Welcome everyone to the 40th Annual J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by Malcolm Kuno, Priyanka Grover, and Caleb Smith from the team. Our next presenting company is Day One. Presenting on behalf of the company, we have CEO Jeremy Bender. I want to remind everybody that there is an ask the question feature in the portal, and if you'd like for me to ask a question on your behalf, just put it in the portal, and I would be happy to do so. With that, Jeremy, take it away. Thank you, Anupam. A big thanks to you and the team at J.P. Morgan for the opportunity to present here. I also wanna thank each of the participants watching the presentation today and the Q&A session. My name is Jeremy Bender. I'm CEO of Day One Biopharmaceuticals and excited to tell you about the company today. If we go to the next page, I wanna just emphasize that I will be making forward-looking statements today. On the next page is a summary of the company, slide three. Day One was created to address the innovation gap between pediatric and adult patient populations living with cancer and life-threatening disease. What that means is we focus on targeted therapeutics, in particular, clinical development of programs that are in... That tested in patient populations that have genetic alterations for which our programs are specifically addressed. Our goal is to move as quickly as we can to pediatric populations, which really differentiates us from many of the targeted oncology companies that are out there. We do that work in order to move as quickly as we can to generate clinical data and to move into registration. We do that work in parallel with the work that we do in adult oncology populations. We've been pretty successful since our launch in 2020 in building out a team, in advancing our lead program, Tovorafenib or DAY101, and expanding our portfolio and resourcing the organization. As I mentioned, the team is deeply experienced in oncology, in pediatric oncology specifically, and rare disease more broadly. That crosses all of the key functions that we'll need to continue expanding in future years. Our lead program is an oral pan-RAF, type II pan-RAF inhibitor. It's CNS penetrant, and it's in a pivotal study in relapsed pediatric low-grade glioma. This is an indication for which there are no approved therapies and for which we have the opportunity to establish a new standard of care. The pivotal study rests on some early encouraging data that was generated through an investigator-sponsored trial at Dana-Farber that I'll tell you about in a subsequent page. It's data from that study that has led to our Breakthrough Therapy designation from the FDA in that indication. We also have Rare Pediatric Disease Designation, which in combination with the Orphan Drug designations that we've established, will make us eligible for a priority review voucher upon approval. That relapsed pediatric low-grade glioma indication is really the tip of the iceberg for the development plan for Tovorafenib and for our broader portfolio. There are opportunities I'll tell you about for additional Monotherapy development of Tovorafenib, as well as a combination development of Tovorafenib and of pimasertib, one of the MEK inhibitors that we in-licensed from Merck KGaA, in the first quarter of last year. The company has a strong financial position. We have cash projected to take us into 2024, which will be critical as there are a number of key milestones that I'll tell you about as well, between now and that time. On the next page, you'll see a diagram of my senior team. As I mentioned, this is a group that has deep experience in many settings, both big and small companies, in particular in transforming organizations to grow and meet new challenges. That really comes to the fore in the oncology setting. This is a group that has decades of experience and judgment in that oncology setting, in particular in the pediatric oncology space, where the network of relationships and the experience we have in assessing and developing clinical programs, we think will be quite important given the tight-knit nature of the global investigator community in the pediatric oncology setting, as well as the relationships with global regulators will be critical for collaborating to define registrational pathways. The next slide is a diagram of our pipeline, and what I wanna emphasize here is each of the development programs that we have ongoing or planned. For Tovorafenib, that includes three Monotherapy studies. The top line is FIREFLY-1, our pivotal study in relapsed pediatric low-grade glioma. This is a study that's been ongoing since the second quarter of last year. This is also a study that we'll provide an update on in the first half of this year. That update will be on a subset of the patients from this study. It will include both safety and efficacy data from those patients that have been on therapy for a minimum of six months. Around the time that we announce that interim data, we will also discuss and initiate a phase III study in the frontline pediatric low-grade glioma market. This is the FIREFLY-2 study, which we will also initiate in the first half. That study will be a randomized phase III global study intended to support indication expansion into the frontline setting in this space. That constitutes the pediatric development plan. The bottom two lines are the work that we're doing in solid tumors