Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript & Summary

All right. Good morning, everyone. We're going to get started. So it's my pleasure to welcome you this morning. My name is Michael Metzger, I'm the CEO of Syndax. A 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. So we will be making forward-looking statements. Here is our disclosure. Syndax is a company on the move. We're driving innovation and long-term value for patients. And we have what a few companies our size have in terms of accomplishments. We've gotten drugs approved actually and brought them to market. So 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. And 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. And importantly, we have a solid financial position. We're driving the profitability and we have the opportunity to fund all of our programs fully. So 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 first -- our 2 first and best-in-class medicines: Revuforj and Niktimvo, as you all know, have done very well last year, this year annualizing about $200 million in revenue, as we're going and growing towards profitability. So very well set up for success. And 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 those assets as we expand. First, with Revuforj, we will be positioned to be the first to front line, 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 front line 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. So 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 SNDX4321 and also 62122. Now these are -- this is -- follows our first and best-in-class way of approaching things. For 4322, this is a mutant-selective allosteric EGFR inhibitor for non-small cell lung cancer. So 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-licensed 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. And that's what we think we can do with this agent. It's targeted for IND submission at the end of the year. So we are really well positioned now to talk about what comes next for this asset. Very exciting. And then 62122 is a next-generation menin inhibitor for MF. We all know that we learned a lot about menin inhibition. We've been driving the science from the beginning. This is an internally generated asset. So 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. So we're in a very good position to take this science forward and exploit the mechanism in myelofibrosis. And 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. So 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, 4321 in non-small cell lung cancer, and 62122 in myelofibrosis. So a full set and complement of opportunities. So I'm very excited to be joined today by wonderful group of speakers. In addition to me, I'll have Nick Botwood, our -- Dr. Nick Botwood, our Chief Medical Officer and Head of R&D; as well as Peter Ordentlich, our -- Dr. Peter Ordentlich, our Chief Scientific Officer and Founder. And as well, joining us both in person and online, Dr. Crispino from St. Jude's Research Hospital. He'll be covering the MF portion of our talk today. Dr. Toby Maher from the University of Southern California. He will be covering IPF, he'll be online. And Dr. Michael Eck from Dana Farber Cancer Institute. He'll talk about the asset that we've in-licensed, 4321, as well as his breaking science and breaking developments and research in lung cancer. So now just a bit on our agenda for today. Nick, I'll hand the baton to Nick in a minute, and 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 4321, which is our allosteric inhibitor. And then we'll close from there. There'll be Q&A throughout, so you'll see every section, we'll break it up with Q&A. So we'll have an opportunity to pause and ask questions. We'll be closing the session around 11:00. And so just to give everybody a sense of timing, and we'll go from there. So 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, and we'll go from there. Thank you.

