Good morning, welcome to the last day of the 41st annual JPMorgan Healthcare Conference. My name is Dave Prawraj, I'm an associate, part of the JPMorgan Healthcare investment banking team. Today, I have the pleasure of introducing Chimerix and their CEO, Mike Sherman. In the audience, we also have CTO, Dr. Joshua Allen, and CFO and CBO, Mike Andriole. Please note, there will be time for Q&A at the end of this session. A mic will be passed around for any questions that you have. Thank you, take it away, Mike. Thanks, Arvind. It's great to be here back in person again. It's especially energizing when you've got some exciting things to talk about. I'd love to take the opportunity to give you an update. For those that don't know, Chimerix is an oncology-focused company headquartered in the Research Triangle in North Carolina and have a phase 3 program in a mutant form of glioma that we're really excited about the data we've generated there and the path forward for that drug in our pipeline. I will make some forward-looking statements during this presentation. Please refer to our most recent SEC filings for a more complete disclosure of risks and uncertainties. You know, Chimerix is in a unique situation from many companies, particularly these days. It starts with the phase 2 data we've generated on our lead drug that sets the stage for a phase 3 trial that we're really highly confident in. When we designed the trial to generate that phase 2 data, we were sure to isolate single agent activity of this drug to ensure that we had a definitive signal of that activity and efficacy. When we translate that into the durability of responses that we saw on other forms of clinical benefit, the internal consistency of that data is striking. Really no surprises in what you would expect to see from an active agent. What's been more recently interesting is the disclosure by other parties, including academic institutions, which essentially support the findings of the activity of this agent in including survival endpoints. We'll talk a little bit more about that data. Importantly, this is in a patient population that's genetically selected and frankly, a genetic target that is stable during the course of the disease, and it creates a unique opportunity in transitioning phase 2 to phase 3, where you'll ensure the same homogeneity of patients. The other thing that's maybe unique about the program is the level of risk for the commercial opportunity. Often getting through the clinical risk is the ticket to play in the commercial setting, and then you have a whole new level of risks to face. In this case, this is a universally terminal disease with no effective therapies. Unfortunately, there aren't many therapies in development. Those are very early stage compared to ONC201. There is not much competition in the space. During our market research, before we acquired the drug, we found universal awareness of the program based on the data that had been generated. As we see the opportunity here, it's a quite straightforward path to a $750 million market opportunity for the first indication alone, and a revenue opportunity that doesn't come with substantial costs. A break-even and profitable level of revenue is quite low. This is all within an organization that has a real capability, demonstrated capability. This is a management team that has gotten approval of 2 of the last 3 agents that we've touched in phase 2 and hope to make that 3 out of 4 as we advance ONC201. We're also fortunate to have a very strong balance sheet, particularly in this environment, and that comes on the heels of the sale of TEMBEXA, which in and of itself, while we're focused on oncology, there's potential non-dilutive revenue continuing from TEMBEXA with additional milestones and royalties possible. I would also say this is a management team that's has a track record of creating value in creative ways. In a marketplace such as we're in, there are a lot of interesting opportunities to create value, especially when you have financial flexibility. Our pipeline includes a number of drugs. I'll spend most of the time discussing dordaviprone as it's known, or ONC201 and our phase 2 data and the transition to phase 3. Three products in the pipeline today that I'll touch on. A unique aspect to how we're funding that pipeline, as you'll see the collaborators listed, we're able to focus most of our capital and manpower capabilities to the ONC-201 path as we are leveraging external capital to bring forward these pipeline assets to really make sure that we are turning a card that gives us confidence in the activity of those agents before we double down and invest aggressively our own capital. in a way, keeping some dry powder knowing that the external opportunities are also significant and it, and it creates a high bar for anything that we would invest internally on. Let me transition now to ONC201 and the phase II data we've generated, which really that data is the reason why this drug is universally known among the physicians who treat these patients. Let's start with the disease that we're focused on H3K27M mutant diffuse glioma. It's a, it's a mutation that is relatively recently codified by the WHO, and is identified as an automatic grade four. As I say, it's invariably lethal, and the treatment consists of a standard radiotherapy 6-week regimen, followed by frankly palliative or