Welcome to Viracta's R&D Day, both to everyone here in the room in New York, but also to those joining us remotely. Viracta, for some of you who may not know Viracta so well, we were founded in 2015, and our mission is to treat and prevent virus-associated cancers. You'll see that today, our focus is gonna be on our lead program, Nana-val, which is an all-oral combination of nanatinostat and valganciclovir, and we'll hear more about that in a minute. For those of you who don't know me, my name is Mark Rothera. I've been 33 years in the biopharmaceutical industry. I have been CEO of Viracta for the last year, and really, during my career, I've been fortunate to help build and lead the build of 6 previous biotech companies and now, Viracta, the 7th. In that journey, my primary purpose has been to bring to the world meaningful medicines for rare and specialized diseases. That's why I joined Viracta, because I think that Nana-val represents a medicine that's in at the intersection of oncology and rare disease. We're looking to treat EBV-associated cancers, which cross lymphoma subtypes as well as solid tumors and individually, within a particular lymphoma or a particular solid tumor. But collectively, when you add all this together, I think this represents a really important, a very important medical intervention for the future that we're looking to bring to help a lot of patients with EBV-associated cancer. And I think at the same time, represents a very attractive commercial opportunity. During the course of today, we'll be making some forward-looking statements. So this is what Nana-val's about. Roughly 2% of world cancers are EBV-associated. That's more than 300,000 new cases a year. And what we have decided as a company is to focus on three lymphoma subtypes and two solid tumor subtypes to start with. So on the left, you can see peripheral T-cell lymphoma, DLBCL, and PTLD with their associated EBV positivity rates. And on the right, you can see nasopharyngeal carcinoma and gastric cancer, and again, those associated EBV positivity rates. Why are we here? And you're gonna hear more about this from thought leaders in the field who've wound up. For example, DLBCL, left, DLBCL right, and we look at survival, they do substantially worse than those that are EBV negative, and there isn't a targeted treatment for these patients. That's the mission that we're on, to help fulfill significant unmet needs and bring a valuable medicine to the world in the process. Really, we are focused on maximizing the opportunity of Nana-val. It's a pipeline in a product, and you can see there are adverse outcomes. We have EBV, we have an, a well-tolerated, all-oral combination that targets and kills EBV-associated cancer cells. What's new today is we're gonna share with you new data in the lymphoma area from our pivotal NAVAL-1 study and from an enlarged and extended follow-up of our 201 study. And that was the phase Ib study we undertook in, in the lymphoma area. And we're also going to share with you for the first time, five dose cohorts of dose ranging in the new frontier, which is the solid tumor setting. Maybe just for those who are not familiar with the company, we're also a very lean operating model company. Dan, our CFO, will allude to, we're burning around $8 million-$9 million a quarter, and really, we're spending our dollars on development to bring forward milestones for this program and trying to get Nana-val to market as quickly as we can. So I mentioned that we're joined today by two expert opinion leaders. We're delighted to have them with us today. Firstly, I'd like to introduce Pierluigi, or PG, Porcu, who is Professor of Medical Oncology, Director of the Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology at Thomas Jefferson University. He's also co-leader of the Blood Cancer Center of Excellence, Sidney Kimmel Cancer Center at Jefferson Health. Dr. Porcu is a key opinion leader with 20 years of experience in translational and clinical research in lymphoma, serving as a chair or member of multiple steering committees and data safety monitoring committees for national and international clinical trials, scientific advisory boards, and grant review panels. Dr. Porcu is a member of the ECOG-ACRIN Lymphoma Core Committee. Dr. Porcu's laboratory work is focused on discovering targetable mechanisms of lymphomagenesis in T and NK cell lymphomas. I would also like to introduce Rob Baiocchi, Professor of Internal Medicine, Associate Director for Translational and Clinical Science in the Division of Hematology at The Ohio State University. Dr. Baiocchi is a medical oncologist who specializes in the treatment of patients with blood cancers. Dr. Baiocchi joined the faculty at The Ohio State University in 2005, and currently holds the position of fully tenured Professor of Internal Medicine, as well as serving as the Associate Director for Translational and Clinical Science in the Division of Hematology. Dr. Baiocchi earned recognition by being named to the Castle Connolly list of regional top doctors for the years 2016 to 2018. As a dedicated member of the Leukemia Research Program at the OSU CCC James, Dr. Baiocchi's clinical research focuses on patients with aggressive lymphomas, PTLD, and AIDS malignancies. Dr. Baiocchi has taken on a leadership role in supervising research efforts within the lymphoma group in the Division of Hematology. Collaborating extensively, Dr. Baiocchi's laboratory works alongside clinical researchers at both the division and national levels, conducting correlated laboratory work for multiple clinical trials. Thank you both for joining us. Also from the Viracta team, I'm delighted to introduce Ayman El-Guindy, our Chief Scientific Officer. Ayman El-Guindy, Ph.D., joined Viracta more than two years ago as Chief Scientific Officer. He has over 25 years of experience studying the role of viruses in cancer. Prior to Viracta, Ayman spent a decade as a faculty member at Yale University School of Medicine, most recently as an associate professor in the Departments of Pediatrics and Pathology. At Yale, Dr. El-Guindy ran a laboratory focused on the involvement of oncogenic herpes viruses in the etiology and prognosis of cancer. His group studied the fundamental role of EBV protein kinase in pathogenesis as a potential target for drug development, which is the pillar of Viracta's mechanism of action. Additionally, Ayman had made seminal contributions to understanding of oncogenic viruses, which are reflected in his peer-reviewed publications, numerous grant awards from organizations such as the American Cancer Society, and his recent election to the governing board of the International Association for Research on EBV and Associated Diseases. And last but not least, I'd like to introduce Darrel Cohen, our Chief Medical Officer, who joined Viracta two months ago. That probably feels like quite a lot longer, Darrel, straight in. As Chief Medical Officer, he oversees the clinical development and regulatory advancement of Nana-val in EBV-associated malignancies, contributing to the strategic expansion of our pipeline and serving on the executive leadership team. Dr. Cohen is a hematologist oncologist with over 25 years of oncology, clinical research, and drug development experience, mostly at Pfizer Oncology, where he was involved in multiple successful regulatory submissions of new targeted cancer drugs such as Sutent, Xalkori, and Ibrance. So thank you both. What we're going to do today is in a minute, we're going to look at the Nana-val mechanism of action with Ayman. Then we're going to dive into three areas where we're going to explore, you know, the unmet need, but also new data. Starting with the PTCL area, where Pierluigi Porcu and Darrel will speak to the unmet need and the new data. Then going on to DLBCL, which we're going to discuss as a unique entity when it comes to the EBV form, and showing you some new data from the phase Ib/2 study. And then we're going to move to the solid tumor program and share that dose-ranging data and our next steps for the NPC study. And finally, I will close with some market opportunity slides and some milestone slides, so you can see the bigger picture of how we see things evolving. We will have a Q&A at the end, so please keep your questions for the Q&A, and those who are joining remotely, you'll be able to send your questions in remotely as well. So with that, I'm delighted to invite Ayman to speak to the mechanism. Ayman? Thank you, Mark. So we have a very elegant mechanism of action. It basically uses two small molecules. It's a two-step mechanism of action. We refer to it as the kick and kill. And And these two small molecules, one them is nanatinostat, which is an HDAC inhibitor, potent and specific. It specifically targets HDACs one, two, and three. It's not a pan-HDAC inhibitor. And it it's a strong inducer of the EBV lytic cycle and of the viral protein kinase BGLF4, and I'll come to that in a minute. The second molecule is valganciclovir, which is a prodrug and becomes activated by this viral protein kinase I was referring to, which is activated by nanatinostat. I thought today it would be really nice to share with you this neat video about the mechanism of action. So let's hope it works. Epstein-Barr virus, EBV, is a common herpes virus. 95% of the world's population has been exposed to EBV. EBV was the first human virus to be identified as a causative agent for cancer and is etiologically linked to a variety of lymphomas and solid tumors. EBV positivity has been linked to lower survival rates for some lymphomas and is associated with approximately 2% of all cancers. EBV is commonly detected in tumor samples using in situ hybridization of the abundant EBV-encoded RNA, also referred to as the EBER ISH assay. EBV exists in cancer cells in a latent state, avoiding detection by the host immune system. In order to selectively target EBV-positive tumor cells, a kick-and-kill approach is employed using two small molecules: nanatinostat and valganciclovir, the prodrug of ganciclovir. During latency, EBV does not express the viral kinase needed to activate ganciclovir. Ganciclovir on its own, therefore, has no cytotoxic effects. The kick comes from nanatinostat, a class I selective histone deacetylase inhibitor, capable of modifying gene expression by opening up areas of silenced DNA so that the transcription machinery can bind to viral DNA and activate expression of lytic viral genes. Nanatinostat induces the expression of the lytic EBV viral protein kinase, BGLF4, in tumor cells. The BGLF4 viral protein kinase phosphorylates ganciclovir into its active form. Phosphorylated ganciclovir is an analog of the nucleoside guanosine. Activated ganciclovir can inhibit both cellular and viral DNA polymerase, interfering with the process of viral and cellular DNA synthesis. This triggers apoptosis of EBV-positive tumor cells. Thus, combining valganciclovir with nanatinostat results in the sensitization of EBV-positive tumor cells to ganciclovir, a unique targeted approach to the treatment of EBV-positive malignancies. Where on EBV, you can activate expression of the viral protein kinase, which then modifies ganciclovir into its active form. Now, what I would like to do is, in the next three slides, is to provide evidence that we are actually, that this combination, the Nana-val combination, is tissue or tumor agnostic. So I will show you three slides. One is about lymphoma, preclinical data. The other one is about nasopharyngeal carcinoma, and the third is about gastric cancer. So let's start with the lymphoma. So in this slide, you can see here, this is a FACS analysis, the upper panel. And you can see here the cells that actually migrated from the lower part to the circle here. These are cells that were activated. They are now expressing this viral protein kinase that activates the kill. And what I want to point your attention to is that we're using nanatinostat at nanomolar concentrations, meaning it's very potent and very specific. Are we activating the kinase? Absolutely. You can see that in the RT-PCR expression here of this viral protein kinase, where we're seeing up to 700-fold increase in expression of this viral protein kinase in lymphoma cells. How about nasopharyngeal carcinoma? So for nasopharyngeal carcinoma, with it, I'm sharing with you this experiment. This is again, the rate-limiting step, which is expression, activation of the lytic cycle and expression of the kinase. And you can see here we're using different concentrations of nanatinostat. And as you increase the concentration of nanatinostat, you see increase in the signal here. This is a protein, the BGLF4 protein, that activates the lytic cycle. It's the best marker for lytic cycle activation. If you like visuals, we also have cells we looked with using confocal microscopy. And