on different therapeutic areas and diseases. But I think drugs that have a clear therapeutic index, where they have very significant clinical benefit that differentiates them from existing drugs in the class, either on the basis of efficacy or ideally both efficacy and safety, there's still a very clear path forward, and the accelerated approval mechanism is very relevant. I think outside of the specific disease areas we're speaking about, there are drugs that have been approved under accelerated approval that have shown to potentially have detriment with respect to overall survival when moved up into earlier phase or late-phase clinical trials in frontline settings, where you lack for competing risk of death, mortality from the malignancy itself. So I think while the accelerated approval mechanism has its, you know, newer challenges and there is greater rigor, I think that, in some instances, that's resulted in benefit for patients. We can think of drug classes, like PI3K, for instance, that have been removed because confirmatory trials all demonstrated, a clear and clearly unfavorable risk-benefit for patients. Whereas if you had looked only at single-arm trials utilized for accelerated approval, you never would have seen that. So I think it's important, you know, I think it does require, some advanced planning, and I do think that it does require us, you know, to make, good development decisions very early in the course of our, of our planning. Peter, Bill brought up Project Optimus earlier, but just the OCE is always launching new projects, every year, and often they're around for a couple of years. I'm not keeping track of them all. Yeah. They're hard to keep track. And often they're around... It turns out they're like Project Optimus had actually been technically around for a couple years- Yeah before the investment community realized that it existed. Any that you would highlighted, you know, that are have been around for a little bit or are being launched that you, that you think are particularly impactful, and we should be watching out for, for this space? Yeah, I would say, I mean, Optimus itself is important in the context of accelerated approvals, I think because part of it is obviously that the rigor, I think it was the FDA, is that right? The Omnibus Reform Act, that kind of introduced this, more rigorous approach to accelerated approvals, December 2022. And since then, there's been this demand for confirmatory trial timelines and post-accelerated approval trial designs, et cetera, and often started before the accelerated approvals. And I think RP2D is very important in that context because it is obviously related to the therapeutic index, and different drug classes have different benefits. So the benefit risk is always an important thing. It's always worth remembering that the IO therapies can be deadly, right? They are lethal. They can cause autoimmune storms. They can kill people, but the benefit completely outweighs that. Other compounds that don't have the same durability maybe have a more narrow tolerability to use. So I think the therapeutic index is so important in the context of all these. The different OCE programs, I think there's the equity access, I think is extremely important in lung cancers. race, ethnicities, and age, and so forth, socioeconomic status, all these programs are important. So we have the community representation. When we are going into more stratified approaches, we need to make sure that it's still benefiting as many people as possible. But I think in general, I would say there's a lot of center of excellence efforts that all, I think, are geared towards trying to streamline our development and bring therapies to the market, and that it's dynamic. The rigor of that will continuously, I think, increase over time because we have more and more treatment options. So- And- In particular, I wanna emphasize and, There is a project, Project FrontRunner, which also is going for a few years, which we suggest to choose the appropriate line of therapy where you develop it. So let's say, just like Kim said, was the idea to go as much in front as possible because it helps the patient the most. Then there is this project, Project Silver, which is for inclusion of all the people. Then there is the project called RTOR, something I forgot, where FDA is trying to help companies to provide earlier the safety and efficacy data before the entire NDA is submitted, to speed up the approval outside of the accelerated approval if a drug eventually is important. So I do believe that FDA is—there is a couple of other projects, but FDA is trying to help the companies and actually has specific projects for small biotechs and all the academic incubators that is trying to do pre-IND or IND in academic setting, etc. I see FDA not to be sort of. But I do see FDA as an extremely helpful body to help. And if you talk to them early enough, and if you talk to them frequently enough, especially in the context of Fast Track designation, I think they are helpful. Great. Any other projects that anybody on the panel would highlight or? There is Project Catalyst as well. Project Precision. Yeah. There are many projects. Yeah. Okay. Maybe we'll move into company-specific questions now, and so that we're not accused of picking favorites. We'll go alphabetical by company. I think in the middle. So, Peter, Acrivon, it starts me off, but so you get to go first. First, you touched on it a little bit in some of your answers to the prior, but you want to kind of just for the people who are maybe not as familiar with Acrivon, describe the AP3 platform and kind of