All right. Good morning, everyone. We're going to get started. It's my pleasure to welcome you this morning. My name is Michael Metzger. I'm the CEO of Syndax. Warm welcome to everybody joining us in person today, and also online. We're thrilled to give you an update on our progress as we advance innovation for patients and bring more opportunities for great therapies to patients. We will be making forward-looking statements. Here's our disclosure. Syndax is a company on the move. We're driving innovation and long-term value for patients, and we have what few companies our size have in terms of accomplishments. We've gotten drugs approved, actually, and brought them to market. We are a fully integrated commercial organization now with a track record of success, and we're looking to expand on that success. We've built world-class R&D capability, both in the company and outside the company through our collaborations. We have a deep and growing pipeline, which we'll talk about in great length today, which has this opportunity, multiple opportunities for blockbuster products. Importantly, we have a solid financial position. We're driving to profitability, and we have the opportunity to fund all of our programs fully. We are well-positioned for the next stage of growth. We're advancing the standard of care in acute leukemia, as well as in chronic GVHD with our two first-in-best-in-class medicines. Revuforj and Niktimvo, as you all know, have done very well last year, and this year annualizing about $200 million in revenue as we're growing and growing towards profitability. Very well set up for success. Really, it's about the patients. It's about driving innovation for patients and expanding upon what we've already done. We've treated thousands of patients already. Some of our patients are shown here on this slide, and we're looking to expand on that even more and bring more innovation forward. I'm excited, very excited today to talk about our expanding pipeline and our next phase of innovation and growth. All of you know Revuforj and Niktimvo on the left. We have more work to do with both of those assets as we expand. First, with Revuforj, we will be positioned to be the first to frontline, and we are expanding in combination with multiple agents in order to bring this product to more and more patients. Niktimvo, likewise, we're going to be in the frontline, before long with combinations, standard of care agents, and we look to expand upon what we've done already with GVHD. Furthermore, Niktimvo has the opportunity to go to areas such as IPF, big opportunities. We'll talk about that today as an adjacency to what we've done in chronic GVHD. Very exciting next phase of growth for Niktimvo as well. We are building on what we've already done with Revuforj and Niktimvo. Now we turn the page and focus a little bit today on our next set of assets, our exciting set of assets. First, I'll highlight SNDX-4321 and also 62122. This follows our first-in-best-in-class way of approaching things. For SNDX-4321, this is a mutant selective allosteric EGFR inhibitor for non-small cell lung cancer. It's a novel approach, a novel mechanism to bring to this disease where there's high unmet need and we can make a difference. This is an in-license asset from Dana-Farber Cancer Institute, very important leading scientific organization in our community. We were able to in-license this on favorable terms and drive the science forward. It's really our sweet spot. What we do is we translate the best of early science into the clinic and generate proof of concept quickly, that's what we think we can do with this agent. It's targeted for IND submission at the end of the year. We are really well-positioned now to talk about what comes next for this asset. Very exciting. SNDX-62122 is a next-generation menin inhibitor for MF. We all know that we've learned a lot about menin inhibition. We've been driving the science from the beginning. This is an internally generated asset. We have a library of next generation menin inhibitors, which we think are fit for purpose. This will go into MF, and it's potentially a disease-modifying agent. We've learned and we've published data. As of this week, there was a Cancer Cell paper that was published really highlighting the importance of this mechanism, potentially in myelofibrosis. We had data at ASH as well and really kicked that off. We're in a very good position to take this science forward and exploit the mechanism in myelofibrosis. As I said, this is a fully owned set of assets that we have developed at Syndax. We're targeting submission for this asset in 2027. As you look across our pipeline, what's exciting is we have multiple blockbuster opportunities. First, acute leukemia with Revuforj, GVHD, and now potentially IPF with Niktimvo, SNDX-4321 in non-small cell lung cancer, and SNDX-62122 in myelofibrosis. A full set and complement of opportunities. I'm very excited to be joined today by wonderful group of speakers. In addition to me, I'll have Nick Botwood, Dr. Nick Botwood, our Chief Medical Officer and Head of R&D, as well as Peter Ordentlich, Dr. Peter Ordentlich, our Chief Scientific Officer and Founder. As well, joining us both in person and online, Dr. Crispino from St. Jude Children's Research Hospital. He'll be covering the MF portion of our talk today. Dr. Toby Maher, from the University of Southern California. He'll be covering IPF. He'll be online. Dr. Michael Eck from Dana-Farber Cancer Institute. He'll talk about the asset that we've in-licensed, SNDX-4321, as well as his breaking science and breaking developments in research in lung cancer. Now just a bit on our agenda for today. Nick, I'll hand the baton to Nick in a minute, he'll cover both our R&D capabilities, as well as take you through our pipeline. That's the first section. We'll also talk about Revuforj and our next-generation menin inhibitors, followed by Niktimvo, as well as SNDX-4321, which is our allosteric inhibitor. We'll close from there. There'll be Q&A throughout, you'll see every section we'll break it up with Q&A, we'll have an opportunity to pause and ask questions. We'll be closing the session at around 11:00 A.M., just to give everybody a sense of timing, we'll go from there. Very exciting day of presentations. I'm looking forward to it. Hopefully you are as well. I'm going to pass it over to Nick, we'll go from there. Thank you. Thanks, Michael. Thank you, Michael, and thank you all for coming. I'm very excited to spend the next couple of hours with you all, reviewing with our collaborators some of the developments in our R&D portfolio and our exciting and evolving pipeline. It's an exciting time to be at Syndax, and I'm excited to share the science that we think bears such promise for patients to come. Let me start a little bit about what I think makes Syndax really special and differentiated as a biotech, that we have built an incredible R&D engine with some of the best talent across the industry to really deliver on this extremely promising portfolio. We have what I would absolutely call now a world-class R&D organization. This is an organization that already has a proven track record of taking great science, translating it into the clinic, coming up with innovative clinical development plans, filing it, approving it, and then commercializing it successfully. This is an extraordinary track record for this biotech. I'm incredibly proud to lead this organization. We have individuals with deep expertise now in menin inhibition, in CSF1R inhibition, and recently through the hiring of some great new leadership and talent, now deep expertise also in the development of novel assets in non-small cell lung cancer that, as you will hear through the day, is going to be foundational to our future success. We have, I think today will be a very good showcase of that, we have also incredible relationships and collaborations with leading researchers, and new discoveries, which are really catalyzed by these collaborations we've had over many years now as a biotech that positions us very strongly to continue to lead the science and to harness innovation and the best science. I think, again, today will be a great showcase of that in example. We also have very deep science. We have deep mechanistic understandings. We were the first to identify menin inhibition. We were the first to validate the concept of CSF1R receptor antibodies in GVHD, and that is really based on our deep understanding of the science and then translating that science into the clinic, and we have a proven track record of being able to do that. We do now also have, and I'm happy you were all able to join us here in our offices in New York, we do also have deep in-house expertise covering all of the key disciplines that support world-class research and development. We have outstanding discovery partnerships. We have a leading development organization, CMC, of course, regulatory, and of course, a commercialization organization. Having spent a lot of my career in large pharma, I would also say we're now right-sized to deliver, but also to be extremely efficient and nimble in terms of decision-making and governance. We're able to move extremely quickly to harness the best science and then translate that, making quick and appropriate decisions to really deliver well for our patients. Just a little bit about the track record before we get into the new stuff, which is really talking about our leadership and our scientific leadership with menin inhibition and Revuforj. This dates back over a decade now to 2016, where revumenib and axatilimab were in-licensed pre-IND. We are going to talk about similar models today. We were the first to clinically validate menin inhibition in acute leukemia. We were the first company to approve a menin inhibitor, now, as you all know, a very hot space in KMT2A, subsequently an SNDA in NPM1 acute myeloid leukemia. We were also the first to initiate a randomized study in newly diagnosed frontline AML. We were the first to present and collaborate on data that you will hear about today for the potential of menin inhibition and revumenib in the treatment of myeloproliferative neoplasms like myelofibrosis, and we are excited to review that. Equally, we were the first to clinically validate CSF1R inhibition in GVHD, and we are the first approved and only approved CSF1R in GVHD. The timelines for this are quite impressive. We achieved three FDA approvals between revumenib and axatilimab. Both drugs were approved in about five years from IND to FDA approval, which is a very impressive track record, and that is something we want to build on, and we believe we have the people and the capabilities to be able to do that. Let me touch just briefly on the existing portfolio of studies that is probably quite familiar to you. We have obviously a deep and extensive program with revumenib, and I will talk a little bit more about that in a minute. We have now added to the revumenib book of work a proof of principle study in myelofibrosis, which you will hear more about. We have an extensive program of work with axatilimab, our CSF1R antibody, with now an important proof of concept in idiopathic pulmonary fibrosis, which will be the focus of one of the sessions you will hear about today. What I am really excited about is to add two new assets to our pipeline. This is an incredibly exciting portfolio of studies for us to be able to execute against. We will focus today and go deep into the science of allosteric inhibition in EGFR mutant non-small cell lung cancer. We will talk deeply about the science that underpins the role of menin and menin inhibition in myelofibrosis and our new menin inhibitor 62122. For the first session, and we are going to have three sessions today, I want to talk about advancing our leadership in menin inhibition. We are very well-positioned, and I would say in a very strong position to continue to drive the leadership in menin in acute leukemia, and we remain laser-focused on acute leukemia, but also into indications beyond that where we feel menin inhibition could have an important role to play. We come from a foundation of having the broadest indication and clinical activity of any menin inhibitor. We are the only menin inhibitor approved in NPM1 and KMT2A translocated acute leukemia in adults and children. We're the only menin inhibitor with now presented data in the subset of NUP98-R, which we're excited about, area of high unmet need. We have a really broad integrated evidence generation plan. We call it integrated evidence because we're somewhat agnostic to whether that's company-sponsored, investigator-sponsored, or a collaborative proposal. We are simply generating data that might support registrations, might support guideline-informing data, or potentially could generate data that either supports clinical practice or a new signal to take into a new development program. We have, as you will hear about today, a library of next-gen menin inhibitors. This was an internally developed library, which aligns very nicely with our leadership in menin because we have already revumenib in the clinic to generate proof of principle data that will support accelerate the development of our next-gen menin 62122. We have, of course, underpinning all of this, which you'll hear about today, incredibly strong scientific partnerships because of our reputation to do this. We have collaborations with world-leading scientists and clinicians that will catalyze these promising scientific discoveries into breakthroughs for patients. I'm not going to spend too much time talking about the development program with revumenib. I think it's quite familiar to you now. Suffice to say, we have a very broad development program that supports all of those ambitions, registration, life cycle management, signal seeking, and practice informing. I would like to highlight a couple of things. First is that we remain a laser focus on our two pivotal registrational studies, the EVOLVE-2 study in patients unfit for treatment with intense chemotherapy, which is a combination with venetoclax, and our 7+3 combination in frontline patients that are fit to receive intensive chemotherapy. Those studies are both up and running. We have great momentum in terms of site activation internationally, and enrollment is really picking up, and the teams remain laser-focused on executing those studies to take those, hopefully with a positive outcome, towards new therapeutic options for all patients with newly diagnosed AML, and we're very excited about the potential of that and the progress we're making with those studies. That's in blue at the bottom of the slide. The two studies I just wanted to highlight in yellow on the slide were really there just to highlight the innovation that we're doing and continuing to drive our leadership. The first is in maintenance. The role of menin inhibition in patients that have had a transplant is an area of important research. We were the first study to now have a prospectively randomized approach, again, in collaboration with the Dana-Farber Cancer Institute, identifying and clarifying the role of Revuforj in a maintenance setting after HSCT. That study is called the MAINTAIN. It's now on ct.gov. We have the RAVEN study, which is again novel, innovative, and differentiated from other menin development programs. This is looking at patients with KMT2A-relocated AML who would be otherwise fit for intensive chemotherapy. It's actually in combination with venetoclax. The hypothesis being that you can get those patients to transplant without the need for intensive chemotherapy and therefore with less associated morbidity. We have this already well-established and robust overall development program for revumenib. We