All right, welcome to the Viracta team. Welcome to everybody to this afternoon's presentation. We've got Mark and Darrel here with us. Thank you so much for joining us. Really appreciate your time this afternoon. Welcome, welcome to Miami. Before we jump into some of the nitty-gritty, maybe I, I'd love to give you a minute or two to give us a broad overview of where Viracta is at right now and what you're excited about going into 2024. Wonderful. Well, thank you for the invitation. Thank you. Much appreciated. Just to remind you, we are a company that's focused on the treatment and prevention of virus-associated cancers. And our lead program, Nana-val, which is a combination of two oral agents, is really focused on improving the lives of patients with EBV-associated cancer. And there's about 2% of the world's population of cancer patients that is impacted by EBV-associated cancer, and for the most part, they have a much worse prognosis than patients that are EBV negative. Really, there's a lack of targeted treatments today for that group, and we are pretty much the only game in town that's looking to focus specifically on addressing that patient need. And we're actually in a pivotal Phase II trial in EBV-positive relapsed, refractory lymphomas, and we can speak a little bit about that. Excitingly, we're also in the late stages of a dose-ranging effort in EBV solid tumors, advanced solid tumors. So ultimately, I hope we will end up with a tumor-agnostic EBV cancer label, but I think it'll be an iterative process to get there. But, I think we occupy a very unique space in the cancer field. Well, I guess, in the EBV positive space, also, we have some cell therapies. Atara works there as well- Correct. - especially in that, PTCL post-transplant, Yeah - setting. Yeah. I'd love to hear your thoughts about the difference between cell therapies, EBV-directed cell therapies, biologics, and your oral therapy. Yeah, no, I think it's very exciting that there's a medicine that is being developed for EBV-positive PTLD, so post-transplant. Okay. That's roughly about 10% of the opportunity that we're looking at with Nana-val, which is being developed for a range of EBV-positive lymphomas, such as peripheral T-cell lymphoma, DLBCL, EBV-positive, as well as PTLD, because I think an all-oral combination is going to be very attractive for these patients. But also, we're looking at the solid tumor frontier, so we're looking at nasopharyngeal carcinoma, gastric cancer. And really, that's just the beginning. Which are substantially EBV positive- Yeah - subsets. Yeah. Can you talk a little bit about the relative market size of the EBV-positive subset of some of those key tumor types? Sure. So as you look at the lymphomas that we're prioritizing, 'cause there's more- Of course. But we've taken three to start with. So if you look at PTCL, around 40%-65% of that is EBV positive. If you look at DLBCL, it's between 5% and 15%, and it's a large area- Very large ... but 5%-15% actually have a much worse prognosis with EBV positivity. If you look at PTLD, it's somewhere in the region of sort of 60%-80%, so it's a high level of EBV positivity. If you look at nasopharyngeal carcinoma, it's sort of the 80%-90% level. Correct. Gastric cancer, about 8%-10%, but again, it's a huge area. You know, what is unique is we're looking to target and kill EBV-associated cancer cells. Well, let's talk a little bit about mechanism of action. Sure. It's an oral therapy, obviously. We've seen, in the context of HDAC inhibitors and others there, how are you differentiating on mechanism of action, and what's driving specifically to EBV-positive cancers? Sure. So I'll start, and maybe, Darrel, you can take on the, the relay from here, but, you know, we're using nanatinostat, which is an HDAC inhibitor, at a low dose, so it's not being used as a typical HDAC. As a typical HDAC. It's actually being used to switch on the production of EBV protein kinase. So-called the Kick and Kill sort of mechanism. Kick and Kill mechanism. The production of EBV protein kinase leads to switching on or converting valganciclovir, which is an antiviral, into its cytotoxic form that kills the cell. Right. So it's a Kick and Kill mechanism. So I don't know if you want to add anything, Darrel, but- Yeah, well, compared to other HDAC inhibitors, which have received accelerated approval, for example, in the treatment of patients with relapsed or refractory PTCL, we're combining the nanatinostat with the valganciclovir in that Kick and Kill mechanism of action. And that has translated into dramatic response rates in our preliminary clinical data, which have essentially doubled the objective response rate, greatly improved the complete response rate, and also doubled the duration of response compared to other HDAC inhibitors as a monotherapy. Well, I definitely wanna dive deeper into those clinical responses that you've announced, but before we do that, just to clarify, as you said, this is a lower dose HDAC. How much of your mechanism is driven by the antiviral kill versus the more traditional HDAC inhibitors acting at a higher concentration? So, you know, we- Is it, is it really comparable? We chose nanatinostat because of its high selectivity and potency for switching on the latent EBV virus and enabling the production of EBV protein kinase. And that, you know, allows the valganciclovir, the antiviral to cause apoptosis ultimately. But my point is, you know, maybe we shouldn't be thinking about this as an HDAC combination at all. No. This is not really comparable to a traditional HDAC. We shouldn't think about it as HDAC plus. It's a separate mechanism. It's completely separate. Exactly. All right. So now let's, let's revisit those clinical results that you talked about. Obviously, in some of these viral-driven, virally-driven cancers, the prognosis is especially poor, even compared to other subpopulations in those indications. What are the appropriate comps for these viral positive subsets that we should be looking at when we try to comp your