Presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the Nuvectis website following the conclusion of the event. I'd now like to turn the call over to Ron Bentsur, Chairman and Chief Executive Officer of Nuvectis Pharma. Please go ahead, Ron. Thank you very much, Tara, and thank you all for tuning in. We really appreciate your time this morning. And I particularly wanna thank the KOLs who are with us today. The tech team, I need slide control, please. Thank you. So, with us, and by the way, I can probably take up the entire time of the call today just to talk about the credentials of the KOLs that are on this call, but obviously I need to be a little bit more succinct. So, in a nutshell, we have three world-renowned KOLs, each in his respective field. So, the first one to speak will be Dr. Bradley Monk, who's at the University of Arizona in Scottsdale. He's one of the leaders, co-director of the GOG. The GOG is probably the world's most important consortium when it comes to women's oncology. They've been involved in, you know, all the key studies that we can think of that have occurred in ovarian and cervical over the last few years. So, Dr. Monk will be talking about, you know, give an overview of the treatment paradigm in ovarian cancer, and, you know, give a perspective on the drugs that are out there and the unmet medical needs, et cetera. Second to speak will be Dr. Ramez Eskander at the University of San Diego, also a top clinician in the area of women's oncology. Dr. Eskander will talk about the unmet medical need in ovarian and also about NXP800 and how that can potentially play a role in this setting. Third to speak will be Dr. Gordon Mills from University of Oregon Health and Science University. Dr. Mills is a top expert in the area of translational science as well as genomics in oncology. And again, we're very pleased to have all three of these individuals speaking today. And of course, after the scripted part, we'll open it up for Q&A. There will be clearly some forward-looking statements made today, so I do encourage anyone who's interested in the Nuvectis story to read our public disclosures, our public press releases, including the risk factor section, which appeared in the 2022 10-K, which came out a few months ago. So again, I do encourage folks to read that. And I'll provide a very brief update on Nuvectis before handing over the baton to the experts. So for many of you who may not be familiar to the story, Nuvectis is focused on precision medicine for unmet medical needs in oncology. The lead compound is NXP800, for which we have obtained a Fast Track designation for the first key indication that is out of the gate, as part of the phase Ib program, and that is platinum-resistant ARID1A-mutated ovarian cancer, which is comprised almost entirely of patients that have ovarian clear cell carcinoma or ovarian endometrioid carcinoma that also bear the ARID1A mutation. The phase Ib, certainly this portion of the phase Ib is being done in collaboration with the GOG consortium, which I talked about, and also the European group, ENGOT, which is kind of the GOG equivalent in, on the other side of the pond. We also have Orphan Drug designation obtained for NXP800 for a different indication called cholangiocarcinoma, which is cancer of the bile duct. The phase Ia dose escalation has been completed, and we started the phase Ib recently. The second compound that we have is NXP900. This is the compound that actually started the phase Ia dose escalation study yesterday. We announced it yesterday. This is a compound with which we're targeting the Src kinase family, including perhaps the main culprit within the Src kinase family, which is a kinase called YES1. In terms of the management team, many of you have known us for a number of years. We've been involved in several companies, and our track record I think is a fairly good one. We've gotten three drugs approved for four different indications in the U.S. over the last eight or nine years at three different companies that we're involved with. And on top of that, we're able to obtain ex-U.S. approvals, European, Japanese, and so on. So a little bit of housekeeping on the company, we do have cash runway into the first half of 2025. Again, this is just a snapshot of the companies that we're involved with, Keryx, UroGen, and Stemline. Over the last decade or so, I was CEO of both Keryx and UroGen, a long-standing board member of Stemline. Enrique and Shay, the co-founding partners of mine at Nuvectis, worked extensively with me at Keryx and then... Became heads of clinical and regulatory at Stemline. And up above, you see the drugs that were approved. So Auryxia was the Keryx drug, JELMYTO was UroGen, and Ozanimod was the Stemline drug that was approved. And I think what's important to mention is that JELMYTO and Ozanimod were both for unmet medical needs in oncology. So we are fairly well-versed in terms of, you know, moving the ball down the field and eventually getting drugs approved for unmet medical needs in oncology. This is a quick description of the pipeline of-- with respect to where we are now. So NXP800, which by the way, in terms of the mechanism of action, is a GCN2 kinase activator, and that'll be talked more about in the presentation to come. So the compound completed the phase Ia dose escalation. It's currently in the phase Ib, where we're starting to look not just for safety and tolerability, but also for efficacy. And the first indication out of the gate is platinum-resistant ARID1A mutated ovarian, which, as I mentioned before, is comprised almost entirely of ovarian clear cell and ovarian endometrioid. And again, just to make sure people understand that it's being done in collaboration with these two very important consortiums, GOG and ENGOT. NXP900 also a very exciting compound, and we started the phase Ia dose escalation for that compound yesterday. So, you know, obviously, that's gonna start marching forward as well. So again, just to rehash, some key highlights, we're at a point where we've got two clinical stage precision medicine oncology assets. I think that's a fairly enviable position to be in. We do expect the initial preliminary data readout from the phase Ib that is ongoing now for NXP800, the lead compound in the first quarter of 2024. That'll be on a subset of patients from the phase Ib study. And of course, over the next three months or so, we hope to add additional target indications as part of the phase Ib framework. So things like cholangiocarcinoma, endometrioid, those are the kinds of things that we have in mind. You can see the designations that we've been able to obtain. I spoke about that a minute ago, but again, just to repeat, Fast Track designation has been obtained for the lead indication, which is platinum-resistant ARID1A mutated ovarian cancer. And we also have Orphan Drug designation obtained for cholangiocarcinoma. There have been a number of preclinical meetings and presentations that have occurred, and there are gonna be more in the