Disc Medicine, Inc. (IRON) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to Disc Medicine's MF Anemia KOL event. [Operator Instructions] As a reminder, today's program is being recorded. And now I'd like to introduce your host for today's program, John Quisel, CEO. Please go ahead, sir.

Welcome to the Disc Medicine myelofibrosis anemia day. As a reminder, this is John Quisel speaking, CEO here at Disc. And I'm here with Will Savage, our Chief Medical Officer; and Pamela Stephenson, our Chief Commercial Officer. We are thrilled to be joined by Dr. Prithi Bose and Dr. Aaron Gerds, two leading physician scientists in the myeloproliferative neoplasm space. Now I hope everyone saw our first quarter earnings release earlier this week. We are progressing well towards NDA filing with our lead program, Bitopertin for EPP patients. But today, we want to take a deep dive into our second program, DISC-0974, looking at the need for new therapies to treat anemia of myelofibrosis. Dr. Bose and Dr. Gerds are with us today to provide expert insight into the disease and treatment landscape. Before we get started, I'll cover a few preliminaries. We will be making forward-looking statements, and these should be taken in context with respect to materials that we have filed with the SEC and have posted on our website. Additionally, Bitopertin, DISC-0974 and DISC-3405 are investigational agents and are not approved for therapeutic use in any jurisdiction worldwide. So turning now to our agenda. I will give a brief introduction to Disc and an orientation of our portfolio, then we'll get right into the discussion. Dr. Gerds will provide an overview on anemia of myelofibrosis and what this disease looks like and means for patients. Then Dr. Bose will talk through the current treatment landscape and emerging therapies in development, including DISC-0974. Then Will will review the Phase Ib data for DISC-0974 that was initially presented last December at ASH and we'll speak to our ongoing Phase II trial. And finally, Pamela will provide insights on the anemia of myelofibrosis market opportunity. For those who may be newer to Disc's story, we are a hematology company, and our pipeline targets fundamental pathways of red blood cell biology. Our current pipeline focuses on heme metabolism with our lead program, Bitopertin, and iron metabolism, which we'll be focusing on today. While today's focus is anemia of myelofibrosis, by targeting these fundamental biological pathways, our portfolio is designed to address a broad range of hematologic diseases from ultra-rare disorders to highly prevalent ones. And this range of disorders is shown along the bottom of the slide. We are developing three clinical stage molecules. The first, Bitopertin, is a small molecule GlyT1 inhibitor, which we are developing in a rare disease called erythropoietic protoporphyria. As we have discussed previously, we have completed a Phase II program. And based on that data, we have aligned with the FDA on pursuing an accelerated approval path, and we plan to submit an NDA in the second half of this year. We also recently shared that our APOLLO trial, which is designed to support full approval of the drug, is officially up and running. Our second asset, DISC-0974, is the focus today. This is a monoclonal antibody that suppresses hepcidin and mobilizes the iron by inhibiting a target called hemojuvelin. And we are developing it in anemia of chronic diseases with anemia of myelofibrosis as the lead indication. Our third program, DISC-3405, is also a monoclonal antibody and acts in the exact opposite way as DISC-0974. So it induces hepcidin to restrict iron through a target called TMPRSS6. And we plan to study this program in polycythemia vera and potentially other diseases of iron overload. So here is all of that laid out in a pipeline chart, and I'll just call out the ongoing trials for DISC-0974, which are a Phase II trial in anemia of myelofibrosis and a Phase Ib trial in anemia of non-dialysis-dependent chronic kidney disease. So focusing in on DISC-0974. Again, the therapeutic hypothesis for this drug is around hepcidin suppression. By decreasing hepcidin, DISC-0974 makes more iron available to support red blood cell production, thereby enabling red blood cell formation, particularly in the setting of anemia of chronic disease. To provide a bit more detail, looking at the left-hand panel, hepcidin is the key hormone that regulates how the body stores and manages iron. More hepcidin means iron is trapped in the liver and spleen with less iron available to support erythropoiesis. By suppressing hepcidin, you can release iron stores, enabling better dietary