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 bear such promise for patients to come. So 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, and 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. And I think, again, today will be a great showcase of that in example. We also have very deep science. We have deep mechanistic understanding. 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. And we do now also have, and I'm happy you're 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, commercialization organization. And having spent a lot of my career in large pharma, I would also say we're now rightsized to deliver, but also to be extremely efficient and nimble in terms of decision-making and governance. We are 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. So 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. And this dates back over a decade now to 2016, where revumenib and axatilimab were in-licensed pre-IND, and we're going to talk about similar models today. We were then the first to clinically validate menin inhibition in acute leukemia. We were the first company to approve the menin inhibitor, now, as you all know, a very hot space, in KMT2A, subsequently an sNDA in NPM1 acute myeloid leukemia. And then we have -- we were also the first to initiate a randomized study in newly diagnosed frontline AML. And we were the first to present and collaborate on data that you'll hear about today, for the potential of menin inhibition in revumenib in the treatment of myeloproliferative [ neoplasis ] like myelofibrosis, and we're excited to review that. Equally, we were the first to clinically validate CSF1R inhibition in GVHD, and we're the first approved and only approved CSF1R in GVHD. And the time lines for this are quite impressive. So we achieved 3 FDA approvals between revumenib and axatilimab, both drugs were approved in about 5 years from IND to FDA approval, which is a very impressive track record. And that's something we want to build on, and we believe we have the people and the capabilities to be able to do that. So 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'll talk a little bit more about that in a minute. And we've now added to the revumenib book of work, a proof-of-principle study in myelofibrosis, which you'll hear more about. We have an extensive program of work with axatilimab, our CSF-1R antibody, with now an important proof of concept in idiopathic pulmonary fibrosis, which will be the focus of one of the sessions you'll hear about today. What I'm really excited about is to add 2 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, and we will talk deeply about the science that underpins the role of menin and menin inhibition in myelofibrosis. And our new menin inhibitor, 62122. So for the first session, and we're going to have 3 sessions today, I want to talk about advancing our leadership in menin inhibition. So 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. And we're the only menin inhibitor with now presented data in the subset of NUP98R, 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 they're somewhat agonistic to whether that's a 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 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 in 62122. And we have, of course, underpinning all of this and 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. So 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. But 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. But I would like to highlight a couple of things. First is that we remain laser focused on our 2 pivotal registrational studies. The EVOLVE-2 study in patients unfit for treatment with intense chemotherapy, which is a combination with [ Veneza ] 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. And that's in blue at the bottom of the slide. The 2 studies I just wanted to highlight in yellow on this slide were really there just to highlight the innovation that we're doing and continuing to drive our leadership. The first is in maintenance. And the role of menin inhibition in patients that have had a transplant is an area of important research, and 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. And that study is called [ The Maintain ], it's now on ct.gov. And then we have the RAVEN study, which is, again, is 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, and it's actually in combination with Veneza. The hypothesis being that you can get those patients to transplant without the need for intensive chemotherapy and, therefore, with less associated morbidity. So 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 NPM1, exciting [indiscernible] we talked about with MUP98R 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, and it's very exciting science. Myelofibrosis, so you may ask why myelofibrosis. Why did we pick myelofibrosis as our next life cycle management indication? Well, 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. And 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 time frame. 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. So 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 derisk 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, and 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 and it presents multiple distinct scaffolds with composition of patents that last well into the late 2040s. Now 62122, that you heard a little bit more about today, is a next-gen inhibitor was actually the first molecule to emerge from our library. And we are anticipating the submission of the IND in 2027 and 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. And it also has quite profound activity against some of the common resistance mutations. So it's an extremely attractive molecule to take into settings like myelofibrosis. So on that note, I'd like to introduce our next speaker. And 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 Division of Experimental Hematology at St. Jude's Children's Research Hospital. He is an