upcoming conferences that occur in October. So stay tuned for that. And this is kind of the overall market potential when you think about the ARID1A mutation across a variety of tumor types. And of course, the big vision for a company, for a compound such as NXP800, is to be able to obtain a tumor-agnostic type of an approval. Obviously, that would be very nice to be able to achieve. And here you can see some of the patient numbers that we're talking about with respect to the potential target indications. Moving on to the next slide. So again, just a quick snapshot of NXP900. So NXP900 is a very potent and specific inhibitor of the Src kinase family, which also includes the YES1 kinase. And we're starting to focus more and more on cancers of squamous cell origin. We think that mechanistically, and obviously, based on the preclinical data that we have so far, it makes a lot of sense. So we're starting to definitely gravitate towards that area, and that will be described in more detail. What's interesting about NXP900, again, without stealing the thunder from, the upcoming presentations, is that, it's highly selective, unlike the other, multi-kinase, Src, multi-kinase inhibitors that also inhibit Src, that are out there, drugs like dasatinib and dasatinib, which have a whole host of systemic, side effects, largely due to their promiscuous, profile. So this drug, NXP900, is highly specific and rationally designed from the get-go, from day one, to be specific. That was the purpose of designing the compound, to try to create kind of a pure, Src inhibitor. And also, we believe that there is a mechanistic rationale that could play out very favorably in favor of NXP900, and that is the fact that NXP900 is able to shut down both the scaffolding and the catalytic domains of the Src kinase and basically to generate a complete shutdown of the kinase. We've seen a lot of preclinical data that's been generated. There's gonna be more to come. This is a very exciting program that is moving forward, and the phase I-A started, so this is officially clinical stage right now. And the market opportunity for NXP900 is also fairly sizable when you think of all the different angles to that NXP900 can help attack. You can see cancers of squamous cell origin, some of the numbers there. And also as it relates to the Hippo pathway, which is also of particular interest for us, as we're developing NXP900. One can think about, cancers with, the NF2, mutation, and you can see the prevalences, within those different realms. Again, you know, very nice, niche opportunities there as well. And, finally, just to rehash some of the housekeeping. So we finished the first quarter—the second quarter, I'm sorry, with $24.5 million of cash. We expect to finish the second quarter with about $22 million of cash. So we run a very tight ship. The average, quarterly, burn rate is between $3 million-$3.5 million-ish, something like that. The stock is fairly tightly held by the insiders and the greater than 5% shareholders. You can see about two-thirds of the stock is held by the three cofounders, as well as some of the top shareholders. And in terms of the research coverage, there are three banks that cover us right now, HC Wainwright, Ladenburg, and Roth. You can see the names of the analysts, and I'm sure you're familiar with some of the names. With that, I'll turn it over to Dr. Monk. So again, thank you very much for attending and for taking the time, and Dr. Monk, with no further ado, thank you. Thank you, Ron. Good morning. Good to be with my friends, and I think I know many of you. I'm here in Phoenix, and yes, it's still hot, but hopefully not for long. I'd like to talk to you, though, about ovarian cancer. We've been busy, and quite frankly, I'd like to give you a report of what we're doing. These are my declarations of interest, as well as the Nuvectis team today. So I think many of you know, and it was mentioned, Ron, thank you, we have a nonprofit organization called the GOG Foundation. And the GOG Foundation is not only within GOG Partners, which I co-direct, but it also is part of NRG Oncology. NRG Oncology is funded by the NCI. Dr. Eskander and I are here, are gonna talk about GOG Partners. It's basically funded by pharma, or we fund our own studies because we think that we should reinvest the, the money that, we're a part of. Let's see if I can figure out the... That's great. This is a paper that we wrote two years ago about who we are. I refer you to it. I'm the first author. Dr. Eskander, who's in San Diego, is here. But this sort of explains why and how we do what we do, but this is the what. Okay, so I think you're all familiar that we have informed the standard of care across all tumor types. Ron, you said ovary and cervix. I'd like to report that we received endometrial cancer approval of frontline immune therapy on July 31st. Both first line, both recurrent, all three cancers. Nuvectis has said, "Brad, will you list all of the approvals that you've received through the GOG?" I said, "No, because the font would be too small." We're not always right, we don't always win, but we absolutely hate to lose, and I wouldn't be with you today if I didn't have confidence in this platform, and in this molecule, and in this indication. I'm happy to report that the incidence of ovarian cancer is falling. We're identifying women at risk, we're doing risk-reducing surgery, and so it's falling. But the prevalence, the number of women that are fighting it, is 8-12x higher. And why is that? It's because of the accomplishments that the team has done with partnerships, such as Nuvectis, to bring medicines to the clinic. So there are fewer cases initially, incidence, but there are more women fighting it, prevalence, and that's founded on the success of the medicines that we're developing as a group. So, I think all of you know that ovarian cancer is a heterogeneous entity. We have the most common high-grade serous carcinoma, and that would be where PARP inhibitors are in the clinic. Low-grade serous, I think you're familiar, we work with Verastem, with a FAK and a RAF/MEK inhibitor. We're here today to talk about clear cell and endometrioid tumors. These frequently have an endometriosis as a precursor. They are different entities, and we haven't gotten Orphan Drug indication yet for this with the FDA, but we will. The FDA is still learning, I'm still learning, too, that these are really separate diseases with separate genetic makeups. Really, opportunities to do drug discovery. So on the right here, you see a common thread between clear cell and endometrioid tumors. I mentioned on the left that high-grade serous tumors is really BRCA and p53, and I also mentioned low-grade serous is RAF, RAS, MEK/ERK. So, mucinous tumors are so rare that we probably cannot do discovery, but we can definitely do clear cell and endometrioid studies, and that's what we're doing. So what percentage of ovarian cancer patients are clear cell and endometrioid? Well, it's ethnically related. In the Asian