iron absorption and enabling better red blood cell production. And with -- this approach can potentially treat a wide range of anemias. In particular, we expect this approach to have application in anemias of chronic disease as hepcidin tends to be elevated in those inflammatory disease environments. Now looking at the right-hand panel to go through how DISC-0974 works. It's an antibody against the target heart called hemojuvelin or HJV. And this target is known from both human and mouse genetics as a critical and specific regulator for hepcidin expression. And we know that HJV is functionally specific to hepcidin and iron regulation through genetic validation. There is a disease in humans called juvenile hemochromatosis, which is caused by a knockout of hemojuvelin. And the only manifestations of this disease are lower hepcidin and elevated iron levels. So we went into this program expecting this to be a clean target and a highly specific tool for modulating hepcidin. So far, the clinical data have supported this expectation. So with this approach, we established proof of mechanism in healthy volunteers. And then our goal was to go after initial proof of concept in the anemia of myelofibrosis and anemia of chronic kidney disease. We have now completed enrollment of the Phase Ib portion of our MF study and have presented a proof-of-concept dataset at the American Society of Hematology in December 2024, and Will, will review that data later today. Our CKD Phase Ib trial is ongoing, and we shared single-dose data from that study at ASN, the American Society of Nephrology, meeting last year. And that data showed generally effects headed in the right direction, and we look forward to seeing that dataset mature as we move into the multiple dose portion of that study. Together, these datasets should give us a strong basis to potentially expand into other forms of anemia of inflammation as well. Now before we get into the KOL discussion, I want to give some high-level context on myelofibrosis and the history of how this disease has been managed. Myelofibrosis is a blood cancer, and it has three main clinical manifestations: Enlarged spleen, debilitating constitutional symptoms and anemia. For a long time, there were no real treatments for myelofibrosis. So it was all about symptom management, supportive care and in the most severe patients, maybe trying some non-targeted chemotherapies or removing the spleen. With respect to anemia, the treatment would be blood transfusions, and many patients became dependent on transfusions, which are very hard on the body. Eventually, drugs like the erythropoietins and danazol came along to help manage anemia generally, and these drugs have been used off-label in myelofibrosis with modest benefit. As Dr. Gerds will discuss, anemia in MF is complex and multifactorial and is fundamentally tied to the pathophysiology and progression of the disease. The big advancement in MF treatment over 10 years ago now was ruxolitinib, a JAK inhibitor. And then this was followed by newer JAK inhibitors that have come behind it. Ruxolitinib has made a big difference in managing spleen size and constitutional symptoms in myelofibrosis patients, but it is a myelosuppressive drug. And in a lot of cases, it actually makes cytopenias such as anemia worse. So there have been many approvals in this field, and there continues to be considerable drug development in MF. But fundamentally, the way that anemia is treated in this disease has not changed and significant unmet need on this front remains for these patients. So our objectives for today's presentation are really to convey why a new treatment for anemia of MF is so needed and what a truly differentiated treatment would mean for this market. Our guest speakers will give an overview of MF anemia, the role of hepcidin in the pathogenesis of the disease and the high burden on patients. Then our speakers will turn to how anemia in MF is managed today, the limitations to current treatment options and what a meaningful anemia-targeted product profile would look like. We'll then talk through the emerging profile of DISC-0974 based on our Phase Ib data and how we aspire for DISC-0974 to be positioned in the market. Now I'm excited to turn it over to our KOL speakers, starting with Dr. Gerds, who will give us an overview of MF anemia. Dr. Gerds is a hematologist-oncologist at the Cleveland Clinic. He is also an Associate Professor at Case Western Reserve Medical School, running the clinical research office at their cancer center and has been a principal investigator in many clinical trials for myelofibrosis, including Disc trials. Please go ahead, Dr. Gerds.

