2024 RBC Capital Markets Healthcare Conference. My name is Supavud Thongthip, and I'm Assistant Vice President working with Gregory Renza, one of the Senior Analysts at RBC. We are pleased to have Viracta Therapeutics with us. Joining us is Mark Rothera, the President and CEO, and Darrel Cohen, the CMO of the company. If you have any questions for the team, we'll have a quick Q&A session in the end. With that, Mark and Darrel, thank you for joining us. Maybe if we can just get started by if you could tell us a little bit about Viracta and the kick-and-kill mechanisms, you know, the so-called kick-and-kill mechanisms of Nana-val that's being developed in EBV-positive malignancies. Well, firstly, thank you very much for the invitation today. Perhaps I should share the breaking news that I'm delighted that we're joined today by Mike Faerm, our new Chief Financial Officer, who's here in the audience. Delighted to have him on board. Viracta is focused on virus-associated cancers. As you've just pointed out, our lead program is called Nana-val, and it's directed at EBV-associated malignancies, which is about 2% of the cancer burden worldwide. We're bringing to the world here a very unique mechanism of action. It's a first-in-class. It combines the proprietary nanatinostat with an antiviral valganciclovir for what we call the kick-and-kill mechanism. So what that really means is a cancer cell that has a latent EBV virus in it, we kick that out of its latent state into its lytic active cycle with nanatinostat. It enables the production of EBV protein kinase, and that converts valganciclovir into its active cytotoxic form that kills the cell. Hence, kick and kill. And, you know, to start with, we're testing Nana-val now in a pivotal phase II study in relapsed refractory EBV-positive lymphomas. But we're also doing dose ranging in EBV-associated solid tumors. And we can speak about that later. So we're very excited about that program. And, you know, it really has a unique potential in the world of cancer. Thank you. Thank you. That is very helpful. And you mentioned that peripheral T-cell lymphoma or PTCL is now heading towards a pivotal study. I'm just curious, why was PTCL, you know, EBV-positive PTCL, selected as the lead indication? Maybe if you can tell us a little bit about the rationale and, you know, potentially the opportunities in PTCL. Yeah, you're absolutely right that in the lymphoma area, we're focused on PTCL, DLBCL, and PTLD, and PTCL is our lead cohort. That's the one we want to get approved first through FDA filing for accelerated approval. The reason we're focused on PTCL first is this is an area of huge unmet medical need. Right? If you think about a patient with EBV PTCL, they have a very poor survival prognosis. So only one in 10 patients will survive five years. So it's a really aggressive lymphoma. And there is no standard of care today in second line. So what we're wanting to do is to help patients with EBV PTCL and establish Nana-val as a standard of care for these patients. Wonderful. And you recently shared the Stage 1 data between Nana-val and PTCL, comparing Nana-val to nanatinostat, and we see the differentiation there, you know, in terms of response rate. Just wondering if you can put that into context. How does that data look, you know, compared to the earlier study, the Study 201? And what does it kind of point you to, you know, compared to existing options in PTCL? Sure. Well, let me lead off by saying that based on my vast clinical development experience, a key success factor for the successful clinical development of an oncology therapeutic is observing anti-tumor activity in early clinical trial while you're dose finding. And that is exactly what was observed with Nana-val during its dose finding phase I-B, II study, where, for example, in PTCL, an overall response rate of 50% was observed with a 38% complete response rate and a duration of response, a median duration of response that lasted 17.3 months. We're delighted to report that in our first stage of our NAVIGATE 1 study, which was designed in collaboration with the FDA with an eye toward potential future accelerated approval, where you're right, there was a randomized component comparing Nana-val combination therapy to nanatinostat monotherapy to reassure us and the FDA that both drugs in the combination are contributing to its efficacy, that Nana-val is simply not another HDAC inhibitor. Rather, it's more than that. It is leveraging the kick-and-kill mechanism of action that Mark mentioned is so important for an EBV-targeted agent in that it substantially had more anti-tumor activity than nanatinostat monotherapy, suggesting that both drugs are needed in the combination and with a favorable safety profile, predominantly hematologic and gastrointestinal nature, mild-to-moderate severity, generally manageable, reversible, and consistent with what was seen in the earlier clinical trial. Now that we've treated over 130 patients with relapsed or refractory EBV-positive lymphomas, quite favorable safety profile, suggesting that with additional patients, we should continue to see this level of anti-tumor activity that could ultimately support an accelerated approval in this rare, serious, life-threatening disease with, as Mark mentioned, very poor prognosis. Great. Now you have that data in hand, and I know you have guided to, you know, having a conversation with the FDA. I'm just curious, you know, to the extent that you can share, what do you plan to discuss, you know, with these datasets? I know obviously you'll probably touch on the path toward registration. Just curious, you know, if you could maybe wire us with a bit of color on, you know, what do you hope to discuss and what do you hope to get out of that meeting? Sure. Well, let me preface my response by saying that the FDA put a guidance for industry out in March of last year regarding clinical trial considerations to support accelerated approval of oncology therapeutics. In that, while they certainly prefer the use of randomized clinical trial to support both accelerated approval and concurrent full approval, they still preserve the option in selected cases for accelerated approval based on single-arm clinical trials, particularly in the rare disease setting where