will, however, continue to follow the science to unlock the full potential of menin inhibition, and we have a proven track record of doing this now, starting with KMT2A approvals in MPN, exciting data, as we talked about with NUP98-rearranged disease. We now have studies looking at the role of revumenib prospectively randomized in that post-transplant setting. Today, we're going to talk about myelofibrosis and potentially indications beyond that. It's very exciting science. Myelofibrosis. You may ask, why myelofibrosis? Why did we pick myelofibrosis as our next life cycle management indication? Clearly this remains an area of high unmet need. These patients are symptomatic, associated with significant morbidity and mortality. We have, as you will hear today, compelling preclinical data that Dr. Crispino will review and was awarded best of ASH, and as Michael highlighted, was recently published. It's an extremely good strategic fit for us with our leadership in the menin inhibition space. We also think it has the opportunity for us to generate an early clinical signal, and that allows us, should we be successful, to pivot into more full development in a very rapid timeframe. It's not going to take a long time for us to be able to identify whether menin inhibition does indeed have a role in myelofibrosis, which based on the preclinical data, we have a very strong feeling that it might have. Let me touch a little bit on our leading menin inhibition and leading that into the future with our library of next-gen molecules, plus our ability to de-risk this library of molecules with revumenib to generate proof-of-principle data. Our intent is to deploy this next-generation menin inhibitors into new areas where we will be starting with myelofibrosis. These are rationally designed molecules informed by our deep molecular understanding of revumenib's interaction with menin. Importantly, these are wholly owned assets with no financial encumbrances. It presents multiple distinct scaffolds with composition of patents that last well into the late 2040s. 62122, that you'll hear a little bit more about today, is a next-gen menin inhibitor. It was actually the first molecule to emerge from our library. We are anticipating the submission of the IND in 2027, into the clinic in the latter part of 2027. The profile of this so-called next-gen menin inhibitor is very attractive. It has extremely high potency. It has increased selectivity without off-target effects like hERG. The PK is optimized with extremely little, if any, drug-drug interactions. It also has quite profound activity against some of the common resistance mutations. It's an extremely attractive molecule to take into settings like myelofibrosis. On that note, I'd like to introduce our next speaker. I'd like to introduce Dr. John Crispino, who's been a close collaborator of ours for many years. Dr. Crispino is the Director of the Division of Experimental Hematology at St. Jude Children's Research Hospital. He is an internationally recognized hematology researcher whose pioneering work has significantly advanced the understanding and treatment of myeloproliferative neoplasms, as well as other disorders. We are absolutely thrilled to have him here to discuss the landmark research he recently led with support from our scientific team, which led to the discovery of menin as the novel target in myelofibrosis. It gives me great pleasure to introduce Dr. Crispino. Great. Thanks, Nick. It's a real pleasure to be here today to tell you about our research, which was, again, just published last Thursday online in "Cancer Cell," and it's an open access paper. I'll cover some of the highlights of that today, and I encourage you to take a look at the paper to see the primary data. Myelofibrosis is a myeloproliferative neoplasm, an MPN, that affects about 20,000 people in the United States. It's associated with extramedullary hematopoiesis contributing to enlarged spleen and enlarged liver. That's due to the increased hematopoiesis in that tissue. There's increased levels of inflammatory cytokines that mediate the debilitating symptom burden and bone marrow fibrosis that accompanies cytopenias. Stem cell transplant is the only curative option, but 90% of MF patients are not candidates for transplants due to age or comorbidities. JAK inhibitors, including ruxolitinib, are the current standard of care for the vast majority of patients. While these JAK inhibitors reduce symptom burden and splenomegaly, they do not appreciably affect or reduce fibrosis or the mutant allele burden. Most patients stop responding to JAK inhibitors within two to three years with poor outcomes. This is why it's an area of high unmet medical need. Myelofibrosis is characterized by an accumulation of atypical megakaryocytes, which are the cells that derive platelets. These cells contribute directly to the fibrosis by secreting cytokines, which lead to increased collagen deposition. Emerging data from my laboratory has shown that menin is a novel dependency, particularly in the proliferative megakaryocytes in their progenitor cells that I'll refer to as MKPs. We know from our work that menin inhibition suppresses megakaryopoiesis by down-regulating key KMT2A menin target genes such as MEF2C and MEIS1. It selectively affects these MKP cells. In our studies, revumenib showed striking anti-tumor activity in several preclinical models of the MPNs. These include the JAK2V617F mouse, the MPL or MPL W515L mouse, which I'll show you the data for, and another mouse called MPL S504N, as well as also PDX mice that I'll show you. Our work then supports further investigation of menin inhibition in myelofibrosis. Interestingly, it targets pathways independent of targeting the JAK-STAT pathway. It's an orthogonal pathway by transcriptional downregulation of these key target genes. Our recently published preclinical data show that revumenib selectively inhibits megakaryopoiesis. First, I'll show you data from liquid culture assays of human CD34 positive cells cultured with revumenib. On the left, you can see that the percentage, as well as the absolute numbers of MKPs derived in culture, are significantly reduced. We also see subsequent effects on the immature megakaryocyte fraction and the more mature megakaryocytes treated with revumenib. Not shown here, in colony-forming assays of megakaryocytes, revumenib has an IC50 of about 300 nanomolar to block the production of those cells. By contrast, you see that erythroid colonies and granulocyte macrophage colonies are not affected by revumenib as doses up to 20 micromolar. We importantly show that loss of menin phenocopies the effect of the drug, confirming an on-target effect. We used single-cell RNA sequencing approaches to demonstrate this. I'll first start on the right, which is the revumenib-treated cultures. Again, I'm showing that the numbers here of the MKPs are vastly reduced by treatment with revumenib, as are the immature megakaryocyte fraction. On the bottom, we're looking at UMAP data, which is a single-cell RNA sequencing approach that lets us look at individual cells within the culture. I'm showing you seven cell populations. You can see in the circles that revumenib has this profound effect to reduce the MKP population and the subsequent development of megakaryocytes. On the left is using a CRISPR approach to knock out the menin gene. We use two different so-called guide RNAs to down-regulate menin, guide one and guide 13. On the left graph, you can see that knock out of menin with two different guide RNAs significantly reduces the MKP population and also reduces those immature megakaryocytes. On the bottom, again, through this single-cell RNA sequencing data, you can see that the knockout again recapitulates the effect of the drug where there's downregulation of both the MKP population and the MKs. I'm going to show you today just one mouse model. This is the MPLW515L model. It's a very aggressive model of myelofibrosis. The phenotype predominantly is bone marrow fibrosis, very high increases in the white cell count, high increases in the platelet count with very modest effects on the erythroid lineage. They also develop splenomegaly and enlarged livers. The vehicle-treated mice in this model succumb to the disease typically five weeks post-transplant. What I'm showing you here then is in blue are the control treated mice, in orange are the revumenib-treated, in blue ruxolitinib, and in yellow is the combination of ruxolitinib with revumenib. You can see first the white cell count that all three treatment arms show reduced white cell count, but especially the yellow line here, the combination is very effective at normalizing the white cell count. Similarly, for the platelet count, we can see that all three treatment groups reduce the platelet count. Ruxolitinib has an intermediate effect compared to revumenib, and the combination again is even stronger at reducing the platelets. I think on the right, what's the most important takeaway from the right graph where we're looking at hemoglobin is that the drug treatments, including the combination, does not cause anemia in this animal model. If we look at the spleen weight in this particular mouse model, you can see in orange that revumenib did not reduce the spleen weight. This is not true in the JAK2V617F model. In the paper, you can see that that had a very strong reduction in the spleen size. This MPL S504N mouse that I'm also telling you about, we see the reduction in spleen size there. ruxolitinib in this study led to a significant but modest decrease in spleen size, the combination importantly normalizes that spleen weight. On the right, you can see that all three treatment arms are giving enhanced survival, those untreated mice are dying again about five weeks post-transplant. Let's talk about the bone marrow environment and the fibrosis. We know revumenib alone and in combination with ruxolitinib suppresses the level of TGF-β, megakaryocyte accumulation, and fibrosis more than ruxolitinib alone. If you first look on the left graph, this is looking at a cytokine, TGF-β, which promotes fibrosis. It's produced by megakaryocytes and other cells in the marrow. Revumenib, in orange, gives a significant reduction in TGF-β levels. Does ruxolitinib, the combination is much more potent at that. In the middle graph, we look at the percentage of megakaryocytes within the bone marrow. Here, we again see that revumenib has this very strong ability to eliminate these atypical megakaryocytes that are characteristic of myelofibrosis. Similarly, the combination is as effective. In contrast, you can see that ruxolitinib, as we know, does not affect this megakaryocyte population significantly in these animal models. Finally, on the right, we're looking at the reticulin grade fibrosis, which could be zero, one, two, or three. Typically, these untreated mice have a fibrosis grade of either one or two. Treatment with revumenib as a single agent or in combination with ruxolitinib essentially prevented fibrosis from developing in any of the mice in this study. I would say we've done a lot of preclinical studies with four different mouse models, only one mouse in all of those studies treated with revumenib had a grade one fibrosis. Really the strongest drug that we've seen to eliminate fibrosis or at least prevent the development of fibrosis. ruxolitinib in patients has a very limited activity on fibrosis. Here in the mouse model, it's variable, some of the mice respond and some still have a fibrosis. You can see some of this histology here. This is looking at the bone marrow of the treated mice. The top row is hematoxylin and eosin stain. You can see on the upper left, I don't know if you can appreciate, there's lots of these large cells there that are clustered. Those are the atypical megakaryocytes that are characteristic of myelofibrosis. In the revumenib-treated mice, we see that those atypical megakaryocytes are gone. That's compared to ruxolitinib, where you can see that there still remains this abundance of clustered atypical megakaryocytes. Finally, on the far right, you can see combining revumenib with ruxolitinib reduces or eliminates those abnormal megakaryocytes and also normalizes the bone marrow cellularity. The combination is particularly strong in this model, as well as in the JAK2V617F model. Again, you can see that in the manuscript. The bottom is looking at degree of fibrosis, we can show that revumenib alone or in combination with rux, again, completely eliminates fibrosis or prevents it. ruxolitinib, in this example, we're showing you a case where it is active, it is variable in those mice. Finally, we looked at patient samples. On the top, we're looking at in vitro treatment of patient samples with revumenib. These are patients that either have a calreticulin mutation or JAK2 mutation. The MPL mutation is about 5% or 10% of the patients, whereas the calreticulin mutation may be 30%, 40%, and the rest would primarily be JAK2, though some patients triple negative. You can see that those patient samples all responded to revumenib. On the left is the CFU-MK, so megakaryocyte colonies. You can see those are significantly reduced with revumenib. Similarly, the megakaryocytes, the immature and the more mature megakaryocytes are reduced. Finally, importantly to us, looking at these MKPs, which we think are the disease drivers, those are reduced by treatment with revumenib, even with the mutations. Finally on the bottom, we generated a patient-derived xenograft model of myelofibrosis using an MF patient sample injected into immunocompromised mice. This is treated with a single agent, revumenib, you can see that revumenib reduced significantly the proportion of human CD45 tumor cells that are in the peripheral blood. In the bone marrow in the middle, you can see that human CD45 positive cells, the numbers of those cells in the bone marrow are significantly reduced treatment with revumenib as a single agent. Finally, on the far right, hematopoietic stem progenitor population of CD34 positive, CD38 negative HSPCs are significantly downregulated upon treatment with the drug. The last data slide is to look at the target genes. We can see here we're looking at three key target genes, MEF2C in the middle, MEIS1 on the left, and PBX3 on the right. In the top row is looking at these megakaryocyte progenitor cells. You can see that all three are significantly reduced upon treatment with revumenib. On the bottom graph, we're looking at the megakaryocytes. In those cells, MEIS1 is not significantly downregulated, MEF2C and PBX3 are downregulated. In the manuscript, what you'll see is we can show that knockout of MEIS1 or MEF2C can phenocopy the effect of revumenib. Importantly, overexpression of MEF2C can partially alleviate the effect of revumenib on the MKP numbers, indicating that that is indeed one of the key target genes of the drug in the megakaryocyte lineage. I'll summarize our data in this slide. Menin inhibition suppresses megakaryopoiesis. Here I'm saying in times of stress or disease, when the progenitors are highly proliferative. What I mean by that is in our liquid culture assays, we're expanding the megakaryocytes and cytokines. In the animal models of myelofibrosis, as in patients, there's a massive expansion and proliferation of the MKP population. In those settings, menin is a particularly strong vulnerability that can be targeted with revumenib. This on-target effect in myelofibrosis is driven in part by downregulation of MEIS1 and MEF2C. Revumenib has antitumor effects in multiple MPN mouse models, as both a single agent and in combination with ruxolitinib. Revumenib and ruxolitinib appear to synergistically suppress myelofibrotic cell growth by targeting the