you can see here, as we use five nanomolar and going up to 500 nanomolar, you see the rate of increase in these cells that switch into the lytic cycle. So that's for nasopharyngeal carcinoma. For gastric cancer, I chose a different slide. This is an in vivo experiment. We'll start first with the in vitro experiments, and you can see again, it does affect as we are titrating the concentration of nanatinostat, we're activating the lytic cycle. But also when you look at in an animal model, this, we're using here EBV-positive gastric cancer cells. These are naturally infected with EBV, and as we, when we combine nanatinostat with ganciclovir, that's when we get the best antitumor activity. This effect here is statistically significant, as you can see on the panel on the right-hand side. So I don't want to take too much time sharing with you preclinical data, but basically what I'm trying to say is that we have a mechanism of action that's tumor agnostic, that can target both or, you know, not just l-lymphomas and as well as solid tumors, whether it's nasopharyngeal carcinoma or gastric cancer. With that, I'll stop, and I'll pass the mic to Mark again. Thank you, Ayman. So now we're going to look at how does this mechanism of action in the clinic deliver from a clinical results perspective, but also we'll start with the unmet medical needs. So I'm delighted to invite Professor Pierluigi Porcu to the stage. Okay, good morning, everyone. So I'm a medical oncologist, and I treat patients with lymphoma, and do research work in the laboratory on T-cell lymphoma. Let me say first, how much of a pleasure it is to be here with you today, and how much of a pleasure it has been to work with Viracta over the past almost 10 years now. It's we share a passion for the science, and particularly the science of EBV and virus-associated malignancies. And then we share this vision of actually taking this new combination therapy to the clinic and to patients worldwide. I'm gonna start with some definitions because, as you will see in the course of this presentation, definitions change, and, especially when we're looking at, reports of statistics, frequencies, epidemiology, and so on. It's, you know, as names change, those numbers will change. These names have changed over time. So, for example, we use a lot of the word, the peripheral T-cell lymphoma. We have already heard it this morning. Well, peripheral T-cell lymphoma, it's a really historical term that is all-embracing as a definition of lymphomas of T-cell and NK- cell lineage. The reason why it's called peripheral is because during the course of the differentiation of normal lymphocytes, there are two steps. One is the differentiation at the central level, so in the bone marrow and the thymus of the body. Then the second step is in the peripheral lymphoid organs. All these lymphomas develop from cells that have passed the initial differentiation phase, and they go into the peripheral lymphoid organs. That, that's what they call peripheral T-cell lymphomas. Now, peripheral T-cell lymphoma nowadays really only defines a particular subtype of a mature T-cell neoplasm, and it's called PTCL- NOS. That's one of the diseases that we're going to discuss today as well. Another big umbrella definition is cutaneous T-cell lymphomas, which are a type of skin specific lymphoma that has been known for decades and now is kind of used primarily to describe a type of extranodal T-cell lymphoma of the skin. Physicians and patients very often use this definition to kind of distinguish cutaneous T-cell lymphoma on one hand from peripheral T-cell lymphomas, which are more disseminated, nodal and so on. The real modern definition of these lymphomas now, according to the WHO and, and the ICC in particular, is mature T-cell neoplasms. So this kind of eliminates the word lymphoma because some of these are leukemias and, and, their, you know, the classification now really distinguishes all these different, malignancies as nodal-based, extranodal, leukemic, and cutaneous. Once again, when we look at the distribution of numbers here, a few from the top, these are all lymphoid neoplasms that are diagnosed in patients. And, it's, you know, some of them are non-Hodgkin lymphoma, some of them are Hodgkin lymphomas. And then, depending on the cell lineage, which is shown here, some of them are B-cell neoplasm. For example, this is, you know, some of the malignancies that Dr. Baiocchi is gonna show and talk about a little later. What we're focusing on right now are these, the T and NK cell neoplasm. And how many of these neoplasms are diagnosed every year? Depends on how you define it, but altogether, if you look at the data from the American Cancer Society, out of about 80,000 cases of non-Hodgkin lymphoma a year in the United States, about 8,000 of them, so 10% are T and NK cell neoplasm. Now, people often think about peripheral T-cell lymphomas are rare diseases, and they are. But if you look at Hodgkin lymphoma, which is on the other side, Hodgkin lymphoma is just as frequent as the peripheral T-cell lymphoma. So I don't think anybody's having any issues about thinking how to do clinical development, drug development, taking drugs to market in Hodgkin lymphoma, and we should think about exactly the same way in peripheral T-cell lymphoma. One of the most striking features about these malignancies is, number one, the fact that they are diagnosed everywhere in the world, but there is a significant heterogeneity of distribution in terms of the frequency and the type. This is true particularly for certain types, which I'm going to highlight in a second. But it's really kind of true across all the different, all the different T-cell malignancies. So what this slide shows, on the top is the fact that depending on the size of the circle that you see there, and with the list of the subtypes of T-cell malignancies, in some cases, some of these malignancies will be significantly more frequent in certain areas. So for example, if you look at here in China, this particular type of lymphoma called ENK T-cell lymphoma, extranodal NK T-cell lymphoma, is very significant in terms of incidence. On the other hand, there's another type of lymphoma called angioimmunoblastic T-cell lymphoma, AITL, which is particularly common in the Northern European states. The most common type everywhere is called PTCL NOS, which is really kind of a generic definition of peripheral T-cell lymphoma. In this category, every year that goes by and our classification schemes change, becomes, you know, more and more defined, and we're kind of chipping off subtypes out of that big category. I'd like to point your attention to the bottom part of this figure, because it's really, really important in terms of the way we look at populations, and this is particularly focused on the United States. Depending on race and ethnicity, the frequency of each one of these types of lymphomas can be extremely different. For example, if you look at the bar with the peripheral T-cell lymphoma, NOS right here, and you look at Blacks, Blacks have a very significant higher incidence of this type of lymphoma compared to other races. And on the other hand, in Hispanics, you will have, you will have a significant higher risk of developing anaplastic large cell lymphoma, or in Asian Pacific Islanders, angioimmunoblastic T-cell lymphoma. So I, I think that as we look at the distribution of these malignancies and we look at risk and causing factors, I think it's important to keep these differences in mind, particularly as we look, as we go forward, we look at EBV, at the role of EBV. Now, one of the key things about taking drugs to the market, drug development, and improving outcomes of patients is really sort of how do we set the benchmarks for what's going on right now? And in T-cell malignancies, these benchmarks have been slow in coming, particularly with accurate data. I'm showing this because this is probably one of the most reliable and accurate long-term outcome data for peripheral T-cell lymphomas, comes from the Swedish Lymphoma Registry, which is shown there, enrolls essentially 95% of all adult lymphomas in Sweden. This is a data set that I use also to sort of to quote when we try to define what the percentage of all lymphomas that are peripheral T lymphoma, because in this particular registry, 7.4% of all lymphomas were peripheral T-cell lymphomas. This, by the way, excludes the cutaneous T-cell lymphomas right here. So if you add the cutaneous T-cell lymphomas, this percentage will increase, and that will take us to about the 10% that I was discussing at the very beginning. The one thing that is striking here, again, is that how poor the outcome of these type of malignancies is in this long-term registry with a 7.9 years median follow-up at the time of the publication, which is now much, much longer. And if you look at the progression-free survival at five years, for the vast majority of these malignancies, with the exception of one single subtype, which is an outlier, but all, for all the other ones, the progression-free survival at five years is about 26%. And if you look at the progression-free survival at two or three years, it's about 30%. So 70% of the patient with peripheral T-cell lymphoma, within two years, really kind of progress. So I'm gonna divide this into the kind of landscape in frontline and then the landscape at relapse/refractory disease. And to do that, I thought that maybe a good way to start would be to kind of outline how the pathway and the algorithms for the frontline treatment is at the institution where I work, Jefferson Sidney Kimmel Cancer Center. So I'm gonna walk you through how we are going to sort of approach the patients when they come in with a newly diagnosed peripheral T-cell lymphoma. The first thing we do is to determine whether the current standard of care frontline chemotherapy, which is called CHOP, is appropriate because there are some subtypes that are particularly aggressive and will not respond to CHOP chemotherapy. And then, at that point, just based on the diagnosis, we know we have to do something different, and those diagnoses are listed on the right side of the slide. We start with that. All these lymphomas right here are lymphomas, where even though the outcomes, as I have shown, are not particularly good, but we feel that the CHOP-based chemotherapy is still appropriate. The next point of sort of stratification, and this is standard of care, is based on the expression of this marker called CD30. And that is based on the fact that CD30 is expressed on a significant fraction of these lymphomas, and there was a randomized clinical trial called ECHELON-2, was published several years ago, that showed that the addition of a monoclonal antibody that targets CD30 had an impact in terms of overall survival and progression-free survival in patients who expressed CD30. So when the patients express CD30 in at least 5%-10% of the cells, we add this antibody to the chemotherapy. Once again, this is standard of care. If the lymphoma does not express CD30, then we do chemotherapy with the you know the regular chemotherapy regimens without adding brentuximab. For all the other subtypes where CHOP is not appropriate, there's really no standard of care, even on the frontline, for these lymphomas. At that point, there are certain chemotherapy regimens that are used, and most of these patients, if they achieve a remission, will go on to an allogeneic transplant if they're eligible. Now, this slide here is kind of a historical overview. In terms of chronologically, if you wanna think about it, goes from top to bottom. I'm gonna walk you through this. The reason why I'm showing this is because, if you look at some of the studies, some of the old studies, for example, the one on the top, at the top, that's a study that came out of the British Columbia Cancer Agency, back from the 1990s, essentially. Of course, back then, the diagnosis of peripheral T-cell lymphoma was different from what it is today, the treatment was different, and so on. And then going down, these are all retrospective, kind of either registry studies or, cooperative group studies. And if you-- You know, the outcomes, as you can see, are, fairly different from what the outcomes that I just showed from the Swedish Lymphoma Registry are. I think that probably a good way, of once again, looking at the outcomes here based on these, the last two prospective, at the bottom, prospective trials, is once again, these data are consistent with what I was showing, the two-year progression-free survival, about 30%-36%, and the other study was about 40%. So those are our benchmarks for, frontline therapy. If you look at the top there, right here, these are the complete remission rates that have been observed in the three, two to three year