clinical data? Maybe I'll start by quoting survival in PTCL. If you look at EBV positive PTCL, which is roughly half the population, they have an 11% five-year survival rate. If you look at EBV-negative, it's substantially better. So we're really trying to address that really poor prognosis patient population. And in fact, the data that Darrel was quoting against, you know, traditional HDACs was in the entirety of PTCL, including those patients that are EBV-negative and therefore generally do better anyway. So when we look at our data, we really need to look at it in the context. We're looking to address a particularly high unmet medical need, and with ORR rates that are double what an HDAC inhibitor has produced in the entire population. Yeah, quite excellent. So let's think about the translation of your early results to the larger trials that you're now running. How do your thresholds on ORR from the phase one translate as we look into larger studies? It's reminding me that the patient population has shifted a little bit. Is that all right? The patient population has been focused on our three most important indications in our pivotal Phase II NAVAL-1 trial, from six cohorts down to three, where we think we have the largest probability of success, and we will deliver the most value to patients, namely relapsed refractory PTCL, DLBCL, and PTLD. The study is designed as a two-stage Simon design, where the first stage is designed to essentially as a futility analysis, where we're basically ruling out the absence of activity that would portend a low probability of hitting the much higher response rates and durations of response that we are targeting. And in keeping with that, we recently reported that the PTCL cohort basically proceeded from Stage 1 to Stage 2 after five patients were enrolled, with two of those patients achieving complete response that are still ongoing as of this day, which translates to a 40% objective response rate and complete response rate. In those- In those patients. Small number of patients. If that continues, it will certainly make a, a large difference compared to the available standard of care, for patients with relapsed refractory PTCL. Makes sense. Maybe I could just add that that data was entirely consistent with the previous 201 study, Phase I, II study. Yeah. So that gave us some reassurance that, you know, we're seeing a very similar signal. And in that study, by the way, because we have a lot more follow-up, we saw a median duration response of 17.3 months. Really? And what was the, remind me the distribution of indications in those patients? I'm talking just about the PTCL one. Entirely in the PTCL. There are other cohorts. That's, that's- So if you take- Quite remarkable ... I think the eight patients that were available in PTCL, we saw a 17.3-month duration of response. Relatively small cohorts, but really excellent looking data. So, what's the regulatory path in these, obviously, high unmet need- Yeah ... selected patient populations? Presumably, you could hit regulatory milestones with relatively modest phase two trials. And... Correct. What's your plan there? So our plan is, as you know, Darrel was mentioning, we already declared we're advancing to Stage 2 for PTCL. So our plan is, we're pretty much at the end of Stage 1, is to enroll Stage 2, go to the FDA with 21 patients worth of data, 'cause Stage 1 is 10, Stage 2 is a further 11. Sure. You know, assuming we continue to see these ORR rates around 40%-50%, good duration of response rate, as I said- On even 24 patients. That would be, I think, a great dialogue to talk about, well, how many more patients- What do you need? Do we need to satisfy a regulatory approval from an accelerated approval perspective? Our assumption is that it's gonna be around 60-90 patients in total. Could you do that in a single-arm Phase II? We could. I think we can do it by just continuing enrollment in- Yeah. Yeah, we can just- Continue to expand. ... expand our current trial in a single-arm trial. And again, we're gonna make the case that that response rate essentially doubles what's been seen with other HDAC inhibitors in this space, most notably belinostat, which is still on the market for the treatment of relapsed refractory PTCL patients, or romidepsin, where the response rates are on the order of 26%, lasting around 8.5 months, with a complete response rate on the order of 10%-15%. And again, as Mark mentioned earlier, in a patient population that included both easier to treat EBV negative PTCL patients, along with the more difficult to treat EBV positive ones. What about NPC, where, as you say, you have a predominance of EBV positive cancers, in that setting where admittedly standard of care is not?... Not thrilling, could you get away with a single arm trial, or do you need a control group? I think the jury will be out a little bit on that because we are in dose-ranging right now. Right. You know, we're very excited about deploying in the solid tumor setting, which, you know, is distinctly different to lymphoma- Sure. ..you know, pretty assertive regimen of what we call a split daily dosing, having seen already two responses in our dose-ranging, but we're sort of, we have no dose-limiting toxicity so far. It's well tolerated. So we're upping the game here 'cause we think we can hopefully deliver, you know, very meaningful benefit in these patients. And then we're gonna sort of go into the phase two study, you know. So I think it's a little premature to- Well, I'm give you direction on that ... thinking about, the eventual goal of getting tumor-agnostic- Uh ... EBV positive labels. Yeah. We've seen that the agency has been, after seeming to open the door to that, has been very cautious about that in recent years. Have you had conversations with them already about what would be required for this sort of population? Well, that is the plan, but I remind you that we're dealing with patients with relatively rare diseases that are serious and life-threatening. Yes. Really, the alternative treatment options