Hi, everyone. My name is Maury Raycroft. I'm one of the biotech analysts at Jefferies. It's a great pleasure that I'd like to welcome Mike Andriole, the CEO of Chimerix. We're gonna do fireside chat format. Thanks for joining us today, Mike. Maybe just start off, if you want to give us a one-minute intro to Chimerix. Sure. Yeah, happy to, Maury, and I'll start by saying thank you for the invitation to be here. It's always great to be at the conference, particularly when there's so many exciting things underway at the company. Chimerix is a clinical- stage oncology biotech company. We're developing a class of small molecules called imipridones. Our lead program is dordaviprone, which is in a randomized phase III global study for a mutated form of high-grade glioma, which is a... Any brain cancer is a field of very, very high unmet need. This particular mutation confers an automatic grade 4 by WHO criteria, so a very, very aggressive tumor and a situation of a very, very high unmet need. I'm looking forward to talking about where we are with that program today and where we see the future over the next year or two. Got it. Yeah, it's a great intro, and you've got the phase III underway. Maybe provide a status update on the phase III. From our understanding, you're currently at about 138 sites worldwide, and you're on track to report data in 2025 for this. Maybe talk about the design and the study. Yeah. So we started this study about a year ago, quickly, enrolled into, or activated about 140 sites globally. We're in 13 countries. This is an ultra-rare tumor, so we're casting the net pretty wide. Enrollment is going, well, right now. Feel good about where we are for first interim overall survival data, next year. There are two interim, survival assessments in, in this study. The first at half of the OS events, which we're expecting in, in 2025, the second at 75% of the events, which could also be in 2025, maybe 2026, depending on a few variables and final OS we expect, later in 2025. Got it. And I don't know if you can comment on just enrollment milestones, but when do you need to reach full enrollment in order to get to that first readout in 2025? Yeah, we haven't given enrollment. We're more focused on events, so we haven't given enrollment assumptions. But we're feeling good about where we are in terms of enrollment, obviously, to give the guidance on the requisite number of events towards... And I would say even go a step further and say really the middle part of next year for first interim OS. So feel good about where we are from that perspective. Got it. Yeah, that makes sense. And, in your fourth quarter 2023 update, you said that you were looking at ways to optimize event rates. What can you tell us about how event rates and error bars for events have changed since the fourth quarter? And how has that affected the timing for data for the study? Yeah, so timing is a function of enrollment and event rates, right? It's probably premature to change our only assumption we have right now on event rates for survival. That's coming in sort of as expected as error bars around that. I think as we get to a larger sample size of events, we'll be in a position to be more granular on our guidance, but it's already fairly granular, and we haven't made any changes to our original forecast. Got it. And, once you report initial data in 2025, maybe talk about next steps or gating factors for filing for approval, and what are your latest thoughts on potential for an accelerated approval path with PFS data? Yeah. So, to recap the endpoints for this study, there are two interim OS assessments, again, likely to be in 2025, maybe into 2026. I think success out at either of those interims on survival in this patient population would be sufficient for approval. That's what we would expect. PFS, we've also allocated alpha to a PFS endpoint. To be clear, it's not our expectation that PFS is necessarily a surrogate for survival in this population. That having been said, we're not aware of any studies that have been run in this population that measure time to event endpoints on a randomized basis and have proven a positive outcome. So in the scenario where we were to hit on PFS, I think we'd sit down with the regulators and have a discussion about what that means in the context of Project FrontRunner, given the unmet need in this population, to see if there's a path for accelerated approval. But to be clear, that's not, not a surrogate endpoint with the FDA right now. Got it. Understood. Mm-hmm. Can you just remind me if you're using one or multiple CROs for this study, and talk about the logistics of how relevant parties are gonna get access to interim survival data from the study? We've got a lot of CROs for the study, but we have one primary CRO that we're working with in collaboration with our medical team, our medical affairs team, our clinical operations team. We're not outsourcing this entirely. We have a big presence from Chimerix, cross-functionally, in execution of the study. So now there is an IDMC set up as those events and those assessments occur, there's a protocol in place to communicate that back with our team. Got it. Okay, and for when you report data, I know we have a ways to go until we get there, but is there anything more you could say about how you plan to analyze and disclose the data to the public? I would expect that we'll issue some sort of a communication or release as we go through those interim survival assessments, whether they're favorable or we continue on with the study per the IDMCs. Expect there be an external communication as we hit each of those milestones. Got it. Okay. And for your study design, you're testing two doses with once weekly and bi-weekly dosing, with the 625 mgs of dorda. Yep. You said that it, a hazard ratio of 0.68 versus placebo, would be considered a success in the study. What are your expectations