regulation of key MKP genes and JAK-STAT signaling respectively. I should point out, in the manuscript we show again that these are targeting orthogonal pathways, that revumenib does not suppress JAK-STAT signaling as a single agent. Instead, it targets, again, those atypical megakaryocyte progenitors through a transcriptional pathway. We do see formal synergy in treatment with cell lines, and then again in mice, we see the combination is more effective. We believe that menin inhibition may be complementary to other emerging targeted therapies in myelofibrosis, such as mutant CALR-targeted antibodies and the next generation of type two or JAK2 mutant selective inhibitors, which then again target the JAK-STAT pathway orthogonally. Finally, our study provides the rationale for further clinical investigation of menin inhibitors in the MPNs, and I believe Nick will talk next about the clinical studies. Thank you very much, Dr. Crispino, for that very nice overview. Let me talk briefly about the next steps building on that groundbreaking research publishing Cancer Cell with the very nice editorial accompanying it from colleagues at Memorial Sloan Kettering. We're going to leverage revumenib to inform and de-risk the development with our next-gen menin inhibitor 62122 in myelofibrosis. As we've talked about, those data are now published in manuscript. Our intent is to initiate a revumenib proof of principle trial in the fourth quarter of this year. We will in tandem be submitting an IND for our next-gen menin inhibitor 62122 in 2027, and we're progressing very well with the components of the IND to be able to submit that next year. We would then intend to initiate a phase I of SNDX-62122 in myelofibrosis in 2027, so next year. Being able to leverage all of the learnings from the proof of principle study with revumenib as the proof of principle for menin inhibition in myelofibrosis, and we believe that that will really offer us the opportunity to accelerate the development from that phase I in myelofibrosis with a much deeper understanding of the tolerability, the dosing, and potential traditional and novel combination approaches in the treatment of myelofibrosis, Dr. Crispino highlighted the potential of some of those combinations in the future. I'd like to just highlight briefly the phase I/II proof of principle trial that we have planned in MF, which we are anticipating starting at the back end of this year. This study is done in partnership with the Myeloproliferative Neoplasm Research Consortium, or MPN-RC Consortium. This study is not yet on clinicaltrials.gov. We do have permission to share this slide with you today from Dr. John Mascarenhas, who's collaborating with us very closely and with Dr. Crispino on this study. I'll just highlight some of the key components in terms of how we're thinking about this study. This is obviously a study in the various forms of myelofibrosis. This is in slightly higher risk patients in order to be able to demonstrate a benefit, but patients with sufficient platelet reserves. It's going to be about 30 patients and will compose of two cohorts. The first cohort will simply establish the tolerability of revumenib and the concept of menin inhibition in the treatment of myelofibrosis for patients that have had a prior treatment with JAK inhibition. The second cohort will look at the combination of adding revumenib to ruxolitinib in patients that have had prior treatment with a JAK inhibitor for greater than 12 weeks but have shown an incomplete or inadequate response. We will look to see whether the addition of revumenib actually adds additional efficacy parameters, looking at some of the standard international criteria for responses in myelofibrosis that include things like splenic volume reduction. We'll obviously look at symptom burden. We will also look at a number of correlatives, including, of course, platelet count recovery, white cell counts. We will look at MK cells, as Dr. Crispino was just describing. Importantly, we will look at potential disease-modifying endpoints. As you just heard, this is not a characteristic of JAK inhibition. Our hope and expectation is menin inhibition may actually lead to a decrease in variant allele frequency or mutation burden, reduce inflammatory cytokines, common inflammatory cytokines like TNF-alpha, TGF-β, and IL6, and also reduce the bone marrow fibrosis that is so common in these patients. We'll look at all of these endpoints, our expectation is working closely with the MPN Research Consortium, we will generate data that would very much inform and accelerate our development with our next-gen menin 62122 when it's ready to take into the clinic. That's just a high-level overview of the study we have planned. On that note, we'd be very happy to take your questions on this first section to do with revumenib and next-gen menin inhibition. Please. Great, thanks. This is Kevin on for Corinne at Goldman Sachs. Just a question on how you're thinking about the development strategy in the context of next-generation JAK2 inhibitors that are being developed in myelofibrosis. Thanks. Maybe I'll start, Dr. Crispino, you may well want to offer a perspective. I think that there are certainly new opportunities in myelofibrosis. The approach with the MPN Research Consortium is first and foremost to validate the preclinical findings, number one. Number two is to establish additive activity when you combine with a traditional JAK inhibitor like Jakafi. As Dr. Crispino was articulating, and maybe would like to comment, there are a number of other novel approaches, including CALR antibodies, that it might be interesting to look at preclinical data in, that's something we have planned, which we might then translate into the clinic. Dr. Crispino. I would just emphasize that, again, we showed the combination with ruxolitinib has this additive or improved activity. I think it's definitely worth doing some more preclinical studies looking at these next-generation JAK inhibitors, and that is one of our intentions as well as the CALR antibody. I think we will do some preclinical studies that will help inform where to go with it in the clinic. Okay, great. Brad Canino. Hello? There we go. Brad Canino with Guggenheim. Thanks so much for the presentation, really interesting data. Question around the additive platelet reduction effect. Maybe first to Dr. Crispino, what proportion of patients will have adequate platelet reserves like are being enrolled into the study? And then maybe both to you and to Nick, confidence level on being able to manage the additive platelet and thrombocytopenia effect that you're seeing while maintaining dose intensity and efficacy in this combination. Thank you. Right. Correct. I think, if you don't mind, I'll flip it over to Nick. Please. Because he can tell you about the specifics for the trial first. Yeah. That's a great question, Brad. One of the criteria of the trial is that patients do have adequate platelet reserves going onto the study, so it has to be greater than 75. They have to have that. Obviously, us recording platelet count recovery is one of the important endpoints of the study. Again, we want to be able to translate the preclinical findings into the clinic, we will be first and foremost assessing tolerability and also identifying the optimal dose of revumenib, whether it's the 160 or the 270 dose will be to be defined in the study, and also importantly, the tolerability of the combination with JAK. Those are all things and what that would do to the platelet count. Those are all very much in scope as part of this phase I/II, and that's one of the benefits of having a program where we can assess those with revumenib and translate all of those findings because we'll be working very closely with the MPN-RC Consortium into our development program with SNDX-62122 when that starts in the near future. Do you want to add to that? No, again, I think the key is going to be to monitor the platelet count throughout. In our animal models, as you saw, the combination with ruxolitinib does reduce the platelet count further than the single agent. Again, I think in the combination studies in particular, you need to be monitoring those platelet counts very closely. Hi, thanks. Great presentations. For Dr. Crispino, I thought it was interesting that the data you showed for the MEN1 knockouts didn't actually look as good as revumenib, which I thought was sort of surprising but interesting. I'm wondering if you could comment further on that first. Excellent question. That has to do with the efficiency of the targeting of menin. I didn't show you the data. It's in the paper. When you sequence to count the number of indels, to look at the efficiency of the CRISPR reaction, it's not 100%, it may be 70%. I think a lot of that represents just those non-targeted cells remaining. Also, I was wondering if this next generation menin inhibitor is also metabolized by CYP3A4 or not, or if you don't know yet. It actually has very little interactions in terms of its PK, and we're not anticipating any significant DDIs. That's one of its potential advantages as we optimize the molecule given all of our understanding of the menin backbone and the framework. We're not anticipating that. Thanks. Fais Khurshid from Jefferies. Thanks for taking the question. I want to understand for the next generation menin, in what ways do you think it'll improve on what you see with revumenib in these preclinical models in MF? With this initial phase I study that you're doing with revumenib, how does that enable accelerating the next generation if that proves out successful? Great. Two great questions. Dr. Crispino, do you want to address the first one to do with? Yeah. We've actually completed the first preclinical study with the 62122. We show there's a dose-dependent effect. The higher dose that we're using, we see essentially the same preclinical outcome as the 0.1% revumenib in chow that we've used in the published data. It certainly looks as good, if not better. We haven't pushed the dose at all. We just are at two doses. We show the higher dose phenocopies the revumenib. To your second question, we have a compelling preclinical hypothesis. The data are compelling. We have to validate that in the clinic. That's always the way. It happens sometimes, not always. Our ability to do that with revumenib really gives us a head start. It also gives us the opportunity to leverage the extremely good collaborations and relations we have, like with the NPM1 Consortium. This is a leading academic group across 15 leading centers in the U.S. Working with them is really going to give us an advantage. There's a lot clinically we still need to understand about menin inhibition in MF. I think there are many questions and hypotheses raised to do with platelet counts, to do with tolerability, to do with the ability to actually impact the disease burden. We'll learn a lot about that through our close collaborations, such that when we're ready to start the phase I, it will catalyze our ability to start the phase I. We'll understand about the dose, the tolerability. We'll also understand which of the really relevant endpoints we want to be looking at in terms of the extent of splenic volume reduction, the impact on platelets, the impact on fibrosis, and many of the other endpoints and correlators we'll look at in the phase I. Having a deep understanding of all of those, working closely with Dr. Mascarenhas, Dr. Crispino, and collaborators across the NPM1 Consortium, really will help us when we have the SNDX-62122 IND ready and able to go into the clinic. We'll be considerably ahead of the curve than we would be if we were simply starting a phase I with a new asset without any understanding of the role of menin inhibition in myelofibrosis. I'm excited about generating all of that data and then having a next-generation menin inhibitor, which has been optimized for all of those characteristics that you would like it to be optimized for in a disease like myelofibrosis, and that'll really allow us to accelerate. Stephen Willey from Stifel. Was just wondering if Dr. Crispino could talk about the translatability of these preclinical assays in terms of cytokine reduction, and then what is observed in terms of symptomatic improvement in the clinic. I know you showed SVR reductions in the preclinical models, but it's often on TSS70 where these combo approaches fall short in the clinic. Yeah. In mice, it's obviously challenging to look at symptoms. What I can tell you is the mice certainly look better. They move around well. They survive much longer. Our take on it is that it's showing that kind of activity. Obviously, in patients, there's different symptoms that we look at. I think it's very hard to translate what we see in the mouse to know how that symptom burden is really going to be changed in people, except, again, to say that the mice seem to be doing better. The translatability of the TGF-β levels, that was your other question. Certainly, in the mouse models, as we show, we see really strong reductions in that, accompanied by the loss or prevention of fibrosis. I think that that will likely be seen in the patients, and we will be doing those correlative studies to look at levels of TGF-β as well as other cytokines with therapy. We'll be able to answer that in more detail soon. Thanks for the presentation, guys. Salim Syed from Mizuho. On the trial for revumenib. I noticed the data's being generated for second half 2027, at least the clinical activity data, and you also listed for 62122 IND submission in 2027. Is there a minimum level of data that you're looking for from the revumenib trial before the IND submission? It won't be gated, but I anticipate we'll have preliminary data that would inform a phase I with our next-gen menin in time for the phase I. They're not gated. They're not dependent on each other. Whether that's been presented or published or not, or whether that's just through dialogue with the NPM1 Consortium is to be defined. We will have data that will allow us to accelerate in terms of the dose selection, the endpoints we think are of interest, and many of the other correlatives that we'll be looking at. Again, translating the preclinical findings into the clinic is our first step, but it's not gated, so we could start it in tandem. With all of the learnings emerging, that would inform the phase I, and we're really quite confident that will accelerate the development. You'll be getting data as you're producing it, correct? Sure. We'll be collaborating really closely with the group. They're very invested in this, and they know the program with 62122 as well. We're progressing well with the IND and forming data, the package. We're feeling confident about that and should have it in clinic in 2027. That would sync up very nicely, we believe, with data emerging from the work we're doing with the research consortium. It should all come together very nicely as a development program and enable us to be leading in that space. Okay, great. Thanks so much. Steve Sabba, Dorset Opportunity Fund. Just sort of expanding on the prior question, if the revumenib proof of concept isn't gating, what is rate-limiting for 62122 going into the clinic because 2027, that's a big spread of possible dates. Peter, do you want to talk a little about that? Yeah. We're going through the IND-enabling work currently. That just puts us on track for the IND submission sometime next year. We just have to get through some of the key rate-limiting talks, things like that. It's pretty standard IND submission timelines. Okay, thanks. Just on the proof of concept trial, do you have an idea of how will you be giving us data just when you have the full number of patients in a