populations, it's more than twice what it is in the Caucasian population. In the U.S., which is not just Caucasian, I get it, it's about 1/3. And what percentage of those patients have an ARID1A mutation? It's as high as 2/3, I would say 50%-60%. So it's a substantial proportion of patients. We know who they are, and we know what they do. And what happens is they do not respond to chemotherapy the way the more common high-grade serous prototypes. So that's why we're here this morning. We've made a lot of discovery in the first-line management of ovarian cancer, and we're proud of it, and that's what this shows. But this is really high-grade serous. This is really PARP, okay? This is really bevacizumab, and quite frankly, really irrelevant to what we're here to talk about. So don't get distracted by our prior accomplishments with anti-angiogenics bevacizumab, which you know is Avastin, or the PARP inhibitors. We have three now approved in ovarian cancer. This is different, and this is talking about platinum-sensitive or platinum-resistant ovarian cancer. We generally bring medications to the clinic that are in platinum-resistant. That's because the bar, quite frankly, is lower and the need is higher, and we partition those patients, as I already said, into histology, molecular signature, and number of chemotherapy regimens. This trial that we're running with NXP800 is 1 to 3 priors. PROC, platinum-resistant recurrent ovarian cancer, was undefeated, undefeated for a decade. We had got bevacizumab approved in 2014. You can see that bevacizumab was added to chemotherapy. It is the standard, and you can see on the, on the left that there is improvement in progression-free survival, small improvement in overall survival, and an improvement in overall response rate. That's why the FDA says you have to have prior bevacizumab in these sorts of trials. So, and they're looking at that, you know, SORAYA from ImmunoGen, all those patients were bevacizumab pre-treated. It didn't translate into the label, but I don't want you to look at this AURELIA 2014 FDA approval and say, "Well, we have to beat this metric." We don't. We have to beat a lower metric, which I'll show you on the next slide. But I want to remind you that we're experienced here, and the Nuvectis team also has experience in utilizing the key programs in the FDA to improve the timeline, particularly accelerated approval, priority review, fast track, which they already have, and breakthrough. And we're good at breakthrough therapy designation. I mentioned Verastem. We have breakthrough therapy in a rare tumor, low-grade serous, and we're working feverishly to get that here. These would be the really the accelerated approval metrics, and you can see you know in the one to three priors, it's very low, and that's what we are trying to fix. We're trying to beat these historical or synthetic controls, and we've done it many times. We've gotten accelerated approval through the GOG many times, okay? And so we're not always right, but we hate to lose, and we're very proud. I'm sorry for the font, but we're very proud of our most recent accelerated approval in ovarian cancer, which happened on November 14th for mirvetuximab. And so although PROC or platinum-resistant recurrent ovarian cancer is undefeated, we broke through, and we're gonna break through again. And we broke through here with a response rate of 31%, which to the FDA's mind, was better than the 10%-15% that I showed you, which was the historical benchmark. Big accomplishment, biomarker-driven, okay? And that's what we're doing here. Same number of lines of therapy, one to three priors, biomarker-driven, folate receptor alpha, as you know, is about 35%. This is higher, but it also is histology restricted, so in the end, it's about the same positivity rate. This is what we got, a 31% response rate, even some complete responders, and we're confident that we're gonna be successful in clear cell ARID1A and endometrioid as well, recurrent ovarian cancer. The dose optimization here and getting the right dose is important. I wanna applaud the Nuvectis team for studying two doses early on. There's nothing worse than showing an effective dose, but not being the right dose, and you hear me talk about that. Initially, we're studying 50 and 75 in a 22-patient cohort to get the right dose. And if both are active, obviously, at least three responders, we'll look at the totality of the data, which includes PK, and safety, and then we'll have the dose going forward, ultimately, hopefully, adding to Breakthrough Therapy designation accelerated approval with a confirmatory trial. I get it that it's a rare tumor. I get it. I get it that rare tumors are uncommon. I get it that the natural history has been poorly understood, although it's now becoming better understood, but we can study rare tumors, okay, in these networks, such as the GOG, which I'm proud to be a part of, and come visit when it cools off. I'm here in Scottsdale, Arizona. We have two medical schools here, the University of Arizona and Creighton, and my hospital system is HonorHealth, and it's good to be with you this morning. Thank you. Take it away, Ramez. Good seeing you. Ramez and I work together on a daily basis, and one of the smartest guys I know. And it's, you know, I don't know how you measure achievement, but his, you know, last New England Journal paper was on March 27th. That's pretty good. He is first author. Go ahead, Ramez. Take it away. Thank you. Thank Thank you for the kind introduction, my friend. It's a pleasure to see you all this morning. Thank you for taking the time. I will try to be efficient. There will be some content where there's a little bit of overlap, so we'll go over that a bit more quickly. But of course, we would like to ensure that we are approaching this to emerge from this conversation understanding the relevance of both the opportunity and the clear cell ovarian and endometrioid ovarian space, but also the relevance of this drug and the opportunity in patient population. My declaration of interests are shown above, for all of you and, of course, for the Nuvectis team. So ovarian cancer, as alluded to by Dr. Monk, is a heterogeneous disease, and you can see here, if we look at the molecular makeup of clear cell and endometrioid histologies, we can see that the drivers of these malignancies are independent and not overlapping with high-grade serous, low-grade serous, and mucinous histologies. And that's particularly relevant because historically, we used to lump all of these histopathologies together, and we would indiscriminately enroll these patients onto trials, examine therapeutic agents, and many times see ineffective results. But we've gone away from that as our understanding of the disease has evolved. And I will say that if you look at the prior studies that have informed treatment in ovarian cancer that were alluded to by Dr. Monk in his presentation, GOG 218, only 2.9% of the accrued patients on that trial had clear cell histology. Importantly, those were