internationally recognized hematology researcher, whose pioneering work has significantly advanced the understanding and treatment of myeloproliferative neoplasis 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 a novel target in myelofibrosis. So 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. So 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. So myelofibrosis is a myeloproliferative neoplasm in MPN that affects about 20,000 people in the United States. And it's associated with extramedullary hematopoiesis contributing to enlarged spleen and enlarged liver. That's due to the increased amount of [indiscernible] in that tissue. There's increased levels of inflammatory cytokines that mediate debilitating symptom burden, and bone marrow fibrosis that accompanies cytopenias. Now 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. So while these JAK inhibitors reduce symptom burden and splenomegaly, they do not crucially affect or reduce fibrosis or the mutant allele burden. And most patients stop responding to JAK inhibitors within 2 to 3 years with poor outcomes. And this is why it's an area of high unmet medical need. So myelofibrosis is characterized by an accumulation of atypical megakaryocytes, which are the cells that derive platelets. And these cells contribute directly to the fibrosis by secreting cytokines, which lead to increased collagen deposition. And 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. So we know from our work that menin inhibition suppresses megakaryopoesis by down-regulating KMT2A menin target genes such as [ MEFF2C ] and [ MES-1 ]. It selectively affects these MKT cells. And in our studies, revumenib showed striking antitumor activity in several preclinical models of the MPNs. These include the [ JAK2V617F mouse ], the NPL or NPL W515-L mouse, which I'll show you the data for, and another mouse called MPLS504N, as well as also PDX mice that I'll show you. And our work then supports further investigation of menin inhibition in myelofibrosis. And interestingly, it targets pathways independent of targeting the JAK-STAT pathway. It's an orthogonal pathway by transcriptional down-regulation of these key target genes. So our recently published preclinical data show that revumenib selectively inhibits megakaryopoiesis. And first, I'll show you data from liquid culture assays of human CD34 positive cells cultured with revumenib. And on the left, you can see that the percentage as well as the absolute numbers of KPs 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, about 300 nanomolar, to block the production of the cells. And by contrast, you see that erythroid colonies and granular site macrophage colonies are not affected by revumenib as doses up to 20 micromolar. So we importantly show that loss of menin phenocopies the effect of the drug, confirming an on-target effect. So we use single cell RNA sequencing approaches to demonstrate this. And I'll first start on the right, which is the revumenib treated cultures. And again, I'm showing that the numbers here of the MKPs are vastly reduced by treatment with revumenib as are the immature megakaryocyte fraction. But on the bottom, we're looking at data UMAP data, which is a single cell RNA sequencing approach that lets us look at individual cells within the culture. And I'm showing you 7 cell populations. And you can see in the circle is 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. And we use 2 different so-called guide RNAs to down-regulate menin, Guide 1 and Guide 13. And on the left graph, you can see that knockout of menin with 2 different guide RNAs significantly reduces the MKP population and also reduces those immature megakaryocytes. And then on the bottom, again, through the single cell RNA sequencing data, you can see that the drug -- the knockout again recapitulates the effect of the drug, where there's down-regulation of both the MKP population and the MKs. So I'm going to show you today just one mouse model. This is the NPL-W-515L model. It's a very aggressive model of myelofibrosis. And 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. And they also develop splenomegaly and enlarged livers. And the vehicle-treated mice in this model succumb to the disease typically 5 weeks post transplant. So 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 then in yellow is the combination of ruxolitinib with revumenib. And you can see, first, the white cell count, that all 3 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 treatment -- 3 treatment groups reduced the platelet count. Ruxolitinib has an intermediate effect compared to revumenib. And then 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 will 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. And this NPL-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, but the combination importantly normalizes that spleen weight. And then on the right, you can see that all 3 treatment arms are getting enhanced survival, and those untreated mice dying, again, about 5 weeks post-transplant. Now let's talk about the bone marrow environment and the fibrosis. So we know revumenib alone and in combination with ruxolitinib suppresses the level of TGF-beta, megakaryocyte accumulation and fibrosis more than ruxolitinib alone. So if you look on the left graph, this is looking at a cytokine TGF beta, which promotes fibrosis. It's produced by megakaryocytes and other cells in the marrow. And revumenib in orange gives a significant reduction in TGF-beta levels, so does ruxolitinib. But 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. And then finally, on the right, we're looking at the reticulin grade fibrosis, which could be 0, 1, 2 or 3. And typically, these untreated mice have a fibrosis grade of either 1 or 2. With 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. And I would say we've done a lot of preclinical studies with 4 different mouse models, and only 1 mouse in all of those studies treated with revumenib had a Grade 1 fibrosis. So really