The H.C. Wainwright 26th Annual Global Investment Conference. My name is Kyle Meury, and I'm an analyst on the H.C. Wainwright Corporate Access team. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to public and private companies across multiple sectors and regions. We have a total of 24 publishing senior analysts and over 636 companies covered across all sectors. Please visit hcwco.com for more information. Please join us for one-on-one meetings, corporate presentations, and panels that will be available live and streaming on September 9th, through September 11th. With that said, have a productive and enjoyable day, and I'd like to introduce Mike Andriole, CEO of Chimerix. Thank you. Thank you, Kyle, and really appreciate the invitation to speak today. It's always a pleasure to be back at the conference, particularly when there are so many great things to update folks on right now at Chimerix. I will be making some forward-looking statements, so please refer to our SEC filings for a full review of risks and uncertainties. As many of you know, Chimerix is a clinical stage biotech company focused on cancer research and development. Today, I'll be speaking predominantly about our lead program, dordaviprone, also known as ONC201. I'll speak just a bit about our second-generation program in the same field, ONC206, and briefly talk about TEMBEXA, which has been in the news lately, and some of our financial rights to that program. Let's start with dordaviprone and ONC201, and just provide the foundation for our phase II data set that we've communicated here in the last several years, which really underpins our decision to move this program into a phase III study, which I'll detail more in this presentation. First, talk a little bit about dordaviprone and where it's being developed. The drug is being developed in a form of high-grade glioma called H3K27M-mutant diffuse midline glioma. H3K27 is a very, very difficult diagnosis within brain cancer. Frontline radiation therapy really remains the sole standard of care. Unfortunately, it has just a transient benefit. These tumors tend to occur when they occur in the midline structures of the brain, which make them very difficult to resect, infeasible to do so. The mere existence of this particular mutation renders it an automatic grade four by WHO criteria. Unfortunately, historically, it's been invariably lethal, and what we've observed, both in the second line recurrent setting and in the frontline setting, are consistently longer rates of survival and overall survival for patients treated with dordaviprone compared to historical controls. This really underpins our decision to move this program into a randomized phase III study to get definitive data. But I'll share with you the data that we generated in phase II in more detail here on the following slides. The phase II efficacy analysis was done on 50-patient cohort, really the first 50 patients from our phase II studies that met a set of criteria that were agreed to by the FDA and by Chimerix and our legacy organization, Oncoceutics, to really isolate the monotherapy effect of dordaviprone in single-arm studies in monotherapy studies. The overall response rate of those first 50 patients who met that criteria was 30%, using RANO-HGG and/or RANO-LGG assessment criteria, and that was done by dual reader, blinded independent central review. By the way, RANO-HGG is really measuring the contrast-enhancing portion of the tumor and tumor volume in RANO-LGG, the non-contrast-enhancing portion of the tumor. Our perspective, and increasingly the perspective of the field, is that tumor volume shrinkage by either criteria is clinically relevant and clinically meaningful. RANO-HGG criteria, if you look solely at that assessment, the response rate was 20%. The time to response was over eight months, so 8.3 months, and then the duration of response, so in addition to the time of response, was over 11 months, 11.2. Incorporating stable disease, and again, stable disease in this particular setting of recurrent diffuse midline glioma is by some measures an important and clinically relevant outcome when you would expect rapid and immediate disease progression in this setting. So a disease control rate of 40% in those 50 patients, and the percentage of patients who were progression-free at 6 months was 35%, and at 12 months was 30%. Looking at only RANO-LGG criteria by dual reader, blinded independent central review, we see a response rate of 26%, and landmark rates of survival at 12 and 24 months of 57% and 35%, respectively. We also saw improvements, and this is important, that were observed in terms of performance status, how well each patient was doing. And reductions in corticosteroid use, which can be really important in this patient population. All serious adverse events were considered not related to dordaviprone by Chimerix. This is what's called a waterfall plot, a graphical depiction of the data that I just summarized. Again, this is in a recurrent H3K27M glioma, and on the top portion of this chart, you can see the RANO-HGG or enhancing response rates that require a 50% reduction in tumor volume from baseline, and then that must be confirmed on a subsequent scan to be considered a response. It also requires confirmation of other forms of clinical benefit. So again, no increase in steroid utilization, no deterioration in performance status. If either of those occur, that would invalidate what would otherwise be a radiographic response. So increases our confidence that the activity that we're seeing is real, and supported by other forms of clinical benefit. At the bottom half of this chart, the waterfall for RANO-LGG or non-enhancing portion of the tumor, a 26% response rate. In RANO-LGG, minor responses are included in that assessment criteria, so a 25% reduction in tumor volume, confirmed on a subsequent scan, and a partial response being greater than a 50% reduction. As importantly as the overall response rate, the durability of those responses is so critical in this patient population. You really would expect at recurrence that all 50 of these patients would progress immediately and relatively rapidly, given the lack of a standard of care, for this patient population. You can see the blue lines on this chart represent patients who had stable disease by blinded independent central review, and the green lines represent patients who had