progression-free survival that we're looking at. Because the frontline landscape is far from where we want it to be, a lot of effort went in, in trying to improve on CHOP, and one of the latest sort of attempts was to add a drug that was, is approved in the relapsed setting called romidepsin to CHOP. And a large phase III randomized clinical trial was conducted and was published relatively recently, and unfortunately, it's a negative study. So if you look at the median progression for survival in this fairly large cohort between the two arms, romidepsin CHOP and CHOP, right here, you will see that, there's no difference. And once again, if you think of benchmarks, you know, here, for both cohort, the median progression for survival was 12, 10-12 months. In this particular, trials, kind of a subgroup analysis, a planned subgroup analysis, was, for the most part, negative and not necessarily exciting, with one single exception. If you look at the histology types right here, the only type of T-cell lymphoma where there was a little bit of a hint towards statistical significance for this was angioimmunoblastic T-cell lymphoma. And the reason why I'm looking at this is because angioimmunoblastic T-cell lymphoma is a type of a T-cell lymphoma that can be often associated with EBV. So what's the landscape in refractory relapsed peripheral T-cell lymphoma? These are... It's a kind of a compilation of outcomes from phase II studies looking at patients with relapsed refractory disease. Some of these studies led to the FDA approval of the drug, particularly the ones with the asterisks at the bottom. And once again, the scenario and the landscape is pretty consistent. If you look at the median progression for survival for patients who have relapsed refractory diseases, anywhere between 1.6 months, right here, all the way to 4 months, with one single exception, and it is brentuximab vedotin for this particular subtype of T-cell lymphoma, which responds uniquely well to brentuximab vedotin. If you look, if you use the same drug in other types of peripheral T-cell lymphoma, your progression for survival goes back to to the same that all the other drugs have. So in the relapsed refractory setting, this is what we have going on right now, which clearly is not a good place to be. So to kind of go back to the approach that I showed in the frontline, this is how we approach peripheral T-cell lymphoma, relapsed/ refractory at at Jefferson. And of course, with the exception of the ALK-positive anaplastic large cell lymphoma on the left side of this figure, that's a lymphoma that has kind of a uniquely favorable outcome, so it's treated different. But all the other types on the right side of this slide, as you can see, that clinical trials are really sort of one of the key options that, if available, patients should be referred to. If they're not eligible for clinical trials, then people will get some type of multi-agent chemotherapy, and then if they're eligible for transplant, try to go to transplant. Most patients are not eligible for transplant. But as we see the patients at that point, the thing that we do right now in clinical practice is really to see whether or not they have a type of T-cell lymphoma that is defined as follicular helper T-cell type or not. And the reason why we do that is because the follicular helper T-cell type lymphomas, which include angioimmunoblastic T-cell lymphoma right here, seem to be particularly responsive to the HDAC inhibitors, such as romidepsin, and nanatinostat, of course, is an HDAC inhibitor as well, or some of these other drugs as well. All the other ones are not particularly responsive to this. But what we do now at Jefferson and all the other sites that have the NAVAL-1 study open with Nana-val- As we look at EBV status, because if the patient is EBV positive, then we will enroll the patient in a clinical trial. And this is where I think that really this is gonna become much, much more important in the future, because this would you know the ability to look for EBV and the ability to have a targeted therapy for EBV positive lymphomas is gonna change the way we approach peripheral T-cell lymphomas, relapse refractory. This is just a list of all the other drugs that are available right now. Very few of these drugs actually are approved for relapse refractory disease. So what's the emerging landscape now for this? Clearly, there's you know, it's an open open field, completely open, and there is you know, a significant activity in drug development. Which ones of these agents will kind of show activity and will be positive? It's hard to know because all of these trials are really very early in the phase of development with the exception of the NAVAL-1, which is a phase, which is a phase II in the targeting EBV. When you look at I mention about cellular therapy, because that's a question that comes up very often, you know, CAR T. The only the really kind of cellular therapy product that was looking of interest and was in clinical trial was this CD5 CAR myeloid cell from another company called Myeloid Therapeutics. This study actually, unfortunately, just recently closed and because of the manufacturing issues with the manufacturing of the product. So, all of this as kind of an introduction to EBV-positive PTCL, because that's where we think a big opportunity is. So we did a study at Ohio State in collaboration with Dr. Baiocchi, actually, and Brad Haverkos, who was a fellow at the time, and now is a faculty at the University of Colorado. And we looked at patients with peripheral T-cell lymphoma, where we had data on the presence of EBV in the peripheral blood, actually. And we had multiple patients where we were following longitudinally with that, and we found out that out of 61, where we really had the pre-treatment EBV data, 15 were EBV-positive and 46 were EBV-negative. So we had... And this is a breakdown of the types of lymphoma altogether. We had the opportunity to look and follow these patients over time and try to determine whether EBV had an impact on survival. It clearly did in a statistically significant way here. If you look at the patients who had positive EBV detectable before therapy, their survival was clearly inferior to the patients who did not. In addition to that, even though there's absolutely no statistical power here at all, but this is more of a kind of patient-by-patient analysis and follow-up, which I think still has significant value, because patients were followed longitudinally with that, you know, once they had a positive EBV study. You can see here on the top of the 15 patients who were positive for EBV at diagnosis, and there are 6 of them that really never cleared their EBV, even during treatment. And if you look at the outcome of those patients, even though two of them eventually became negative, but all six of them died of progressive disease. And of the patients who had EBV positive at before therapy, and then they cleared their EBV, their prognosis seemed to have been a little better. Again, this is not a statistical analysis in any way, but in terms of kind of the patient, direct patient follow-up, I think it's certainly hypothesis building. And I think we want to definitely have additional data. Some of the top, some data like this will be available in the NAVAL-1 study. Finally, I wanna leave you with I think an important study that really kind of looks at the frequency of EBV-positive T-cell lymphoma. This is a modern, recent study from France. The reason why I like it is because they had a very specific definition of what EBV-positive was. And EBV-positive, as I showed, is mostly defined by EBER in situ hybridization, and these investigators looked at the French lymphoma group, and they defined positivity based on a score, either one, two or three, with an increasing number of EBV-positive cells. And if you look at the different scores here, and you combine them all together, of course, there were a number of patients who had no EBV positive cells, but of the patients who had EBV positive cells, if you put them all together, about 49% of the patients had EBV positive peripheral T-cell lymphoma with the different subtypes that are shown right here on the left. So if we have to quote a percentage, at least based in France, I would say about 50% is a good percentage to quote. Conclusions, as I think I showed, peripheral T-cell lymphoma clearly has a very poor prognosis, and even in the front line combination, really, we don't have a good standard of care that needs to be improved. Once you go into relapse refractory disease, the prognosis is even worse, and we do feel there is an opportunity for the EBV positive subset here to be used for targeted therapy. And there's no other standard of care at this point for relapse refractory PTCL. and then the targeted treatment for patients with EBV-positive PTCL, we feel could provide an important addition to the treatment. So with this, thank you very much, and then I'll be happy to answer any questions down in the question and answers. Thank you. Thank you very much, Professor Porcu. Now, having looked at the unmet need that there is in PTCL, we're going to share with you new data from our phase Ib/II study, as well as our ongoing pivotal phase II study, NAVAL-1. And then for that, I'm going to invite Darrel Cohen, CMO. Thank you, Mark. Good morning, everyone. So as Mark had mentioned earlier, I joined Viracta approximately two months ago, attracted to its lead investigational product, a precision oncology medicine, which has shown substantial activity in early clinical trials, demonstrating the power of precision medicines, and doing so in a number of heavily pretreated, relapsed or refractory, advanced cancers. Which portends a very high probability of clinical development success and the ability to potentially benefit additional, advanced cancer patients with high unmet medical need. And I hope to show you and update you some of those data, coming away with the, the potential that this innovative new product has to offer patients. So our flagship, clinical study of nanatinostat and valganciclovir, here at, Viracta, is our NAVAL-1 trial. This is a multinational, open-label, phase II study of Nana-val, orally administered at its recommended phase II dose, determined from the preceding phase Ib/II study 201, in a variety of patients with relapsed or refractory EBV-positive lymphomas. And this study, we consider a pivotal one, because it was designed in consultation with the FDA, with an eye towards potentially preserving the opportunity for accelerated approval, if we are able to demonstrate substantial and durable responses with a favorable safety profile in a reasonable number of patients. And this study, therefore, was designed as an adaptive Simon two-stage design. As you can see, enrolling 10 patients in the first stage, in a variety of EBV positive lymphoma cohorts, and with a primary overall response rate endpoint, if an overall response rate threshold was met, then an additional 11 patients would be enrolled in Stage II for each lymphoma subtype that met those criteria. Then at the end of Stage II, where we see promising clinical data and antitumor activity, we would take those data to the FDA, and discuss our plans for expanding Stage II, both in terms of the numbers of patients, as well as the design and timing of a clinical benefit commitment study. I'd like to draw your attention to three aspects of this study on this slide. The first is something we announced a couple of months ago, and that is, instead of investigating Nana-val in every possible EBV-positive lymphoma, we've decided to focus our resources on those lymphoma subtypes that have the highest potential for clinical commercial success, based on their relative incidence, high unmet medical need, and positive phase Ib/II study data. These are shown here, namely PTCL, DLBCL, and PTLD. Second aspect is that the FDA also asked us to actually enroll 20 patients with advanced relapsed or refractory EBV-positive PTCL patients in Stage I, so that we can randomize them to receive either the combination of valganciclovir and nanatinostat or, nanatinostat alone, really to assess the insufficiency of treating these patients with a viral inducer without the antiviral agent to kill the cancer cell. And then thirdly, you'll see here that the EBV-positive PTCL cohort we announced in June successfully met the overall response rate threshold and advanced to Stage II. And here is the data that supported that decision. You can see that the threshold for advancing into Stage II was two responses out of the first 10 patients enrolled in Stage I, essentially to exclude futility. And what you can see here is that in NAVAL-1, those two responses were observed in the first five of those 10 patients, for an overall response rate of 40%, and both