the strongest drug that we've seen to eliminate fibrosis or at least prevent the development of fibrosis. Now ruxolitinib in patients has a very limited activity in fibrosis. Here in the mouse model, it's variable. So some of the mice respond and some still have fibrosis. So you can see some of this histology here. This is looking at the bone marrow of the treated mice. The top row is hematoxylin [indiscernible]. You can see on the upper left, I don't know if you can appreciate, there's a lot 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. And finally, on the far right, you can see combining revumenib with ruxolitinib reduces or eliminates those abnormal megakaryocytes and also normalizes to bone marrow cellularity. So the combination is particularly strong in this model as well as in the JAK2V617F model. Again, you can see that in the manuscript. And then the bottom is looking at the degree of fibrosis. And we can show that revumenib alone or in combination with rux, again, completely eliminates fibrosis or prevents it. And ruxolitinib, in this example, we're showing you a case where it is active, but it is variable in those mice. And then finally, we looked at patient samples. So on the top, we're looking at in vitro treatment, a patient samples with revumenib. And these are patients that either have a calvarticular mutation or JAK2 mutation. The NPL mutation is about 5% or 10% of the patients, whereas the calvarticular ticket mutation, maybe 30%, 40% and the rest would primarily be JAK2. There's 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 in revumenib. Similarly, the megakaryocytes, the immature and the more mature megakaryocytes, are reduced. And then finally, importantly to us, looking at these MKPs, which we think are disease drivers, those are reduced by treatment of revumenib even with the mutations. And then finally, on the bottom, we did -- we made -- generated a patient-derived xenograft model of myelofibrosis using MF patient sample injected into immunocompromised mice. This is treated with a single agent revumenib. And you can see that revumenib reduced significantly a 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. And then finally, on the far right, hematopoietic progenitor population of CD34-positive, CD38-negative HSPCs are significantly down-regulated upon treatment with the drug. And then the last data slide is to look at the target genes. And so we can see here, we're looking at 3 key target genes, [ MEF2C ] in the middle, [ MES-1 ] on the left and PBX3 on the right. And the top row is looking at these megakaryocyte progenitors [indiscernible] and you can see that all 3 are significantly reduced upon treatment with revumenib. And then on the bottom graph, we're looking at the megakaryocytes. In those cells, [ MES1 ] is not significantly down-regulated, but [ MEF2C ] and PBX3 are down regulated. In the manuscript, what you'll see is we can show that knockout of [ MES1 or MEF2C ] can phenocopy the effect of revumenib. But importantly, over-expression 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. So I'll summarize our data in this slide. So menin inhibition suppresses megakaryopoesis. And 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 of in myelofibrosis is driven in part down-regulation of [ MES1 ] 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 regulation of key MKP genes and JAK-STAT signaling, respectively. And 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 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 [ CAL-R ] targeted antibodies and the next-generation type 2 or JAK2 mutant selective inhibitors, which then again target the JAK-STAT pathway orthogonally. And 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. So let me talk briefly about the next steps, building on that groundbreaking research published in Cancer Cell with the very nice editorial accompanying from colleagues at Memorial Sloan Kettering. We're going to leverage revumenib to inform and derisk the development with our next-gen menin inhibitor 62122 in myelofibrosis, as we've talked about those data now published in manuscript. Our intent is to initiate a revumenib proof-of-principle trial in the fourth quarter of this year. We will intend and 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 Syndax 62122 in myelofibrosis in 2027, so next year, but being able to leverage all of the learnings from the proof of principles [indiscernible] 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. And 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. And this study is done in partnership with the Myelo-Productive Neoplasia Research Consortium, or MPNRC consortium. This study is not yet on clinicaltrials.gov. We do a permission to share this slide with you today from Dr. [ John Mascarenas ] who's collaborating with us very closely with Dr. Crispino on this study. And I'll just highlight some of the key components in terms of how we're thinking about this study. So 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 for patients with sufficient platelet reserves. It's going to be about 30 patients, and will compose of 2 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 then 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. And we will then 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 [indiscernible] including, of course, platelet count recovery, white cell counts, we will look at MK cells, as Dr. Crispino was just describing. And then importantly, we will look at potential disease-modifying endpoints. As you just heard, this is not a characteristic of [indiscernible] inhibition. 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, TGFBeta IL-6, and also reduce the bone marrow fibrosis that is so common in these patients. So we'll look at all of these endpoints, and we -- 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. So that's just a high-level overview of the study we have planned. And 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. So please.