for the weekly and bi-weekly dose cohort results, and what delta would you need to see between dorda arms to pursue a label with more frequent dosing? Yeah, so we are evaluating two treatment arms compared to control in this study. One is essentially at the phase II dose and schedule. As we talk to FDA and other regulators about the design of this study, within the context of Project Optimus, there's always a bias to have more data, more dose exploration, particularly since this particular program was well underway by the time Project Optimus was adopted. And so, we've incorporated a second treatment arm that essentially provides a double dose of dordaviprone in this study. So you're getting 625 mg on day one, and again, 625 mg on day two, which I think gives an incremental tailwind, perhaps to the probability of the study. Those arms are powered based on the phase II data, which was in the second line setting. We're moving up to the front line setting. And so between a combination of moving in the earlier treatment paradigm, where we expect to see broader levels of treatment effect, and having a potentially double dose arm of dordaviprone, that will be independently compared to control, we think, are both tailwinds to the outcome of the study. Got it. Makes sense. And for this study, you're enrolling newly diagnosed patients, which have higher performance scores immediately following frontline radiation, which a recently published subgroup analysis suggests should lead to better tumor responses. Can you remind us of your powering assumptions and whether those assumptions are based on the frontline subgroup population or the overall phase II population? Yeah. Yeah, like I just said, they're powered off of the phase II, but we've got a couple of learnings from that, and including moving into the earlier treatment paradigm that we think makes sense. We have excluded lower performance status patients from the phase III, which isn't all that unusual. A PS of 60 or below were excluded from the study. And so we're studying patients with a baseline performance status of 70 or above, which is really where we saw activity in the phase II study. Got it. There's high unmet need for this indication, like you mentioned. Yeah. What are the efficacy bars for success in the frontline setting when considering regulatory approval, and then what doctors want to see in order to adopt the drug? Yeah, you know, it's, this is an unusual situation, as I think you know more, the unaided awareness of this particular drug, dordaviprone, in the context of H3 K27M-mutant glioma, is exceedingly high. So if you go out and talk to neuro-oncologists and physicians who are seeing and treating these patients, there's a broad recognition of the activity that we have seen to date with this drug in this population. Given the fact that, you know, really there are very, very few treatment options for this patient population, they'll get upon diagnosis, it's very difficult to resect these tumors. They tend to be in the midline structures of the brain, where surgery and resection is invariably difficult. Radiation therapy is the standard of care. Oftentimes, the patient will get a chemotherapy temozolomide, but, you know, that's been shown to have little benefit in patients who are MGMT unmethylated. Most of patients with this particular mutation, call it over 90%, are MGMT unmethylated, so temozolomide's not expected to have much of any, survival benefit in that setting. And so given the scale of the unmet need, after radiation, it's pretty quickly, patients and their caregivers, and their physicians are looking towards investigational agents, and this is, I think the most promising agent in the field. Certainly the most mature in terms of clinical development, in the field, and I would expect rapid adoption if it's approved. Got it. Makes sense. And maybe we talked a little bit about your phase II experience, but maybe talk about what's different from the phase II versus the phase III, and just key findings from the phase III that helped de-risk the ongoing phase III. Yeah. Again, so we're moving from the second-line recurrent setting, where we saw meaningful signals of activity and overall response rate of 20%-30%, depending on how you measure that. That was correlated with many other forms of clinical benefit, including performance status improvement, corticosteroid improvement, overall survival hallmarks of rates of survival at 12 and 24 months that we think are significantly above natural disease history. So all of that gives us great confidence to move into the phase III. And so as we move from second line to front line, we expect to see, based on the phase II data, larger treatment effects. In part because you've got generally speaking, a better performance status at baseline. You also have a lower tumor burden, generally at baseline, which is also a variable that was correlated to higher rates of response. So taking those variables and then adding to it the second treatment arm, where you're essentially getting a double dose, gives us, you know, some degree of confidence. Got it. And maybe talk about early stopping scenarios at your upcoming interim efficacy analyses, and the efficacy benchmarks that would trigger those scenarios. Yeah, so as I mentioned earlier, we have two interim survival assessments at 50% and 75% of the events, and then the full survival assessment at, I think it's 327 events. The hazard ratio that we estimate we would need to hit to hit the full OS is 0.73. Again, we've got two shots on goal on each treatment arm in the full OS. Moving to the 75% interim assessment is a 0.64 estimate of hazard ratio to declare a success. And then the first interim assessment at 50% of the events, we really need to see a pretty meaningful treatment impact of 0.52 on their hazard ratio. That's powered similarly to the treatment effect that we saw in the phase