the conduct of randomized clinical trials is not so feasible. Of course, as you know, Nana-val is pursuing a rare indication. In fact, it has orphan drug designation here in the U.S. for patients with T-cell lymphomas. We basically want to align with them that the emerging clinical data that we've seen, together with our plans for expanding the clinical trial, particularly in patients with relapsed refractory EBV-positive PTCL and eventually EBV-positive DLBCL and PTLD, will be suitable for accelerated approval, first ensuring that the randomized clinical portion they just described convinces them, as it convinces us, that indeed you need both drugs to continue development and that it's simply not another HDAC inhibitor. Secondly, that we can align on the number of patients that we need for sufficient confidence in the efficacy and, of course, the safety of the product. And then also, we want to align on the design and the timing of a randomized clinical trial that would be used as a clinical benefit commitment study in the post-marketing setting. Certainly, if they support our proposals on all three aspects, then that would constitute a successful meeting. Got it. I'm just trying to triangulate, like, you know, you mentioned the patients number. Just curious if you can expand a little bit on that, you know, just based on, you know, what we've seen historically so that, you know, we can get a sense of, you know, how big would the trial need to be and what would the timeline, you know, for execution look like? Sure. Maybe I'll begin and Mark can elaborate. But just to give you an idea of past precedent, there's really nothing approved for the treatment of relapsed refractory PTCL save brentuximab for patients with CD30-positive systemic ALCL or possibly crizotinib for the treatment of mainly pediatric patients with ALK-positive ALCL. So there really is nothing approved for PTCL indications, so PTCL, NOS, AITL, the primary population that we're studying. And in that space, all there really is is salvage chemotherapy, clinical trials, and a few drugs that have received accelerated approval, an HDAC inhibitor and a cytotoxic agent. If you look at their product labels, the response rates that supported those accelerated approvals were on the order of 25%, with a complete response rate on the order of 10%-15%, and a duration of response on the order of 8.5-9.5 months. So far, Nana-val is exceeding those benchmarks. If we continue to demonstrate that in additional patients, we're confident that we could achieve accelerated approval as well. Mark? I think, Darrel, some of those that you quoted, they had around, what, about 120, 110 patients in their studies. So you could take that as a reasonable surrogate. I mean, the efficacy that we're showing is greater. So there is a case for perhaps fewer, but we'll see. That is part of the dialogue. You know, and if you think of it big picture, you know, we've seen tremendous acceleration on the enrollment of patients, and we continue to, I think, see that, you know, expand further. And so big picture, I could see us finishing enrollment in 2025 and filing an NDA in 2026. Got it. Got it. And then, I mean, as you alluded to it already, and then I think you also have additional patient data from stage two in PTCL you'll be sharing with us later this year too, right? So would that be basically, I think in total it would be 21 patients. So that would be what we would see going into, like, the next phase of development. Yeah, I mean, we've basically committed to sharing data from stage 1 and stage 2 in Q3, so not too far away now, which will be a 21 patients' worth of data. We had 10 in stage 1 on the combination, and now we will have 21 on the combination. And quite a lot of that data we will have been sharing with the FDA along the way as part of this dialogue. Got it. And I think in the first quarter earnings press release, I think you kind of teased to, I see it as a teaser, to the engagement with the Japanese regulatory body. And just curious, what's your thought there and what's the plan for ex-U.S. development? Yeah, we're very excited about the outcome of that discussion with the Japanese PMDA because Japan is an important market. It's a very big country, 127 million inhabitants. There's a high incidence of EBV cancer. And, you know, typically companies are asked to do a phase I-B, you know, safety PK bridging study before being able to enroll patients in a global study. But we have successfully negotiated to include Japanese patients now directly into the global study, which is a real win. And I think that'll be also a further accelerator if you think about the fact that we're enrolling well, but Japan is not yet part of that. You know, that'll further accelerate our enrollment in the PTCL arm. The other thing I'm excited about is Japan is one of the countries that does offer the potential for a full approval based on a single-arm open label study on the basis of ORR. So that will be our next discussion with the PMDA, which is kind of what is the threshold for a full approval? You know, how many Japanese patients would we need to include in the global study and what kind of threshold would lead us to a full approval? Not even an accelerated approval, a full approval. So it's quite an exciting opening. Got it. That is super exciting. We'll certainly keep an eye on that. Now, I think earlier you already mentioned this, that obviously you have the dose ranging ongoing with DLBCL and PTLD as well. Just curious if you could maybe tell us a little bit about the current status of that study and what do you plan to share with us? You know, this year are you going to get to the point of potentially selecting additional indications to expand? Tell us a little bit about that. Yeah, I would say that the next two cohorts behind PTCL, which are DLBCL and PTLD, are roughly 9-12 months behind. We have been focusing predominantly on enrollment into PTCL as our lead indication. But we're very excited about, for example, DLBCL, where EBV-associated DLBCL has a much worse prognosis than patients that don't have EBV. You know, there are distinct biological features. There's this distinct mutational landscape of these patients. And standard of care doesn't seem to be doing the same job in