in patients 12 and above, so adolescents and adults. Right now, we have an ongoing study of Monotherapy Tovorafenib that we initiated in the second half of last year called FIREFLY-1. The patients in this study are those that we think are most likely to benefit from Monotherapy Tovorafenib or pan-RAF inhibition. It includes patients that have BRAF and CRAF fusions, as well as CRAF amplifications. We also think there's the opportunity to expand Tovorafenib development in combination with pimasertib into patient populations that have other activating lesions in the MAP kinase pathway. To that end, we'll initiate an additional sub-study as part of FIRELIGHT-1 this quarter, first quarter of 2022, exploring that combination. That will have a dose-finding portion as well as a dose expansion portion once we have the cohorts that have specific interests. I'll talk a little bit more about the design of that in the subsequent page as well. On page six, what you'll see is a mechanism of action slide for this agent. As I mentioned, Tovorafenib is a type II RAF inhibitor. Like type I RAF inhibitors, Tovorafenib does inhibit the V600E and V600K alterations that are often found in melanoma, and we've seen clinical activity of this agent in that setting previously. In addition to inhibiting those changes, because of this molecule inhibits a dimeric RAF kinase signaling, we can also target a broader set of genetic alterations in and that means RAF alterations, but also other MAP kinase alterations through the use of this agent. We have also seen activity in that other setting where you require a dimeric RAF kinase signaling to see aberrant and tumor growth. That's notable in the case of RAF fusions in particular, where we've observed responses as Monotherapy for Tovorafenib in a couple different clinical settings. The first of which I'll start telling you about in the next slide, page seven. Page seven summarizes an investigator-sponsored trial called PNOC014 that was initiated at Dana-Farber Cancer Institute. This was a study, a phase I dose-escalation study of Monotherapy Tovorafenib, a once-weekly dose in relapsed pediatric glioma patients. This study treated a total of nine patients. Of those nine patients, eight of them had a RAF fusion, seven BRAF fusions and one CRAF fusion. Among those eight patients, what we observed from this study is five responses, two CRs and three PRs, as well as two patients that had prolonged stable disease. Very encouraging signs of efficacy in this patient population. The AE profile here was tolerable and fairly straightforward as expected. We saw some skin rash and hair color changes as the most frequent AEs. Overall, this early data was quite encouraging for future development in the same clinical setting. This is a dataset, I should say, that we then reviewed with the FDA, and it was this data that led to our Breakthrough Therapy Designation. We also, of course, through this study, were able to identify our phase II dose, which we're using now in our pivotal study of 420 mg/m² per week. The next slide shows the spider plot, the efficacy results, from the PNOC014 study, and I wanna highlight a couple of important features of the results. The first is that these were active and growing tumors at the time these patients entered the study. If you look at the left-hand portion of this graph, you know, the tumors from the patients that we brought into this study were actively growing and progressing. We went back and obtained the antecedent scans for these patients in order to demonstrate this, which we think is an important aspect of the efficacy results we've observed. Once on therapy, what you see is quite significant reductions in tumor burden. This is the measure here of tumor burden is RANO, which is a regulatory standard for brain tumors with the FDA. That's the Y-axis. Again, you see rapid, deep, and durable responses, you know, with Tovorafenib Monotherapy treatment. Very, again, very encouraging activity. The next page is a summary of our AE profile in the same patient population. I call your attention to the orange columns in the middle. As you can see, very, very few grade 3 AEs, just a single CPK elevation in one patient. All of the remainder of the AEs were grade 1 and 2 and reversible, and manageable. Again, the most frequent AEs that we observed with this agent in this patient population are rash, as well as hair color changes, which is Achromotrichia. The fact that this is a fairly tolerable profile, we think is quite important, as we consider the potential clinical benefits of keeping patients on therapy for long periods of time in this patient population, that AE profile will become more and more important. Notably, we did not observe any dose reductions in the phase I program here under PNOC014, which again shows a very tolerable safety profile. I also do wanna contrast that with one of the other MEK inhibitors that has been studied in this patient population, Selumetinib. That's the table on the right. As you can see, there are significantly more grade three and four AEs for Selumetinib in the same group of patients. And you do see some of the skin effects and cardiovascular and ocular toxicity that can be associated with MEKs in this patient population as well. Overall, a differentiated safety profile and one that looks quite tolerable. As you think about treating patients for long periods of time with a once-weekly oral regimen, this looks like a fairly attractive approach for patients. The next slide is a summary of our ongoing pivotal study, FIREFLY-1. This is a single-arm, open-label phase II study, approximately 60 patients total. The primary endpoint here is overall response rate based on that RANO criteria that I mentioned previously. In this study, we are enrolling patients that have BRAF alterations, in particular, those patients that have a BRAF wild-type fusions, the KIAA1549 fusion, as well as patients that have a BRAF V600 alterations. Among those two patient populations, it's the patients that have the fusions that constitute the bulk of BRAF altered pediatric low-grade glioma. 