and what that's enabled you to do. And, as you finish that up, you can kind of lay out the trial that you're running now. Yeah, it's a computational science-driven, phosphoproteomics-based platform with two integrated underlying technology pillars, mass spectrometry-based phosphoproteomics, and then an automated, quantitative, multiplex biomarker platform, which has a number of deliverables and it includes uncovering of resistance mechanisms, and identify indications prior to clinical trial therapy start, trial start. We have also just developed a new molecule, a development candidate, which aims for clinical monotherapy development, where we can use it for biological assay. Or basically, the underlying technology enables you to measure the drug-induced effects on the activity state of signaling pathways in any normal cell, disease cell. We have started focusing on oncology, but obviously the platform is broadly applicable outside, especially where you don't have genetic alterations, autoimmune, metabolic. So it's a new approach where it's new science coming in, but science we've known for many, many years, signal transduction-based, but just with a level of resolution and quantitation that is at a whole different level. So it's machine learning enabled, and it's necessary to interpret these things. The actionability is very, very big. In our case, we generate a massive amount of data set every 12 days. We have around 50 million quantitative data points for compounds to profile, and we can use that to optimize them. If you can imagine, you have a high-resolution picture of the effects of any compound on signaling network inside a cell. You can also appreciate that you can match that with what's driving a disease cell, because you can compare that with normal cells, and that's really the foundation of this approach. We've turned it actionable, and we have now seven proven deliverables, which include some of those I said, and we were proud to receive a clearance for registrational intent trial, have received Fast Track designations, and also Breakthrough Device designations for our OncoSignature Test. This is coming together now in a nice approach. But the company is completely centered around that ACR-368, our checkpoint two inhibitor in license from Eli Lilly, is our first asset, and now we have a dual WEE1 partial PKMYT1 inhibitor that's very, very selective and very, very single agent active, so. What kind of lay out the trial design for 368, and you're expecting to report some data later this year. Yeah. Just kind of lay out the size of that data update. Yeah. So, we have in past trials that Lilly sponsored, they demonstrated single agent activity in platinum-resistant ovarian cancer. We used our approach to identify new indications and predicted that endometrial and bladder would be sensitive as well, and we have confirmed that in some early initial soft reads, that's indeed the case. So what we're doing is there's around 30% of patients that are positive for that biomarker. We called it OncoSignature with the three biomarkers that predict monotherapy sensitivity. And we have turned that into a registrational intent this time, a two-stage trial. And we have the remaining patients are treated with ultra-low dose of gemcitabine. We are talking about 1% of standard dose, not half or quarter. It's very, very low dose, so it has no activity on its own, but it sensitizes to ACR-368, we predict in a proportion of patients. So we are reporting more mature data on this data for this first half of this year. Both the Phase IIb registrational intent and the Phase Ib/2 exploratory combination with ultra-low dose and in all three indications. And it will be data-driven. It'll depend on. We have a lot of images coming on CT scans over the next two months, so a lot of these will be added to that. So we'll be completely data-driven as we've been so far. I will switch to Jeff real quickly. You, you brought the lead, the lead that's relevant to this panel, asset of yours, the MICA, the antibody. Just can you review the mechanism there? Because I, I think people are maybe not super familiar with that mechanism- Sure. and also the design of it. I think what distinguishes the 619 mechanism is much the focus of cancer immunotherapy has been around the activity of solely T cell immune-directed responses, antigen presentation requiring mechanisms of action. What's unique about the mechanism of CLN-619 is that the target of the antibody, which is a regular Fc-competent monoclonal antibody, are MICA and MICB, which are stress-induced ligands that are upregulated in almost all malignancies, if you look. And by upregulation, they allow cells to be recognized by immune destruction, both innate and adaptive immune system cells. But proteolytic mechanisms in the tumor microenvironment cause MICA and MICB to be shed, and as a consequence, the tumors evade immune surveillance. The antibody, CLN-619, binds near the site of proteolytic cleavage and promotes stabilization of MICA and MICB on the cell surface, by which MICA and MICB can now reengage with NKG2D on both NK and T cells. And because the antibody is Fc-competent, ADCC and ADCP are both important parts of the mechanism of action, and we've recently shown in some of our translational work that the antibody is indeed doing what we expect it to do, and that is increasing the expression of MICA and MICB in patients who are treated with the antibody. We'll keep going down the line. Maria, a few months ago, you showed some lunresertib data, actually at a meeting down the street. And then, do you want to kind of highlight the takeaways