cohort, or will you be sort of dribbling out data? How do you plan to do that? Well, this is a great question. It's a collaboration with the NPM1 Research Consortium. It's under their sponsorship. We're obviously collaborating closely with them. We're aware this is a very competitive space. Dr. Crispino's data has obviously generated a lot of interest. We're aware of that. We want to continue to lead in menin inhibition. We will be working very closely with the NPM1 Consortium, MPN-RC Consortium. Data availabilities and publication plan is to be defined. I'm absolutely sure there will be emerging signals and data that will help inform a phase I program. Hey, this is David Dai from UBS. I'm just double-clicking on the drug profile for 62122. You mentioned that this is higher potency, better PK. Maybe just can you tell us a little more about what kind of PK profile that you've seen here that's different from revu? At the same time, have you done any kind of comparison head-to-head compared to other next-generation menin inhibitors and from other competitors? Yeah, great question. Peter, do you want to address a little bit? Yeah. Profiles emerging? Without talking too much more beyond what we have on the slide, I think clearly potency has been something we focused on. The potency is significantly improved compared to revumenib. We talked a little bit about the on-target selectivity. The profile of the molecule is highly attractive in dialing out some of the things that have been observed with menin inhibitors as a class. Similarly, just in terms of the resistance mutations that we had actually identified and spent some time on. We've targeted and dialed out quite a bit of that in this molecule. It's just a better molecule. It's got a lot of features in terms of what you might expect for a next-generation molecule, potency, selectivity, and certainly targeting the mutations that have been identified for the first-generation. I'd maybe just add that we've been working on this through collaborations for several years now and have a deep understanding of the chemistry of these menin inhibitors, and we have a library of them and have been able to optimize the molecular structure, the chemical structure, if you will, for all of the things you'd want in an optimized next-generation menin inhibitor, including PK potency, activity against the menin inhibitor, lack of interaction in terms of metabolism and drug-drug interactions. The selection of 62122 was the opportunity to select of a series of molecules that we've been developing over several years to pick the best, which we think will be really well-placed to develop in the first instance myelofibrosis and really accelerate its development there. It's really optimized from a selection of a number of chemical structures that we have been collaborating on and optimizing over several years now. Hi, this is Ellen Horste from TD Cowen. Just wondering if you think the improved tolerability will allow you to use 62122 in other MPNs like ET or PV. Well, maybe I can comment clinically, I know Dr. Crispino, you had a perspective on this as well, maybe you want to. Yeah. Certainly ET patients with elevated platelet counts, many of them are resistant or intolerable to hydroxyurea. I think given our data and preclinically and what we've seen in the clinic, that looking at the activity in ET, I think is something that should be, from my perspective, should be pursued. Yeah, I would agree clinically, obviously the MPN-RC Consortium study includes patients that have progressed through essential thrombocythemia to become advanced, also polycythemia rubra vera. There is interest, I think, once we've established the tolerability and proof of principle to look at some of those other settings. I think that's definitely of interest based on that observation. Any additional? Hey, guys. Adam from B. Riley on for Mayank. Great presentation. Thanks for having me. I'm curious, the patient sample work that you showed it was in CALR and JAK2 mutations. I was wondering if you have any insight as to whether the MKP and the HSPC reduction holds across the full mutational spectrum, or if there's a specific subset effect there? Yeah. The mouse models included the JAK mutant and the MPL mutant in two different studies. The patient samples were calreticulin mutant or JAK2 mutant. We can show that there's activity across the board. The calreticulin animal model actually doesn't work very well. All right? We actually attempted that, but we couldn't get the mice to get the disease even after 20-some odd weeks. I think with the patient data, I believe it'll be active across the mutational spectrum. Yeah. Great. Well, that concludes our first session. It now gives me pleasure to move us on to the next one. Thanks. Bringing Peter to the podium. Thank you. Great. Yeah. Thanks so much, Nick. I have to say, it is so wonderful to be able to talk and spend a few hours talking about the innovative science that we have going on here at Syndax. Before passing it on to Dr. Maher to tell you more about IPF, just wanted to spend a couple of minutes reminding you about axatilimab and a little bit overview of the mechanism of action, then spend a little time on an overview of our development program to date. axatilimab, as you may know, is a monoclonal antibody. It is an IgG4 subtype that was designed specifically to block the CSF1R, or colony-stimulating factor one receptor. Its only activity is to block the ligands, the IL-34 and CSF1, from binding to the receptor. No effector function was built into the antibody. Think of it just as a ligand-blocking antibody, which we think is important for its function, but also the tolerability profile that we have observed to date. Monocytes and macrophages that are derived from these monocytes are quite important immune cells. They fight infections, like bacteria infections, and they also go into tissues, and those macrophages are there to have certain functions, including tissue repair. There is a lot of biology that has gone into sort of describing how these monocytes and macrophages function. Obviously, important cell types. CSF1R signaling pathway is the key growth factor pathway for these cell types. It regulates the maturation, the proliferation, activation of monocytes and monocytes into macrophages in the tissue. Blocking CSF1R has been shown to have this great effect of down-regulating both the levels of monocytes and macrophages, but also, importantly, their activity profile. In disease settings, like many immune cells, if the disease, sort of these cells go awry or are dysregulated, you have an overabundance of activity. You can have inflammatory effects through certain cytokines and growth factors, and you can also have this effect of fibrosis, which is really the wound repair or tissue repair that gets uncontrolled. We know there are disease settings where inflammation and fibrosis play a role. We will hear about that certainly with IPF. We have experience in our graft-versus-host disease setting, which I will tell you a little bit about. We know that this is an important physiological process, and then when it goes awry, that CSF1R blockade is quite effective in normalizing it. If we go to the next slide. Basically, just to give you a sense of our development program to date. We licensed this in, as you heard, a number of years ago. After some initial development work, we focused in on some science that was very compelling, that was published in models of transplant. In these mouse models that actually develop GVHD that resembles quite a bit the human disease, they have manifestations within lung and skin, and those, in fact, were inhibited by using a CSF1R antibody in those mouse models. Based on those data, we started a phase I program. As you've heard, we have a lot of firsts. We, of course, were the first to clinically validate CSF1R signaling and inhibition for this particular disease of GVHD. The first patients treated in our phase I responded, which was incredibly gratifying to see. We continued the phase I. We did a cohort expansion, those data led to our pivotal study called the AGAVE study, which, as we know, read out positively and led to the approval of axatilimab and Niktimvo in 2024. Subsequently, we, along with our partners at Incyte Pharmaceuticals, launched Niktimvo in early 2025. As you've heard, that launch has gone extremely well. We continue to see benefit for patients, which we're, again, super excited about and happy to see. One of the things similar to our revumenib program that we've been focused on with our partners at Incyte is to advance from this setting of the approval is after two prior lines of systemic therapy, the goal is to move this into earlier lines of therapy as a way to basically try to prevent those fibrotic manifestations from happening. If we can move that earlier in disease, we may see a more prolonged benefit for patients. Not to mention increasing the number of patients that can ultimately benefit. Incyte has been leading two studies in the frontline setting. One of them is actually quite novel. It's combining with ruxolitinib as a steroid-sparing approach. The idea here is currently standard of care is for patients to get steroids in the frontline. Steroids, they can be on these for years, and they have a lot of comorbidities. The idea could be, which is extremely exciting for the community and for patients, could you come up with a steroid-sparing regimen? That trial has been ongoing, and we've heard and have indicated that those data will be available by the end of this year. We're really looking forward to those data. In addition, there's a phase III study that's ongoing that's also frontline. That's steroids plus/minus axatilimab. This is, again, a registration-oriented study that should read out hopefully in 2028. Again, super exciting sort of movement of the axatilimab program from the current setting into the earlier frontline settings. We've spent a lot of time thinking about where else can we look for benefit in targeting macrophages and such through CSF1R inhibition. We ran a prioritization exercise a number of years ago, we had our compelling data from our clinical experience. We have preclinical data in a number of IPF mouse models, there's a lot of literature actually supporting the role of monocytes and macrophages in pulmonary fibrosis. That, plus the commercial opportunity, allowed us to prioritize and rank IPF as sort of the number one leading indication for us to move axatilimab into. We started a phase II study called MAXPIRe a number of years ago, and we reported that we completed enrollment to this study earlier this year. That puts us on track to having our top-line data in the fourth quarter of this year. Again, from a science perspective, it's a large experiment, so it'll be actually really great to see the result because the benefit that we've observed in the patients with lung involvement in GVHD has been quite promising. We will move quickly, once we see the data, to start a phase III trial, and that means that currently we have an IV formulation for axatilimab. The phase III would be planned to be run with the IV formulation. Work with our colleagues at Incyte is ongoing for subcutaneous product development, and we anticipate that all of this would converge at the time of data from the phase III, so that we would have a subcu administration form available, sort of peri-launch of the Niktimvo, or axatilimab, if you will, for IPF. Beyond that, again, we're really eager to see where else we can translate the data that we've observed in terms of targeting macrophages and monocytes from this inflammatory and sort of fibrosis aspect. We have a whole list of indications that we have in line to follow on things like scleroderma, interstitial lung disease associated with scleroderma, chronic lung allograft dysfunction, and others. We think there's quite a bit of promise in terms of axatilimab program. Our lineup today is actually really incredible, I'm eager to pass this on to Dr. Maher, who currently he's Professor of Clinical Medicine and Director of Interstitial Lung Disease at the Keck School of Medicine of USC at the University of Southern California. Dr. Maher is considered to be a global thought leader in the field of interstitial lung disease and has really prioritized the investigation of novel and innovative discoveries in terms of the disease and translating those into the clinical setting and has done so with an incredible track record of that. He's been a member of our steering committee from the beginning as we established our phase II study, We're really thrilled to have him here and have him participate in this discussion. With that, I will be passing it on now. Dr. Maher is not obviously in the room, We'll be watching his presentation on the screen. Great. Thank you very much. Hopefully, everyone can hear me and see me. Sorry not to be there in person, but a pleasure to be here discussing, I think, the importance of the axatilimab program in patients with idiopathic pulmonary fibrosis. I thought I would just give a little bit of background to bring everyone up to speed on the disease itself and the unmet need before touching on axatilimab itself. For those of you not entirely familiar with pulmonary fibrosis, the lung, as we know, is an organ of gas exchange, and it's designed as such. We've got, as you can see in the photomicrograph here on the left-hand side, the sort of beautiful lace-like architecture of the lung with each of those little pink bounded spaces being an alveolus where the gas exchange happens. On the right-hand side, we've got a cartoon graphic of the human lung, and the different regions. We have the main airways. These then divide about 27 times until you get down to the alveolar space. When we talk about interstitial lung disease and pulmonary fibrosis, we are talking about a group of diseases that essentially cause scarring and destruction around the wall of the alveolar space. In the context of axatilimab, which has also been tested in GVHD, the primary abnormality that we see in the lung in patients with GVHD is fibrosis of that terminal airway. If you look at the bottom right-hand picture of the little alveolus, in GVHD, the fibrosis happens around the neck of that little airway that joins the alveolus, and in idiopathic pulmonary fibrosis, it happens around the outside. If we go to the next slide, this is just a picture illustrating what we see in the lungs of patients with fibrotic lung disease. Once idiopathic pulmonary fibrosis develops, we see this ultimately architectural destruction of the lung with laying down of huge amounts of collagen and fibrotic tissue. It's that fibrotic tissue and architectural destruction that leads to respiratory failure because the lung no longer works to get oxygen into the body. Next picture or next slide. Idiopathic pulmonary fibrosis is a disease of older adults. Typically affects men in their 60s. About three-quarters of patients are men, for whatever reason. It does seem to be of increased incidence in patients who've spent a lifetime working in dusty or smoky environments or who have smoked in the past. What we see is this scar tissue, which if you press advance, gets progressively worse over time. Here you go. You don't have to be an expert in interpreting thoracic CTs to see how the texture of the lung changed between those two slides. That's the same patient 18 months apart. Once pulmonary fibrosis develops, it becomes inexorably progressive, and without treatment, the average patient will die about three years from onset of symptoms due to respiratory failure. If we move on to the next slide. This is the current classification scheme for fibrotic lung diseases. I'm