a steady reduction in tumor volume until it crossed 50%, a confirmation on a subsequent scan of at least a 50% reduction, and then the durability of those responses, in many cases, exceeding 18 months in a patient population where really median overall survival at recurrence would be expected to be less than six months. We view these data in a way as unprecedented and really underpins our excitement and enthusiasm to move this program into a randomized phase III study. In terms of the safety profile of dordaviprone, our safety database includes 422 glioma patients, really well tolerated across the board. If you look at high-grade treatment-emergent adverse events, grade 3 or higher, are relatively modest. Really, the most frequent adverse events were fatigue, nausea, lymphocyte count decreased, each being less than 2% in terms of a grade 3 or higher treatment-emergent adverse events. Just over 2% of patients experienced a treatment-related adverse event that required a modification in study drug or a discontinuation. Overall, a fairly benign safety profile in this very serious disease. In terms of clinical pharmacology, 245 subjects have participated in our clinical pharm studies, reviewing the food effect studies, QT studies, drug-to-drug interaction, renal-hepatic impairment, mass balance. The full complement of clinical pharmacology studies have been done on this agent, and again, 245 patients included. All of that underpins our decision to move into phase III. I'll briefly summarize the ongoing phase III study, which we call the ACTION study. It's currently enrolling. This is a randomized, double-blind, placebo-controlled study that's ongoing in 13 countries. It's assessing 450 newly diagnosed diffuse glioma patients who harbor this H3K27M mutation. So there are a couple of key differences between this study design and the phase II data that I just reviewed. One of which is we're moving from the recurrent setting, which was our phase II experience and data analysis, into the frontline setting. Patients at diagnosis will move on to radiation therapy. There'll be a brief period of time between radiation therapy and when they'd be eligible to be randomized into the ACTION study, and then would be randomized to one of three treatment arms, either dordaviprone once weekly, so six hundred and twenty-five milligrams once a week, which was the phase II dose and schedule, or a more intense dose and schedule, so dordaviprone twice weekly at 625 mg on day one, and then another 625 mg on day two. This is really in response to the ongoing importance of dose optimization work with regulators and making sure that we fully explore dose optimization with this agent. And the third treatment arm would be control, which in this case is placebo, with the endpoint here being overall survival. We have also allocated part of our statistical plan alpha allocation to progression-free survival, with secondary endpoints being typical in this patient population, measuring steroid responses, performance status improvement, quality of life parameters, and neurologic function. In terms of data points and readouts, we would expect first interim data from this study to occur in the third quarter of 2025, so about a year away. The first interim assessment will occur at 50% of the events for overall survival, likely followed sequentially by progression-free survival is our current best thinking, and then a second interim assessment at 75% of the events for survival followed by final OS assessment at 327 events. Each of those endpoints are independently powered and compared to control. And so each of those will read out for each arm of the study. So once a week dosing versus control, and twice a week dosing versus control will each be assessed and, you know, evaluated independently of one another. In terms of the market opportunity for dordaviprone, there's about 21,000 newly diagnosed gliomas in the United States each year. The vast majority of those happen outside of the midline structures of the brain. Only about 4,000 of those 21,000 occur in the midline structures of the brain, but we think that's the most frequent place where you'll find this mutation. About 40% of those 4,000 patients will harbor the H3K27M mutation. Outside of the midline, so on the non-midline gliomas, about 17,000 patients, and roughly 2% of those, we believe, would harbor the H3K27M mutation. So in total, of course, that's gonna vary year to year, but in terms of a broad estimate, we believe there's about 2,000 patients affected by this mutation in the United States. When we extrapolate that to Japan and the top five markets in Europe, we think there's about 5,000 patients in the top seven markets globally, and again, there are no approved therapies specifically for H3K27M mutant glioma. If you apply those 5,000 patients in those top seven markets, considering ultra-orphan drug pricing, in this case, this is a mutation that, again, is most often found in children and young adults. We believe the market opportunity is approximately $750 million globally for this particular agent. Few effective therapies exist. We really expect low barriers to adoption if this drug were to be made commercially available and approved. There's currently high unaided awareness among neuro-oncologists of this particular program. The mutation's routinely identified by existing diagnostics, which is helpful in terms of not needing to materially change behavior of what's occurring in the marketplace currently. And we think longer term, this is potentially combinable with other glioma therapies, given the current safety profile that we're seeing. The fact that this is an oral therapy taken once or twice a week, there's a convenient dose that would be taken at home. We think it has the potential to be a backbone-type therapy, if approved for this particular indication. Patent protection for this lead indication extends into 2037, and the United States has the potential for patent term reinstatement of up to five years beyond that. In terms of opportunities beyond H3K27M mutant glioma, we look for areas of the body that have high expression of the dopamine receptor D2, which is one of the two driving mechanisms of action of this particular agent. There's an adrenal tumor that has very high expression of DRD2 called pheochromocytoma or paraganglioma. That is a mouthful, so I'm just going to refer to that as