Thanks so much for the kind introduction, John. It's a pleasure to be with all of you today to discuss a very important topic and a topic that's near and dear to my heart, anemia in myelofibrosis or also known as myelofibrosis-associated anemia. And the reason that we talk about it is a couple of different things. One is it's a common problem in myelofibrosis. And two, it is prognostic. And it is oftentimes difficult to treat. And we're going to cover all these topics here in the next few parts of the slide deck before we start to pivot on ways we can work on this anemia and make it better for our patients. So myelofibrosis, just to give a little bit of background, is a disease of abnormal proliferation of hematopoietic cells in the bone marrow. And so it's kind of odd to be thinking about anemia or low red blood cell counts in a disease where there's overproduction of red cells, but the marrow becomes diseased over time from all this overproduction and release of cytokines, and that really inhibits the ability to produce adequate numbers of red cells. This environment in the bone marrow is very inflammatory. White blood cells are part of the immune system. So it makes sense that these deranged immune cells produce cytokines and other inflammatory markers leading to the development of fibrosis and this erythropoiesis. There's ineffective erythropoiesis because of the scar tissue itself as well as the inflammatory cytokines. We're going to cover the mechanisms of the anemia in myelofibrosis in a few slides, but really, that is a hallmark of the disease. Kind of a unique thing we see in myelofibrosis is this thing called extramedullary hematopoiesis or bone marrow cells outside of the bone marrow. The bone marrow becomes so sick and inhospitable, these bone marrow cells need to find other places to grow. And so sometimes we'll see EMH or extramedullary hematopoiesis in the liver or spleen or adipose tissue. I recently had a patient who had EMH in a breast lesion. We thought she had breast cancer, but it turned out to be just EMH from her disease. And of course, that's with the hallmark symptoms of constitutional fevers, night sweats, itchy skin, spleen enlargement and other cytopenias. Although we're going to spend some time talking about myelofibrosis, I admit it is considered to be a rare disease. It is a chronic blood cancer or chronic leukemia with a prevalence in the United States of about 25,000 people. On average, patients are around the age of 65 at the time of diagnosis. The 5-year survival rate is variable depending on different prognostic factors within one's given disease. But on average, if we take all patients diagnosed with myelofibrosis, the 5-year survival rate is around 50%. A large number of these patients will ultimately progress to acute leukemia or also known as blast phase MPN, where the blasts build up and it's a very aggressive disease, again, akin to acute leukemia. The other kind of end consequence of this disease is [ Fanc ] bone marrow failure, where the bone marrow is so sick and deranged, it cannot produce adequate white blood cells, red blood cells or platelets. Again, the therapeutic focus is -- the three areas of therapeutic focus for this disease are really centered around what we see clinically. One are the constitutional symptoms, fatigue, night sweats, itchy skin, bone pain, weight loss. The other is splenomegaly, the other kind of key hallmark. And spleen can enlarge for a couple of different reasons. One, of course, is the development of extramedullary hematopoiesis in advanced disease. But also, the elevated cytokines leads to expansion of the splenic tissues. And this splenomegaly can lead to early satiety and even infarct in the spleen as well as increased splenic as well as abdominal thrombosis. So real important symptoms to address. But of course, the other thing and the reason why we're here discussing it today is anemia and other cytopenias. Anemia can result from a number of different factors as we're about to talk about. But again, it's kind of the third of the triad of symptoms we approach in this disease. Anemia is prognostic. A patient with anemia will fare more poorly than a patient who does not have anemia. And so much to the point where we actually include it in our most common prognostic models. Although this is a disease, it's a blood cancer, it's a leukemia, there are no staging systems. And so we rely heavily on these prognostic models to determine who has aggressive disease and who has less aggressive disease. And hemoglobin over and over again comes up as a prognostic factor, so having a low hemoglobin. And even in the MIPSS70, our most advanced and modern prognostic scoring system that includes genetic mutations and high-risk factors of the like, still hemoglobin or anemia moreover, remains as an adverse prognostic marker even when age has fallen out of the model. So anemia is also a severe manifestation of this disease and the pathobiology really surrounds kind of four main points. One is ineffective erythropoiesis due to bone marrow fibrosis. The fibrosis takes up physical space within the bone marrow. There is suppression or treatment effect from JAK inhibitors. And so Dr. Bose is going to talk a little bit about JAK inhibitors in the next portion of our presentation today, but it's a common consequence of the most commonly used treatments. The spleen can become enlarged, as we mentioned before, and sequester red cells, leading to increased destruction of those red cells. And then due to cytokine being elevated, we see anemia of inflammatory block via elevated levels of hepcidin. All these things can work together against the patient and the patient's anemia might be multifactorial. It may have some ineffective erythropoiesis due to fibrosis and adverse mutations. There