experimental care after that. Median survival tends to be around 1 year, following relapse, the median survival is 6 months or less. I refer to some of the third-party data that's been published recently, including a presentation at the most recent Society for Neuro-Oncology conference, their annual meeting, where a consortium of academics published data on a population of patients with this H3K27M mutation, those that had been treated in their institutions, who had received ONC201 versus those who had not. It was consistent and frankly validated by yet another third-party analysis not shown here that ONC201 seemed to be the one factor that influenced survival in these patients in Cox regression analysis. It was the only variable, demographic or otherwise, that was predictive of overall survival outcomes in the recurrent setting, doubling median overall survival. Particularly interesting in the frontline setting, where you not only more than double the median survival, but you see an immediate separation in those in those curves. Mind you, this is not randomized data. This is based on prior patients being treated, but the findings are consistent wherever we look. This frontline is a foreshadowing of our phase 3 trial where we have advanced the development. We also did our own natural disease history, which was consistent with these findings, a median survival in patients not treated with ONC201 of around 5 months, and survival at 12 months, or less than 1 in 4 patients survive in 24 months, 11%. In the ONC201 phase II data set, we saw a doubling of that median and doubling or tripling the survival at each of those 12-month and 24-month endpoints. Again, very consistent results we continue to see across data sets. I referred to the phase II data. This is the data set of 50 patients which were carefully identified and essentially prospectively defined prior to gathering the data. The intent was to identify the first 50 patients that met a set of criteria that would allow us to assess the single-agent activity and efficacy of ONC201 with a primary endpoint of RANO-HGG response, tumor response. This is really the strictest definition of response. It includes both imaging and other clinical elements in the criteria. From an imaging standpoint, it requires a 50% reduction in the tumor, and it's recognized as the gold standard in assessing this. We evaluated this in a blinded independent central review, essentially regulatory quality assessment of this data set. We saw 20%-30% response rates, depending on how it's measured. 20% RANO-HGG, which is essentially measuring the enhancing tumors, image-enhancing in tumors, and in RANO-LGG, the non-enhancing tumors at 26%. When you combine those, essentially a 30% response rate in one or the other. What was still a or really a question when you see responses like this in a population of patients who you don't expect to see responses in. In fact, there really hasn't been a documented RANO-HGG response in this population under these circumstances where you have sufficient washout from prior radiation and other therapies to ensure that you're truly assessing single-agent activity. The question though is really around durability. Too often, if you've attended brain cancer conferences, you see that you'll get responses occasionally, but they're all too often fleeting. In this case, the median duration of response was 11 months. This is particularly compelling given the fact that the median onset or time to response was more than 8 months. It's a gradual onset of response followed by a quite durable maintenance of that, of that response of following treatment. When we asked investigators and Key Opinion Leaders prior to generating this data. Which frankly was prior to us acquiring the asset. They said that, you know, a 20% response rate and anything with a 6 months durability would be clinically meaningful. This goes far beyond what we had expected. The other thing I would note is that you can see, by those patients, you know, roughly if 20% of patients responded, another 20% had some tumor shrinkage or stability of disease. There was another 60% that progressed pretty rapidly. This is partly a function of the stage of the disease where you're treating. If you wait till the relapse, you've got a bit of a runaway train. One of the things that, especially for a drug that takes some time to work, that moving that to an earlier line, we think is gonna be quite promising. This all comes in a safety package that is also compelling. It's one of the rare drugs where in oncology, where you can evaluate it in a healthy volunteer study, where we dose escalated to the phase 2 dose and saw only grade 1 toxicities. Toxicities you'd expect of an agent that's has crossing the blood-brain barrier with headache, fatigue, some nausea, and vomiting. Importantly, in our 200 patient, 200 plus patient database, the patients that were treated that were with disease, we found very few grade 3 or higher events. In fact, the most common was fatigue, and it only occurred in fewer than 3% of patients. It will foreshadow again a strategy in phase 3 where we believe we have an opportunity, even though there's strong rationale for this phase 2 dose to increase that dose to instead of a once a week setting to a twice a week, day 1, day 2 dosing, and we believe could has the potential to drive even more activity as there's