Great. 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 myofibrosis.

Maybe I'll start, Dr. Crispino, and you may [indiscernible] perspective. So 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. And then as Dr. Crispino was articulating, and maybe would like to comment, there are a number of other novel approaches, including [ CALAR ] antibodies that it might be interesting preclinical data in, and that's something we have planned, which we might then translate into the clinic. But Dr. Crispino?

No, I'd 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 [ CALAR ] antibody. So I think we will do some preclinical studies that will help inform where to go within the clinic. .

Brad Canino with Guggenheim. Thanks so much for the presentation, really interesting data. A 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?

Right. If you don't mind, I'll flip it over to Nick because he can tell you about the specifics for the trial first.

One of the -- it's a good question, Brad. One of the criteria of the trial is that patients do have adequate plate reserves going on to the study. So it has to be greater than 75. So they have to have that. And then 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. So 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. So those are all things -- and what that would do to the platelet count. So 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 consortium into our development program with 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 a single agent. So again, I think in the combination studies, in particular, you need to be monitoring those platelet counts very closely.

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.

Yes. Excellent question. So that has to do with the efficiency of the targeting of menin. So [indiscernible] 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 nearly -- it's not 100%, it may be 70%. So I think a lot of that represents just those non-targeted cells remaining.

Okay. And then also wondering if this next-generation 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 DDI. So that's one of its potential advantages as we optimize the molecule given all of our understanding of kind of the menin backbone and the framework. So we're not anticipating that.

Faisal Khurshid from Jefferies. I want to understand for the next-generation menin, in what ways do you think it will improve on what you see with the revumenib in these preclinical models in MF? And then with this initial Phase I site that you're doing to revumenib, how does that kind of 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 the MF?