70% of pediatric low-grade glioma is BRAF altered, and among that 70%, about 85% consists of the fusions that we're enrolling in the study. As I mentioned, this is a study where we'll have an interim update in the first half, and we'll be in position, assuming the data are positive and moving forward to a filing to put the NDA in place in 2023. Let me also tell you about, starting on the next slide, the patient population that we're targeting here. What you're looking at are incidence and prevalence estimates for those patients that have pediatric low-grade glioma that have both received a systemic therapy and have those BRAF alterations. These are the patients that, should they require an additional systemic therapy, will be eligible for therapy, assuming we have an approval on the basis of FIREFLY-1. As you can see, there is a substantial both incident pool of 1,100, and a prevalent pool of approximately 26,000 here in the US The reason that you see such a large prevalent pool, relative to the incident pool, for an oncology indication is that, the bulk of these patients, 90%+, do survive into adulthood. As a result of that, the goal of therapy is very much to arrest the tumor growth, shrink it if possible, preserve function, and prevent some of the safety effects or side effects that can result from subsequent therapies. This is the overall patient population that we'll be addressing in the relapse setting with this particular study. Of course, the frontline setting is an additional opportunity. That's the low-grade glioma story for us. I also want to tell you briefly about the work that we're doing in adult patients. At the time that we in-licensed this program, there were data from approximately 225 patients that had been treated with Tovorafenib previously. The bulk of those patients were melanoma patients that had V600E alterations in their tumors. Among those patients, we did see responses that looked quite similar to what you observed with type I BRAF inhibitors. Tovorafenib is active in adult solid tumors in the V600E setting. It also, through the once-weekly regimen that was established for this program, has a differentiated safety profile relative to those type I RAF inhibitors and relative to some of the MEK inhibitors that can be used in the adult solid tumor setting. In particular, we do not observe any of the Ophthalmologic or Cardiovascular liabilities associated with MEK inhibitors or any of the effects of paradoxical activation that can be observed with the type I RAF inhibitors, the prior generation. On the basis of that data set and the early data that we observed for a RAF fusion patient, we've now initiated a Monotherapy study. One reason that we're as optimistic about the potential activity in this Monotherapy study as we are is that if you look on the next page, 13, we've also observed a CR from a compassionate use patient in this case, a spindle cell carcinoma patient that's been treated with Tovorafenib. This is a patient that, like the low-grade glioma patient, has a wild-type RAF fusion. In this case, it's a different molecular fusion than what you often observe in pediatric low-grade glioma, but also a very encouraging outcome. This patient had been on therapy on Trametinib, had achieved a response, and then progressed on Trametinib before being put on Tovorafenib and achieved a rapid CR and is still on therapy today. Again, in the extracranial setting, very encouraging signs of activity for Tovorafenib in RAF fusion patients. That's the patient population, that extracranial group of RAF fusion patients that we'll be targeting in our Monotherapy FIRELIGHT-1 study, which is summarized on page 14. This is a study that is now ongoing and again, will enroll patients that have BRAF and CRAF fusions, as well as CRAF amplifications. We're going to look at two patient populations specifically. One is a melanoma cohort, the other a tissue-agnostic cohort. We've separated that out just to simplify and see if you know most common group of melanoma patients, we observe a signal there or in a tissue-agnostic or both before we decide whether we'll progress this. The final element of the development program is the combination of work that we'll do with pimasertib. What you see on page 15 is an overview of the pimasertib program. This is an allosteric MEK inhibitor that we brought in from Merck last year, as I mentioned. It is an orally bioavailable program that has undergone extensive non-clinical and clinical development work by Merck previously, spanning over 800 patients. It has a safety and an efficacy profile that is quite similar to other MEK inhibitors that you may be familiar with, and has a significant body of data that will allow us to move