likely gonna be some variability among patients in the PK. This is a space you'll often hear that brain cancer is a really challenging space, and there are a lot of drugs that have, you know, perceived to have performed in a phase 2 and then gone on to fail in a phase 3 trial. Why is this different? Why do we feel that ONC201 data set gives us more confidence? There really are a number of reasons. The first is that in many cases, these decisions were made based on to advance to phase 3, based on combination trials where you really can't get a confident signal of the single agent activity. Now, rarely were those done in genetically defined patient populations. You've got significant heterogeneity and disease. Speaking of combinations, in some cases, the combination included agents that are anti-angiogenic in nature, particularly Avastin, and it's widely known that those can yield pseudoresponses. Even where you see response rates of 20%-30%, in some cases, we now know that those responses were essentially fooling us in terms of the longer term potential benefit, particularly in terms of survival. We're not seeing those translate into survival. Yet, it's also confounding not only your overall response rate, but it confounds your progression-free survival. To have a phase 3 design where we generated true bona fide single agent activity without the presence, particularly of anti-angiogenic agents, measured those responses as is, partly addressing that angiogenic pseudoresponse by using RANO criteria and a blinded assessment, really all of the standards that you'd like to see in confirming that this drug is truly active. We've launched our phase 3 trial. We use the annual meeting of Society for Neuro-Oncology in November to kick that off. It was really a quite exciting, energizing environment. A lot of interest among physicians. Not only did we sort of capitalize on meeting with a really small community, relatively small community of physicians that treat these patients, to accelerate their interest and participation in the trial. What we found was sort of this organic process of referrals, where sites that either aren't gonna open immediately and maybe open a few months down the road that have patients in the pipeline, start referring those to sites that'll be open earlier. It was exciting to see that energy around this program. Unfortunately, it's largely because there aren't a lot of options for these patients. What you always look for in a phase 3 trial is minimizing the change. For sure, the patient population that we're evaluating is the same as the population we identified in the phase 2 trial, these H3K27M mutant diffuse glioma. The difference is we're moving as opposed to post-relapse, moving prior to relapse and immediately following radiation. So in this period where you'd otherwise be monitoring post-radiation for relapse, we'll be able to benefit from receiving the drug. As a result, get the drug for a longer duration, which relative to my prior comments and sometimes you have runaway disease following relapse, get in front of that. We're randomizing to three arms, the phase two dose of once weekly, a more intense dose of the same dose on day one and two, so twice a week, and then a placebo arm. We're measuring overall survival and progression-free survival as alpha-allocated endpoints, with primary endpoints, overall survival. PFS gives us some flexibility for a potential accelerated path within the phase three trial if it reads out positively. Now, I've mentioned some of these points already in terms of our confidence and how this trial is differentiated from historical trials in the space, but simply put, our confidence is based on the notion that the responses we've seen to date, we know are real, we know that they matter, and we actually expect that they would improve in this setting in phase 3. We know they're real because of the isolation, as I've mentioned, the fact that they're durable, the fact that they're multifocal, and the fact that this genetic marker tends to be present throughout the disease if it's positive, is certainly helpful and supportive of that. We've assessed those in the most stringent criteria. We know they matter because of the consistency we see across endpoints, outside of response rate, other forms of clinical benefit, in the patients that responded, they tend to be the ones, or they were the ones that also survived for more than 24 months. They were also the ones who had performance status improvement. They were also the ones where physicians were able to reduce their steroid use. We've seen this validated by external analyses as well, as I shared earlier. While we're not counting on enhanced activity in the phase 3, you never do, you count on an erosion activity typically, and our trial is designed with that assumption. Yet, moving it to an earlier line based on the data, not only our own data, but external data would suggest you'd have a more active agent, and the addition of the higher dose arm should also add to that probability. We expect the initial data from this trial to read out in 2025, with the final data coming in 2026. That first readout would be early in 2025. We would be able to stop the trial at that first interim overall survival endpoint at 164 events if it's positive. We sized that or we powered that endpoint essentially assuming that the phase 2 effect