Yes. So we have actually completed the first preclinical with the 62122. And so we said there's a dose-dependent effect, and that the higher dose that we're using, we see essentially the same preclinical outcome as the 0.1% revumenib in child that we've used in the published data. So it certainly looks as good, if not better. But we haven't -- we haven't pushed the dose at all. We just are at 2 doses, and we showed the higher dose has phenocopies to revumenib.

And then to your second question, we have a compelling preclinical hypothesis, the data are compelling. And we have to validate that in the clinic. That's always the way. I mean it happens sometimes, not always. So our ability to do that with revumenib really gives us a head start. So it also gives us the opportunity to leverage the extremely good collaborations and relations we have like with the MPN1 consortium. This is a leading academic group across 15 leading centers in the U.S., and 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 on hypothesis 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 collaboration, 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 are 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. Mascarenas, Dr. Crispino and the collaborators across the [ MPN1 ] consortium really will help us when we have the 62122 IND ready and able to go into the clinic. So we'll be considerably ahead of the curve than we would be if we were simply starting a Phase I with the new asset without any understanding of the role of menin inhibition in myelofibrosis. So 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 will really allow us to accelerate.

Stephen Willey from Stifel. I 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 [ VR ] reductions in the preclinical models, but it's often on TSS50 where these combo approaches fall short in the clinic.

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 beta levels, that was your other question. So certainly, in the mouse models, as we show, we see really strong reductions in that, accompanied by the loss of the -- 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 level of TGF beta as well as other cytokines with therapy. So we'll be able to answer that in more detail soon.

Thanks for the presentation, guys. Salim Syed from Mizuho. Just on the trial for revumenib, I noticed the data is being generated for second half '27, at least the clinical activity data. Then you also listed for 62122 IND submission in '27. Is there a minimum level of data that you're looking for from the revumenib trial before the IND submission?

No, it won't be gated, but 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 [indiscernible] whether that's just through dialogue where the MPN consortium is to be defined. But we will have data that will allow us to accelerate in terms of the dose selection, the endpoints we think of interest, and many of the other correlators that we'll be looking at. Because again, translating to preclinical [indiscernible] in the clinic is our first step, but it's not gated. So we could start it in tandem, but with all of the learnings emerging that would inform the Phase I, we're really quite confident that will accelerate the development.

And you'll be getting data as you're producing it, correct, for the...

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 informing data, the package. We're feeling confident about that and should have it in clinic in 2027. And that would sync up very nicely, we believe, with data emerging from the work we're doing with the research consortium. So it should all come together very nicely as a development program and enable us to be leading in that space.

Steve Saba, 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 -- what is it, 62122 going into the clinic? Because 2027, that's a big spread of possible dates.

Peter, do you want to talk a little bit about that?

Yes. We're going through the IND-enabling work currently. And though that just puts us on track for the IND submission sometime in next year, we just have to get through some of the key rate limiting tox, things like that. And so it's pretty standard IND submission time lines.

And just on the proof-of-concept trial, do you have an idea of how you will be -- will you be giving us data just when you have the full number of patients in the cohort? Or will you be sort of dribbling out data? How do you plan to do that?

Well, it's a great question. It's a collaboration with the MPN1 Research Consortium. So it's under their sponsorship. We're obviously collaborating closely with them. We're aware this is a very competitive space, and 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. So we will be working very closely with the MPN1 consortium -- MPN consortium. Data availabilities and publication plan is to be defined, but I'm absolutely sure there will be emerging signals and data that will help inform a Phase I program.

This is David Dai from UBS. Just to double-click on the drug profile for 62122. You mentioned that this is higher potency, better PK. Maybe just tell us a little more about [indiscernible] profile that you've seen here that's different from their view. And at the same time, have you done kind of a comparison head-to-head compared to next-generation menin inhibitors like from other competitors?

Great question. Peter, do you want to address that bit?

Yes. Without talking too much more beyond what we have on the slide, I think clearly, potency has been something we focused on. So the potency has 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. And similarly, just in terms of the resistance mutations that we had actually identified and spent some time on, so we've targeted and dialed out quite a bit of that in this molecule. So 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.

And 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 interaction. So the selection of 62122 was the opportunity to select 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 [indiscernible] development there. So 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.

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, I can comment clinically, but I know, Dr. Crispino, you had a perspective on this as well. So maybe you want to...