not central pathology reviewed, so one could argue that it may be even less than that. In the Aurelia trial, which has really established our, quote-unquote, “platinum-resistant,” backbone per se, of chemo and bev, you can see that 2% were clear cell histology. It's really unclear to any of us whether these therapeutic interventions are effective in a meaningful way in a clear cell ovarian cancer population, because those patients actually were not selected for meaningful interpretation on those trials. Many of our contemporary trials in the ovarian cancer space exclude clear cell histology because of the concern about identifying an effective opportunity for those patients. We know overall in the United States, ovarian clear cell carcinomas account for about 10% of epithelial ovarian cancers. As Dr. Monk alluded to higher prevalence in the Asian population, nearly a third or a quarter of those patients have clear cell carcinoma of the ovary. It's a distinct biology. It's a distinct clinical behavior. Patients tend to be younger at age of diagnosis, which has an impact, of course, on the outcomes of these malignancies in these patients' lives, and it can be associated with endometriosis in about 25%-50% of cases. These are endometriosis-associated carcinomas. Unfortunately, the prognosis is quite poor when patients are diagnosed at advanced stage or develop recurrent disease. The median overall survival is 10 months. 10 months, which of course highlights the unmet medical need in this space, and it was what fuels us to continue to want to work with companies like Nuvectis in identifying novel and effective treatment strategies, which are dearly required in these patient cohorts. Now, ARID1A has emerged as a very appealing target in the clear cell space, as well as in the endometrioid ovarian cancer space. Why? Because of this premise of synthetic lethality. Some of us recall the conversations about PARP inhibitors and efficacy of PARP inhibitors in BRCA-mutated patients because of the premise of synthetic lethality. It's a similar paradigm here. The NXP800 activates the kinase GCN2. GCN2 normally phosphorylates eIF2 alpha and inhibits translation, and then you get a vulnerability of ARID1A-mutated tumors because they're increasingly dependent on ARID1A to facilitate translation, so it drives cell death. So the mechanism of action is rational. It is capitalizing on a molecular aberration to drive a synthetically lethal response in these patient cohorts. Now, just briefly, I want to mention that there has been an attempt to, for effective drug discovery in multiple arenas in the ovarian clear cell space and to some degree, in the high-grade endometrioid space. Anti-angiogenic therapy was examined. If you look at GOG protocol 254, this is before the evolution of, GOG Partners. This was a phase II trial of sunitinib, and I just want to highlight, if you look at the progression-free curve here, nearly all of the patients, all of the patients came off at first assessment, 80% at progression, median PFS of 2.7 months, highlighting the fact that, again, we need to do better. If you look at the ENGOT-OV36 trial, which looked at nintedanib, an alternate multi-TKI with anti-angiogenic effects, again, median progression-free survival of 2.3 months, with an objective response rate of 2%. So highlighting, once again, the unmet need. You may ask, but Ramez, there's been a lot of noise around the therapeutic efficacy of immunotherapy in ovarian clear cell carcinomas. And so I've highlighted some of our trials looking at immunotherapeutic strategies in ovarian cancer. Some of these trials enrolled clear cell cohorts. They were not statistically designed whatsoever to answer the, a question in a clear cell population, but in the forest plots, they pull out the clear cell patients with a suggestion that those clear cell patients may derive a greater benefit to immunotherapeutic strategies. But I will caution you to say that we don't know what the molecular characterization is of these responders, and we clearly know that there is a proportion of clear cell patients, 5%, maybe 10%, that have mismatch repair deficiency or high tumor mutational burden that could drive these responses. So although there is potentially an immunotherapy signal, until we understand and clarify the molecular characterization of these tumors, we may be incorrectly assuming there's efficacy across the board, when in reality, this is limited to the mismatch repair deficient or TMB-high cohorts. You can see here the PEACOCK and the Innova results presented at ESMO 2022. Again, clinical trials looking at opportunities for immunotherapeutic approaches to try to improve response in these clear cell patients, but molecular characterization was not adjudicated. BICR was not confirmed in these patients, and this was not a blinded, not a randomized study. Central path review wasn't required. And again, it's sometimes difficult for pathologists to define the disease, and an expert GYN pathologist is required to confirm clear cell histology, and what's unique about the responders was never really informed. There was additional randomized trial of immunotherapy, immune checkpoint inhibition in ovarian clear cell carcinoma called the MOCHA trial. The median progression-free survival of durvalumab, quite modest, seven weeks, median PFS of 14 weeks with physician's choice chemotherapy, failing to improve outcomes again and highlighting the need to do better. NRG-GY016 was an NCI-funded trial looking at pembrolizumab plus epacadostat, and again, it was trying to use this combinatorial approach to enhance immune checkpoint response via IDO1 inhibition. Of course, we know in other solid tumors that IDO1 inhibition has not shown to be promising. Nonetheless, this trial did accrue. The primary endpoint was a 21% objective response rate. Similar limitations to the prior studies. Again, only 64% had MMR status known. Were these the responders or not is unclear. Were these confirmed responses? There was no BICR, and there's no central path review once again. I will say that the reason I also wanted to highlight these studies is many times there's a concern, well, clear cell ovarian carcinoma is a small cohort of patients. Is this a feasible study to accrue? Every one of these studies exceeded accrual estimates and closed earlier than anticipated, clearly indicating that there are plenty of patients with recurrent clear cell ovarian cancer who are eligible for treatment and need effective therapeutic strategies. So what do we know? We know we need a better understanding of the molecular microenvironment of these malignancies. ARID1A has emerged as a therapeutic target, and hopefully, with evolution of drug development, Nuvectis's compound NXP800, we can capitalize and take advantage of this with a synthetically lethal approach. Distinguish between prognostic and predictive biomarkers is critical across all of these studies because we have not done a good job of that. I will also say here, this was an adaptation of what we use in endometrial cancer to the ovarian clear cell space. 