could be repeated in phase 3, and I've just outlined why it actually may be enhanced. While typically these first interim, earlier interims are a long shot, I think there's reason to believe that this is certainly a potential early stopping point. We'll also look at progression-free survival, which you'd expect to hit shortly thereafter, in 2025, and that could be the basis, if positive, that we would approach the FDA for a potential acceleration of the approval process where they would likely take a look at, in a blinded fashion, the overall survival data set and ensure that it's trending in the right direction. Then again, final overall survival in 2026. I should mention as well that a reminder that we've got alpha allocated not only to each of these endpoints, but to both arms of the trial independently. Whether the phase two dose or that higher dose could be the basis for a positive endpoint. I referred to earlier the probability of a successful commercial launch here is one that we believe would be a somewhat atypical rapid ramp to peak revenue in the neighborhood of $750 million. A part of that is because these patients are already routinely identified by existing diagnostic tests, and partly because there really are no other opportunities for treatment for these patients. Orphan drug pricing would also be favorable and, in particular, because this predominantly affects pediatric or children and young adults, could be insulated from the Inflation Reduction Act as very little exposure to Medicare. I mentioned the pipeline. I'll move quickly through that. ONC206, a second drug in the pipeline, is currently enrolling in dose escalation, both in adult and pediatric, in collaboration with the NIH and the Pediatric Neuro-Oncology Consortium. ONC212 is approaching a potential advancement to IND. CMX521 is actually from our antiviral library. I remain committed to my earlier statement that we are a oncology-focused company, and yet we have a library of antivirals that through grant money and actually, manpower resources from University of North Carolina, they are essentially screening our library to identify assets of potential value, which, as we retain the rights to all of these assets, we'll do that all day long, and if there's an opportunity and we see compelling data, would seek to partner those. Each of these have the potential for catalysts during the course of the year. The other thing that sort of hearkens back to our antiviral business, while TEMBEXA is now in the hands of Emergent BioSolutions, we and we have the roughly $240 million in the bank and roughly $30 million that the team is able to generate in really the first few weeks of a mpox outbreak because of really effective planning, having product ready to go. We maximize the value of TEMBEXA currently, and then have the potential for if there are additional options exercised by the U.S. government, $31 million of milestones would be triggered with each of those exercises. Beyond this existing contract would trigger royalties in the U.S. and essentially the next dollar of revenue outside the U.S. would also trigger royalties. Still an opportunity for non-dilutive capital coming from this drug. Again, a program that we believe is highly likely to translate from phase 2 to phase 3 success, and with that success, highly likely to achieve meaningful profitability from this single program with relatively small investment in commercial infrastructure, and an organization that's highly capable and flexible to create additional paths to value. We ended the third quarter with $285 million in cash. During the course of this year, we'll have a good opportunity to provide updates on the execution of that phase 3 program, as well as updates on the earlier stage pipeline. In this environment where, we, you know, got a flexible balance sheet and a lot of assets out there that are probably undervalued or under-resourced, it creates an opportunity for us to also consider things outside of our pipeline. At a minimum, it sets a very high bar for how we would approach investing aggressively in our next generation drugs. With that, I'll wrap it up and open it up for questions. I'll kick it off. Can you talk more about the rationale for the second, more intensive dosing arm in your proposed phase 3 trial? Josh, go ahead and handle that one. Yeah, happy to elaborate on that. I mean, the first place I would start is to comment on the confidence in the phase 2 dose that is being used in the phase 3 study first. As Mike has already presented, it's been responsible for producing a durable objective responses accompanied by clinical benefit. The rationale for that dose comes from a large series of empirical observations pre-clinically that show saturation of the effect with once-weekly dosing. In addition to the frequency, we have a high degree of confidence that the dose itself that we're giving is in excess of target engagement thresholds and is sufficient to maintain downstream engagement for up to a week after a single dose. We've proven that both in preclinical models as well as in patients with brain tumors. We're very confident in the phase 2 dose that is being taken forward. However, we've arrived at a second dose schedule being used in the phase 3 in addition, that's based on preclinical studies showing in vitro, if you take that same dose, in certain glioma cells, sometimes