not going to go into it in detail, but the reason to put it up is to say that idiopathic pulmonary fibrosis is simply one of many diseases that causes scarring of the lungs. The reason that we've tended to focus on IPF for clinical trials is that it's both the most common and the most aggressive form of fibrosis that we see in our clinical practice. About two-thirds of my patients will have other diseases. In recent times, we've seen the use of anti-fibrotic drugs effectively across the full range of diseases, not just IPF. There's a real opportunity to make a difference across a much broader range of patients, and you've already heard scleroderma-ILD mentioned as a potential opportunity in the future. That's certainly another example of a disease group, where we see fibrosis as an important and life-threatening complication. Next slide. I'm not going to go into this slide in detail. This is just describing the pathogenesis of pulmonary fibrosis. Suffice to say that over the last 10, 15 years, we've made huge strides in understanding the disease. We do ourselves a disservice by calling it idiopathic and suggesting we don't know the cause. In reality, it's a disease of aging that arises in genetically susceptible individuals after a lifetime of damage to the lung. Once the process develops, what we see is activation of pathways involved in the normal wound-healing response. Importantly, once the disease is up and running, we see activation of multiple cell types in the lung, including epithelium, fibroblasts, endothelium and, importantly from the perspective of axatilimab, the inflammatory cells within the lung. If we go on to the next slide. Over the last 15 years, we have seen an evolution in the treatment landscape. In 2014, we had the approval of pirfenidone nintedanib. After a barren spell of negative trials, we saw nerandomilast, a PDE4 inhibitor, approved last year. In the last 12 months, we've seen positive results from the TETON trial of inhaled treprostinil, and we're currently awaiting readout from the phase III admilparant trial of the LPA receptor 1 antagonist from BMS. Hopefully, we've got on there axatilimab as a hopefully successful treatment in the future. If we go to the next slide. Although it's been important having treatments available and although those treatments have almost certainly improved survival for patients with pulmonary fibrosis, the reality is that despite having had pirfenidone nintedanib for a decade, my patients are still dying from respiratory failure. We might have delayed death from the disease, but we certainly haven't come close to preventing it. The graph on the right is work that we did with patients on long-term anti-fibrotic therapy that essentially estimates that even with treatment, patients with pulmonary fibrosis are losing 10 to 15 years of life expectancy due to the disease itself. A huge unmet need remains. If we go to the next slide. Not only that, the drugs that we've had up until now, pirfenidone nintedanib, have had challenges with tolerability, that's actually led to a very low uptake in their use in the United States. The graph on the left was work that was done with the Optum insurance database, showing that only about 25% of patients were being offered anti-fibrotic therapy. A lot of the reason that larger numbers weren't being offered treatment was because of concerns about side effects and tolerability in a slightly older population. The graph on the right just shows the discontinuation rates with nintedanib and pirfenidone, which approach 50% at one year. We have drugs that physicians were reluctant to use, and when they did use them, patients struggled to stay on them. Again, speaking to the huge unmet need. If we go to the next slide. This was work that my group did when I was back in London. Essentially, we had an interest in the macrophage monocyte axis in driving the disease. Worth remembering that our lung is our only internal organ that is exposed to the outside environment. We are breathing in air, which brings with it pollution, viruses, bacteria, into our body. We have a highly developed immune system within the lung, and the central cell that provides immune surveillance is the macrophage. We are born with macrophages in our lung, and there is a population of macrophages that never goes anywhere near the bone marrow, spends its whole lifetime in our lung and replicates there. When we get infection, we are reliant on bone marrow-derived monocytes that traffic through the bloodstream into the lung and then differentiate into alveolar macrophage-like cells to provide additional immune support in moments of infection. The bone marrow-derived and the lung-derived alveolar macrophages have slightly different phenotypes. The work we did originally was just to look at how those change over aging. As we get older, more of our monocytes are coming from our bloodstream. Those monocytes have a different phenotype to the ones that are resident in the lung. Importantly, in people who develop IPF, what we see is an exaggerated form of aging with an ever-increasing number of the monocytes in the lung coming from the bloodstream, and those monocytes then having an increasingly pro-fibrotic phenotype when we assess them based on their cell surface characteristics. On the right-hand side was work we did looking specifically at CSF1R. If we look in the lungs of patients, we find elevated levels of CSF1R in IPF patients. The higher the levels, the worse the prognosis for that individual, the more rapidly progressive their disease. On the far right-hand side is a photomicrograph. You can perhaps pick out the macrophages, which are the cells with a little brown rim around them. That brown rim is just indicating where the CSF1R is located, which is on the vast majority of the macrophages in the fibrotic lung. Next. This was additional work. This was work done by a group in Stanford, just showing that circulating monocytes, so the precursor cell to the alveolar macrophage, are predictive of outcome in patients with pulmonary fibrosis. The more circulating monocytes, the worse the outcome. We and other groups have subsequently replicated this finding in multiple cohorts, again, just emphasizing the importance of the monocyte-macrophage axis in driving fibrotic lung disease. Next. I am not going to go into this because you have already heard about it, but mechanism of action of axatilimab is very much to be targeting the macrophage monocytes. I think this is important for a number of reasons. Firstly, because I believe this cell type is intimately involved in driving disease. Secondly, it is not really an axis that is being targeted at the moment. Traditionally, with anti-fibrotic drugs, there's been a lot of focus on the interaction between alveolar epithelial cells and fibroblasts, but very little focus on the role played by the immune cells, particularly the macrophages within the lung. Next. You've heard about some of this data. This was the trial of axatilimab in patients with GVHD. As I've already alluded to, GVHD causes fibrotic complications in the lung, but the fibrosis is different to what we see in IPF. Like I've said, in IPF, the fibrosis is around the wall of the alveolus. It causes the lung ultimately to shrink. With GVHD, the fibrosis is around the terminal airways, so it's sort of circumferential fibrosis that squashes the terminal airways shut. That causes narrowing of the tubes. It makes it hard for the air to get into the alveolus and for gas exchange to happen. We increasingly recognize that the mechanisms that drive fibrosis, whether it's in the lung, kidney, liver, or whether it's in the alveolar compartment or around the airways, all those mechanisms tend to converge on a set of common pathways. For me, it was exciting to see the data from the GVHD study, because axatilimab in those patients with lung disease appeared to have clear benefits on the lung, suggesting potentially that it's having an anti-fibrotic effect in that scenario. About 45% of patients in this study had lung involvement, so not all of them. But of those that did, over half showed a treatment response with the therapeutic dose that's been moved forward into the clinic. Next slide. I think the other benefit of this trial is it tells us about the tolerability profile of axatilimab, which is excellent, and certainly compares incredibly favorably to the drugs that we have available to us for treating idiopathic pulmonary fibrosis. I think that's very important because my vision for the future of treatment of pulmonary fibrosis is that we will be using combinations of therapy, and therefore vitally important that we have combinations that we can use together. One of the other issues we've tended to see is a lot of drug-drug interactions with the small molecules that we have available to us. For instance, nerandomilast interacts directly with pirfenidone, which leads to reduced drug exposure and reduced efficacy. With axatilimab being a monoclonal antibody, that's certainly not a problem that we anticipate with this program. Next slide. Then this was data presented in an abstract at ATS, just looking more specifically at that group of patients with lung involvement by GVHD in the pivotal trial. Again, just emphasizing the fact that that 0.3 mg/kg dose was associated with the best lung responses, and that even patients with very severe small airway fibrosis. The patients with the lowest FEV1 values were showing improvements with treatments. That's impressive because in clinical practice, this is the group of patients that we have always struggled to treat. Next slide. You've heard mention of this. This is the MAXPIRe trial. This is the trial that has been ongoing in patients with idiopathic pulmonary fibrosis. It's a fairly conventional design, dare I say. We've been running IPF trials for 20+ years now, so we have a fairly good idea of what an appropriate design looks like. I think a few things to point out, this is a six-month study. I think increasingly we've looked to do six-month studies at phase II because that slightly longer period of time gives us confidence both in the efficacy but also in the safety of the drug. The readout is the same that we use in other trials, change in forced vital capacity. You can see the numbers. This is a reasonably sized phase II study that should answer the question definitively one way or the other as to whether axatilimab works in IPF. As I've said, based on the data that we've seen in GVHD, and based on our knowledge of macrophages, I'm certainly very optimistic that we should see a positive result and hopefully move forward to phase III. If my last slide, please. Just in summary, hopefully, I've convinced you IPF is an important disease. It's deadly. I didn't tell you the incidence, but it affects about one in every 100 deaths that occurs in Europe and the U.S. is due to IPF. Although it's considered a rare disease, it really isn't that rare. Nerandomilast is on target to achieve sales of between $3 billion and $5 billion in its first year, which again, I think speaks to the size of the market. I've told you about the challenges that we've had with current treatment, the fact that patients still die from respiratory failure despite the availability of antifibrotics. I've told you about the important role of monocytes and macrophages in the disease, and why I think there is translatability of the data that we've seen from the GVHD population with axatilimab, and why that gives me great hope and excitement about their IPF program. Thank you very much. Great. All right. Thank you so much, Dr. Maher. I guess we have some time for Q&A. Of course. Hey, guys. Fais Khurshid from Jefferies. Thank you for taking the question. One for Dr. Maher and one for the company, please. For Dr. Maher, thanks for explaining the hypothesis for axatilimab and IPF. Could you tell us a little bit about how you see the strength of this hypothesis in phase II relative to other drugs, given that you've been involved with pretty much everything in IPF drug development? For the company, can you remind us what the stats powering threshold is for the study and if you're seeing blinded data from the study? Thank you. I didn't major on the pathogenesis of IPF, but I think there are multiple mechanisms that are activated in the fibrotic lung. I'm optimistic that several of the programs that are up and running will hopefully lead to effective treatments. I think if we look to the pulmonary hypertension space as a sort of analogy, what we've seen there over the last decade is the evolution of a very focused combination approach to treatment that in pulmonary hypertension, where you've got similar complexity of disease mechanisms, true success in improving outcomes for patients with PAH has been driven by combining drugs with different mechanisms. I don't feel there's any contradiction in the fact that I'm working with multiple companies going after different mechanisms because I think my clinical practice in the future will be combining those. Given the complexity of disease, I think a lot of those mechanisms are all important. I think it's not that I'm saying today that macrophages are important, and tomorrow I'm going to say that the angiotensin II receptor axis is important. I think both, all of these axes are important, and I think one of the challenges we have pre-clinically is teasing out how we should be prioritizing the targeting. I think the advantage that the axatilimab program has is the data from GVHD because I think the insights from GVHD are important in interpreting probability of success in IPF. I think that distinguishes it from other programs where once you've put all the phase III programs to one side, everything that's currently at phase II, we're essentially waiting on data. At the moment, we have to weight all of those phase II programs relatively equally, and any differences that we might interpret between them are really based on preclinical science that we know has a poor track record of predicting efficacy in the clinic. For me, the biggest reason for optimism is that effect that we've seen in GVHD, and my belief that fibrosis, whether it's circumferential airway fibrosis or IPF, have a lot of similar overlapping mechanisms, and that's what gives me true reason for being optimistic. Related to the second part of the question, I don't know, Nick, if you wanted You want to cover it? I'm happy to. I just don't know if we've disclosed this. Oh, okay. I can talk a little bit. Firstly, the study is blind, we have no access to the data. It's an ongoing randomized placebo control study. As we're guided towards data availability in Q4, we don't know. We have talked a little about the primary endpoint. The study enrolled well. It was targeted to enroll about 135 patients, actually over-enrolled because of the momentum and enthusiasm to enroll into the study. We had over 140 patients, it's very well powered to detect what we would consider a clinically meaningful difference in forced vital capacity, which is the primary endpoint of the study. We'll obviously look at the FVC. We'll also look at the percent reduction or improvement in FVC compared to control. Given all of the historical data or recently reported out data, I should say, for other agents in this disease, we have indicated that something in the order of 30%-40% would be a very meaningful and clinically relevant improvement. We will look at the totality of the data. We'll look at the absolute difference in FVC. We'll look at the% difference. We'll look at all of the other markers. As Dr. Maher just outlined, we're very encouraged by what we anticipate to be a very tolerable profile, and we're also very encouraged by the ability of the drug to combine. We