of those responses were complete responses, which are still ongoing as of the data cutoff date this past June. The median duration of response obviously has not yet been reached. And these data, together with the continual expansion of our clinical trial multinationally, as well as the sunsetting of the monotherapy arm after Stage I, should substantially increase patient enrollment moving forward. Putting these data into context across both of our studies of Nana-val, looking specifically at the phase Ib Study 201, together with the NAVA-1 study, you can see that the substantial response rates are consistent. As of the data cutoff of October 2021, which by the way, formulated the basis for the recent publication of 55 patients treated with the capsule formulation of Nana-val, Blood Advances earlier this year. There were 11 patients in that group who had relapsed or refractory PTCL, six of whom were EBV-positive, and there was a 67% overall response rate with a 50% complete response rate, together with a stable disease, resulting in an 83% clinical benefit rate. Now, the study also incorporated a bridging formulation pharmacokinetic study to additionally evaluate nine patients treated with the tablet formulation. The tablet formulation of Nana-val was introduced in order to improve blend uniformity and its stability, and potentially set Nana-val up for a potential fixed Nana-val and valganciclovir dose combination in the future for commercialization. Of those nine patients, two of those patients had relapsed or refractory EBV-positive PTCL. Those patients did not respond to treatment, but still, the overall response rate remained quite healthy at 50%, with a complete response rate of 38%, which actually compares favorably with what we saw with the tablet formulation moving forward in one study that you previously saw. And as an aside, it should be noted that the safety and pharmacokinetics of the tablet were comparable to that of the capsule, enabling us to comply. What was remarkable is that the when you look at the median duration response of those six responders in this swimmer plot, the median duration response was actually extended to 17.3 months, with additional follow-up beyond that October 2021 cutoff date. To put this into context, excluding the patients with systemic ALCL who may be treated with brentuximab or Xalkori, the vast majority of PTCL patients, the available treatments for them, be it a chemotherapy, HDAC inhibitor, or antimetabolite, dramatically exceeds the approximate—their approximate nine month median duration of response that have supported their accelerated approvals. So, and this is also—this long duration of response is also testimony to the probability of positioning these early daily well for future success. When you look at the safety profile, this is actually combines all 64 patients, the 55 patients treated with the capsule on the phase Ib/II Study 201, together with the tablet formulation across multiple relapsed or refractory lymphoma subtypes. You can see that the profile was generally well-tolerated and quite favorable for this advanced cancer patient population, because the majority of treatment emergent adverse events were mild to moderate in severity, and frankly, very common to hematologist oncologists, as they were predominantly hematologic and gastrointestinal in nature, together with some increased creatinine, not uncommonly seen with valganciclovir. In addition, there were no study treatment-related deaths. So this profile, as an aside, also sets this product up not for only successful monotherapy development, but also for future combinations with other standard anti-lymphoma or anti-cancer therapies. But we believe that Nana-val is well-positioned for potential accelerated approval in patients with relapsed or refractory positive PTCL. And the reasons are shown here. We're dealing with a rare, serious, life-threatening disease without alternate available treatment options, thereby representing an unmet medical need population. These patients, as Dr. Porcu pointed out, have a very poor survival despite available treatment options. Magnitude of the response rate so far has been quite encouraging, and most remarkably, with a very long duration of response. And of course, as I just mentioned, a very favorable, and certainly manageable, if not reversible... We hypothesized that we may only need a total of 60-90 additional—I'm sorry, 60-90 total relapsed or refractory EBV-positive PTCL patients, namely an additional 40-70 patients after Stage II, if indeed the results we're seeing early on hold up at the end of Stage II, for approval. But of course, that needs to be confirmed with the... The reason we believe this, in part, is if you look at the past precedent of the other agents in this space that have received accelerated, including the HDAC inhibitors, belinostat or romidepsin, as well as the antimetabolite pralatrexate. You can see their overall response rates were on the order of 26%, with a complete response rate between 8% and 15%, and a duration response of around 8.5-9.5 months. And this pales in comparison to what we're seeing with Nana-val. In fact, it's Nana-val, we're seeing almost double the overall response rate, twice the complete response rate, as well as duration of response. And so if the past precedent required over 100 patients, and we're able to sustain this level of substantial antitumor activity with more patients, then we feel we can get to the finish line faster with fewer numbers of patients. Again, that's pending FDA confirmation. So what's next? Well, we hope to complete enrollment of Stage II sometime in 2024. Again, if those data support the earlier emerging response rate data with a continued favorable safety profile, we would meet with the FDA and align on a potential accelerated approval pathway, as well as I mentioned earlier, the design and timing of a clinical benefit commitment study. And then we would expand the post Stage II expansion cohort accordingly, and of course, publicly present the data supporting that expansion. If we're successful, we can complete that part of the NAVAL-1 trial sometime in 2025, setting ourselves up very well for potential regulatory submission under fast track designation that we've already achieved in the US, possibly even approval as early as 2026. With that, I will turn- Thank you very much, Darrel. So that is an overview of the PTCL program, the unmet need, and the Nana-val data. We're now gonna move to the second priority lymphoma program in DLBCL, and I'm delighted to hand over to Dr. Rob Baiocchi, to tell us a bit about the uniqueness of EBV DLBCL. Thank you, Mark. Thank you for the invitation to come today and, for all of you, being here. So we're talking about a topic that's been near and dear to my heart, for many, many years. I got my start in the EBV field, when I was a graduate student, at Roswell Park Cancer Institute, where I studied Epstein-Barr, and how it drives lymphoproliferative diseases like lymphomas. Been very interested in biology of EBV, and how this applies to human disease, and actually got my clinical start with PG at Ohio State, several, many years ago, and, I have continued on that pathway. So I view this collaboration here with Viracta really in a very positive, just with tons of enthusiasm. Now, if you were to pick up a textbook in virology and read about what EBV does and how its biology is, it's very dogmatic. It's cut up into these compartments that EBV infects people, then it becomes pre-latent, then latent, and there's a whole series of different latencies, which is how the virus survives in our bodies. Those latency forms are associated with specific kinds of diseases. I'm sorry to tell you that its biology is a lot more dirty than that. It's never clear. It's never like this, okay? But I like to put this up because this illustrates a couple of important features of the virus and how it interacts with its host, us. You know, when EBV infects us, at least in the developed world, most of us get it by the time we're in our teens or twenties. In the low, middle-income countries, underdeveloped world, people are getting infected by the time they're 18 months old. They live with this virus for a long time. So the context of EBV and how it translates to disease in societies like ours versus Sub-Saharan Africa are dramatically different, and that's something we can touch on later. But the virus does hide away and stay with us, and usually, we handle it just fine. But as immune deficiency or as aging happens, and we'll talk about other potential things that set people up for these diseases, EBV can escape, and it can really reprogram B- cells and cause them to do things that they normally wouldn't do, which is undergo immortalization and transformation. So there's a variety of diseases that are lymphoid, that it's associated with. PG laid out the nice summary on T- cell, but also natural killer cells, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphomas, Burkitt's primarily in endemic malarial regions. regions. And the other thing this virus has the capacity to do, even if it's hiding and transforming a B- cell, it's the virus is still there, and it's in the malignancy. This whole concept of using a pharmacologic trigger to reactivate the virus and create a therapeutic vulnerability is super interesting. I'm gonna show you a couple examples of why I think this is something to really pursue and go after. The first point I wanna make is that the EBV-positive diffuse large B-cell lymphoma is not your run-of-the-mill diffuse large B-cell lymphoma. DLBCL is the most common lymphoma, about 20,000 cases per year in the United States. And in 2003, it was observed first by this group led by Oyama, that found that in people who were elderly, and they defined that as people over the age of 60, that there was a subtype of lymphoma that was EBV-positive, where these patients did particularly poorly with standard therapy. This work went on and really described through many, many trials, that this group of patients, elderly patients, really did very bad. The World Health Organization recognized this, and brought this as a classification of malignant lymphoid malignancies that they put out every few years, that included this entity as a provisional entity. That means they were still trying to study it. Then new information, unique pathways, unique mutational landscapes, and a whole lot of other biologies unfolded over the past five to 10 years. In the most recent version of the World Health Organization classification for hematologic malignancies, it's now a designated unique entity. That's important because I'm gonna show you data that really makes the point that this is a unique disease in many ways. Here's the first. So these patients who have EBV-positive DLBCL do poorly. They're usually a little older, they have high risk prognostic scores, very poor performance status going in, and poor response to treatment. As you can see here, this is a paper that was done back in 2006, but you can see all lymphomas that are EBV-positive did poorly, and patients with DLBCL did particularly bad, and this is with standard R-CHOP or CHOP chemotherapy. In a paper by Kieron Dunleavy in the AIDS Malignancy Consortium, also showed that patients getting R-EPOCH, which is a more aggressive lymphoma regimen, also, if they were EBV-positive, they did poorly. So the group of patients, when treated with standard of care, and this is summarized by all these reports here, really shows a pretty dismal overall survival compared to the patients who have EBV negative diffuse large B-cell lymphoma, where the response rates and the overall survival is far more superior. So we know it's a clinically unique entity, because patients don't do well. What else? Well, if you look closely at its pathology, there are many unique features of EBV positive DLBCL. So first of all, it's a non-germinal center phenotype. What does that mean? There's different stages of B-cell development. Germinal center is more of the terminal development, where it's migrating more toward what's called a plasma cell. And in general, you think a more developed cancer, a more mature cancer is gonna be better. Well, these lymphomas are typically much more aggressive, even EBV-negative, and they're distinct from other types of diffuse large B-cell lymphoma. But there's a diverse morphology. This doesn't look like a typical post-germinal center DLBCL, because there are many morphologies. When you look at it under the microscope, you'll see a polymorphic phenotype in one patient, where you have all sorts of cells infiltrating. You'll see occasional tumor cells, almost looking like a Hodgkin's lymphoma type picture, and then you'll see this other group that has this monomorphic. And the interesting thing is, regardless of