from that data? And then there's going to be several combo updates over the next few months. Just kind of what are you trying to prove to demonstrate there, and what's the goal to have that program in the next few months? Lunresertib is a first-in-class PKMYT1 inhibitor that is selective for PKMYT1, and the role of PKMYT1 is related to the cell cycle and specifically activation of the CDK1 pathway. The data that we presented showed that the monotherapy PKMYT1 inhibition is causing definite tumor activity. However, the efficacy in the tumor is moderate. So, we understand very well why, because to phosphorylate to activate the CDK1 you need to have both tyrosine 15 and tyrosine 14 phosphorylated, change phosphorylation, and the CDK tyrosine 14 is coming from the PKMYT1. However, WEE1 is causing the effect on tyrosine 15. So one of the mechanism is for, for the eventual mitosis problem that we all want for, for the tumor cells, we need to have affected both the 14 and 15. There is an alternative pathway, and this is what we are evaluating with the Debio 0123. There is an alternative pathway that we are looking into for the ATR, where there is a redundant pathway via CDC25, where you really have to inhibit the ATR-driven pathway to help the CDK1. So we are, in the combination with lunresertib and camonsertib, we showed that while the efficacy of lunresertib alone is moderate, we had like 7% response rate. In actually endometrial carcinosarcoma, there was a responder long term. When you combine the ATR with PKMYT1, suddenly the response rate rises in the RP 2D to 50%-60%. So the and the ATR is used at half of the dose. So there is definitely a proof of the preclinical data that we generated, that the synergy for the impact is operative in clinic. So what we are doing now is we are progressing the development or the further testing in gynecological malignancies of the lunresertib and camonsertib. We are doing the expansion. And we started the collaboration with Debiopharm that has a very specific WEE1 inhibitor. And people will know very well how important it is to inhibit both PKMYT1 and WEE1, but we need to decide which opportunity is better and for which tumor between the camonsertib, which definitely already proved the efficacy, but there is no yet proof of the efficacy of PKMYT1 inhibition and WEE1, which we'll start this trial immediately. Okay, we'll do Bill next. So can you first start by talking about how the cell-free platform improves upon traditional ADCs? Because that is going to help set the stage for talking about the ReFRaME trial and expectations for the interim data. Thanks. Sutro has a cell-free protein synthesis technology. We take the machinery inside the cell that is utilized for in vitro transcription and translation, and we harvest it from the cell, and then we do a biochemical synthesis reaction to create the antibody of interest. And in our case, because we have a proprietary way of inserting a very reactive, non-natural amino acid that is ideally suited for click chemistry, we can place that non-natural amino acid anywhere we want in an antibody. So we've created drugs that have a drug antibody ratio of 2, 4, 8, and pre-clinically, 12 and 16 using this technology. We make an antibody in less than 24 hours, so we're able to actually do structure-activity relationship on many different forms of a molecule that you might want to advance. For Luvelta, we chose folate receptor alpha as the target because we were following on the heels of some work that ImmunoGen had done, and we thought this was a very robust target for women with ovarian cancer. We thought that the molecule, though, could be optimized. Older ways of making antibody drug conjugates created heterogeneous mixtures, meaning that the drug to antibody ratio was an average. It was around 3.5-4. If it was lower than that, the drug was probably not potent enough. If it was higher than that, there were all sorts of problems making the molecule and keeping it robust as a, as a therapeutic agent. Nonetheless, there was a theory that controlled heterogeneity was going to be fine from a regulatory standpoint and would benefit patients. In fact, Elahere is a molecule that is a hetero- that is a mixture. It's not a homogeneous molecule. The next generation molecule is designed to be more homogeneous. Our theory was that if you could compete homogeneous molecules, you could identify the single best species. So we looked at multiple points of attachment, we looked at multiple drug antibody ratios, we looked at different linkers, and we looked at different warheads. We have tubulin inhibitors, we have exatecan class warheads. Our future drugs largely will have exatecan class warheads on it. So STRO-003 and STRO-004, which are outside the bounds of this panel, have an exatecan warhead and a beta-glucuronidase linker. So we're able to actually tease out how to optimize the molecule pre-clinically to give it the maximum chance of success once it enters the clinic, and the payloads have evolved through the time as well. So from that standpoint, we think we're able to identify pre-clinically a molecule that can have a broader therapeutic window, which I agree is quite important for patients, and therefore... And also have a greater opportunity for success in treating women with late-stage ovarian cancer. Luvelta also, by the way, treats endometrial cancer patients. We presented last year data that suggests that if you have a tumor proportion score greater than 25%, late-line endometrial cancer patients, you can actually have a response rate around 30%. This drug also works in a very rare form of