70%, nearly 70%, had ARID1A mutations, so it is a very common molecular aberration in ovarian clear cell patients, and the majority of these patients were what we call copy number low or no specific molecular subgroup from the ProMisE algorithm. Again, additional studies highlight the frequency of this molecular aberration. We understand that this exists, and we believe that this is a therapeutically targetable molecular change, and that's why we're so excited about this clinical trial and this drug. I will pivot briefly. Endometrioid histology ovarian cancers, about 10%, sometimes up to 15% of epithelial ovarian cancers, but the majority of these are actually low grade. A smaller percentage are high grade, grade 3 endometrioid ovarian cancers. Treatment recommendations for grade 2 or 3 are analogous to high-grade serous ovarian cancer, and that's because of the thought of, the molecular drivers may overlap, particularly driven by p53 mutations. But we also know that ARID1A loss in endometrioid ovarian carcinomas is associated with a very poor clinical prognosis, and ARID1A loss has been identified in the TP53 mutated population, again, highlighting compromised, prognosis. And this was a study that was in Nature Communications in 2022, really looking specifically at endometrioid ovarian carcinomas to try to inform future treatment strategies. So I know that was a lot of information packaged into a relatively short time. Of course, eager to answer any questions anybody has, and I thank you so much for giving me the time to talk about these diseases. Next up, Dr. Mills, will speak. Dr. Mills, are you, are you there? I am. Great. Okay, I'm going to move a little further back in the drug development program and talk about NXP900 and why this is a very exciting agent to take forward to the clinic. And the first is that, and I will detail this, is that it has novel characteristics that were mentioned earlier, that make this different from other potential Src YES1 inhibitors, and excitingly, the phase I trial has just opened. This is really a summary figure of the aspects of where this particular inhibitor fits, and it's clear that Src and YES1, and actually the whole Src family, integrate signaling from multiple cell surface signaling modules, making that a very important target. Src is a well-validated therapeutic target, as are other members of the family. However, we've not been able to inhibit it effectively. It's important to remember a key comment that was made earlier on, that Src functions both as a scaffold and as a kinase, and that inhibition of one or the other of those functions is insufficient to block the major activity of Src. And then, studies by this group and by ours and others, have shown that the Src family converges on another critically important family pathway, called the Hippo pathway, one which we've played a major job in characterizing members of the pathway. Okay, next slide. There we go. I do want to note my potential conflict of interest. It's important that you have these to look at in terms of potential. And I've noted the Nuvectis's potential conflicts in detail here. Now, this particular slide talks about one of the key advantages of NXP900 over other Src family inhibitors. This is a dendrogram of the kinase family, looking at targets on the left-hand side for NXP900 and on the right-hand side for dasatinib. Dasatinib is used clinically as a Src family inhibitor, but you'll note it's probably easier to list the kinases that are not inhibited by dasatinib than those that are. In contrast, when you look at NXP900, there is this cluster on the left-hand side that is inhibited efficiently by NXP900, and that is the Src family of kinases, and relatively little off-target activity, which has a great potential to decrease the toxicity of this compound. The second major advantage of NXP900 is that it blocks both the catalytic and scaffolding activities of Src. Critically, it does that by locking Src in an inactive conformation. The other inhibitors of Src are catalytic domain inhibitors that trap Src in an open, active conformation, where the scaffolding activity of Src is actually increased by the inhibitors. The SH3 domain can bring in YAP of the Hippo pathway, other signaling pathways. In contrast, NXP900 binds to Src and Src family members in an inactive conformation, and ensures that the scaffolding agents at the SH3 and SH2 domains are trapped and unavailable for binding to other compounds. So you have both activities here, inhibiting the catalytic activity and blocking the scaffolding activity of Src family members. This is just one example of the inhibiting activity of NXP900 on Src catalytic activity. This is data on the left-hand side in vitro, and what you can see, compared to three other inhibitors of Src, that the target here, phospho Y416, is inhibited by NXP900 very efficiently at very low doses. So this is an indication of efficacy and potency. And on the right-hand side, you see the data in vivo, where you have dasatinib causing a modest decrease. You can see the brown color here, compared to vehicle. In contrast, NXP900 completely removes the brown color, meaning it has blocked the phosphorylation of the phospho-Src moiety. And these were 24 hours after treatment, suggesting that this is both efficient and rapid. Now, one of the intriguing observations that came up when a study of NXP900 was done across many different cell lines was that components of the Hippo Pathway, that I mentioned earlier, were markers of sensitivity to NXP900. If you look on the left-hand side, you can see a series of cell lines, and this is looking at mutations in different genes. You can see that one of the key markers here in red is NF2, which is a top key mediator of the Hippo pathway, and so it was a highly significant association with sensitivity to NXP900. On the right-hand side, you can see that a number of intriguing compounds came up. Those in green are actually members of the Hippo pathway, and the key one down at the bottom is YAP, the mediator of Hippo, that I will show you in a moment. And then in looking at correlation with phosphorylation, which is how the Src and the Hippo pathway function, you can see that phosphorylated YAP, the key mediator of the Hippo pathway, was a marker of sensitivity to NXP900, and that actually, I believe, is using our phosphorylation analysis from reverse-phase protein arrays. Now, why move this forward? So I'm going to show you some data that has been published on the Hippo pathway, and on the left-hand side, you will see data on the Hippo pathway in squamous cancers. The right-hand side is that same map that I showed you earlier, with Src being at the top of the Hippo pathway, or YES1 specifically at the top of the Hippo pathway. And YAP, which is a target of YES, as is TAZ, are aberrant in a very significant portion of highly common squamous carcinomas: cervix, lung, head and neck, bladder, and others. And