what type of morphology we see under the microscope, all those patients do badly, okay? Unlike PTLD, where you have a polymorphic PTLD, which is occasional tumor cells and a sea of immune cells, versus monomorphic, which is like a diffuse large B-cell. Two very different outcomes with those patients in the PTLD. DLBCL world, regardless of morphology, they do bad. They have B-cell markers, high proliferative index, as you see here at this, you know, near 100% Ki-67. They're monoclonal. They are always EBV positive, whether you call it 1%, 10%, or 100%, that's not been defined. But suffice it to say, if an EBV signal is positive in a DLBCL, that patient gets lumped into a category of very poorly, very poor outcomes. Latency pattern is variable and needs to be studied more. And new data has emerged showing CD30 expression, potential vulnerability for drugs like brentuximab. But the other really key feature here is that these tumors display a very cold tumor microenvironment from an immunologic standpoint. So you wonder, what's the impact gonna be with CAR T cells, bispecifics, brentuximab? You wonder if this particular group of patients will be more refractory to immune therapy, and I have an example that I'll show you. And then the other interesting thing that I'll touch on now is the unique mutational signature. This is just a whole different animal.... So when we look at the mutational landscape, nice paper by Frontzek Group in Leukemia this year. They did targeted sequencing of recurrent somatic copy number variants in 60 EBV-positive DLBCLs, and they used this typical tool called a LymphGen classifier, which showed that less than 20% of these EBV-positive lymphomas corresponded to one of the established molecular DLBCL subtypes that's defined by this LymphGen. So, you know, 80% of these EBV-positive DLBCLs don't look like a diffuse large B-cell lymphoma. The recurrent mutations were odd. NOTCH mutations, STAT mutations, JAK-STAT mutations, epigenetic mutations involving KMT2D and TP53, FOXO1. These are all mutations that are unique and really just pointing out the features that truly need to be dug into and investigated. And then from an immune signature standpoint, amplification of chromosome 9p24, where the PDL1 locus is. These are amplified, and these tumors express tons of PDL1. You know, that's an immune suppressive tumor microenvironment marker, and I'll show some data on that. And then a recent paper by Cho in Cancers showed a TET2 signature and another mutation, this LILRB1, which is a immune suppressive marker that interferes with class I antigen presentation. So the other interesting thing about a mutational landscape is this feature of clonal hematopoiesis. Remember earlier I said that we don't know that why some people are vulnerable to developing these types of diseases. Well, clonal hematopoiesis, CHIP, it's called Clonal Hematopoiesis of Indeterminate Potential. This is becoming a field that is really pointing toward the importance of genomics and vulnerability to develop all sorts of diseases, hematologic, cardiovascular, liver, I mean, every system is affected by CHIP, and in particular, lymphoma. If these guys did this targeted RNAseq in 100 patients with EBV-positive DLBCL, and compared it to 700+ patients with EBV-negative, and the features that they found were these TET2, ASXL1, DNMT3A, and TP53. These are the top four CHIP-related genes that were found to be mutated in EBV-positive DLBCL. What does that mean? Well, that's unique to EBV-negative. MYD88 mutations, typically found in all DLBCLs, virtually absent in EBV-positive lymphomas. This genomic landscape of this class of lymphomas is distinct from other EBV-positive lymphomas. Okay, so if you look at EBV-positive DLBCL compared to plasmablastic lymphoma, Hodgkin's lymphoma, extranodal NK/T-cell lymphoma, they don't look alike, even though the virus is present. Again, pointing toward the unique nature of this type of disease. Super interesting thing here is that the top most frequently mutated genes in this group of lymphomas, seven were of myeloid type. So lymphoid malignancies typically have lymphoid CHIP features, lymphoid mutations. This is a myeloid mutation landscape. That's just unusual. We don't know if these are somatic mutations limited to the tumor versus post mutations, but that's something that needs to be explored. But regardless, it's an interesting feature. The other thing that's interesting about this, nice paper by Chris Flowers' group, a couple years ago, showed that patients with African American ancestry did particularly poorly who had diffuse large B-cell lymphoma and showed the same mutational profile of myeloid CHIP genes. Then when you think about this and how the outcomes of these diseases and the types of disease frequency you see in sub-Saharan Africa, it's off the charts. It's the number two malignancy in men in places like Ethiopia and Kenya. So again, there's a lot of interesting genomic features here that really translate and kind of make sense when you look at different subpopulations. This is just a collection of the different mutations from this paper. And then to talk about the immune evasion and immune suppressive microenvironment. This is a paper that showed that patients with EBV-positive DLBCL contained a much higher percentage of tumor cells that had PDL1. And when those tumors had PDL1 in them, and then T cells that had migrated to the tumor that were PD-1 positive, which is virtually 100% of the EBV-positive DLBCLs, the survival was just dismal. Okay, and that makes sense. And then other studies, you know, the one I talked about with that other mutation that points toward MHC dysfunction. You know, these are collective features that identify this as a disease that may not be a great disease for immune therapies, at least in the upfront setting. And we already know that patients who get CAR- T cells don't have a universal good response, right? It might be upfront, but then the durability of that response falls off. I wonder what we're gonna see if we start looking a little deeper into this group of patients. How does EBV contribute to the pathogenesis? We have that mutational landscape that's new, the immune microenvironment. The virus is jam-packed with all sorts of genomic open reading frames that drive signaling, immune escape, mitochondrial dysfunction, epigenetic dysfunction, molecular mimicry, angiogenesis. It's across the board. If you look at the features that are required for driving cancer, EBV fulfills every single one of them. Sounds bad, but there's also room for opportunity to go after some of these unique features, unique targets, unique pathways, and that's what I believe Viracta is onto here. You know, when we bring EBV oncogenes into the picture, like latent membrane protein, we know that it can set signaling pathways up to really drive stress response, NF-kappa B signaling, especially in this group of lymphomas. Programs that drive B-cell development and keep it in the B-cell development pathway. Epigenetic remodeling, where you see this LMP oncogene drive an arginine methyltransferase epigenetic program, a DNA methyltransferase epigenetic program, a lysine methylation program. These are all intertwined and interrelated. And when you introduce agents like nanatinostat, you have the capacity of remodeling, not just the viral genome and drive kinase target expression, but also the host genome, to lower the apoptotic threshold, to change the survival pathways that the host cell uses, and it gets hijacked by the virus to drive perpetual growth and survival. So I'll just end with a case report that I think brings home several good points here about this disease. This is a 31-year-old patient of mine who had HIV. He was on antiretroviral therapy and was controlled with an, from an HIV perspective. He presented with a 60-pound weight loss, fevers, diffuse bulky lymphadenopathy, and here's his PET scan. You know, bright, diffuse lymphadenopathy, some extranodal disease. He gets biopsied, and it's a germinal center, a non-germinal center, CD30 positive, EBV positive, diffuse large B-cell lymphoma, really just hitting the criteria that you know that we're looking at here. So I treated him with R-EPOCH, and after two cycles, he showed disease progression. R-EPOCH is a combo rituximab chemotherapy regimen, and it's an aggressive regimen that has a good outcome with most diffuse large B-cell patients. He developed respiratory failure with disease progression, went to our MICU, was on a ventilator. I gave him another salvage regimen called RICE, which is a higher dose, more intensive chemotherapy. Then after he got extubated, stabilized, outpatient, we then gave him more salvage therapy with GDP. Then he came in with an unsteady gait, couldn't function, couldn't speak, and had this really large mass that we biopsied, and it was the same exact lymphoma that was, that he was diagnosed with in to begin with. We gave him high-dose methotrexate regimen called RMPV, and his disease progressed. So at this point, we then tried to bridge him to CAR- T cells. Yescarta is the product that we've given to most HIV positive patients, and he developed cytokine release syndrome, and the MRI showed disease progression again. So after that, we took what we've learned from our work in the past, where we studied how you can induce kinases with low-dose radiation. We had first reported this many years ago in Cancer Research using a rat model, but also showing our first patient who had a primary CNS PTLD. And the idea here was to give this patient some palliative radiation and put him on an antiviral regimen, which contained ganciclovir and AZT, rituximab, and a steroid to reduce the swelling. And what we found here was the same kind of result we've seen in our paper that we published in Clinical Cancer Research, where there was a 90% complete response rate when we used just the antivirals alone, no radiation. So in this case, this patient, after 30 days, had an improved MRI, clinical status, all of his symptoms went away. We continued him on oral AZT and ganciclovir. Ninety-day post-MRI showed continued improvement in the MRI. We just literally yesterday got his ctDNA from the CSF, and it was negative, which indicates a complete response. And he's on ibrutinib maintenance and is being considered now for an allogeneic stem cell transplant. So targeted therapy at these kinases can be very potent and long-lived. And I'll say we have a study following up on this antiviral regimen, giving rituximab, AZT, ganciclovir, and we have an additional 20 patients on it, and the overall response rate remains the same, the survival remains the same, with almost just less than 10% of patients developing progressive disease. So we've done this in other patients with plasmablastic lymphomas that are EBV positive, low-dose radiation, this GCV regimen, and they both had complete responses going out two years. My point being is that this is a horrible disease. We can't treat it like we do other lymphomas. We can't just keep on going with the chemo. And CAR- Ts, who knows what it'll look like when we get that. Hopefully, get more data out of the large trials, and we kind of just, you know, look at and dissect out which ones were EBV positive and how'd they do. That's something we hope we can do soon. So to summarize, this is a unique entity defined by WHO. It's more aggressive clinically. It's associated with very distinct biological features from a genomic standpoint, epigenomic standpoint, virus standpoint. Most studies show poor outcome with standard of care therapies, and the majority of EBV positive DLBCLs belong to a group of lymphomas called non-germinal center, also associated with a poor prognosis. So our future considerations from a regulatory standpoint. Should the efficacy of a new therapy targeting EBV-positive DLBCL, like Nana-val, be compared to standard of care? And this could be considered as a discussion with the agency on this as a unique disease entity. Also, can we make the case that this is not adequately treated with current standard of care? I think we can. I think the retrospective data clearly shows it. I'm really looking forward to getting the data from the CAR T and teasing that out. We want to really work together to collect real-world evidence from this area. With that, I'll pass it back off to Mark, and appreciate everyone listening. Look forward to the discussion. Thanks. Thank you very much, Professor Baiocchi. I, I think we're very convinced about the distinct difference of EBV-associated DLBCL and the worst prognosis of these patients. Now, I'd like to hand back to Darrel, who's going to speak to the data that we have in DLBCL from our 201 study. Thank you, Mark. When you think about clinical development of a novel, cancer agent in a serious life-threatening disease with