if you maintain that concentration for longer than 24 hours, you need to actually go out to 48 hours, to maximize the effect, and that can be pragmatically achieved by giving the weekly dose just on the second consecutive day, so something like a Monday, Tuesday dose schedule. There's good reason to believe that this dose schedule may actually increase the efficacy that we've already seen in the phase 2 setting. In addition, there's a number of other reasons why introducing a second dose into the phase 3 study made sense. One is that, as Mike has commented on, there's nothing else out there for these patients. They really want access to this drug. We knew going in that we wanted to enrich the probability of patients accessing ONC201 over placebo. We already had in mind, something like a 2-to-1, you know, enrichment ratio. Being able to split that dose up into 2 different levels and incentivize enrollment was important. The other thing that I'll mention is, FDA and their push for Project Optimus, with regards to dose optimization. We were very cognizant of this going into the design of the phase 3 study. The place where this dose optimization push comes from, we're already in a good position with ONC201 because the intention is to, in general, try to back off of maximum tolerated doses, which is baked into the arrival of the phase 2 dose already. What we hadn't satisfied was in the phase 2 setting, really there was just a single dose that had been evaluated, and what the agency is looking for is dose-response relationships to pick that sweet spot with safety and efficacy. To satisfy that requirement, we went ahead and incorporated a second dose into there. We think it checks multiple boxes, right? It gives patients essentially a double the dose, so it's a good incentive for enrollment. We think it increases probability of success. We think it satisfies potential, regulatory questions that could come downstream. You may have said this, Josh, and I missed it, but it's not a dose that's new to clinical development. It's one that we've had in patients and know is well tolerated. Got it. You know, as your phase 2 data is quite compelling, and you mentioned FDA feedback, can you elaborate on feedback itself and if there's any potential for accelerated approval based on the data you've seen so far? Yeah, we, I believed and still believe that this data represents, I think the spirit of what I think initially or historically would qualify as a candidate for accelerated approval given the risk benefit in this particular setting and the dearth of options for these patients. That having been said, we've watched other companies interact with the agency and watched other ODAC and the challenges that the FDA has or barriers and hurdles they've put to accelerated approval in with single arm data. While the FDA didn't close the door as we brought back, you know, more a complete safety profile, and have completed a number of the clinical pharmacology studies that they'd asked us to do and which all were quite positive, it was clear that the work that they would require, the additional data that they would require, would both add to the timeline and substantially add to the cost. Ultimately, the phase three trial is something that would be required in any event. From a focus standpoint, we decided to focus our energy on the phase three trial. I'll say that one unintended consequence of that is, you know, since sharing with our KOLs and our investigative sites that strategy, it certainly has raised the importance and urgency around enrollment in the phase 3 trial. This is the path to getting this drug to patients, and physicians are aware of that and are on their toes to help deliver. Switching gears a little bit. Given your strong balance sheet, how are you thinking about business development, M&A, potential part-partnerships? Yeah. Thanks, Dave. You know, we always are evaluating external opportunities, so we never turn that process off. There's a lot of reasons to stay engaged in that marketplace. As Mike alluded to, there are, you know. We find ourselves in an enviable position of having a really strong balance sheet heading into, 2023 with, you know, potential, force and dry powder to invest in other projects. We're carefully thinking about capital allocation here, whether that capital is invested internally in ONC206 or ONC212. We're being thoughtful about how we evaluate those opportunities using external capital and resources right now to bring those forward while we focus on ONC201, and we're really doing signal finding. you know, if we find the right signal and justify continued investment, and progression of those into our pipeline, certainly we'll put the balance sheet and invest in those accordingly. They also have to meet any bar for an external asset that we might find that could also be interesting. Whether it's internal innovation or external innovation, you know, our job is to make sure we've got a good understanding of what the options are for the next $1 invested, and we're thinking about that very carefully as we move into 2023. The good news is we're not in a position where we have to do anything. Right now the focus is on the ACTION study ONC201 and getting that trial enrolled. Thank you. Any questions in the audience? If not, I'm happy to give everyone some time back, and thank you so much. Thank you. Thanks again.