might be splenomegaly, there may be high hepcidin levels. And so one treatment for anemia may not work for every patient. So having multiple agents to treat anemia is really incredibly important in this disease. As I mentioned earlier, this is a disease of inflammation and via a disease of inflammation, we see elevated hepcidin levels. This figure here shows that, that patients with myelofibrosis have elevated hepcidin levels. Think of it like a patient with rheumatoid arthritis or some other inflammatory disease where we do see the anemia and inflammatory block occurring via hepcidin. Hepcidin, again, being a master iron regulator, kind of plugs those holes and doesn't allow the iron to be available for adequate erythropoiesis. I already mentioned earlier in the presentation that not only is anemia prognostic, but it's prevalent. And roughly 40% of the patients at the time of diagnosis will have anemia, significant anemia with a hemoglobin less than 10. Within 1 year of diagnosis, 60% of patients will have significant anemia. And over the course of time, over one disease course, virtually every patient will develop anemia. And that's really important because, again, it's prognostic and it relates to symptoms. And when patients become transfusion requiring, that is extremely detrimental on their everyday quality of life. And patients will develop transfusion requirements. 1/4 of patients at the time of diagnosis will be transfusion requiring. 45% of patients will be transfusion requiring within 1 year of diagnosis. And again, nearly every patient, if given long enough, they don't go undergo a transplant or pass away from something else, will require transfusions at some point as this is a progressive disease. Kind of circling back to the story about anemia being prognostic, it's not only just prognostic in a general sense within prognostic models, but there's actually a dose response curve to the anemia. We talk about effective medications having the dose response curve where we increase the dose of the medication, and we see the increase in effect. The same thing happens with anemia. The more severe the anemia, the worse their survival is. So the figure on the left here shows that a survival curve for patients with no anemia and every curve drops as anemia becomes more severe, mild anemia, moderate anemia, severe anemia with associated median survival dropping from 95 to 59 to 41 to 25 months. The same goes if you divide patients based on transfusion dependency or independence, where the survival drops with transfusion-dependent patients. So anemia, again, is prognostic as well as prevalent. And kind of circling in on to the anemia of inflammatory block, which again is a key component of the anemia in patients with myelofibrosis. Hepcidin ferritin levels are associated with worse prognosis and survival, independent of other risk factors in patients with myelofibrosis. So the higher the hepcidin level, the lower the survival. And that kind of points to probably a couple of different factors. One, again, relates to the anemia of disease, which again of itself is prognostic, but it probably also relates a lot to the severity of the inflammatory response within the bone marrow microenvironment, thus a more deranged bone marrow, again, linking to inferior survival. So not only is it prevalent and prognostic, but there might be some more to the biology than just simply having a low red blood cell count. And it doesn't take a kind of too much of a conjecture to go from anemia to -- symptoms to a worsening quality of life. And a patient who has anemia has increased fatigue, worsening functional -- physical functioning. They want to go up a flight of stairs, but are short of breath by the time they get to the top. They may have a limited ability to perform their roles, whether at home or at work. There's, of course, a psychosocial impact. Anemia is associated with worse mental health, lower social functioning and reduced satisfaction with emotional role. And then also within the health care system. So anemia, in addition to lost patient functionality and potential work hours within that of society, we also see more access to health care by patients who are anemic, more hospital visits, more ER visits and more health care costs. Transfusions in particular, are incredibly expensive and time consuming. Think about it, a patient gets their blood drawn one day and they're found to be anemic and needing a transfusion, then they got to get a type and cross. It could take a few hours to get that type and cross done and then a few hours to actually get the red cells and get the transfusion. And by the end of the day, a patient may have lost most of their light hours getting a transfusion. If that happens once a week or every other week, that can be a significant burden not only on the patient, but on the health care system as well. And as we -- as you may know, red cells are a resource that's scarce. The blood banks are in constant shortages, and this puts a strain on the entire system when patients are getting lots of transfusions. So to kind of sum things up here, Anemia is a prevalent and severe and prognostic manifestation of myelofibrosis, inflammation leading to elevated hepcidin and iron dysregulation is a key driver. JAK inhibitors help manage symptoms, and Dr. Bose is going to talk about that in a little bit, can manage symptoms and spleen size, but also can worsen anemia. So kind of the different basis of pathobiology for anemia and myelofibrosis. Anemia and transfusions are associated with poor prognosis and survival in myelofibrosis. Anemia symptoms significantly impact health care utilization and quality of life. And all these are important reasons why we need additional and better therapies to treat myelofibrosis-associated anemia.