high unmet medical need, like, EBV-positive DLBCL, which sits in a landscape of EBV unselected DLBCL with a number of treatment options, be it chemotherapy, antibody-based therapy, CAR T-cell therapy, even, bispecific T-cell engagers now, it seems quite daunting. But I hope, Dr. Baiocchi and, and I can convince you that if EBV positive DLBCL is not the same biologically or therapeutically, as EBV negative DLBCL, because it has a significantly worse prognosis, because it is a unique disease subtype, with its own classification designated by the World Health Organization, because it has a distinct biological feature and mutational landscape, as well as an immunosuppressive tumor microenvironment, then there may actually be a lane for a EBV-targeted agent like Nana-val to sail. And the reason is because there are no approved treatments specifically targeting EBV positive DLBCL. And so if we can get the message out, that message out and encourage more EBV testing of patients with DLBCL, because we now have an actionable investigational product in clinical trials, specifically the NAVAL-1 clinical trial, available to those patients, and convince treating physicians, investigators, and regulators that EBV positive DLBCL may not respond the same way to standards of care, then we should be able to not only enhance enrollment onto our NAVAL-1 clinical trial, but also provide a meaningful new treatment to these patients desperately in need. As mentioned earlier, EBV positive DLBCL was one of the three prioritized indications for continued enrollment in NAVAL-1 because of its relative incidence, its high unmet medical need, and favorable phase Ib/II study data, which we'll show and update you. Right now, we're evaluating in the third-line treatment setting, excluding patients who are otherwise eligible for hematopoietic stem cell transplant or CAR T-cell therapy. And so because of that, because there are really only fully approved CAR T-cell therapies in the second- and third-line treatment setting, we're also eyeing the possibility of allowing investigation of second-line DLBCL patients as well. Also, because when a variety of patients with heavily pretreated, advanced, EBV-positive relapsed/refractory DLBCL were enrolled in our phase Ib/II study, specifically 10 of them, seven who received the capsule and an additional three who received the tablet, there were nine response-evaluable patients, and you can see they consistently had an overall response rate, quite impressively, of 67%, with a complete response rate of 33%. And this included patients who didn't even respond to first-line chemotherapy, such as R-CHOP. What's more remarkable is that the median duration response in these six responders has not been reached, and the three responding patients are still on study treatment with duration of responses of 11 months, 37 months, and 42 months as of May 2023, and still ongoing. So again, testimony to not only the therapeutic efficacy of the product, but also its tolerability to support chronic daily dosing. But what's next? Well, just as in the case of our PTCL clinical development program, we hope to complete enrollment of Stage I and Stage II, Stage I of the study in 2024 and advance Nana-val into Stage II, if the phase II data support the previous phase Ib clinical trial data. We hope to present those data in 2024, and successfully complete enrollment of Stage II, and like for PTCL, meet with the FDA to align on a potential accelerated approval pathway. Hopefully convince that EBV-positive DLBCL is a distinct disease with no available treatment options, specifically for that subtype. And then present those Stage II data in 2025. So, and the microphone back over to Mark. Thank you, Darrel. That completes the focus on our lymphoma program. What we're gonna do now is transition to the new frontier. This is the solid tumor program, and we're gonna share with you the phase Ib data, as well as some very important preclinical findings that will support dose escalation. I think I'm gonna hand that straight back to you, Darrel. Thanks, Mark. Good to see you all again. So it shouldn't surprise you that with an EBV-targeted agent like Nana-val, we're gonna want to investigate it into every EBV-associated cancer, wherever it may be. That includes advanced solid tumors beyond lymphoma. And that includes nasopharyngeal carcinoma, as shown here, as well as gastric cancer. Now, nasopharyngeal carcinoma is a serious, life-threatening disease, primarily endemic to Southeast Asia, but also seen in the U.S. and Europe. The available treatment options are not very good. Basically, chemoradiation and possibly salvage chemotherapy with or without immunotherapy with a PD-1 inhibitor. But after that, there are really no good alternate treatment options for these patients, and they have a relatively poor prognosis at that point. So, we designed this phase Ib/II study to address this high unmet medical need, basically to establish a phase II dose, specifically in this patient population, and then take that phase II dose into phase II clinical trial to further evaluate its efficacy and safety in an additional 60 patients randomized to receive either Nana-val alone or in combination with pembrolizumab. And additionally, take that phase II dose to explore other EBV-positive solid tumors, including gastric cancer, as you can see there, and some other rare tumor types in an additional 10 patients. So here are the initial data from the phase Ib portion of this study. These data were presented at the ESMO Immuno-Oncology Conference last year. But just to remind you, or if you're seeing this for the first time, we started at the recommended phase II dose of 20 mg once daily, four days a week of nanatinostat, and valganciclovir, 900 mg per day. That was used in the positive lymphoma studies. Then we increased the dose from 20 mg up to 40 mg once daily. What you can see on the far right, where each circle represents a separate patient, we saw some stable disease at the first dose level, but interestingly, a partial response at dose Level 3. And this response, again, was in a heavily pretreated patient. The patient received three prior lines of standard chemotherapy, radiation therapy, progressed, and is still ongoing over seven months after the data cutoff date and is still ongoing today. So there's opportunity to dose escalate further, and the protocol was amended to evaluate higher dose levels. But before doing so, emerging non-clinical data were revealed that suggests we may be able to modify the dosing regimen to enhance antitumor responses. And for that, I'm turning the mic over to Ayman, our Chief Scientific Officer, to review those. Thank you, Darrel. So, what we did, we did some experiments, based on our understanding of the biology of the virus and the, the pharmacokinetics of our drug. And we basically, the idea here is to maximize the efficacy of nanatinostat by maximizing expression of this viral protein kinase, which is the enzyme that activates the kill. And what we found was, that basically we need to treat nanatinostat, treat these cells, for about eight hours in order to get maximum expression of this viral protein kinase. But we know from our pharmacokinetics that nanatinostat lasts in the circulation for about four hours. So the question was, how do we account for the additional four hours that we need to cover for? And the idea was to split the dose of nanatinostat. So instead of using, for example, 40 mg as a single dose of nanatinostat, we'd split the dose into two doses, four hours apart. We did PK modeling, and we looked at, you know, based on patient pharmacokinetics data, and we found that this actually works really well. So we took that into an animal model, and you can see here on the right-hand side, these are specimens from EBV-positive gastric cancer. If you look at this panel here, these are animals dosed with single doses of nanatinostat. This is how much expression of this EBV protein kinase, the enzyme that activates the ganciclovir. But if we do the split dosing, you see a significant increase in expression of this viral protein kinase. So that was quite encouraging. So we took this one step further, and we looked at antitumor activity. Does this correlate with antitumor activity? And if you look at the blue line here, or the blue curve, these are animals dosed with single doses of nanatinostat. If you look at the green curve, these are animals dosed with split doses of nanatinostat, and we see a significant increase in antitumor activity when we do the split dosing. So this was the rationale for using split dosing, and so for that, I'll turn it back to Darrel. Thank you, Ayman. So in the design of a protocol amendment to explore higher dose levels, it only made sense to evaluate this new split dosing regimen to see if we can safely drive additional antitumor responses. So we incorporated these two additional dose levels, basically, 20 mg of nanatinostat as a split dose of 10 mg, 4- hours apart, as well as 30 mg of nanatinostat in divided doses, 20 mg and 10 mg, 4- hours apart. Again, four days a week, together with valganciclovir on a dose-intensified basis. Again, when you see the preliminary results that have not yet been presented publicly, but will be presented in an upcoming international congress, you can see that there's been some additional stabilization of disease, and again, an additional partial response at the highest dose level, which is very interesting. The other interesting feature, again, when you look at this in combination with the earlier dose level, there's a suggestion of a dose response because we're starting to see responses, partial responses at the higher dose levels. The other interesting finding is that if you compare dose level two of 30 mg administered orally once daily four days a week with the same 30 mg split into two doses, 20 mg and 10 mg, 4- hours apart, again given once daily four days a week. You can see there was none of the four patients at dose level two responded, but you had one partial response, plus a couple of disease stabilizations when you split the dose, suggesting adding clinical benefit of doing so and supporting the hypothesis that was generated non-clinically. In fact, if you look at this patient who was treated with the 30 mg once daily on a split dosing regimen, you can see this patient was a 56-year-old male with recurrent metastatic EBV-positive nasopharyngeal carcinoma. This patient had actually failed prior chemoradiation therapy and chemoimmunotherapy, including pembrolizumab. And you can see a baseline has evidence of a posterior mediastinal tumor in the lymph node chain adjacent to the spine, as well as another one in the midline retroperitoneal area. And again, these are just representative sections. The disease was more extensive than that. And you can see at week eight, there's been about a 40% reduction in that tumor size. And again, this is impressive for any patient with pretreated advanced solid tumors, let alone in a phase I dose escalation study. And again, this patient actually was diagnosed with this partial response early in August, and completed a week 14 scan very recently, is still on treatment. We're waiting for confirmation that this response is still ongoing. When you look at the safety profile across all of the dose levels, including the once daily and the split dosing regimens, you can see that the treatment-related adverse events were generally manageable, if not reversible, as the majority were mild to moderate severity, and again, primarily gastrointestinal and hematologic in nature, with some increased creatinine related to the valganciclovir. Generally familiar to treating oncologists. And again, there was no dose-limiting toxicities at any of the dose levels observed. This gives us the opportunity to potentially dose escalate even further, and evaluate even higher split dosing levels. But before doing so, additional non-clinical data emerged that suggested that we may be able to optimize the dosing regimen even further. I'll pass the mic back to Ayman. Thank you, Darrel. So, we basically... As you can see, we have partial responses. We're seeing stable disease, but we haven't seen any DLT, so definitely there is room for improvement. And the idea here from this, these sets of experiments, basically was to analyze, you know, four days on, three days off strategy in solid tumors. And what we found, which was extremely interesting, is that when we give the drug for four days, you know, you suppress tumor growth, but then when you leave it for three days in solid tumors, the tumor starts growing again. And so, what we decided to do was basically, let's change the dosing regimen, so we do it daily dosing, and you can see nice control of the tumor growth here. And that's... I apologize for this close