this suggests that there is a major opportunity for targeting the Hippo pathway in squamous cancers. And if you look at the bottom, you will see, with the blue and red line, in all of those cancers, those patients with abnormalities in the pathway, the red line, do more poorly in terms of outcome, indicating that the Hippo pathway is a driver of the behavior of those tumors, and that the likelihood of efficacy of targeting that pathway is high. And indeed, multiple companies have attempted to develop and target the Hippo pathway, so far unsuccessfully. Now, I do want to note in the right-hand side that the opportunities extend beyond squamous tumors. Actually, in the initial presentation, you heard evidence that the target for YES1 and the Hippo pathway could be important in kidney cancer. And this is clear cell kidney, again, showing with the red line, that if you have an abnormality in that pathway, you do poorly. The same thing on the right-hand side. If you have an abnormality in melanoma, you do poorly, and these are our data from reverse-phase protein arrays. And then in the middle, an emerging and very important cancer, liver cancer. If you have a signature of Hippo pathway activation, you do extremely poorly in a disease that individuals do poorly overall. So the opportunity to target this pathway is actually quite broad across multiple different malignancies.... Now, does this really target YES1 and Src? So one of the key components of the Hippo pathway is that YAP and TAZ need to translocate into the nucleus, where they can activate a specific transcription factor called TEAD, T-E-A-D. And if they stay in the cytosol, they're essentially inactive. So YAP and TAZ are key executioners of the pathway. As I mentioned earlier, genetic aberrations are clearly common and lead to a poor outcome. The YES-Src kinases, as we showed earlier, regulate tumor growth, and this is an unmet need. But I think the important observation here, and it's a little hard to see on these projections, is that you have samples with low or high nuclear YAP. If you treat with NXP900, you markedly decrease the nuclear localization of YAP, suggesting that indeed, YAP is a target of the NXP900 inhibitory effect on Src and YES. Now, does this translate into activity in vivo? If you look here at the question of squamous cell cancers, a broad series of cell lines on the left-hand side, we look at sensitivity of those that are non-squamous. There is activity of the inhibitor, but it's modest. In contrast, those squamous cancer cell lines on the right-hand side are extremely sensitive. If we look at the esophageal cancer and head and neck cancer, two clear examples of squamous cancers where there is a major need, these are cells that have abnormalities with YES on the esophageal cancer and head and neck in the Hippo pathway. What you can see here is, strikingly, not only do you get growth inhibition, but you get regression of the tumors in both models that is maintained over time, and this is really one of the key components of moving a drug forward.. If you have a decrease in growth rate, that is still progressive disease that you would see in the clinic. Regression is what we need to look for if we're going to have a PR or CR in our patients. So if we look at the key movement of NXP900 to the clinic, and this is something that I recommend to all companies, and particularly small companies that are starting the process, is that we are unlikely to have a curative effect or even a major prolonged effect of monotherapy in clinical trials. And indeed, with advanced disease, as you heard earlier, we're going to need combination therapies that make sense and are specific to the tumors that we are targeting. I mentioned earlier that non-small cell lung cancer has a high frequency of abnormality of, of abnormalities in the pathway, and there is a squamous variety. Same thing in terms of colorectal cancer. And if you look on the left-hand side, here are evidence that tumors with resistance to EGFR inhibitors, osimertinib, are resensitized with the NXP900. You can see with the red curve on the left and the green and blue curves on the right of those, you incredibly change the resistance moiety to a sensitive moiety. And so the idea of one potential combination is identified here. And then the second, if we look at the combination with enzalutamide in tumors that are resistant to enzalutamide, you can once again see with two different measurements. The first one of those is just a decrease in luciferase, where you have high levels of blue in the control, and they're gone in the treated animals. Then on the right-hand side, the effect on growth measured by the luciferase activity. We really do have two major activities in non-small cell lung cancer and in prostate cancer. These could be combinations to take forward after the initial phase I studies are completed. Now, as you heard earlier, it is extremely exciting to note that this compound, which has the potential to be active across multiple different diseases, has moved to the clinic in a study of patients with advanced solid tumors. You can see the clinical trial number and the criteria. This is really a standard phase I dose-escalation trial, looking for doses and schedules for phase Ib that will be driven by the equipoise between efficacy and toxicity. The key markers or endpoints are asking whether the target is being hit, whether the drug is having effects over the appropriate period of time, and finally, whether there are abnormalities or dose-limiting toxicities, a very standard phase I trial. Thank you. Thank you, Dr. Mills. I sincerely thank the three KOLs for participating on the call. We are obviously very happy and quite privileged to have KOLs of this caliber collaborating with us and working with us shoulder to shoulder to shoulder day in, day out developing these compounds. Again, we're very grateful. Thank you all very much. With this, I'd like to turn it over to Tara from LifeSci to open it up for Q&A. Thank you. Great. Thanks, Ron. At this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Jonathan Aschoff from Roth. Please go ahead, Jonathan. Thank you, guys. Thanks for doing all this. I guess- Thank you ... for the first two, docs, maybe you guys can think about the best one for this question. But given, given the rarity of ovarian Clear Cell and Endometrioid Carcinoma, you know, is it fair to assume that the phase Ib trial is enrolling, you know, the phase Ib NXP800 trial, that is, is enrolling patients that are truly outside of the current standard of care? And that the current standard of care, although, you know, used in all ovarian subtypes, is really more relevant for high-grade serous than clear cell or endometrioid? You know, I'm happy to take that. The answer is yes. You know, this trial was developed in close collaboration with the FDA, and so we-- they sort of look at all these other available therapies, which as you nicely said, Jonathan, that they look at those as available therapies, and even