Thank you, Dr. Gerds. Switching topics to the current and emerging treatment landscape, I'll hand it over now to Dr. Bose, who is a professor in the Department of Leukemia at MD Anderson with a focus on MPNs. He has also been a key player in clinical development for myelofibrosis and other MPNs, including Disc's clinical trials. Please go ahead, Dr. Bose.

Thank you, John, for having me and allowing me to speak on this very happening area of the current and emerging treatment landscape when it comes to anemia of myelofibrosis. So as you can see on this slide, just sort of taking a high-level view here, the goals of myelofibrosis treatment generally include shrinking the spleen, improving anemia and ameliorating symptoms. And as you can see sort of towards the middle of the slide, there are two endpoints that have traditionally been used, particularly in getting JAK inhibitors approved and note that all four drugs currently approved for myelofibrosis are JAK inhibitors. So these endpoints are, if you will, a bit tailored to JAK inhibitors, I would say. And frankly, these two things are their strong points, splenomegaly reduction and symptom improvement. So SVR35 is the percentage of patients who achieve a 35% or greater spleen volume reduction at 24 weeks compared to baseline. And TSS50 is the percentage of patients that achieve a 50% or greater decrease in their total symptom score using one of the well-established tools. For example, the MFSAF has been used in many of the trials. There's also the MPN-SAF, as you see on the slide here, again, at 24 weeks compared to baseline. Now for anemia, which is a pretty -- I mean, almost a hallmark of the disease, present in like 1/3 of patients, as you heard from Dr. Gerds, at diagnosis and then becoming increasingly prevalent to the point where everybody gets it at some point. We don't really have any drugs approved yet. And so we don't have as well established endpoints, although we are certainly going to talk about some that have been used in the earlier phase trials and also an ongoing Phase III. So the current treatment landscape, again, four drugs approved, all four JAK inhibitors, like I just said. For anemia, nothing approved yet. People use -- we all use erythropoietin and its analogs like darbepoetin. We use steroids. We use androgens, synthetic androgens like danazol. I don't myself use IMiD for anemia, but they have been used and then iron chelation can sometimes be used, of course, to offset some of the iron overload that comes from transfusion. Now there are, of course, many, many drugs being developed for myelofibrosis, some of which have an anemia focus and many of which that do not. And as you see on the left towards the bottom, just some examples here, not intended to be exhaustive, but you have BET inhibitors, telomerase inhibitors, the type II JAK2 inhibitors as well as what's known as mutant-selective JAK2 inhibitors also shown there, drugs that target mutant CALR, these are the driver mutations. So this is an emerging strategy to try and target the driver mutations in a better, more effective way. And then other pathways such as XP01, which is nuclear export, selinexor, great example of that and then navtemadlin, which is an MDM2 inhibitor. There are others, for example, there's a PIM kinase inhibitor. So there are other things, but these are all drugs that are really not meant to be anemia drugs. However, they are rather -- they are meant to be drugs that synergize with the JAK inhibitors and give us deeper responses. Now on the right -- bottom right, you see the drugs that are currently the players for anemia of myelofibrosis. Again, nothing approved, but luspatercept is in Phase III, highly anticipated results, fully accrued trial. We'll discuss some data on that in the upcoming slides. And then, of course, DISC-0974 and then elritercept, which is also a drug somewhat similar to luspatercept. So moving on to the myelofibrosis anemia treatment algorithm. So this is kind of taken from the NCCN guidelines, sort of paraphrased from there. So as you can see, I mean, there's no anemia -- and anemia, and remember, I said this before, that about 1/3 of patients will present with anemia and then everyone will get anemic at some point in the disease course and a good proportion will start to need transfusions. And again, Dr. Gerds covered all this. So as you see -- if you focus on the portion of the slide that hones in on anemia, so you could have a situation where anemia is really the only clinical problem. Now granted that it's uncommon, but it is not a super minority of patients. In my opinion, it's anywhere from 10% to 20% of patients where anemia is the only real issue. And then you also have patients who have the more traditional presentation. They have some symptoms, they have splenomegaly to some degree. And so we're looking at the management