Yes. So certainly, ET patients with elevated platelet counts, many of them are resistant or not -- or intolerable to hydroxyurea. I think given our data and preclinically and what we've seen in the clinic, that there's a -- that looking at the activity in ET, I think, is something that should be, from my perspective, should be pursued.

Yes, I agree clinically. And obviously, the consortium study in patients that have progressed through [indiscernible] become advanced also [indiscernible] but 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.

Adam from B. Riley on for Mayank. Great presentation. So I'm curious, the patient sample work that you showed, it was in CALR and JAK2 mutation. So 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.

Yes. So the mouse models included the JAK mutant and the NPL mutants in 2 different studies. The patient samples were calreticulin mutant or JAK2 mutant. So we can cover -- we can show that there's activity across the board. The calreticulin animal model is actually not so -- it doesn't work very well, right? So we actually attempted that, but we couldn't get the mice to get the disease even after 20-some-odd weeks. But I think with the patient data, I think we can -- I believe it will be active across a mutational spectrum, yes.

Great. Well, that concludes our first session. And it now gives me pleasure to move us on to the next one and bringing Peter to the podium.

Great. Yes. Thanks so much, Nick. So I have to say it's 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. So before passing it on to Dr. Maher to tell you more about IPF, I just wanted to spend a couple of minutes reminding you about axatilimab and a little bit overview of the mechanism of action and then spend a little time on an overview of our development program to date. So axatilimab, as you may know, is a monoclonal antibody. It's an IgG4 subtype that was designed specifically to block to CSF-1R or colony-stimulating factor I receptor. And its only activity is to block the ligands, the IL-34 and CSF-1 from binding to the receptor. So no effector function was built into the antibody. So think of it just as a ligand-blocking antibody, which we think is important for its function but also the tolerability profile that we've observed to date. So monocytes and macrophages that are derived from these monocytes are quite important immune cells. They fight infections, like bacteria infections. And they are also going to tissues, and those macrophages are there to have certain functions, including tissue repair. And there's a lot of biology that has gone into sort of describing how these monocytes and macrophages function. Obviously, important cell types. And CSF1R signaling pathway is the key growth factor pathway for these cell types. So it regulates the maturation, the proliferation and activation of monocytes and monocytes into macrophages in the tissue. And so 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. So in disease settings, like many immune cells, if the disease sort of -- these cells go awry or dysregulated, you have an overabundance of activity. So 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. And so we know there are disease settings where inflammation and fibrosis play a role. We'll hear about that certainly with IPF. We have experience in graft-versus-host disease setting, which I'll tell you a little bit about. But we know that this is an important physiological process. And then when it goes awry, that CSF1R blockade is quite effective in normalizing it. And so if we go to the next slide. So basically, just to give you a sense of our development program to date. So we licensed this in, as you heard, a number of years ago. And after some initial development work, we focused in on some science that was very compelling that was published in models of transplant. And 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. And so based on those data, we started a Phase I program. And so as you've heard, we have a lot of firsts. And so we, of course, we're 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. And we continued the Phase I. We did a cohort expansion. And 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, [ Incyte Pharmaceuticals ], launched Nictimvo in early 2025. And as you've heard, that launch has gone extremely well. And we continue to see benefit for patients, which we're again super excited about and happy to see. And so 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 2 prior lines of systemic therapy. And the goal is to move this into earlier lines of therapy as a way to basically try to prevent those fibrotic manifestations from happening. And so if we can move that earlier in the disease, we may see a more prolonged benefit for patients, not to mention increasing the number of patients that can ultimately benefit. And so Incyte has been leading 2 studies in the frontline setting. One of them is actually quite novel. It's combining with ruxolitinib as a steroid-sparing approach. And so the idea here is currently standard of care is for patients to get steroids in the front line. Steroids, they can be on these for years and they have a lot of comorbidities. And so the idea could be, which is extremely exciting for the community and for patients, could you come up with a steroid-sparing regimen? And so that trial has been ongoing. And we've heard and have indicated that those data will be available by the end of this year. So we're really looking forward to those data. In addition, there is a Phase III study that's ongoing that's also frontline. That's steroids plus/minus axatilimab. And this is, again, a registration-oriented study that should read out hopefully in 2028. So again, super exciting sort of movement of the axatilimab program from the current setting into the earlier frontline settings. Now we spent a lot of time thinking about where else can we look for benefit in targeted macrophages and such through CSF1R inhibition. And we ran a prioritization exercise a number of years ago. And so we had our compelling data from our clinical experience. We have preclinical data in a number of IPF mouse models. And there's a lot of literature actually supporting the role of monocytes and macrophages in pulmonary fibrosis. And so that plus the commercial opportunity allowed us to prioritize and rank IPF as sort of the #1 leading indication for us to move axatilimab into. And so 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. And so that puts us on track to having our top line data in the fourth quarter of this year. So again, from a science perspective, it's a large experiment. So it will be actually really great to see the results because the benefit that we've observed in the patients with lung involvement in GVHD has been quite promising. Now 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, so 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. And so beyond that, again, we are really eager to see where else we can translate that data that we've observed in terms of targeting macrophages and monocytes for this inflammatory and sort of fibrosis aspect. And so 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. So we think there's a little -- quite a bit of promise in terms of axatilimab program. And so our lineup today is actually really incredible. And so I'm eager to pass this on to Dr. Maher, who currently, he's Professor of Clinical Medicine and Interstitial -- and Director of Interstitial Lung Disease at the Keck Medical School at the University of Southern California. But 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. And he's been a member of our Steering Committee from the beginning as we established our Phase II study. And so we're really thrilled to have him here and have him participate in this discussion. So with that, I will be passing it on. Now Dr. Maher is not obviously in the room, and so we'll be watching his presentation on the screen.