are not very good, especially in relapsed refractory PTCL and in recurrent metastatic nasopharyngeal carcinoma. So if we have a product that's delivering 40%-50% objective response rates, with the majority being complete responses that are lasting over a year, year and a half, you know, I think it's gonna I think we've got a very good chance of negotiating an approval pathway- Seems so- Accelerated approval pathway with the FDA. Fair to say that you'd likely get accelerated approval in some of these liquid tumors first, and it might be a broadening to a pan-tumor indication? I think that's how we see it too. I mean, I think, you know, the lymphoma program is ahead of the solid tumor- Sure ... program, and we do think this is gonna be a kind of an additive approach, where we'll get supplementaries after the first, and then hopefully that will lead to a dialogue: "Well, you know, how much evidence do we need to continue to deliver? To add solid tumors? Yeah. Makes sense. What about non-EBV virus-driven cancers? Obviously, the exact agents are a little different in different settings. But, is the general strategy likely to give similarly interesting results in other virally driven cancers? Like, for example, considering a move into HPV or other types… Exactly. I mean, I think, you know, we keep our options open on other pipeline opportunities that we can, you know that are in keeping with our strategy that we can, you know, build on. But I think our primary focus today- EBV ... is the EBV because it really is an open space. Well, it'll keep you busy for long enough, I think. Yeah. We've got five indications already that we're looking to deliver on, and speed to market with our first, PTCL, is our key goal, right? Yes. As a starting point. In our last couple minutes, I do wanna make sure we talk on larger combos, pembrolizumab in indications for which that's relevant. Given high- I guess it's not monotherapy- Nana-val responses already, what's the additional benefit of a checkpoint, and do you expect to see synergy there? Sure. I think there's good biological rationale for combining Nana-val with an immune checkpoint inhibitor. For one, EBV itself has been shown to induce expression of PD-L1 on tumor cells. Secondly, HDAC inhibitors, particularly inhibitors of HDAC3 have been shown to also induce an expression of PD-L1. We even have non-clinical evidence in a non-EBV model combining nanatinostat with an anti-PD-1 agent, showing potent antitumor activity with the combination. With the combination. We're setting up that opportunity in the solid tumor space to capitalize on that, both the biological rationale and the scientific evidence. It makes sense because with substantial antitumor activity, we're starting to see both in lymphoma and now in the solid tumor space with the liberation of viral antigens, combining with an agent that derepresses the immune system stands to greatly improve the antitumor activity. Excellent. All right, well, in our last few minutes, why don't you please remind us where the catalyst path lies- Sure ... through 2024, and what we should be paying attention to. I think we're setting up for a really important 2024 year with a lot of catalysts. If you think of PTCL, we have Stage 1 data, and that is not only in 10 patients that are on Nana-val, but also in additional 10 patients on nanatinostat alone which is essential to the point of the difference between this mechanism of action versus a traditional HDAC approach. Sure. We're also- At the same doses of nanatinostat? Same doses. So we'll be and there was a randomization as part of the FDA requirement in the first 10 to be able to deliver, you know, that data along the way. The expectation would be that that's a subtherapeutic dose of the monotherapy HDAC? Yes, that's right. Because where you—and not that, you know... In literature, you will see that even at lower doses, you sometimes get some response- Sure ... right? But the point is, we're using, in our mechanism, that dose along with valganciclovir- So you see, To make a difference. ... the contribution of parts is- Correct ... is what FDA is after. Exactly. I mean, then we want to enroll Stage 2. We want to go to the FDA next year with that data and discuss the accelerated approval pathway, and also share that data from Stage 2 at an appropriate venue. So I think there's a lot on the lead indication next year. But we're also looking to advance DLBCL and PTLD, you know, complete Stage 1 enrollment, share data from Stage 1, and hopefully advance those as well into Stage 2. That sounds like most of those key data releases are towards the middle or the back half of the year, or you're not providing guidance? Not guiding just yet, but obviously we'll do our very best to make these as early as we can. Right. And then on the solid tumor side, you know, we're excited about the fact we are actually now enrolling into the sixth dose cohort, which deploys a split daily dosing strategy. Which essentially means we're splitting nanatinostat to give a longer kick, and we're going from four days a week to seven days a week nanatinostat in this setting, where it's so well tolerated, we can... You know, given that these are solid tumors, we're trying to get to- You want to make sure you get good penetration. We're going for good- Kick the entire tumor. There we go. Yeah. We saw, you know, good preliminary evidence of that as we started escalating through 4 and 5 of a split dosing strategy, that that was helpful. So I think next year, you know, we want to share data from our new dose levels. All three of the heme indications, solid tumor, new dose levels- Correct. -and FDA feedback. Correct. Yeah. Well, a very busy year. Just in our last seconds, remind me of your current cash position and runway through these key catalysts. So at the end of Q3, we had around $63 million. You know, we're a very lean operating model that takes us through the end of next year. Excellent. Well, thank you so much for your time this afternoon. It's been been an excellent conversation.