II data, and yet this is a much larger patient population, right? And so you'd expect deterioration in that treatment effect as you think about the probability of hitting that first interim. We have, again, some degree of optimism that you might have a higher probability than you might otherwise expect because we're moving into the earlier line, based on that, and because you've got double dose of dordaviprone in one of the treatment arms. Yeah, makes sense. And, in the past, you've talked about positive feedback and enthusiasm you've gotten from the SNO Medical Conference late last year. Mm-hmm. Can you comment on why this study is different versus other studies that have been run in the glioma or glioblastoma settings? Sure. Well, you know, the advancement of this field in the last two to three years has really been extraordinary, and for a field like neuro-oncology that has really been left out of all the advances in oncology over the last 25 years, all of the advances in genetically defined patient populations, selecting patients who are most likely to respond, neuro-oncology has really been left out. And if you look over the last two to three years, you've seen a lot of successes actually in genetically defined patient populations that have a highest probability to see a response. I think you saw this with larotrectinib in the NTRK fusions. You've seen it with BRAF /MEK combo from Novartis. You saw it most recently with Day One's accelerated approval with their RAF inhibitor, and then most recently again with Servier, who just completed a randomized phase III study in IDH-mutant that read out positive, and I think they've got a PDUFA later in the year. So we hope to be the fifth in a string of successful targeted agents in neuro-oncology that are defining smaller patient populations, and yet having success where there really hasn't been any in the field for about a quarter century. But if you go back to what's different about this one than the other four, the biggest difference is this is a high-grade glioma, confers an automatic grade 4 just by the existence of the mutation. So some of those other programs I've talked about are treating areas of very high unmet need, but low-grade glioma, where it's not unusual to live five or 10 years in some of those patient populations. You know, the expected survival from diagnosis with an H3 K27M mutation is about 12 months from original diagnosis and about 5 months from progression, so among the worst of the worst prognoses in all of oncology. And we're proud to be part of this program, trying to spearhead it to get it to patients as quickly as we can. Got it, and this, it's a controlled study, so the results are gonna be definitive for FDA and for doctors as well as- That's how it's been designed. Yeah. And, It's obviously a survival endpoint, so, gold standard endpoint. Great. And, also, you had an interesting update relatively recently, too, where you're pursuing an accelerated approval path with Australia's Therapeutic Goods Administration, or TGA. Mm-hmm. And, you plan to file for provisional registration by the end of 2024. Can you remind how the Australia reg path came about, and are there additional ex-US geographies that would be potential candidates for accelerated approval? Yeah, great question. You know, it was really unusual in my experience. The Minister of Health in Australia reached out to me at the end of last year to talk about access to dordaviprone. I think they-- look, these patient networks with social media are extremely well-organized. There's a recognition, a diagnosis, that there's very few treatment options for patients with H3 K27M glioma, and a recognition of the need to bring and accelerate access to anything that may have activity in the field. And so we've got an expanded access program ongoing in Australia. The consequence of that conversation naturally led us into a provisional approval conversation. In Australia, it's actually a three-step process. Unlike the U.S., it's a three-step process. We've gone through the first of three steps. I think the second step is likely to be favorable, and that would leave the third step, which is just filing for a provisional approval that we would intend to do, assuming that we make it through the second step. Our current plan is to file before the end of the year for that. We continue to evaluate other markets around the world that have a similar pathway and exploring those where we could accelerate delivery of dordaviprone for different markets around the world. I don't have anything to share yet, but when I do, we'll communicate that promptly. Got it, and for that expanded access program, I guess, was there some clinical data that came from that, that was the basis for how, how this started, or? No, you know, we've got expanded access programs in many parts of the world. I think there's certainly a clinical familiarity with this compound as a result of that unmet need. Got it. Wanted to spend some time on your next asset, the 206 program. Maybe talk about that drug and the studies that it's in right now, and how does this drug compare to dorda? Yeah, so we're really excited about this program. This is a second-generation compound to the parent dordaviprone, a program that it doesn't have a generic name yet, but we call it ONC206. It's in 2 phase I studies, CNS basket studies, one at the NIH, which is a company-sponsored study, and then one at PNOC. It's a pediatric neuro-oncology consortium that is enrolling in pediatric population. This is a molecule that is 10x more potent than the parent compound, dordaviprone. We think that's important and meaningful as we think about the activity of this agent. The in vivo and in vitro work appears to compare favorably in almost every respect to ONC201 or dordaviprone, and continuing to advance both of those studies with the intent to show PK and safety data probably at our