quickly into combination studies. We'll initiate that study in combination with Tovorafenib this quarter. That study is summarized on the next page. This is a sub-study that will be part of the FIRELIGHT-1 program. It'll have a dose-finding portion, a dose-finding phase I-B, as well as expansion cohorts in the phase II setting. The specific patient populations that we'll target in that expansion phase will include NRAS mutant melanoma. It will include BRAF altered tumors that of a Class 1 non-V600 as well as Class 2 BRAF alterations. We may also look at fusion patients as well. We'll continue to monitor both the external data that can be generated for these tumors to see what specific patient populations make sense to target in these cohorts, as well as additional preclinical data that we're working on internally. The next page shows a quick snapshot of our financial position. We ended the third quarter of 2021 with just under $300 million in cash. Our cash position will take us, as I mentioned, into 2024. We'll have some of that cash available to continue doing work building out our portfolio through business development activities, which is a key priority for the company. We have no debt. In summary, on slide 18, we've had a transformative 2021, setting up two company-sponsored studies, executing those studies, two key time points and milestones that will occur this year. That will include the update on the clinical data from FIREFLY-1 in the first half, the initiation of our phase III in the first half, as well as the combination work that we'll initiate this quarter of Tovorafenib and pimasertib. With that, I'll close and say that we look forward to a transformational 2022 and beyond. Thanks for your time. We'll look forward to talking with you in the Q&A session. Anupam. To my left is Sam Blackman, CMO, Co-Founder of the company, and to my right is Charles N. York II, Chief Operating Officer and Chief Financial Officer of the company. I just wanna remind the listeners of the session that if you want me to ask a question on your behalf, I'm happy to do so. Just put it in the portal and I will ask. We do have a couple questions in the portal already, which is, for FIREFLY-1 first half update, what is the bar for ORR in your opinion? Anupam, you know, our perspective is that the most important aspect of the dataset that we'll generate in that interim is whether or not this generates clinical benefit for patients. The way that we think about that is by looking at the historical benchmarks in this setting. The largest study of another Monotherapy in relapsed pediatric low-grade glioma is Vinblastine. That's a 50-patient study. This was a study that we referenced in the protocol that we reviewed in the statistical analysis plan with the FDA, and that study showed a 21% overall response rate for Vinblastine in this group. Anything north of that 21% we think will be positive. Of course, the further north, the better. That's the way we think about the sort of efficacy bar. We'll also, of course, wanna see over time how those responses mature. It's important to note that the interim data we'll have coming out in that first half will just be that and we'll look to the full dataset to further expand on what the activity of the agent is. Another question that we have in the portal is, for the interim look later this year, what should we be expecting in terms of patient numbers and duration of follow-up? The duration of follow-up will be a minimum of six months on therapy for all of the patients in that interim. It'll be a spread, of course, depending on the time of enrollment, but it will be a minimum of six months follow-up. The patient numbers we haven't guided to at this stage, Anupam. What I can say is that it will be an appreciable portion of the overall study. We just haven't said the specific numbers. One of my questions is, you know, how do we think about sort of time to response and duration of therapy? Maybe you can remind us of some of the prior data here, and how much duration data do you think regulators will require? I'll ask Sam if he can answer that question. Yeah. Thank you for the question. I think it's important to preface the answer by saying that our focus at Day One is really on delivering solutions that can both change the outcome and change the outlook. For the patients that we care so much about, and aim to achieve a new standard of care. Obviously, for a disease like pediatric glioblastoma, for a number of patients survive, durable responses are really critical, not just the patients, but their families and their treating physicians. We've seen in the phase I study durations that are measured in years, not just single-digit months. We think that even though this is a small number from that phase I study, it's very important as a signal. It's part of what encouraged us to in-license the molecule and develop it in our phase II study. At the end of the day, when it comes to looking at durability of response, you know, the FDA typically, you know, is looking for responses that are not ephemeral. They've commented to us that, you know, responses of at least six months duration are interesting to them. At the end of the day, they're gonna look at the totality of the data, both safety, efficacy in terms of the rate of response, as well as the durability of response in making a decision. Okay. For FIREFLY-1, should we be thinking about the