pediatric AML called the RAM phenotype. That data has been presented at ASH, and we're going to be starting a non-small cell lung cancer study for patients who express folate receptor alpha as well. So that's kind of an overview on the platform, but it's if you get the molecule right, it can go from ovarian to endometrial, to AML, and hopefully to non-small cell lung cancer, because the target is there, and you've got the optimized molecule to affect patients even who have lower expression levels of the target. ... Kim, last but not least. Yeah, starting with a Z. So first of all, thanks to Maria for outlining kind of the role of PKMYT1 in driving, in particular, the S to M, controlling that checkpoint. And so I think she did a nice job of highlighting the importance of PKMYT1. WEE1 is a related protein discovered 50 years ago this year, so we also think that's a good sign for us as a company. We're developing a highly specific WEE1 inhibitor known as azenosertib. And unlike PKMYT1, we believe that there are multiple points in the cell cycle that WEE1 inhibition removes the stops and drives proliferation, lessening those cancer cells' ability to repair its own DNA. And so, the drug dephosphorylates both CDK1, which is important for the G2/M phase, but it also dephosphorylates CDK2, which is important for the G1 to S phase checkpoint. And so in the simplest of terms, the reason we believe we see such monotherapy single agent activity is because of the effects on multiple points in the cell cycle, driving proliferation, leading to mitotic catastrophe. That's what WEE1 inhibition has done. And so last year, we reported a 31% confirmed objective response rate. As I mentioned earlier, in platinum-resistant ovarian cancer, the drug has activity in a subset of endometrial cancer known as uterine serous carcinoma. We've reported a 50% monotherapy response rate. So our company is laser-focused on getting this drug to patients facing PRO in a study known as DENALI. We've committed to an NDA off an accelerated approval in 2026. We also have what we believe will serve as a registrational trial in uterine serous carcinoma to read out in the second half of 2025. Both of those studies are monotherapy, and then this year, we will be presenting two monotherapy datasets in platinum-resistant ovarian cancer. One off of our Phase I, very large study, heavily pretreated, platinum-resistant ovarian cancer and other tumor types in the second half of this year. And then we have everyone had a PARP inhibitor and progressed platinum-resistant ovarian cancer trial known as MAMMOTH, that will read out later this year. Looking at the drug in combination with both the PARP inhibitor, niraparib, but also as a monotherapy. We have a lot going on in the monotherapy azenosertib space, and particularly laser-focused on how do we deliver this drug to women facing platinum-resistant ovarian cancer. We talked a lot about precision medicine, so I have to throw this little plug in. We are also following a number of enrichment strategies, the first of which is cyclin E-defined tumors. I think most people know, whether you're looking at CDK2, or you're looking at what Repare is doing, or what you're looking at Zentalis is doing, cyclin E-driven or defined tumors are here to stay. When you talk to the ovarian cancer experts, they clearly say, "We knew cyclin E predicted poor outcomes of chemotherapy five, 10 years ago." We are utilizing that, and our trials are specifically designed to look at cyclin E-driven ovarian cancer and how those patients and those tumors benefit from the use of monotherapy WEE1 inhibitor. So we're very excited about the data readouts to come over the next 12-18 months. We are getting close to running up on time, and we wanna get the opportunity just real quick. Jeff, everybody else laid out the next data update. Jeff, I don't think you quite did that on CLN-619, so I wanna make sure you're able to. Yeah, sure. I just make two points. So, what I described before was a very generic mechanism of action, and one of the questions we're always asked is, based on our initial data presentation last year at ASCO, we saw a relatively high number of patients with gynecologic malignancies, ovarian, cervical, and endometrial, responding to what is a broadly applicable mechanism of action through preclinical supposition. And I think as we've explored further, we've come to understand that MICA and MICB are under pretty tight control by estrogen. It's not too surprising then, some of the places we've seen activity. And there's also a clear increase in expression by both mRNA and cell surface expression across a number of gynecologic tumors, both the tumors end in normal physiology. Going back to the point about targets, and modality, for us, presence of the target is important, but so is the appropriate tumor microenvironment. In the case of endometrial cancer, where we have initiated disease-specific expansion last year around the time of ASCO, we understand that there are unique uterine NK cells that are very important parts of both malignant and normal physiology, important parts of maintenance of pregnancy, as well as regulating the menstrual cycle. So that we would have seen activity in endometrial cancer is not surprising, but we are currently conducting expansion, both with monotherapy and in combination with PD-1, and hope to share initial or plan to share initial observations from disease-specific expansion in the first half of 2025. Okay. Thank you. Unfortunately, the clock actually off slightly, so we're unfortunately out of time. So we have to cut it off there, but thanks for the-