though they don't work, as Dr. Eskander said. So we have defined a homogeneous population, which is important for an informative study outside of available therapy. That's what we're doing. But it's a great point. But it's-- we have to follow the regulatory guidelines. Okay, maybe for the second one, you might have to follow Ron's guidelines. Is there anything that you guys can say about the phase 1a data for NXP800, you know, outside of the safety data that was already disclosed? Is there anything you guys can say about efficacy that would be appropriate at this time, at least? No, Jonathan, at this point, we can't comment on, you know, what we're actually seeing. But, I think we're all fairly pleased by the progress of the study. Okay, those are my questions. Thank you. Thank you. Thanks for the questions, Jonathan. Our next question comes from Aydin Huseynov from Ladenburg. Please go ahead, Aydin. Hi, good morning, everyone. Thank you for the very interesting presentation. Thank you. Yeah, I have a couple of questions. So first off, first on NXP900. So at the time when dasatinib was developed, I think 10, 15 years ago, there was some preclinical data that was published, and there was single-agent activities recorded in solid tumor cell lines, prostate, breast, glioma, et cetera. But obviously, that never materialized in real life. So could you remind us what went wrong and why these trials never really, you know, brought to any approvals in solid tumors? Yes. I mean, the main problem that dasatinib, for example, encountered were systemic safety issues. And again, I'd like to maybe ask Dr. Mills and perhaps Dr. Poradosu from the Nuvectis team to elaborate a little bit more on that. So it is difficult to know with certainty what causes toxicity with any drug. And I do want to point out that the only factor that is important for drug approval and helping patients is the balance, the equipoise between efficacy and toxicity, the therapeutic index. And the challenge with the previous Src family inhibitors is that, that therapeutic index was very narrow, and the best arguments would be, the first one that I mentioned, is that they have marked off-target activity and hit many kinases other than Src family members. As I pointed out, it may be almost the majority of kinases. And the second part is the concept that is really quite exciting, that in terms of efficacy, you need to block effectively both the scaffolding and catalytic activity of Src family inhibitors, particularly to efficiently block the Hippo pathway. The other inhibitors have actually been shown to increase that scaffolding activity by trapping Src in an open, active conformation. NXP900 traps Src in a closed conformation, which is catalytically inactive and cannot perform its scaffolding function, making it potential that the therapeutic index, efficacy over toxicity, will be markedly improved. Thank you. This is very helpful, Dr. Mills. But... and do you think that NXP900 could be even better in hematologic malignancies, in the indications where dasatinib is approved, CML, ALL, et cetera? I would say that this is something that should be explored extensively. First, with preclinical models, and as you know, the preclinical models, particularly in vivo for hematopoietic tumors, are limited. But I've actually suggested that we look at this to our major heme group here at the Knight Cancer Institute. So yes, it's an exciting opportunity. I think that will follow after we see what happens in the solid tumors. Got it. Thank you. Thank you, Dr. Mills. All right, another question I have on NXP800. So there are these ARID1A-mutated patients. It's a well-known mutation. It's part of FoundationOne panel. So the experts mentioned it's therapeutically targetable, and yet it hasn't been targeted yet. Yesterday, there was another drug that got Fast Track designation for ARID1A. But in your clinical practice, do you think that ARID1A mutation-mutated tumors are better responding to other treatments as well? Or the observation here is that there's just poor outcome of all ARID1A patients. I'll ask Dr. Monk and Dr. Eskander to answer that, please. Yeah, no problem. It's an excellent question. I will tell you that when we've conducted trials, clinical trials in this space, the frequency of ARID1A molecular aberrations in the clear cell is close to 70%. So to your question about, is it a biomarker predictive of a better or worse prognosis? Well, the reality is, the vast majority of patients who have recurrent disease are ARID1A mutated, and they don't respond well to current established therapies. So it doesn't predict an improved response to the treatments that we have, we have to date. So I would- you know, I think we're excited about this as a target, clearly, as messaged by our presentations. I think it's identifying the right drug, the effective drug, that will capitalize on the synthetic lethal opportunity to see a benefit. I think, to your point also, the reason there's strong investment in this space is because we believe that there is an opportunity to target this pathway effectively and improve clinical outcomes. We know Morpheus as well. Yeah. Okay. And we know that FDA is pretty favorable to targeted agents, even if sometimes responses are not as high as we expect them to be, even if they are not, like, 80, 90% sometimes. But what do you think is the minimum threshold for the FDA to see the responses, the minimum ORR threshold, for ARID1A-targeting agents to get the accelerated approval, in your opinion? I could take that, Ron, if that's okay. Sure. Yeah. So that's a, that's a very, very relevant question. And it's not just the point estimate, it's the confidence interval. So... And then the question is, does the confidence interval of the investigational product need to exclude the point estimate of available therapy or exclude that confidence interval? I mean, we think about this a lot. I think that one confidence interval needs to exclude the other. The answer to your question is, is that sort of 10%-15% or so would be the historical benchmark, with a confidence interval that would be close to 15, 16. And then if we can show a response rate north of 20, 25 would be better, 30 would be a no-brainer. And again, the confidence interval narrows with the sample size. We have multiple gates here for proof of concept. As I said, the first proof of concept is to do 22 patients in both the 50 and 75 doses in the luck. You know, we can do whatever... Ron can do whatever he wants, but, you know, if we don't see at least three responders in those 22 patients, I think the chance of technical and regulatory success would be low. Understood. Understood. Okay, thank you so much. Mm-hmm. Appreciate the presentations. Yeah, good questions, Aydin. Thanks for the questions, Aydin. I'll now turn it over to Ron to read the remainder of the questions. Thank you all very much. There are a couple of questions that we received online in the chat. The first question comes from Rose Ann Padua from Vivaldi