think it will make a particularly suitable drug to be used in combination, given the other approved agents, because it has a very differentiated mechanism of action. Broadly, that's what we expect from the FVC, both in terms of the absolute mils difference, 30 to 40 mL, and also the percent difference. We think that that would give us a positive proof of concept, which would take us into phase III. We are planning for success. We're planning for a positive outcome. That means that we are able to front load some of the considerations that Peter was talking about in terms of taking an IV into phase III, relevant regulatory health consultations, and all of the other things that you would need to do to accelerate the start of a phase III, because we're excited about the opportunity and the unmet need. If we do get a positive outcome from the phase II, which we'll report in Q4, we want to be able to start a phase III as quickly as we possibly can. Hi. Good morning. Phil Nadeau from TD Cowen. A question for Dr. Maher on the point that Nick just made. Can you discuss how you will evaluate the results from the phase II trial to give you confidence that a phase III is going to succeed? As you noted, IPF has been an area where there's been a lot of failures and promising compounds haven't succeeded in phase III. What will you look at in the phase II data yourself? Is the 30 to 40 mL improvement that's statistically significant, is that enough to give you confidence that a phase III is going to succeed, or do you look for concordance between the primary and secondaries? Just give us some flavor of what would get you excited and give you confidence in the pivotal. Thanks. This has certainly been one of the challenges in IPF is how to interpret these sorts of studies. I think I would say where there have been failures, I think most of those failures have been due either to a failure of study conduct, over-enthusiastic interpretation of data without applying appropriate statistical testing to account for outliers, or just trying to run before people can walk. For instance, with the Galapagos autotaxin program, we went from a 23 patient study to 1,500 patients. Just from a drug development perspective, the probability of success was always going to be lower. If we look at things like the FibroGen or the Pentraxin programs, I think there were issues with the way that the statistical analyses were done at phase II that led people to overestimate the likelihood of success at phase III. I think what will be important is looking at the handling of data and the statistical plan for this is going to use contemporary approaches that have been used at phase III, the sort of mixed effects models type, which take a much better way of handling missing data and outliers. Primarily, I think the biggest challenge we have is that we are really only left with the FVC data as the data that we can rely on for decision making, because in a study of this size, FVC has sufficient power to show us difference between groups. Other clinical endpoints don't. In a six-month study, we don't expect much mortality. We don't expect much hospitalization. We don't really expect to see meaningful changes in symptoms, either in the placebo group or the active therapy group. It does leave us leaning heavily on FVC in terms of decision making. However, in my opinion, every program that has been built on a robust FVC-based phase II set of data has subsequently gone on to succeed at phase III. I think with this design, if we do see an FVC difference, then I think the probability of success at phase III is high. Then to sort of answer the question that you didn't quite ask, which is a 30 to 40 mL difference important? I would say it is. The FDA's belief is very much that FVC is a surrogate for survival, and certainly the FDA have been very consistent in approving drugs that show any FVC benefit compared to placebo. I think if we saw a 30 to 40 mL difference, which would equate to somewhere between a 30% to 50% relative reduction in the slowing of FVC decline, I think that would be a highly approvable drug that would compete well with existing therapies and anticipated future therapies. Thanks for the question. Just a quick one. Nick, this is Salim Syed from Mizuho. I know you mentioned you're blinded to the data, do you have access to the blinded data? Have you taken a look at it? No. No. No. No? The only thing we can say, obviously from a demographics perspective, that the patient population enrolled mirrors very much the patient population in the recent FIBRONEER studies in terms of the breakdown of who had antifibrotics, which ones, and who didn't. That's very consistent with. Just consistent with. Recently reported phase IIIs, which is encouraging. It's a very representative population. The one thing I would just add is that there has been a Safety Management Committee, DMC, overviewing the study, and they have had access to unblinded data to ensure safety throughout, and not surprisingly, given we know the profile of axatilimab really quite well now it's an approved agent at that dose, no concerns with respect to safety. But otherwise, the study remains blinded to us until we report out in Q4. Thanks so much. Hi, this is Joyce Zhao here for Anupam Rama from JPMorgan. Maybe just a question for Dr. Maher first. What are your thoughts on Niktimvo's potential sub-Q every two-week profile as you think about its role as a combination partner in the future, as opposed to maybe some of the other therapies that are also being developed, another oral, also inhaled therapies. And then for the company, I think in the past you've said you only need one pivotal trial in IPF for registration, if you could just confirm that that's still the case. Thank you. Yeah. To answer that question, I think in a world of GLP-1s, everyone has become incredibly comfortable with sub-Q dosing, both on the medical side of the fence and on the patient side of the fence. We also have experience in the pulmonary space of using biologics for the treatment of asthma. Again, we've not encountered any major challenges with sub-Q dosing. In fact, many patients with asthma prefer the sub-Q dosing to daily inhaled treatment. I think a sort of every two-week sub-Q will actually be quite attractive to patients. The number of people who don't want to use the treatment because of fears over self-injection will be very small. I actually think it's a positive for the drug. As to the single study requirement and such, we can just go based on precedent with the recent approval of JASCAYD, which was based on the FIBRONEER study, one study for IPF. We believe we would have similar opportunity. Just quickly to note, the FDA say that they used Boehringer's phase II trial as the supporting study. There are a lot of similarities between MAXPIRe and the phase II study that Boehringer ran, which was actually a three-month study, with a similar number of patients. Actually used the Bayesian analysis approach to augment a slightly smaller placebo group. MAXPIRe will provide the same supporting data that BI were in a position to submit with their submission package for nintedanib last. Hi. Yigal Nochomovitz at Citi. One for Dr. Maher, then one for the company. I was just wondering, Dr. Maher, if you could comment broadly on the potential for axatilimab, in terms of disease modification relative to the classic agents like pirfenidone and nintedanib, as well as some of the newer ones that have come to market. Then for the company, with regard to the stratification, I know the study mentions by background therapy. I'm wondering if you are enrolling all smokers or if there's some other consideration with regard to smoking status to provide a stratification there between arms. Thank you. To answer the disease modification question, I think one of the big challenges we've had with IPF historically is that the patients we see in our clinical practice, even patients who are considered to have relatively mild symptoms, have already lost more than 50% of their lung to fibrosis. By the time we initiate treatment, the lung is pretty damaged and destroyed, and I think the opportunity for true disease modification has been lost. What we're increasingly focused on as a field is trying to identify patients early, ideally before they have symptoms, where they still have a lot of normal lung tissue. In those cases, we think we have a much better opportunity for disease modification. The reason we haven't really focused on doing that in the last decade is because pirfenidone and nintedanib have been so poorly tolerated. As I've shown you, it's been a struggle to get patients who are symptomatic with the disease to take those drugs, and therefore there was no enthusiasm to try and go into earlier patients and achieve true disease modification. I think with a drug like axatilimab, where we anticipate that it should be incredibly well-tolerated as a biologic therapy, that will really open the door to going after earlier disease and therefore trying to achieve disease modification. I think in all honesty, we're not going to see disease modification in the MAXPIRe study because those patients have relatively advanced disease, but I do think it's an opportunity for the future. As for the stratification factors, I don't think smoking was. I don't think. Consideration. Three strata for background fibrotics or none. Most of the patients were on a antifibrotic, and if I recall, I think that was the only stratification factor, not smoking. In fact, a trivial number of patients smoke with the disease. Yeah. Unlike emphysema, where about a third of patients after diagnosis are still smoking, in IPF, it's single-digit percentage. It's normally about 3% or 4% of patients are smokers. For instance, in the FIBRONEER program, those patients were allowed to be included, and there was no observable difference in their outcome or response to therapy. I don't think smoking is an important confounder for an IPF study. Thank you for that. Hey, guys. Adam from B. Riley again. Thanks for taking the question. Given that the primary endpoint is annualized FVC decline over 26 weeks, a question for Dr. Maher here. I'm wondering if you think that 26 weeks is long enough for what appears to be a macrophage-directed mechanism to separate on the FVC, and if so, could you give some insight regarding what you think would be a clinically meaningful effect size as opposed to statistical? Thank you. Yeah, I think it should be enough. These are highly activated cells that are producing large quantities of pro-fibrotic, pro-inflammatory mediators. There are a number of diseases that are very specifically macrophage driven, and we know in those, that the disease tends to evolve and progress rapidly. I think the target itself is responsive, there's every reason to believe that 26 weeks is more than enough to see efficacy of axatilimab, and I think that the GVHD data essentially speaks to that as well. What is a clinically meaningful difference? As I've already alluded to, the FDA viewpoint is very much that this is a continuous variable that is predictive of survival. Certainly, the regulatory point of view is that any difference is important. One can look to the FDA approval of nintedanib for scleroderma patients, where the agency approved the label extension based on a 41-milliliter delta. I think to convince people in clinical practice, one is probably looking to see a magnitude of benefit that is similar to the existing drugs. Again, if we use nerandomilast as an example, that's already been embraced by the pulmonary community now that we've had access to it for nine months. That essentially led to a 32% relative reduction in FVC decline compared to placebo, and that's been enough for very widespread use. If we use that as the margin for what my colleagues believe to be clinically meaningful, then we're looking at about 60 mL over 12 months, and therefore the 30 to 40 mL that you've heard mentioned today over six months is in that ballpark. If we can exceed that, clearly, that would be even better, I think that is a reasonable minimum standard to aim for. I would just reiterate, you can look at the AGAVE results from the GVHD study. Symptom relief was seen generally in the first month or two, then the majority of responses happened within the first three cycles or first three months. That was actually one of the basis for us actually choosing a 26-week endpoint. Okay. I think we're good to move on. All right. Thank you. Thank you so much. Thank you, Dr. Maher. Thank you, Dr. Maher. Thank you, Peter. It's my great privilege to introduce our next topic, which is around expanding our pipeline into EGFR mutated non-small cell lung cancer with SNDX-4321. This is an exciting and new area for us. Just to introduce this topic before I introduce our next speaker, I just want to take a step back for a moment and introduce the concept of allosteric inhibition, which may not be familiar to all of you. Allosteric inhibitors are actually increasingly reshaping the standard of care in difficult to treat cancers. This isn't a new concept in oncology. I think the first allosteric inhibitor to be actually approved and subsequently become a blockbuster drug was trametinib in the treatment of melanoma, that was followed by osimertinib in chronic myeloid leukemia. Today, we're going to talk about SNDX-4321. The exciting thing about allosteric inhibitors is they really present a novel and differentiated way to target receptors expressed on tumor cells. Allosteric inhibitors actually bind to the non-active sites rather than the ATP binding or catalytic sites on the tyrosine kinase receptor. Essentially, by binding to that allosteric site, they actually induce a conformational change that locks the kinase into its inactive site. It's a very alternative and differentiated approach to the typical catalytic binding ATP tyrosine kinase that we hear so much about. These allosteric approaches can modulate kinase activity with very high specificity, which you'll hear more about, which really optimizes the on-target efficacy whilst reducing off-target toxicity, which is obviously particularly important with EGFR inhibitors, which we're going to talk about today. Our ambition is to address significant unmet needs in EGFR mutant non-small cell lung cancer, leveraging this novel approach. Now, this is a very competitive space. Currently approved and investigational drugs, however, primarily target the EGFR ATP binding site. Common third-generation approved EGFR inhibitors, like alotinib, as the standard of care. I'm sorry, like osimertinib as the standard of care. They actually give reduced benefits for patients with some subtypes of the EGFR mutations, such as L858R, patients that have brain metastases, or any other atypical activating mutations. The next wave of fourth-generational investigation EGFR inhibitors just target further the resistance mutations that form in the ATP binding site. You get smaller and smaller subsets of the EGFR receptor, such as the C797S resistance mutation, which is one of the common resistance mutations to osimertinib. There are other approaches being developed in the clinic, such as bispecific antibodies and antibody drug conjugates. These are IV-administered drugs, and they also come with a significant burden of toxicity. Our approach with SNDX-4321 is differentiated from that, really has the potential to be a first-in-class, again, an area where we have a proven track record of bringing innovative science to the clinic and progressing it with innovative development programs. 