strategy, kind of big picture as to how we manage these patients today. Now again, all four drugs approved are JAK inhibitors. So what are they good at? They're good at spleen reduction and they are good at symptom reduction. And momelotinib in particular, is also good at anemia improvement. So keeping that in mind, if you are just dealing with anemia, I would say -- so again, on the left, if we are just dealing with anemia, I would say my approach is using an ESA or danazol or luspatercept, granted that is off-label, but that is obtainable and we often use it. If there are splenomegaly/symptoms, I will use a JAK inhibitor. I usually do not use a JAK inhibitor if the only issue is anemia. And then moving on sort of to the middle, if you have a patient who are doing well on their JAK inhibitor in terms of spleen and symptoms, you generally want to keep it and you want to add something that can help with the anemia. So today, again, that would be luspatercept, danazol or ESAs, if that EPO level is low enough, or one may want to change to another JAK inhibitor, preferably one with an anemia benefit such as momelotinib or pacritinib. And then if they are on a JAK inhibitor and they are not doing well in terms of spleen and symptoms, well, it makes sense then to switch. So in that situation, one would typically go to any other JAK inhibitor that they were not on as long as it has an anemia benefit. So basically, momelotinib and pacritinib would be the two choices there. And there would be less of an emphasis, I think, in this situation on keeping the drug that is not really doing so good in terms of spleen and symptoms and adding something for anemia, although that could still be done depending on the exact individual circumstance. So ruxolitinib has been around for now 14 years in myelofibrosis, certainly a very, very good drug, and this is really the drug that revolutionized the care of these patients when it was first approved in 2011. So what you're looking at here is data from the COMFORT-I trial compared to placebo in patients with platelets 100,000 and higher intermediate-2 and high-risk patients. So that is our population here, where you had an SVR35 rate of 42% and a TSS50 rate of 46%, really very, very robust response rates there for both spleen and symptoms for ruxolitinib. Now I will say just quickly that there have been other Phase III trials where, say, ruxolitinib has been more of the comparator. And those trials, just to be fair, have shown a lower spleen response rate of around 30%. Symptoms, however, have looked really good, in the 40s. Now again, what's the problem with this drug? Well, it causes anemia. It does not improve anemia, and it causes anemia. So in the first -- anywhere from 12 to 24 weeks, the anemia can be quite significant. It is actually the most common reason for physicians stopping therapy with ruxolitinib or interrupting it, reducing the dose. So it is -- anemia is absolutely something that limits the efficacy of ruxolitinib because it's a dose-dependent drug. So in order to benefit from it, well, you need to be taking it and you need to be taking it at an optimal dose. And that becomes the problem when the drug causes anemia and it often does. So as you can see, 96% of ruxolitinib-treated patients experienced some anemia. More than half were on a suboptimal dose. And real world, if you look at ruxolitinib usage and dosing, it's often something like 10-milligram twice a day that tends to be the most common dose, certainly not the 15 and 20, which you would hope for because those are the doses that were used in the COMFORT trial. And then about half of patients will discontinue ruxolitinib within 3 years for a variety of reasons. Anemia, I already mentioned, is a major one, is the most common one. And then there are other factors such as the response just dwindling over time or certain adverse events for some patients, although generally a very well-tolerated drug. Now there are other drugs. There are four drugs, as we've been saying; fedratinib, 2019; pacritinib, 2022; and momelotinib, 2023. These drugs do have some differences in their targets. So ruxolitinib, JAK1 and JAK2; fedratinib, primarily JAK2, less JAK1; pacritinib, only JAK2, no JAK1, but also IRAK1 and ACVR1; and then momelotinib, again, like ruxolitinib, JAK1 and JAK2, but the anemia benefit coming through the ACVR1 inhibition by that agent. So what you're looking at here in the tables is really just a high-level overview of the efficacy in terms of TSS50, which is symptom response; SVR35, which is spleen response; and then anemia response generally reflected by transfusion independence rates. And then the indications are shown as well. They are all line agnostic. They are all generally for intermediate and high risk. Fedratinib is intermediate-2 and high risk. And then for pacritinib, the platelets have to be less