next quarterly earnings call. We'll share what we have at that point in time and development plans beyond the current phase I, probably by the end of the year. The team's working on that now, but as we look at it, again, compare these two compounds, we're excited that 206 may in fact have the ability to unlock indications outside of H3 K27M-mutant glioma in the CNS, and potentially solid tumors outside of CNS tumors. Got it. Interesting. And for initial overall response rate data from the phase II study- Yeah ... could you potentially have that later this year, and would that be at a medical conference or a company update? You know, we're following several patients right now. It's possible. I think it's unlikely. It's probably gonna be more of a 2025 event in terms of ORR. And the reason I say that, Maury, is even if, as you look at ONC201 or dordaviprone, the time to onset of response in our phase II data was 8.3 months. We're just now getting. As we go through dose escalation, we're up to, I think, 100 mg BID three times a week. And so as we're getting into these therapeutic ranges, we're really keen to look at response rate for these patients, but I think it's gonna take a little time to mature before we're able to share that. We'll share PK and safety data, which is really the purpose of these two studies, you know, as we go from here. Got it. And, what's the overall response rate bar that you would like to see in any given CNS tumor type before advancing 206, and what are the other gating factors for choosing indications for a phase II program? Yeah, great, great question. I'm gonna give you an unsatisfactory or unsatisfying answer. We'll look at, you know, kind of a totality of the data on that. You know, it's interesting, we've got the parent compound that's hitting the same targets, and we have the clinical experience from that to incorporate into this decision framework. We also have the clinical experience from the phase I and the genetic profile and the genetic disposition of the patients that were treated to date, which is, you know, around 70-80 or so in those two studies, and then the in vitro and in vivo work that's been done in human cell lines to give us some direction as to where to take this program. So we'll look at the totality of all of that data and be smart about how we advance this program into phase II, both from a capital and a resource perspective, looking for other signals of activity that we think are enriched, and we'll evolve the program from there. Got it. Makes sense. And as of your first quarter update, you had $188 million in cash with runway into fourth quarter of 2026. Can you talk about just the gives and takes with cash runway, based on dorda and 206 development strategy? Yeah. So I think we had $188 million in cash at the end of the year or at the end of Q1. The prior 12 months, I think our burn rate was around $60 million or so. So, we're guided to cash runway through or into Q4 of 2026. There's a couple of scenarios where we could extend that organically. As you know, we have a partnership with Emergent BioSolutions, have divested TEMBEXA to them, but additional options arising from the U.S. government stockpile triggering additional procurements into their stockpile would trigger milestone payments for us. Each one would be about $31 million of non-dilutive capital. So certainly possible to extend that runway beyond that. In terms of capital allocation broadly, our first priority, of course, is to make sure we've got enough capital to get to the end of the ACTION study. I think we've got many levers at our disposal to accomplish that. And then we've got additional dry powder to start the primary efficacy work on ONC206. So, company's relatively well-capitalized for the opportunities we have in front of us. Got it. And for an Emergent milestone, I think you said that it probably wouldn't be this year, but maybe next year. Is there any more clarity on timing they're providing around this? For 206? No, for Emergent, for TEMBEXA. Oh, I'm sorry. I think it's unlikely that it would occur in this fiscal year for the U.S. government, which ends in September 30. The treatment courses that we, Chimerix, have delivered to the stockpile already will likely expire prior to the end of our runway period that I just described. So there's a reasonable possibility that just replacing that could be a trigger between now and then. You know, there's also a possibility where you could have incremental options exercised beyond that. But, you know, we're conservative in our guidance. We're running our business assuming neither of that happens. It's upside if it does. It's one of the levers we have at our disposal. Got it. So I think we're pretty much out of time. Maybe in closing, if you could highlight key events ahead that investors should be focused on. Yeah, you know, we've gone through... As you know, Maury, we've gone through the last year and a half with very few catalysts. I think we're right now on the cusp of a few exciting things. Coming up at Q3, we'll share PK and safety data on 206 that we have to date. We're into that therapeutic range now. We haven't seen any dose-limiting toxicities to date, but we'll share that update with the marketplace. And then, heading into Q4, our development plans for 206 really for phase II, I expect to be able to share, at least at a high level, if not at a granular level, at that time. Filing accelerated approval or provisional approval in Australia should also occur in Q4. And then, look, we're essentially a year out, maybe, maybe even less, depending on how things go, on first interim assessment for OS on the ACTION study. So I can remember when we started that study, it seemed like we were forever, and now we're, we're inside of, you know, 12 months or so. So, stay tuned for more updates, but, it should, should be a fun year ahead. Great. Thanks so much for joining.