4321 is a mutant-selective allosteric EGFR inhibitor, which allows, potentially, for double drugging. Double drugging is a little bit like a double lock. This is a drug that is potentially particularly well-suited to a combination with osimertinib that may actually enhance the efficacy and delay resistance down that EGFR target. It has very high selectivity, as you will hear, and this supports both its combinability and tolerability. As I've said, has both first and best-in-class potential, as we are anticipating leading in this space. It has a very broad therapeutic window expected from our IND-informing work, it does of course have the benefit of being orally administered, would be a very attractive combination for a combination approach with osimertinib. It now gives me great pleasure to introduce our next speaker, Dr. Michael Eck, MD, PhD, who is a leading cancer researcher at the Dana-Farber Cancer Institute and also professor at the Harvard Medical School. For well over a decade now, he has been pioneering the development of an allosteric approach to EGFR inhibition. We're delighted to have him here with us today to discuss his work on developing 4321, and the potential for this new approach in EGFR-mutated non-small cell lung cancer. Dr. Eck. Thanks very much, Nick, delighted to be here and really excited to have Syndax picking up the torch to take this molecule forward. I should disclose that I am a consultant to Syndax, as a co-developer and inventor of 4321 and related technologies that the Dana-Farber has licensed to Syndax, I'm in line to receive licensing royalty, milestone income, et cetera. I can confirm that Syndax licensed it under very favorable terms for Syndax. Also, before I start, just want to say that I hope to be back to that clean-shaven, smiling face soon. I had an accident on my bike a couple of weeks ago and ended up with a broken nose and a couple broken teeth, not quite put back together yet, but will be soon. What's 4321? We've developed it in my lab in close collaboration with colleagues at the Dana-Farber over the last several years. In particular, Pasi Jänne, a thoracic oncologist, David Scott and Nathanael Gray, medicinal chemists. As Nick very nicely introduced, it binds in an allosteric site that's distinct from the ATP binding pocket. It's adjacent to it, but completely separate, and can actually co-bind to the same receptor molecule at the same time as certain other ATP-competitive inhibitors, including osimertinib, that allows this double-drugging approach. My colleagues and I have published over the years increasingly potent allosteric inhibitors, starting with EAI045, and then more recently, JBJ-09-063. I want to say that we haven't yet published in the academic literature on 4321. It's a structurally distinct molecule built on a different chemical scaffold that addresses some of the issues with the prior compounds, particularly, much improved PK, brain penetrance addresses an issue that the prior compounds had with chemical stability. Also want to add that really developed specifically for L858R mutant non-small cell lung cancer, which is, I'll show you, is a very large patient population with a very significant unmet need. We think 4321 has the potential to change the treatment paradigm for at least a subset of EGFR mutant non-small cell lung cancer. Compound has excellent selectivity. It's orally bioavailable. As I said, it's brain penetrant. I'll show you data demonstrating efficacy in multiple tumor models, both as a single agent and in combination with osimertinib. It's active in an intracranial model. We think that the allosteric mechanism has multiple benefits. This ability to co-bind with osimertinib, enabling double-drugging, which we think could enhance efficacy, delay emergence of resistance, improve selectivity for wild type. As many of you will know, inhibition of wild type EGFR is a dose-limiting toxicity of EGFR TKIs. With the allosteric approach, we think we're, if not entirely, almost entirely avoiding that liability. As a single agent, because of its unique binding site, we think it can address on-target resistance to osimertinib in patients who progress after frontline therapy with osimertinib. As I'm sure all of you are aware, lung cancer is a very big problem. About 200,000 people newly diagnosed annually in the U.S. with non-small cell lung cancer. About a third of non-small cell lung cancer is due to mutations in EGFR. The most common mutations by far are the so-called exon 19 deletions and the L858R point mutations. L858R accounts for 30%-40% of EGFR mutant lung cancer. The DEL19s, about 40%-50%. Atypical mutations, including compound mutations that occur together with exon 19 and L858R, which are referred to as the classical mutations, account for up to 20%. The standard of care for treatment now is osimertinib, with or without chemotherapy. This is for the classical mutations, the exon 19 deletions, and the L858R mutations. While osimertinib, which is a third-generation drug, along with its predecessors, first and second-generation agents, have really transformed the standard of care, there's very significant unmet needs that remain. In particular, as I'll show you, for the patients with the L858R mutations, with CNS disease, and with the atypical mutants, as well as resistance to Osi. Just an outline of what I'll run through in terms of unmet needs and the way in which we think 4321 will address them. Point one, L858R patients have poorer outcomes than those with exon 19 deletions. Actually, L858R patients don't do any better with osimertinib than they did with first-generation EGFR TKIs. It's much better tolerated, it's a very good drug, but doesn't increase overall survival in the L858R patients, in contrast to the DEL19s. 4321, very active as a single agent and in combination with Osi in this model. Probably come as no surprise that patients with CNS metastases fare worse than those who don't have it. 4321 is brain penetrant, as I'll show you, is efficacious in an intracranial model. Patients with atypical mutations have poorer outcomes. We think though we've developed it and really focused on L858R, it turns out it has activity in at least a subset of the atypical mutations we think will have potentially benefit for those patients as well, or at least a subset of them. Because of its distinct binding site, 4321 will have activity against patients who develop resistance to osimertinib due to further on-target mutations in the receptor itself, including not just C797S, but other mutations in the ATP site that confer osimertinib resistance. To the difference in efficacy of osimertinib in the L858R versus exon 19 deletion, from the FLAURA2 study, you can see in breaking things out between DEL19s and L858Rs, that overall survival at 48 months is 47% with Osi without chemo, and 56% with. That compares with L858R patient population, where 48-month survival is only 31% with Osi as a single agent, a bit better at 38% when adding chemotherapy to osimertinib. Point two, patients with CNS metastases fare worse than those without. I'm realizing that I've got the wrong fare here. Obviously, that should be F-A-R-E. Anyway, without CNS metastases, 48% overall survival at 48 months without chemo. Osi plus chemo gets us to 57%. The patients with CNS disease at the time of diagnosis, only 31% make it to that 48-month mark with Osi alone, or 39% with Osi and chemo. I should say that the data here aren't broken out by L858R and exon 19 deletions, but some smaller studies that have looked at that show that, as you might expect, sort of the double whammy of LR and CNS disease leads to a poorer survival and poorer prognosis. It's not rare by any means to have CNS spread already at the time of diagnosis. About 40% of patients will already have CNS metastases, and many more will go on to develop it in the course of treatment. Patients with atypical activating mutations also have a shorter time to treatment failure and shorter overall survival. These are figures from a John Heymach lab paper a few years ago. They've plotted the frequency of atypical mutations, and as you can see, there are very many of them that are low frequency and scattered around the kinase domain. But a few of them are fairly prevalent. The G719X is about 11%. L861Q, for example, between 5% and 6%. As compared with the classical mutations, exon 19 deletions, L858R, atypical patients have a significantly shorter time to treatment failure. I think this is not just osimertinib in this figure, it's any generation of EGFR TKI. The difference would be more striking if we were looking just at third gen. On-target mutations in the receptor are a significant cause of resistance to osimertinib. Many of you will know, many ways to get resistance, so-called bypass mutations or amplification of the MET receptor, that don't have anything to do with EGFR itself. But a significant fraction of resistance is due to further mutations in EGFR. When osimertinib is used in the second line, as much as 20% of resistance arises from on-target mutations. C797S is the most common. That's the residue that osimertinib forms its irreversible covalent bond with. Also, other mutations in the ATP site, L718, L792, G796, and others. When osimertinib is used in the front line, on-target resistance is a bit less common, but up to 12%, with essentially many of the same resistance mutations emerging. More about SNDX-4321. As we've introduced, it's a mutant-selective and potent allosteric inhibitor. It has negligible activity against wild-type EGFR. The experiment in the lower left here is a xenograft study with A431 cells. It's driven by overexpressed wild-type EGFR, whereas EGFR inhibitor afatinib leads to tumor stasis here, as you see in green. SNDX-4321 has essentially no activity, no difference from vehicle control here. It's active against L858R with or without common resistance mutations to osimertinib. On the lower right, you see Ba/F3 cell data comparing SNDX-4321 and osimertinib in an L858R Ba/F3 model. Similar activity to osimertinib. On the far right, you see the introduction of the C797S mutation confers profound resistance to osimertinib but doesn't affect the potency of SNDX-4321. We've also seen activity against a subset of the atypical mutations, in particular, L861Q, one of the more common atypical variants that I pointed out a moment ago. Just want to reemphasize that it has no activity, essentially, against exon 19 deletions or exon 20 insertions. As far as the allosteric is concerned, those might as well be a different disease. SNDX-4321 is highly brain penetrant. As we see here, it's effective in this intracranial xenograft model. This is an H1975 model with a dual subcutaneous and intracranial implant, with the intracranial implant read out by bioluminescence. You see on the left that even a low dose of SNDX-4321 leads to tumor regressions comparable to those seen with osimertinib. And on the intracranial side, on the right, you see at the 25 mg/ kg level, tumor regressions that look a bit better than those we see at osimertinib with a similar milligram per kilogram dose. And SNDX-4321 is very active as a single agent in patient-derived xenograft models. LU6439 is an L858R mutant, non-small cell lung cancer model. And we see here dose-dependent tumor regressions at 5, 15, or 50 mg/ kg of SNDX-4321. Don't know what happened to the lines through there, but anyway, you get the idea. Though it's very active as a single agent, as I've shown you, we think that the more significant opportunity and the bigger unmet need could be addressed with combination therapy with, for example, osimertinib. And the allosteric approach really recommends itself as a combination agent. Because of its distinct binding site outside the ATP site, we expect it to have both essentially orthogonal resistance mechanisms and orthogonal toxicity profile, which makes it ideal as a combination agent. This also the potential for co-binding with ATP site inhibitors, including osimertinib. We have crystal structures that show how the allosteric can co-bind at the same time to the receptor with osimertinib. It's also very clean across the kinome, as you see in this kinome scan data on the right, essentially only hitting the EGFR branch of the kinase family tree. We've done in vivo efficacy studies that show a combination benefit of combining 4321 with osimertinib, particularly notable in seeing delayed tumor regrowth. And this is the H1975 model, again, with the L858R T790M genotype. The mice in this study were dosed for 15 days, then monitored for regrowth. I think you can appreciate that as compared with osimertinib as a single agent in red, 4321 as a single agent in purple, that the combination in green significantly delays regrowth. We saw also improved survival in the combination treatment arm. I have to say, the combination, very well-tolerated. No increased body weight loss as compared with osimertinib alone in the combination arm. Just to wrap up, very much excited about 4321. It's a completely novel approach, well-differentiated from what the rest of the world is doing, crowding around the ATP site with fourth-gen inhibitors. Addresses a very large unmet need that's about half of the size of the osimertinib patient population. Osimertinib is now, I think, about a $7 billion a year drug for AstraZeneca. We think a huge opportunity here for 4321 to improve outcomes for a large fraction of those patients. Highly active as a single agent, again, it's this combination with OSI that we think is really the larger opportunity, the bigger unmet need. Its allosteric properties make it, as I said, the ideal combination partner. Also, that CNS penetrance addresses the very large unmet need from the additional morbidity and mortality that accrues to patients who have that. Also see an important indication here in the atypical mutants, including L861Q. I'll stop there and pass the baton back to Nick. Thanks very much, Mike. Thank you for that very nice overview, Dr. Eck. It's very nice. I was actually at AstraZeneca for over a decade during the development of gefitinib and then osimertinib. I was head of clinical development there and have had close collaborations with Dana-Farber, with Dr. Eck and colleagues for Pasi Jänne for over 20 years and really want to recognize their world leadership in the research on EGFR. I'm extremely excited about this next chapter of targeting the EGFR receptor, which really does present, I think, an innovative and differentiated approach from many of the approaches that are currently out there. I want to touch briefly on what we're doing with this science. This is something that we have been working on now for a few years in collaboration with Dr. Eck and collaborators at Dana-Farber. We are ready to complete our IND-enabling studies quite soon now. Our intent is to have the IND filed by the end of this year, which is extraordinarily exciting. The profile looks very encouraging. That will enable us to initiate a phase I trial in patients, essentially with building on the science that Dr. Eck presented, L858R or other atypical mutations who have progressed after an EGFR tyrosine kinase inhibitor, most likely osimertinib, in 2027. We will evaluate also a combination with osimertinib, ultimately in frontline non-small cell lung cancer for patients with susceptible EGFR mutations. We think that combination of approaches presents a very attractive opportunity for these two drugs to be combined together. One of the attractive, and I would say innovative aspects of taking on a clinical development program like this is it does allow us to demonstrate monotherapy activity very soon after getting in the clinic. Our expectation, unlike many drugs, is that we would see monotherapy activity, and that that would declare itself quite quickly in a phase I experiment. We would hope to be able to report activity by targeting this