than 50 for the current FDA indication. And momelotinib has anemia in its label. So again, to sort of walk you through these numbers, ruxolitinib, I already told you these numbers come from COMFORT-1, which probably reflected this drug in its best light with SVR35, 42%; TSS50, 46%. That was against placebo. Fedratinib, these numbers come from JAKARTA, also against placebo. So 36% for spleen, 36% for symptoms as well. This is all at 24 weeks, just a reminder about that. And then pacritinib and momelotinib is a little bit more complicated because these had multiple Phase III trials. These were never compared to placebo. Populations were different. So one has to be a little bit careful about these. But -- so when you look at pacritinib, you're looking at a range of 7% to 32% for symptoms and 9% to 22% for spleen. So I'll qualify that by adding that these only refer to the 200-milligram twice a day dose, which is the approved dose. So these are not all doses. These are restricted to that dose. And also basically, this is encompassing about 3 -- well, actually, I should say, 2 Phase III trials where, one, the PAC203 trial, where the lower numbers come from was in a JAK-exposed population, whereas the other trial PERSIST-2, which was the basis for its approval and where the higher numbers come from, was more of a mixed population with some JAK exposed and some JAK naive. Now momelotinib, again, similar concept, more than one trial, essentially 2 Phase IIIs being included here as in the U.S. label, the SIMPLIFY-1 trial and the MOMENTUM trial. So the SIMPLIFY-1 trial was a head-to-head frontline trial against rux. So for spleen, the number of 27% comes from that trial; for symptoms, the number 28% comes from that trial. Again, head-to-head JAK-naive against rux. And then the other numbers, the 23% for spleen and the 25% for symptoms come from MOMENTUM, which was the more recently done second-line trial against danazol in a JAK-exposed population. Now if we turn our attention to the rightmost column, it talks about anemia response in terms of transfusion independence. And you clearly see that with rux, you do not get a benefit, right? You see the minus 21% so people becoming transfusion independent on the drug. With pacritinib, they did report the proportion that became transfusion independent of those who were not transfusion independent. So it's not the same thing as saying transfusion dependent. So these were patients who are either dependent as defined formally or just requiring transfusions here and there. So if you took those patients and you saw how many became independent, that number was 24%, and that was from the PERSIST-2 trial. And then at the end, the momelotinib, this drug, of course, is best known among the JAK inhibitors for its anemia benefit. And you can see that, again, across trials, there was a minus 2% to a plus 17% change in transfusion independence rates. All right. So back to the anemia and kind of focusing in on that. So like I said, there are no approved drugs, and we use ESAs if the endogenous EPO level is low, i.e., less than 125, and if their transfusion burden is either 0 or low, those patients can benefit. And you can see here the response rate, 20% to 30%, usually does not last very long, usually not very durable, maybe a year or 2 at most. And then -- but otherwise, in the right patients, certainly a good and easy treatment. Danazol, again, response rates variable, but sort of in that range. Danazol was, by the way, the comparator against momelotinib in the MOMENTUM trial that gave us a good dataset about what this drug can and cannot do. You've got to be careful with this drug in anyone who's had a history of prostate cancer, I would avoid it. It's an androgen after all, and it could certainly feed the prostate cancer. So I'm very careful in using it in those types of situations. It's male hormone derivative. So certainly, there is a potential for masculinizing side effects in female patients. So one needs to be careful about that. And then hepatotoxicity also is real, and I've certainly occasionally seen it. But again, it's tolerated and in the right patient, it can be a useful drug. Glucocorticoids, well, I mean, as you see, a good response rate, but certainly not something one wants to use for any length of time in patients with a chronic disease with anemia. Now luspatercept, of course, quite exciting, already approved for MDS, as you know, and a Phase III trial has completed accrual in myelofibrosis and those results are eagerly awaited, and we will touch on the Phase II data, I think, in a subsequent slide. So again, these are the things we have currently in our arsenal and that we tend to add to drugs like ruxolitinib or pacritinib -- I'm sorry, ruxolitinib or fedratinib. And even frankly, drugs like pacritinib and momelotinib that have their own anemia benefit, it's not uncommon