data in conjunction with a medical conference, or is this like a top-line press release webcast type of scenario? Charles, do you wanna answer that one? Yeah. Of course. Yeah. We anchor that decision, Anupam, it really in thinking about use of the data both with our investigators and our regulators. If you push that thread forward a little bit also into ensuring that it's available in front of our pivotal, excuse me, our frontline trial for FIREFLY-2. What we'll do is we'll determine the timeline that best meets those needs of the investigators and the regulatory side of the house. As the data is complete and ready to go, we'll ensure that we're releasing it at that time. Yeah. On FIREFLY-2, the frontline study here, it sounds like you're waiting for this initial FIREFLY-1 readout. Is that a gating factor to starting that study? Or, what are the gating factors to starting that study? Yeah. Anupam, we're moving forward rapidly with that phase III program, and it's part of the plan. It is not a gated study per se. It's a fairly large effort to get a global registrational phase III launched and requires a fair amount of work coordinating with global regulatory authorities in order to ensure that we have best chance of really expanding. You know, the opportunity to get this to patients into that frontline setting across geographies. That effort has been underway for some time. We're reasonably close to finalizing the details of the study. We would like to see the data from FIREFLY-1 for two reasons. One is to inform some of the assumptions that we'll need to make around the final design of the study. Two, to you know, publish the data from that interim in FIREFLY-1 to generate interest among investigators and prospective patients and families, in order to launch and drive enrollment as quickly as possible for the frontline program. It's a combination of factors, but I would not say that it's a gated decision as much as it is an aligned plan that allows us to really inform the phase III with the phase II results. I know that FIRELIGHT-1 only just started here in November, in sort of adult RAF altered solid tumors. How's enrollment going in that study? Have you seen any impact from the new variant? How do we think about potential timelines there on the data side? Yeah. Yeah. We haven't guided and won't at this point to when data will be available from that FIRELIGHT-1 Monotherapy component. I'll ask Sam to comment on the status of enrollment in the study itself. Yes. We announced our first patient treated back at the very end of 2021. The study remains on track. It's open at least six sites as of today, and a number of sites looking to initiate in the next month or two. As you know, this study is enrolling patients with solid tumors or adolescents and adults with solid tumors that are relapsed and have BRAF-altered fusions, CRAF-altered fusions or RAF1 amplifications. These are relatively uncommon lesions. BRAF-altered fusions represent about 1% of the genomic alterations found in relapsed adult solid tumors. We're employing a number of strategies including choosing clinical trial sites that sequence a number of patients and can readily identify these patients, but also creative ways of either bringing patients from geographies or places in the country or places around the world that don't have this trial open to sites that have the trial open or bringing the trial to sites where it's not open in a just in time manner. We remain confident that we'll be able to enroll independent of any of the effects of the pandemic and overcoming the relative rarity, relative scarcity of these patients. We're able to find them at the sites that we've chosen. On sort of the combination with pimasertib, I think the guidance here is to start that phase I-B/II study this quarter with DAY101. You know, I guess, what are the gating factors to starting that? Sam, do you wanna comment on the study? We are on track. The protocol has been finalized for a couple of months now, and we're in the process of getting it through the site initiation process, and we aim to be on track for initiating site this quarter. Maybe final question from me here. I don't see any questions in the portal, but final question from me here, which is, how should we think about additional business development to kinda supplement the pipeline here with DAY101 and Pimasertib? Thanks for the question. I'm gonna ask Charles to answer that one as well. Yeah, sure. We really looked at business development as part of core basis to what we do here at Day One. We've invested in it very early from our standpoint. We're active in looking at multiple opportunities on a regular basis. Also, as you know, finding the next asset, looking for the next thing that we find compelling doesn't necessarily hang on a calendar as neatly as we'd like. The timing of it does alter and shift. As we demonstrated with the in-license with MEK earlier last year, we're acutely attuned to the market. When we find something that we think fits in our strategy and what we wanna proceed with, we'll aggressively and surgically pursue that opportunity. Okay. Well, I don't see any more questions in the queue. Jeremy and team, I wanna thank you guys so much for a super productive session here. I hope you guys have a great rest of the conference. Thanks, Anupam. Thanks again for the opportunity. I hope you have a good conference as well. Take care.