these patients. So we think there's a real opportunity for a targeted EBV-directed treatment for DLBCL. So one of the things that Darrel did when he arrived was propose that we adjust the protocol to enroll second line. And we're pleased that that protocol amendment has now been, you know, rolled out globally. And so we're now, you know, enrolling DLBCL second line onwards. We intend to share stage one data by the end of this year. Once you have that data, I guess you can decide if you want to go on to stage two, right? That's how it's going to work. Okay. There's a threshold of efficacy if we see that. I was wondering what that threshold? It's at least two patients that have responded out of those first 10 so that we're not dealing with futility. You know, that's not what we expect, but that's, you know, that's why we've set that threshold. Got it. Got it. Thank you. I think, you know, I would like to spend the rest of the time on the solid tumor programs, which is also very interesting. You have the, I think late last year, I think you shared with us that, you know, you were exploring different dosing strategies called the split dosing. Just curious, you know, if you could remind us about the rationale for exploring that split dosings. And I know that you shared that now you add the, I think it's dose level seven, right, most recently? Dose cohort 7. Dose cohort 7. So how has the progress been on the escalation of, you know, the solid tumor program? Right. So just to level set, we're interested in taking Nana-val into clinical development wherever there's the opportunity, wherever we have an EBV-driven cancer, and that goes beyond EBV-associated lymphomas into the EBV solid tumor space, including nasopharyngeal carcinoma where 85%-95% of patients have EBV-associated disease, and even gastric cancer where upwards of 15% of those patients have EBV-associated disease. So we've designed a phase I-B study, phase I-B, II study to evaluate Nana-val in patients with EBV-positive solid tumors, beginning with recurrent metastatic nasopharyngeal carcinoma where the large majority have EBV-positive disease, in a dose finding component where we start at the lymphoma dose level and march on up from there because these patients have less compromised bone marrows and can certainly tolerate the hematologic toxicity much better. And then we have a dose optimization component of the study to confirm the recommended phase II dose. And then a randomized part of the study to look at Nana-val with and without a PD-1 inhibitor, as well as take Nana-val into EBV-associated gastric cancers and other rare EBV solid tumors. And yes, we reported at ESMO Asia Congress last December that we completed five dose levels, 17 patients worth of Nana-val. And so far, so good. No dose limiting toxicities. And by the way, some objective responses along the way, which was encouraging. And so we're now evaluating Nana-val on a split daily dosing regimen, leveraging non-clinical data where in an animal gastric cancer xenograft model, giving the drug a split dose, what it does is it enhances the duration of the kick and thereby enhances the depth and duration of the kill. That was borne out non-clinically, as well as giving the drugs continuously without an interruption also enhanced the anti-tumor control. So we've, the last two dose cohorts have been testing higher dose levels of nanatinostat given seven days a week instead of four days a week. As you mentioned, we've enrolled two additional dose cohorts. We're on track to achieving a recommended phase II dose by the end of the year and hopefully sharing the results of the outcomes of that and hopefully have even more responses that are deeper and more durable. So stay tuned. For that program, is there, like, a threshold that you look for, you know, that, you know, it or is that, would that come later, you know, in the expansion study? Right. Following a recommended phase II dose determination, we then proceed to a phase II dose optimization where we're going to enroll additional patients at two different dose levels of Nana-val. In keeping with FDA's Project Optimus initiative, and depending on those outcomes, it'll help us decide whether there's an opportunity to pursue Nana-val development in recurrent metastatic nasopharyngeal carcinoma as a monotherapy or pursue it in combination with PD-1 inhibitor in the wake of toripalimab, Loqtorzi's approval last October here in the U.S., or both. So we look forward to getting to the phase II component of the study. And just to, you know, just to maybe build on that, in the recurrent metastatic NPC setting, toripalimab achieved a 21% ORR. So I think that's an interesting kind of benchmark. And we'll be looking to see, you know, what we can deliver with Nana-val. Are you going to explore the combination with toripalimab right away in the expansion or would that come later? That would come later. That would come later. Yeah. Got it. What about the, I mean, you mentioned gastric cancer, you know, EBV-positive gastric cancer. Is that the, you know, I'm just kind of trying to think about, you know, what's the broader opportunity? Could be should you perhaps even pursue tumor agnostic, for example? Yeah. I mean, I think we are very excited about the difference here, what Nana-val can do. So far, we've seen responses, you know, in the 201 study, you know, in a range of lymphomas with EBV. We've now seen responses in nasopharyngeal carcinoma. We want to also look at gastric cancer EBV-associated, which is a really big opportunity. So my view is that in time, as we get multiple indications approved, eventually I think we will be able to argue the case for a tumor agnostic label for any EBV-associated cancer. And to remind you, you know, 2% of worldwide cancer burden is EBV-associated. And for the most part, if you have EBV, you do a lot worse. So I think there's a case for having a medicine of this nature available. Great. Any questions from the audience? All right. If there's no further questions, really, thank you so much for being with us today. Really appreciate the insights that we get from you. And we look forward to the updates and, you know, future developments. Perfect. Thank you very much for the invitation. Of course. Thank you. Thank you. Thank you.