Great. Thank you very much. Hopefully, everyone can hear me and see me. So sorry not to be there in person, but a pleasure to be discussing the importance of the axatilimab program in patients with idiopathic pulmonary fibrosis. And 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. So 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 photo micrograph here on the left-hand side, the sort of beautiful laced-like architecture of the lung, with each of those little pink bounded spaces being an alveolus where the gas exchange happens. And then on the right-hand side, we've got a cartoon graphic of the human lung and the different regions. So we have the main airways. These then divide about 27 times until you get down to the alveolar space. And when we talk about interstitial lung disease and pulmonary fibrosis, we are talking about a group of diseases that essentially call scarring and destruction around the wall of alveolar space. Now in the context of axatilimab, which is also being tested in GVHD, the primary abnormality that we see in the lung in patients with GVHD is fibrosis of that terminal airway. So if you look at the bottom left-hand -- bottom right-hand picture of the 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 the 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 a huge amounts of collagen and fibrotic tissue. And 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. So idiopathic pulmonary fibrosis is a disease of older adults, typically affects men in the 60s, about 3/4 of patients are men for whatever reason. It does seem to be of increased incidents in patients who spent a lifetime working in dusty or smoking environments or who have smoked in the past. What we see is the scar tissue, which press advance, gets progressively worse over time. And 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 2 slides. That's the same patient 18 months apart. And once pulmonary fibrosis develops, it becomes inexorably progressive. And without treatment, the average patient will die about 3 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 cause a 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. But about 2/3 of my patients will have other diseases. And in recent times, we've seen the use of antifibrotic drugs effectively across the full range of diseases, not just IPF. So 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. So I'm not going to go into this slide in detail. This is just describing the pathogenesis of pulmonary fibrosis. But 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. And importantly, once the disease is up and running, we see activation of multiple cell types in the lung, including epithelium, fibroblast endothelium and, importantly, from the perspective of axatilimab, the inflammatory cells within the lung. If we go on to the next slide. Now over the last 15 years, we have seen an evolution in the treatment landscape. In 2014, we had the approval of pirfenidone and nintedanib. And then after a barren spell of negative trials, we saw neradomilast, a PDE4 inhibitor, approved last year. In the last 12 months, we've seen positive results from the [ TETON ] trial of inhaled [ PostNL ], and we're currently awaiting readout from the Phase III admilparant trial of the LPA receptor 1 antagonist from BMS. And then hopefully, we've got the axatilimab as a hopefully successful treatment in the future. Now 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 and nintedanib for a decade, my patients are still dying from respiratory failure. So we might have delayed death from the disease, but we certainly haven't come close to preventing it. And the graph on the right is work that we did with patients on long-term antifibrotic 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. And so a huge unmet need remains. And if we go to the next slide. And not only that, the drugs that we've had up until now, pirfenidone and 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 antifibrotic therapy. And 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. And then the graph on the right just shows the discontinuation rates with nintedanib and pirfenidone, which approach 50% at 1 year. So we have drugs that physicians were reluctant to use, and when they did use them, patients struggle to stay on them. So 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 access in driving the disease. Worth remembering that our lung is our only internal organ that is exposed to the outside environment. We're breathing in air, which brings with it pollution, viruses, bacteria into our body. So we have a highly developed immune system within the lung. And the central cell that provides immune surveillance is the macrophage. Now we're 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. But when we get infection, we are reliant on bone marrow derived monocytes that traffic through the bloodstream into the lung, and then differentiate into alveola macrophage like cells to provide additional immune support in moments of infection. And 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. And as we get older, more of our monocytes are coming from our bloodstream. Those monocytes have a different phenotype or the ones that are resident in the lung. And 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 profibrotic phenotype when we assess them based on their cell surface characteristics. And then 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 worst, the prognosis for that individual, the more rapidly progressive their disease. And on the far right-hand side is a photo micrograph, you can pick out the macrophages which are the cells with a little brown rim around them. And that brown room is just indicating where the CSF1R is located, which is on the vast majority of the macrophages in the fibrotic lung. Next. And then this was additional work. This was work done by a group in Stanford, just showing that circulating monocytes, so the precursor cell alveolar macrophage, are predictive of outcome in patients with pulmonary fibrosis. The more circulated monocytes, the worse the outcome. And we and other groups have subsequently replicated this finding in multiple cohorts, again, just emphasizing the importance of the monocyte macrophage access in driving fibrotic lung disease. Next. So I'm not going to go into this because you've 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's not really an axis that's being targeted at the moment, traditionally with antifibrotic drugs, there's been a lot of focus on the interaction between alveolar epithelial cells and fibroblast, but very little focus on the role played by the immune cells, particularly the macrophages within the lung. Next. So 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. So like I said, in IPF, the fibrosis around the wall of the alveolus causes the lung ultimately to shrink. With GVHD the fibrosis is around the terminal airway, so it's sort of circumferential fibrosis that squashes the terminal airways shut. And so that causes narrowing of the tubes. It makes it hard for the air to get into the alveolus then 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. And so for me, it was exciting to see the data from the GVHD study because axatilimab in those patients with lung disease appear to have clear benefits on the lung, suggesting potentially that it's having an antifibrotic effect in that scenario. So about 45% of patients in this study had lung involvement, and 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. And 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. And 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. And again, just emphasizing the fact that that 0.3 milligram per kilogram dose was associated with the best lung responses, and that even patients with very severe small airway fibrosis or the patients with the lowest FB1 values were showing improvements with treatment. And that's impressive because in clinical practice, this is the group of patients that we have always struggled to treat. So next slide, so you've heard mention of this. This is the MAXPIRe trial. So 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-plus 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 6-month study. And I think increasingly, we've looked to do 6-month studies at Phase II because that's slightly longer period of time. It 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, changing [ force vital ] capacity. And 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. And 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 Phase III. So if my last slide, please. So just in summary, hopefully, I've convinced you IPF is an important disease. It's deadly. I didn't tell you the incidents, but it affects about -- about 1 in every 100 deaths that occurs in Europe and the United States is due to IPF. So although it's considered a rare disease, it really isn't that rare. Neradomilast 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. So thank you very much.

All right. Thank you so much, Dr. Maher. So I guess, we have some time for Q&A.

Fai Khurshid from Jefferies. One for Dr. Maher, one for the company, please. For Dr. Maher, thank you 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? And then 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?

Yes. So I didn't measure on the pathogenesis of IPF, but I think there are multiple mechanisms that are activated in the fibrotic lung. So 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, sort of true success in improving outcomes for patients with PAH has been driven by combining drugs with different mechanisms. And so I think it's sort of -- I don't feel there's any contradiction in my -- 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. I think given the complexity of disease, I think a lot of those mechanisms are all important. So 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 preclinically 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 there is -- I think the insights from GVHD are important in interpreting probability of success in IPF. And I think that distinguishes it from other programs where, once you sort of sort of put all the Phase III programs to one side, everything that's currently at Phase II, we're essentially waiting on data. So at the moment, we have to wait 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. So I think for me, the biggest reason for optimism is that effect that we've seen in GVHD, and my belief that fibrosis, whether it's sort of circumferential airway fibrosis or IPF, have a lot of similar overlapping mechanisms. And that's what gives me true reason for being optimistic.

And related to the second part of the question, I don't know, Nick, if you wanted to...