allosteric receptor, which would be the first time that's been reported in non-small cell lung cancer quite early on, and then transition quite quickly, having demonstrated monotherapy activity to a combination with osimertinib in TKI-refractory patients with the intent of pivoting to the frontline very quickly. It's an innovative and accelerated development program with an IND ready to file at year-end, and we are anticipating being in the clinic in 2027. On that, I will open it for questions on non-small cell lung cancer. Hi. Thank you. Steve. Hi. Thank you for taking my question. Andres Maldonado from HCW. Just a quick question on kind of the broad thesis and theory on allosteric targeting. Some allosteric binding targets have been described as transient and almost heterogeneous in nature. Can you comment on once the mutation is garnered, how heterogeneous is that pocket or homogeneous is that pocket, and what that told you about the resonance time of the molecule you needed to make to target? More importantly, when you looked at the binding for osimertinib and any other ATP competitive inhibitors, are you binding at the same KD with 4321 as compared to monotherapy binding? Thank you. Right. Take the first part of the question first. The allosteric site is a site that's essentially opened up or created by the L858R mutation and other similarly acting mutations. You can think of the allosteric as a prosthetic, if you will, that sort of replaces what L858R or L858, excuse me, is normally doing to keep the kinase turned off. There's a key helix called the C helix that moves in and out in EGFR when it's turned off and on. Out is off, in is on. There's a loop flanking L858 that's in the wild type receptor, keeping that C helix propped out and off. With an arginine mutation there, it can't do that anymore, and it opens up this pocket. The allosteric can then bind in. The confirmation that the allosteric is stabilizing is actually a very native-like off state of the receptor, or one that it normally wants to adopt but can't with the mutation. We're restoring that ability. We've done quite a bit of studies with the JBJ series compounds on differences in how a binding of one agent affects the other, comparing osimertinib and other ATP site-directed agents with binding of the allosteric. The JBJ series compounds very dramatically increase the affinity for osimertinib and vice versa. Having osimertinib there increases the affinity for the allosteric. With 4321, that effect is very muted. Very modest, if any, effect on one for binding of the other. Pretty much neutral co-binding. I was initially kind of sad about that. We realized that the same thing was applying with wild type EGFR. Now I feel very reassured that one drug is not affecting the potency of the other, per se, in a binding affinity sort of sense. Hey, Brad Canino with Guggenheim again. On the expectation for monotherapy activity, I guess I want to split that between the two subgroups because we've all seen examples of next-generation drugs getting responses in atypical patients, largely because OC wasn't optimized for that group, but it was for L858R. What patient molecular characteristics do you expect to respond if they're L858R and pre-treated with osimertinib to respond to monotherapy 4231 or 4321? Are you recruiting just the C797S resistant population? If they have off-target resistance, should we still expect a salvage response from this new drug from you guys? Thank you. Oh, yeah, I can start. I think obviously the sweet spot is on-target resistance due to mutations in EGFR and not just C797S, but the other ATP site mutations that you saw on that slide. I think that's one differentiator from fourth gens. The fourth gens in general have been developed to overcome C797S, but not those other ATP site mutations. Could expect a larger response rate with the allosteric than has been seen with some fourth gens because of the ability to cover a broader spectrum of those on-target mutations. With respect to other mechanisms of resistance, never say never, but I don't see an obvious reason to expect the allosteric to work when resistance is not due to on-target mutations. I'll let Nick talk about patient selection. Yeah. Brad, the way we're thinking about this is reflective of that science in terms of the CDP, and what we do know is that we wouldn't be expecting activity in the exon 19 or 20 mutations because they don't have the presence of the allosteric inhibitor. Initially we will exclude exon 19, exon 20, and then obviously the drug was developed specifically for L858R mutations, but we actually think the activity could be broader than that, including some of those common resistance mutations that are characterized by osimertinib, either refractoriness or resistance. We'll have a relatively broad population at the beginning of the phase I, excluding exon 19, exon 20. I think as we progress into the phase I and we begin to see activity, we'll be able to delineate more clearly where the allosteric benefit is most pronounced. I think whatever the expectations for monotherapy activity, and given the preclinical data that you just saw, our expectation is you would see monotherapy activity, but I think it's also particularly exciting the concept of being able to double drug. This is a particularly complementary approach for all the reasons that we just discussed to combine with osimertinib, which really would anchor the receptor in an inactive state. That would also be an important part of our initial phase I development. This is Kevin back on the line for Corinne from Goldman Sachs. Just wanted to follow up on that in terms of just the total package of efficacy that you want to see to give you confidence in the frontline combination, and then specifically on tolerability too. What are you looking for that could give you confidence in that frontline combination in terms of tolerability as well? Well, we are very encouraged by the profile that you just saw and the lack of activity against the wild-type receptor that tends to be the dose-limiting toxicity. Broadly from our IND-informing studies, we are not really seeing any obvious maximum tolerated dose or dose-limiting toxicities as we go into the IND-informing studies in the animal experiments, which is encouraging. We think you should be able to combine quite easily with osimertinib without seeing significant overlapping toxicities. That is the first thing to say. I think in terms of what you would expect to see in terms of efficacy, our expectation is to be able to dose escalate quite quickly into a full therapeutic dose. We would probably want a dose quite high, again, because we have a broad therapeutic threshold. We are not anticipating a lot of activity against wild-type EGFR or any other significant toxicity. We want a dose quite high in order to be able to make sure that we are targeting some of those atypical mutations. I think any activity that we see in a resistant or refractory population to osimertinib as a monotherapy is going to be very exciting, and we were talking about this last night. I think that will in and of itself, seeing monotherapy activity in this area of high unmet need will be exciting. We will then transition into the combination patients that have become refractory, again, we will look for additive or potentially even synergistic activity when we combine with osimertinib. We will see how the phase I progress, but our expectation, again, is if we are going to see a clinical signal, we will see it quite quickly, anticipated with monotherapy activity, and we will be excited to see that. We think we will be able to generate those data quite quickly. Again, as I said, we have recently hired some outstanding leaders in the development of lung cancer, we have great collaborations, including with Dana-Farber, but other leading institutions in both the U.S. and in Asia, where obviously the prevalence of EGFR mutations is a little higher. We will have fantastic collaborators to lead this phase I experiment and really guide us through it as we generate data and see what activity we are getting, and we are excited about that. Hi, great. Yigal Nochomovitz from Citi. I was just curious, you talk about the atypical mutations. Is that including the so-called P-A-C-C mutations, the PACC mutations, which some people refer to synonymously with atypical, or is it different? How many of these atypical mutations have actually been tested? Because the list is quite long. I believe there is. 70 or 80 of them. Would you enroll all of them potentially in the phase I or just certain ones? Sure. Yeah. That's a great question. Do you want to start, Mike? Yeah. Do you want Well. Okay. Go ahead Both Peter and I can comment. Yeah. I can't keep which ones are PACC and which ones aren't straight. You can thank John Heymach for that. We've tested a few in depth and published on them with the earlier allosterics with the JBJ compound. We've done less at the Dana-Farber with 4321, but have done, I think I can say, an animal study in L861Q, where we see very clear efficacy. We've looked at some of the other more common ones also and seen activity. I think, Peter, you may want to comment further. Yeah. We've continued some of the work from the lab there, and as you say, there are actually quite a few of them. We've been working our way down the list, and the majority are responding, obviously at different potencies. We think we'll be able to because our idea is that we can dose high, that we don't see wild-type EGFR as dose-limiting, at least pre-clinically and hopefully clinically. It'll allow us to cover the broad range of these atypical or PACC mutations. I think they're overlapping. There's certainly going to be a few that aren't responsive, but the majority we've tested so far are responsive. That was factored into our consideration around the CDP rather than actively select, because the list is complex and long. We thought we'd deselect, and then we'll learn about activity just simply by deselecting those patients where you really wouldn't expect activity because of the lack of the allosteric inhibitor. We'll include everybody apart from the exon 19, 20s, and then we'll see. Yeah. I would just add that it's a fairly complex space. Many of these are also occurring in tandem together with classical mutations. That's another area I think that it's very important, broadens the potential indication. Just one follow-up. I don't know, I may have missed it, but is it a covalent or non-covalent? I wasn't clear. It's non-covalent. It's reversible. Okay. Yeah. Hey, guys. Fais Khurshid from Jefferies. If you don't mind, I just want to ask a bigger picture question of how did you arrive at in-licensing this asset? Were you looking to get into this area specifically? Was it based on asset availability or something else? Should we expect further BD from you guys? Maybe I'll take the question, and Nick, you could follow on. Nick mentioned his deep relationship, Peter's deep relationships with the Dana-Farber. Obviously, this is an area of high unmet need. The opportunity to be first best-in-class. We keep the bar very high on business development. We've been talking about that for some time now, looking for differentiated assets that we could take forward with the expertise that we have and really make a difference and generate proof of concept quickly, right? This sort of lends perfectly to what we were looking for i n oncology. That was sort of the genesis of it all. I don't know, Nick, if you want to talk anything else about that. No, I think that's it. I think it's just another example of the type of opportunity from our collaborations with these institutes that just fits very well with our model of development, which is translating great science, taking it into clinic and generating a signal quickly, then hopefully progressing from there. It's just a particularly good fit. It's a precision approach, which we're very focused on. It's really a sweet spot, I would say, for us as an R&D organization, as a company to pursue this type of approach. We're very excited about bringing it into the clinic next year and hopefully validating the nice preclinical models that you heard about today. Yeah, I'd just say in terms of future business development, it's how we built the company, right? We've been able to in-license or acquire assets, and do quite well with them, and we expect this to be another one that we'll take forward. Will there be others? We hope so. We hope to do more, keep the bar high, we're now focused on a very nice book of work that we have in front of us, and we'll do everything we can to be successful there. Business development is always something that we think about actively. Thank you. Okay. With that, let's close. All right. Thank you. First of all, I just want to thank all of our speakers today. Wonderful job. Our collaborators in the room and online, thank you for all the questions and the attention today to what we're presenting. Just to recap on where we are as a company, we're in a terrific position with what I'd say a full pipeline of blockbuster opportunities now. Building on what we've created with Niktimvo and Revuforj, we look to expand those franchises, leverage our world-class capabilities, and really drive this deep pipeline of opportunities. Milestones and data will be emerging not only this year but next year and the year after for sure. Solid financial footing, we've taken care of that in terms of capitalizing the company through profitability. We are in a very good position to drive growth and succeed. Just a little bit of a snapshot on where we are with all of this opportunity. We talked about having blockbuster opportunities now in acute leukemia, in GVHD, in IPF, in myelofibrosis, and of course, lung cancer. Five areas of potential growth. When you think about Revuforj, really getting to the frontline first, expanding the use and the opportunity we'll have, and we have had all year data emerging in frontline maintenance, real worlds. We'll have many data sets that'll continue to emerge at medical conferences, and we'll publish on new areas like NUP98 at the end of the year. Myelofibrosis, of course, we're generating data with the Consortium. We'll be starting that and hopefully have data next year, and that will be an important precursor to what we do with our next-generation menin compound in 2027. In chronic GVHD for Niktimvo, two big trials reading out in the coming months and year. We have the axatilimab combination with ruxolitinib in the fourth quarter, and we have the steroid combination next year. Very important opportunities for expansion in chronic GVHD. Of course, IPF, big opportunity. We heard about it today, the MAXPIRe trial reading out in the fourth quarter, and we're excited about that. Then lastly, of course, the EGFR compound will be in the clinic by the end of this year. We think this will be a very swift path to proof of concept, initiating that trial in early 2027 and having data in early 2028. Lots in front of us. Two Phase II readouts this year. Multiple revumenib readouts in acute leukemia and certainly beyond that, and then four assets in the clinic in 2027. Chock-full of good opportunities. I want to say thank you again to all of you for joining us. I want to thank our collaborators. I want to thank the wonderful people who work at Syndax who make this possible, some of whom have made this possible today for bringing this presentation to you all and, of course, patients who make this all possible. Thank you. We look forward to continuing the dialogue. We'll see many of you, of course, in the fall, and on our earnings call coming up. Thank you for being here today and giving us your attention. Have a great day, everyone.