Fund. The question is: Have you thought about combining your lead candidate with reagents or with immunotherapy? I'll answer it very briefly, and then I'll ask maybe Dr. Poradosu to add a little bit more flavor. The answer is yes. For example, we are thinking about and actually putting into action the possibility of starting a combination study with platinum chemotherapy, which is not specifically immunotherapy, obviously. In frontline ovarian clear cell, the KOLs indicated the frontline response rate with chemotherapy, which is the standard of care, there's really not much else available, is very low. It's about 25%, something like that. So obviously, there's a lot of room for improvement in the frontline setting. Obviously, this is different from the phase Ib that we're doing, which is looking at the second-line setting in ovarian clear cell. So there's clearly an effort that is, you know, being conducted right now between us and the GOG to start a study like that as well. And there are a couple of additional thoughts. Enrique, maybe you want to add anything at this point? So yes, with regards to NXP900, we have tested the compound in immunocompetent mice, and we know from that preclinical, those preclinical experiments, that we are not inhibiting at least some components of the immune response, for example, a T cell infiltration. So we know that at least from those experiments, there is no antagonism between NXP900 and the immune response, or at least those elements that correspond to the T cell responses. So that's a good, very good starting point. With regards to NXP900, we haven't tested that potential in immunocompetent mice, but that's certainly a question that we'll like to test in preclinical models. You know, combining with the ineffective agents, such as immune therapy, although there's some exceptional cases, as Dr. Eskander pointed out, really doesn't make a lot of sense. So, our goal is to get late-line, you know, PROC approval, and if we do a combination, it'll be to move it earlier in the line of therapy and to look for ARID1A-like mutations. So expand the population, expand the line of therapy, and then obviously go to other tumor types, and that would be the typical life cycle management. Thank you. So, I'll read another question that came in. This is from a private investor, and the question is: "Due to the extreme need, do you expect the FDA approval for NXP800 or NXP900 indications? Can they occur prior to the generation of phase III results?" So, I'll add a little bit. I'll answer part of that question, then I'll ask the KOLs to address the question as well. So from our experience, and as I mentioned before, as a management team, we've been involved in two approvals for two drugs for unmet medical needs in oncology. In both of those cases, a phase III trial was not required. What we ended up doing was a phase I-A, followed by phase I-B. The total patient pool, for both of these, indications, which were, you know, small unmet medical needs, were, each one was about 50 patients in total, for the phase Ib and the phase IIa, programs, and no phase III was needed. So personally, I believe that the, situation that we have with, ovarian clear cell, for example, is very similar to what we had encountered in the past as a management team, and that a phase III, will not be required. But if the KOLs want to add anything, to that, please. You know, it depends on the rarity of the tumor and the rarity of the condition. So if a phase III trial cannot be done, then, Ron, you are absolutely correct. And we get FDA approval. I gave you multiple examples in my presentation, where we get FDA approval all the time. November 14th was the last time, based on single-arm trials. So it really has to do with the rarity of the tumor. If it's a rare tumor, a single arm may be 50. If it's not so rare, then single arm, 100. But a phase III would be required, and it would have to be substantially enrolled, and those would be things that we would discuss with the FDA. So obviously, we can't give you a definitive answer. Okay, thank you. Another question came in, and I guess this is for Dr. Mills. So, the answer is to elaborate a little bit more about the significance of being able to block both the scaffolding and the catalytic domains of the Src kinase, as opposed to, for example, what dasatinib does, which is blocking the catalytic domain. If you can just explain a little bit more, you know, what that actually means in, you know, in the real world, as these diseases occur. So we can extend this way beyond Src. Many kinases, particularly serine/threonine kinases, as well as kinases at the cell surface, have two major functions. One is their catalytic activity, and I'm gonna leave that aside for the moment because that is inhibited by NXP900 and other molecules. However, the kinases clearly serve a second function of creating a molecular machine by bringing together a series of proteins into a complex, and that's done by the scaffolding activity. That complex is what is functionally active. In many cases, we've been able to show, not just with Src, but catalytically inactive molecules actually are better at forming that molecular machine, and that obviates the activity of the inhibition of the kinase. With the Src family members, they have two major domains that serve that scaffolding function to build a catalytic machine or to build a machine, and that is the SH2 and the SH3 domain, and that brings in a series of members of the Hippo pathway and other pathways. Intriguingly, some of those other members are also kinases and can bypass the activity of the Src inhibition and make that molecular machine highly active. And so the idea of taking a catalytic molecule, like Src, and inhibiting in its closed configuration, where it doesn't form that complex, is exciting. And as I pointed out, this goes well beyond this particular molecule, and indeed, it shows up routinely in our analyses, where we knock out a molecule and have a massive effect, and then we come in with a catalytic domain inhibitor, and the effects are modest. That's because we have a situation where the scaffolding activity is maintained. So here, you've blocked both the scaffolding activity, which prevents the formation of these molecular machines that are active, and the catalytic activity that will amplify the signal. And so it is important to hit both of these effectively. Thank you very much, Dr. Mills. And I'm getting a signal here that we're running up against the clock. So, I think, with that, we will end this session. And again, I wanna thank everybody for participating. I know everyone's time is very precious. I know our KOLs' time is very precious, and we wanna thank them sincerely, and thank you all very much for your time. You know where to find us if you have any follow-up questions. We'd be happy to answer those, and we're always available. And I wanna thank LifeSci also for coordinating all this. Thank you very much. Have a great rest of the day, and we appreciate all of your-