picture, but, you know, you can see that we are really shrinking the tumor as a result of this treatment. So we believe that we're introducing two modifications at this point to our dosing regimen. One is splitting the dose of nanatinostat, which basically activates, maximizes expression of the viral protein kinase, which activates the kill. And we are doing daily dosing, which gives us better control and more efficacy as far as antitumor activity. With these two modifications, we also have the potential to extend our Nana-val patent portfolio. So we've actually filed a provisional patent application for these two changes in dosing regimens. Back to you, Darrel. Thanks again, Ayman. So with these additional non-clinical data suggesting we can do even better on a split daily dosing regimen, we're presently amending the protocol to investigate three higher dose levels, 40 mg, 60 mg, and 80 mg on a split daily dosing regimen. Eighty mg representing the maximum tolerated dose determined in a past phase I study of nanatinostat alone. And so you can see here, we are both increasing the dose and the duration of nanatinostat therapy in the hopes of safely driving further responses and hopefully without dose-limiting toxicity. And again, there's a typo in dose level seven, that is, should be 30 mg and 30 mg, adding up to 60 mg on a split daily dosing regimen. So what's next? Well, we're gonna be presenting preliminary phase Ib data that you just saw at an upcoming medical conference. And in so doing, disclosing our new split daily dosing strategy as we're doing so today. And then hopefully complete phase Ib dose escalation with those additional dose levels in 2024, determine its recommended phase II dose, and present those additional data in time to initiate the phase II randomized part of the study with and without pembrolizumab. And, you know, if we start seeing substantial responses in a pretreated current metastatic nasopharyngeal carcinoma patient population, we may be able to carve out another accelerated approval registration pathway without the need to add pembrolizumab. That would be exciting that we would potentially know that in late 2024 or early 2025. In addition, we're gonna take the recommended phase II dose into patients with advanced metastatic gastric cancer that is EBV positive. About 8%-10% of those patients have EBV-associated disease, together with some rarer tumor types that I showed on the previous slide. That should hopefully also initiate sometime in 2024, and that'll set us up to present those data and potentially further evaluate Nana-val in that population thereafter. So thank you. you. Thank you. I look forward to the discussion, questions, taking your questions and questions later, and I'll hand the microphone back to Mark. Thank you, Darrel. So we're gonna have a few concluding remarks and then some time for Q&A. In the concluding remarks, I do wanna touch on the commercial opportunity. So what you see here is estimates of the epidemiology for the United States for the three key lymphoma subtypes that we've prioritized. What you can see is the annual incidence rates for these, as well as the prevalence of the relapsed refractory population, giving a total potential addressable population that you can see in the column. And the reason we're signaling both to you is that clearly we're studying the relapsed refractory population at this time. But given the nature of this targeted treatment for the EBV populations that don't do so well, we will ultimately be looking for earlier line usage. And you can see to the right, the associated EBV positivity rates. And maybe I can just say a little bit more about these indications and other considerations when you think about the commercial opportunity. Firstly, from a pricing point of view, we are looking to address high unmet medical need, and we've seen very low survival rates in the EBV subpopulations. And so we're looking to bring a valuable medicine to the world that makes a real difference to patients facing a really poor prognosis. Secondly, as I mentioned, we may be in the relapse refractory arena, but in time, we may well look to first-line usage. Thirdly, I think very importantly, you've seen that relative to prior treatments that have been studied in, for example, PTCL, we're seeing a very attractive duration of response. So that speaks to longer usage on Nana-val. With DLBCL, we have not yet been able to calculate a median duration of response since half the responders are still on treatment. Then the final thought here is, what we're looking to bring to the world is an all-oral combination that can be used in the outpatient setting. So again, I think that facilitates adoption and penetration. So we'll develop these themes more in the future, but I think there are many aspects about this program which are commercially attractive. I ought to just briefly touch on the fact we've got here an additional selection of additional countries, such as European countries, Japan, because the other factor here is the global rollout of Nana-val. So we are actively engaging with the European Medicines Agency, with the PMDA in Japan, as well as the FDA, because we want to make this available to patients globally. So to conclude, we've seen with PTCL, with Professor Porcu, you know, EBV-positive PTCL has a high unmet medical need. We don't have approved therapies for relapsed/refractory PTCL, nor indeed, of course, EBV-positive PTCL. And the NAVAL-1 data, the first data that we've shared out of the pivotal phase II study, showed a 40% ORR and complete response rate, and is consistent with the phase Ib/II study, the 201 that was previous to that. And for the first time, we have long duration of follow-up, giving us a long median duration of response on Nana-val. But EBV-positive DLBCL, Professor Baiocchi, I think, made a very convincing case that EBV-positive DLBCL is a unique entity, and we need to address that specifically because these patients are not responding as well to standard of care. And we showed in the enlarged and extended follow-up data from the 201 study, 67% ORR and a 33% complete response rate, and a duration of response that's still being calculated. And then finally, in the solid tumor setting, we showed some phase Ib dose-ranging data with two partial responses and five stable diseases of the 17 patients treated with recurrent metastatic EBV-positive NPC. And we have a real interesting opportunity to optimize the dose using this innovative split daily dosing regimen going forward. I'm not gonna reiterate all the milestones, but this is just a summary of the milestones. Needless to say, we are marching forward as fast as we can with our lead program in PTCL to bring that to market as quickly as we can. But we're also very excited by what's behind that, and also the new frontier opening in the solid tumor setting. So I would like to invite all the panelists to come up, please, and we'll start by taking some questions from the audience here. But I also know that we have questions coming in from those that are remote. And I would also like to invite Dan Chevallard, COO and CFO, to join us. Please. You wanna speak into the microphone or is there one coming? Oh, sorry. Hi, guys. Robert Burns from H.C. Wainwright. Three questions from me, if I may. I guess the first one is to the KOLs. So can you comment on the potential of the cell-based therapies, either CD30-targeted or the EBV-specifics, such as those being developed by Affimed and Atara, in both EBV-positive PTLD as well as the CD30-positive lymphomas, and how would you utilize those potential agents versus the small molecule-based therapies such as Viracta? I can take that. Okay. So the cell therapy landscape right now, at least in peripheral T-cell lymphoma, it's really very, very narrow in my view, at this point, with no clear front runner. It's true that the CD30 targeting CAR-Ts are developing well, but most of the data really are in Hodgkin's lymphoma, which is, you know, the primary target for those. The best of my knowledge is at this point, there's really no good cell therapy product that is looking good in peripheral T-cell lymphomas. And a lot of the studies that, just like the one I showed, with the anti-CD5 myeloid, that really went nowhere. There is a CD38 targeting effort with CAR-T that was just recently published, and they published data on a lot of different diseases. This was in Blood Advances from the Penn Group, and there no data in peripheral T-cell lymphomas, and I know that there are no data in peripheral T-cell lymphoma. Awesome. Thank you. Two more questions, and this is for more of the management team. So since the DLBCL population in the phase I/II trial included patients who only received one prior therapy, I'm curious to know what percentage of those patients who responded were second-line patients and not third-line plus? And if the basis for the prioritization DLBCL is based on that phase I/II data, or if you've also started to see responses in the NAVAL-1 Stage I cohort. Maybe I'll start that one. So we're very mindful of the point that you've made. You know, more and more, as we think of the uniqueness and distinctness of the EBV positive subpopulation, and I think Darrel alluded to this, you know, we really wonder whether it makes sense to just focus on the third line group, that in fact, there really is, I think, an opportunity to extend the NAVAL-1 study to include second line. So that's something that we'll come back to you on. But I think to answer your first question, which was, you know, what proportion were indeed second line treatment, I think that's a pretty high proportion. Yeah, it was the large majority, but hopefully, we convinced you that the line of treatment shouldn't matter if you select patients for EBV-associated DLBCL. And also, I remind you that while this NAVAL-1 study was designed in the third line treatments and predominantly to support an unmet medical need population with no alternate treatment options, since we're excluding patients who are otherwise eligible to receive hematopoietic cell transplantation or CAR T-cell therapy, CAR T-cell therapy is being fully approved, both in the third line and, of course, beyond recently in the second line. It shouldn't matter whether we enroll patients in the third line or the second line to preserve that treatment opportunity, especially if we continue to exclude patients who are otherwise eligible for CAR T-cell therapy. And so we're actively considering making that available. Awesome. Thank you for that response. Last question from me, and then I'll hand the mic back to everyone else. So since the standard of care in frontline NPC is likely to include the use of toripalimab, an anti-PD-1 inhibitor, after, you know, everything that occurred with them, what do you view as the benchmark that NAVAL-- that Nana-val plus minus Keytruda will have to meaningfully surpass for it to become the standard of care in the relapse-refractory setting? Yeah, I'm not sure that the potential approval of toripalimab with chemotherapy in the frontline setting really is gonna affect what happens in an EBV-positive recurrent metastatic nasopharyngeal carcinoma subsequently. We know that in part because we're seeing responses already in patients who've previously received immunotherapy. So, the fact that another PD-1 inhibitor makes it into the frontline setting, I think, if anything, makes it more challenging to move forward with Nana-val in combination with pembrolizumab. And so that's something we're actively evaluating, but it wouldn't affect moving forward if we continue to see responses of Nana-val in our phase Ib and then phase Ib study without the addition of pembrolizumab. So stay tuned. Good morning. Thank you, everyone. Good morning. I have a bunch of questions, but I'll kind of keep it limited. So I was wondering whether or not this interesting split daily dose finding that you're seeing for solid tumors would also be beneficial to lymphoma, and then whether or not there's, you know, again, you're so much further along there, so much closer to the end line, but does it make sense to apply that, or does it scientifically apply to lymphoma as well? That's my first question. Maybe I just start by saying thanks for the question. I think that one of the important distinctions between the solid tumor program and the lymphoma is the state of the patients. And we're looking at long-term chronic use, so the safety considerations are an important factor here. So when we looked at four days on, three days on, in that setting, you know, it was really important to consider long-term chronic use exposure and the safety implications. That doesn't preclude the idea of doing what we just talked about in solid tumors, but I think we're seeing really good data coming through, and we're seeing