PCPG. But as you can see in the top part of this chart, in a investigator-initiated study at the Cleveland Clinic, we saw really compelling responses in what was a salvage therapy, highly refractory patient population. A number of responses in stable disease treated with dordaviprone in that study. Five patients were on study for more than a year at data cutoff. We think the safety profile of dordaviprone also would compare favorably, both in the short term and potentially long term, compared to other treatments, for this particular tumor type. So more to follow on opportunities beyond H3K27M. In terms of other parts of the pipeline at Chimerix, ONC206, this is a second-generation imipridone, second generation to ONC201, really hitting the same targets, but has a 10X higher in vitro potency relative to dordaviprone. We've seen monotherapy efficacy across multiple preclinical models, both within the central nervous system and outside of the central nervous system in different tumors. And we've seen tumor regressions in patient-derived xenograft models. This is an oral dose escalation studies that are ongoing at both the NIH and the Pediatric you know Neuro-Oncology Consortium, ongoing in a number of different CNS cancers. We have seen a monotherapy response in a recurrent glioblastoma patient without the H3K27M. And that's unique because really all other responses we've seen with the parent compound, dordaviprone, have been limited to H3K27M within the CNS. Of course, we also saw responses outside of the CNS in paraganglioma. In terms of status of these studies, we're really now just reaching expected therapeutic ranges, what we think is a biologically active dose of a hundred and fifty milligrams twice a day for three consecutive days. Today, we've had 77 patients evaluable for safety. About 2/3 of those are pediatric, about 1/3 adults. And we're continuing escalation at these intensified doses and intensified frequencies. We hope to get to dose level eleven yet this year, which would be 200 mg twice a day for three consecutive days. This has been well tolerated through these intensified frequencies and exposures in achieving efficacy that we've seen in vivo. In terms of the safety profile thus far, the majority of treatment-related adverse events have been mild to moderate in severity and is consistent with the parent compound, dordaviprone. This is just a graphical depiction of where we are. We see really no adverse events at 600 mg weekly on this chart. I just highlight that that's only in three patients, so more patients will be randomized into that arm of the study, even as we open enrollment in dose level 10, and hopefully into dose level 11. The mechanism of action of ONC206, I spoke briefly about the similar targets to the parent compound dordaviprone. ONC206 has nanomolar activity across a number of CNS tumors, including high-grade glioma and medulloblastoma. The in vitro and in vivo data demonstrates enhanced efficacy while increasing the dose and sustaining the exposure. Tumor regressions and survival extension in the transgenic and patient-derived medulloblastoma models sort of complement our interest in this program, and why we're excited to move this potentially into primary efficacy studies, assuming that we move successfully through the remaining cohorts of the phase I studies that are ongoing. Outside of the CNS, we've seen broadly a broad-based activity across a number of different tumor types as I mentioned earlier, including triple-negative breast and pheochromocytoma and paraganglioma. And we'll continue to monitor some preclinical work that's ongoing, as well as the clinical experience of ONC206 in the ongoing phase I studies as we make decisions on future development plans for this program. Just one other brief corporate update. TEMBEXA, this is an antiviral, brincidofovir, that the company discovered and developed, got through the regulatory approval process in the United States under the Animal Rule. Manufactured over 300,000 treatment courses and shipped those into the Strategic National Stockpile in the United States. We subsequently sold this agent to Emergent BioSolutions, received $238 million upfront in the third quarter of 2022. We continue to be eligible for potential milestone payments associated with that contract with BARDA or the U.S. government up to $124 million in aggregate. There are four options available for additional procurements of this antiviral into the Strategic National Stockpile as a potential countermeasure to smallpox, and each is worth $31 million. Beyond those milestones, if we should exceed one point seven million treatment courses under that contract, Chimerix will be eligible for a 20% royalty on future gross profits in the U.S., and are currently eligible for 15% royalties on all international gross profits. There's additional development milestones that could also be paid to Chimerix related to TEMBEXA. This is particularly relevant and increasingly discussed in the media and lay press due to the ongoing mpox outbreak that is occurring around the world currently, and we'll continue to keep a close eye on that to see if that accelerates any potential economics related to TEMBEXA. So in closing, a really exciting point in the company's history, we've got the phase III ACTION study actively enrolling. We're expecting first interim OS in about a year. It's an agent with what we think is significant commercial potential. We're blessed to have a strong balance sheet, corporate capability, and financial flexibility with $171 million in capital to fund the company at the end of the second quarter, and feel good about the potential for ONC206, which is now dosing within the expected therapeutic range, with no unexpected safety events or dose-limiting toxicities identified to date. So with that, Kyle, I'll close. I want to thank you and the team for inviting us to speak today and giving us an opportunity to review the update of the company, and I look forward to future updates in the months to come. Awesome. Thank you, Mike. And I just wanna thank all of our presenters for taking part in what has been a very productive and informative series of presentations. We appreciate all your time and your effort, and we're very grateful for your flexibility and your presence at our conference this year. So I just wanna thank you again from the H.C. Wainwright team. Sure. Thanks, Kyle.