long-term chronic use. Ayman, do you want to add anything? Yes. Just to add one thing, you know, which is, we have to keep in mind the nature of the tumors we're dealing with, right? Solid tumor versus lymphoma, the tumor microenvironments, and so forth. So that's something that, you know, as we are thinking of split dosing, that's something we have to consider as well. I also think it's important to point out that your preclinical data was using a NPC model, and before this, we didn't have a preclinical model for EBV-positive DLBCL, but we do now, and we'll be collaborating to do those studies. And if there's a remarkable signal, perhaps there'll be a rationale for thinking about that. That's really helpful. And then I... You know, I've been impressed, and I really appreciate both of your time in terms of setting up the stage for just the differential between EBV positive and negative disease. And I'm wondering, you know, with these compelling results, what does it take to accelerate enrollment here? It seems like this is pretty profound, especially in a landscape where maybe responses aren't quite as high as you see with different phenotype or subsets of disease. So I'm just surprised maybe that we're not getting more accelerated enrollment, and maybe that can accelerate now with these data. Thank you. Maybe I'll start that one and say, well, certainly towards the back end of last year, we were still in that post-COVID phase of site initiation delays, but, you know, as we've gone into this year, it's really picked up. You know, it's a very different trajectory. I do agree with you that this data disseminated to the investigator community will no doubt be motivational. I mean, of course, I'd speak to you guys to comment on that, but the point is, you know, the fruits of the labors are there. Yeah, I mean, I agree. First of all, the paper, the Blood Advances paper that just came out about, you know, 4 weeks ago, 4, 6 weeks ago, I think that that clearly starts putting kind of the EBV-positive lymphomas in the spotlight, and there will be more talk about that. In terms of the approval, as I showed, the PTCL sort of relapse refractory landscape is barren right now. And I think that this was in some of the slides, although it probably needs to be emphasized. At the moment, there's no FDA-approved drug for relapse refractory PTCL because those three that were approved, romidepsin, belinostat, and bortezomib, they did either failed their confirmatory studies or they're never gonna do a confirmatory study. So I think it's clearly a high opportunity in PTCL, for sure. Yes, Stephen Willey from Stifel. Maybe a question for Dr. Porcu. Can you just talk about the role of transplant in relapsed/refractory PTCL? What proportion of patients are typically eligible? And then how does that factor, I guess, into the clinical development plan for those patients who are put into a remission with Nana-val? And maybe what would be the regulatory implications of that when you're trying to look at a median duration of response? Yeah. So that's a great question. So I would say that in terms of transplantation, hematopoietic stem cell transplantation, the autologous stem cell transplant, the role for that is, in PTCL, primarily is a consolidation in CR1. If you do an autologous transplant in remission, any other line of therapy, CR2 or later, the data are extremely poor, and therefore the outcomes are no good, and people don't do it. Even in the front-line setting, if you look at real-world data, only no more than 10%-15% of the patients who may be able to get autologous stem cell transplant with PTCL actually are getting it. So it's really kind of it's not having a great, great impact. On the phase Ib study that was just published, patients who had achieved a response, and they were deemed eligible for stem cell therapy, either autologous or allogeneic, some of those patients actually went on. In fact, there were, I think, a couple of patients that were able to go through with allogeneic transplantation that prior to enrolling on the study, had never been in a response status to be able to be eligible for that. So, I think the impact is modest in terms of any kind of regulatory strategy for the kind of positioning of this therapy. Patients may go and be able to have a stem cell transplant later, you know, if they are fit and they have a response. Maybe just a quick question for either the management team or the physicians, but how does baseline viral load or copy number correlate to outcomes, if at all? And does the reduction in that marker over the course of treatment correlate to the depth of clinical response? Maybe, Ayman, do you want to take that? So I'll take that. So, we have been monitoring, and we are still monitoring, plasma EBV DNA, you know, whether it's at baseline or even longitudinally. And, we've seen some correlations where we see some, you know, if a patient responds, you know, then we see a reduction. Sometimes if they don't respond, maybe it doesn't change or it goes up, but it's not in all the patients. And, that's in the lymphoma setting. In nasopharyngeal carcinoma, it's well known that the plasma EBV DNA is a very good biomarker. So that also we are monitoring in the solid tumor trial. Yeah. This is Supawat Thongthip from RBC for Gregory Renza. I have a quick question for Dr. Porcu. PTCL is such a heterogeneous disease, and obviously the commonality in this study is EBV positivity. I'm just curious to hear if you think there might be differences in terms of responses to this treatment strategy. In PTCL in general, EBV positive versus EBV negative, we don't have the data for that really in any kind of granularity, as opposed to, for example, the landscape in DLBCL that Baiocchi here presented. That is because it's such a heterogeneous disease. So I think that at this point, you know, whether it's immunotherapies with checkpoint inhibitors, for example, or it is targeted therapy with HDAC inhibitors, at this point there's not enough information to really tell whether being EBV positive or not would make a significant difference in the response for that. A second question to Dr. Baiocchi. I mean, you presented a number of data to suggest the uniqueness of EBV-positive DLBCL, but I'm just curious if you can point to maybe any ongoing study or the study that you think would get more buy-in from physicians to adopt, you know, or to look into this strategy. I think, for this cohort of patients, that there would be great interest, especially with some of the evolving emerging data here, to enroll patients, with EBV-positive DLBCL. There may be alternate strategies where we could, we could leverage groups like the AIDS Malignancy Consortium, other clinical trial groups, that see these patients. And that may be a potential strategy that we could, we could consider. I also think preclinical work is also gonna raise the awareness as well, and we're poised to really do a lot of that right now with the development of these new preclinical models. So I think we can do several things on different fronts, clinical and preclinical, that will really allow us to raise that awareness and hopefully get better accrual. If I may, just one last question. So on the NPC, the new dosing strategy, I'm just curious, how strict does the four-hour window have to be? I'm just curious if you have looked into that. Like, what if the patients, you know, forgot to take the second dose, like, an hour later? Do you think that could affect the response to the treatment? So we have actually done experiments where we looked at, you know, 2 hours and 4 hours. So it's not and we've done modeling as well, and we think that there is some room for changes. So it doesn't have to be four exactly, like, you know? Yeah. Hey, hi, thanks. Hartosh Singh with Oppenheimer. Apologies, I was a little bit delayed. Great presentations. two quick questions. One is, the potential meeting with the FDA next year in PTCL, for an accelerated approval, type meeting. Was that, something that had been discussed previously? I mean, or, you know, was there an expectation that assuming, you know, you would go to the FDA with data to have this discussion, or would it be a, you know, sort of a novel, approach with the FDA, with PTCL? You want to take that, Darrel? I think the FDA encourages continual communication with them as we evolve our clinical development plans. I mean, I think maintaining a close relationship with the regulators is critical to our clinical development. So, I mean, to answer your question, while there may not be formal decision, you must come back to the FDA to discuss this, which was not the case. That's something we really wanna do to make sure we optimize the probability of not only technical success, but also regulatory success. I should maybe just add, and I don't know if, Dan, you wanna speak to this, but, you know, there was alignment with the FDA in the end of phase II meeting when that design was discussed and aligned on, and the whole principle was that the stage II expansion would open the opportunity to accelerated approval, but the data will speak for itself. Yeah, just to clarify. So when we met with FDA at our end-of-phase II meeting, not just was NAVAL-1 study's design aligned as having registration intent and on a path to accelerated approval, but the natural opportunity for us to revisit with the FDA was at the end—was in or at the end of phase II. That was a pre kind of understood opportunity for us to go back with incremental data and align on that incremental patient requirement, which we talked about. We believe totals of 60-90, which means incremental 40-70, as well as what that null hypothesis would be required to be in order to enable approval. So it's, it's a natural. As the study was designed, it is the appropriate time to revisit with FDA. Great. Thank you, Dan and everyone. And then just to follow up on the safety database. You know, for the NAVAL-1 study, once you, let's say, get PTCL, you know, filed, will the amount of safety follow-up you'll have to do for the next set of expansion cohorts be less? I mean, I guess what I'm trying to get at is that, you know, at that point, does it become a little bit faster to go ahead and group patients and go and discuss with the FDA? Yes, we think so. I think, just as the current emerging clinical data that's quite promising and favorable should motivate continued enrollment. If we have a successful lead program in relapse refractory EBV-positive PTCL, that should definitely not only drive more enrollment, but I would anticipate it's gonna drive much more EBV testing, which will also identify more patients who could be eligible for, for, those other, other cohorts. So the answer is an affirmative yes. Whether we'll need less, more or less safety data so far, notwithstanding the differences in prior treatment histories, that the different lymphoma subtypes, the patients with different lymphoma subtypes are exposed to, we're not seeing any stark differences. So there may be possibility to-- But at the end of the day, it's gonna be a benefit-risk assessment, not only a risk assessment. We're committed to have at least 100 patient safety, which is not far away, and we'll keep building that. And just last, on solid tumors, does the change in the dosing form, you know, the way you're giving that, will that change how the safety database is sort of accrued there or not really? As long as, you know, they're equivalent, the PK/PD profiles, then it shouldn't be an issue. That's correct. We should be able. Well, we're gonna have to present safety data across both of our programs. I should note that the recommended phase two dose is, if we're able to dose escalate even higher, in the solid tumor program, in part because we're able to set higher hematologic parameters for enrollment, but also because these patients' bone marrows are healthier and able to tolerate higher amounts of anticancer therapy. So there'll be that caveat, obviously, but we'll have to obviously present safety data on Nana-val's and monotherapy, across our entire program to support any eventual regulatory submission. If I were to add one thing, you know, it's known that it's a Cmax that contributes to adverse events, right? So right here we are actually splitting the dose, so we're getting lower Cmax, but more area under the curve. So yeah, expect better safety overall. Are there any questions online that we should be taking? Thanks for those that did submit questions online. We've been able to answer them over the course of this Q&A. Okay. I know we received some, but that's great. Well, if there are no more questions, I would like to draw this to a close and once again, thank our panelists, particularly our opinion leaders who came today to speak to us, and also to you for being here. Thank you very much.