to have to add these drugs. I have several such patients. So as we look for a drug specifically for anemia of myelofibrosis, what are the attributes we would like that drug to have? So on the left, it should work across severity levels of anemia, right? So transfusion dependent or not so, or mildly so, it should work across the board. Should work on its own. Remember, we talked about that 10% to 20% of patients who do not need a JAK inhibitor. So you would want something for them. It should be able to work with any JAK inhibitor, not necessarily just rux, but now that all four are seeing increasing use, should work with any of them. And should be able to optimize their dosing. Again, this is probably most true for rux. Rux is a dose-dependent drug and you want to be able to deliver 15 or 20 milligram twice a day to get the -- in fact, 20, if you go strictly by published models. 20 twice a day is the ideal dose of rux that you want to be able to achieve and that can be hard because of the anemia. So you would want to try and optimize that and frankly, help the drug do what it is best at. And then, of course, we would want response rates that are superior to what we currently have. The right -- the portion of the slide on the right, I think we already went over. That's just there to remind you of the current approach in those who are not on a JAK inhibitor or are on a JAK inhibitor and are either doing well in terms of spleen and symptoms or not doing well in terms of spleen and symptoms. Okay. So here we go with the investigational drugs. So we have, of course, DISC-0974, the anti-hemojuvelin antibody that we are talking about today. And then we also have the activin receptor-ligand traps, luspatercept and elritercept. There are minor differences between the two. But in general, they are both activin receptor-ligand traps. So in terms of hemojuvelin, basically a positive regulator of hepcidin. So this is an antibody directed against hemojuvelin, the idea being to down-regulate hepcidin, but this is not through ACVR1 inhibition, as you heard in regards to pacritinib and momelotinib, but rather through hemojuvelin, the only drug I'm aware of that does this. And so again, the idea being to down-regulate hepcidin production. If you down-regulate hepcidin production, you essentially free up iron for the bone marrow to use for erythropoiesis with less iron than being sequestered in the reticuloendothelial system. So you just free up the iron basically. So subcutaneous administration every 4 weeks, Phase II currently ongoing. They have the optimized dose and the Phase II is rolling out right now or has started at this time. So again, patients who are transfusion-dependent or non-transfusion dependent, who are on a JAK inhibitor or are not on a JAK inhibitor. So really for all these different cohorts. And before we get to the response rate, so moving across to luspatercept and elritercept, so those drugs are activin receptor-ligand traps. What that means is that there are these ligands belonging to the TGF-beta superfamily, which binds to the activin receptor. And what you're really doing with the trap agent is that you're sequestering those ligands away and preventing them from interacting with the activin receptor. And when you do that, you impact SMAD 2 and 3 signaling and essentially remove the terminal block on erythropoiesis. So these ligands through the activin receptor tend to suppress terminal erythropoiesis and you're sort of releasing the brakes on that and allowing the red cell maturation to proceed. In fact, luspatercept has been called an erythroid maturation agent. Again, subcutaneous, luspatercept, as said several times, they have completed a Phase III study. Elritercept in Phase II has been presented a couple of times now at ASH and EHA. Now with luspatercept in particular, they did study different cohorts in the Phase II, but the Phase III is actually only studying patients on a stable dose of a JAK inhibitor who require transfusion. And that's really what is meant by those green checkmarks for those boxes. So JAK inhibitor, stable dose, requiring transfusions is the population for the Phase III. However, in the Phase II, they did look at all four scenarios. And then elritercept also earlier phase drug, so clearly does have some data in all the four different situations. So JAK inhibitor or no, and transfusion-dependent or non-transfusion dependent. And then with the results portion towards the bottom, we also clearly show you here the number of patients we are talking about, the luspatercept study a little bit bigger. And this is all Phase II. There are no Phase III data in the public domain from luspatercept, just to be clear, this is all Phase II here. So as you see for transfusion-dependent patients, the endpoint is always becoming transfusion independent. And so that is shown here, 40% to 80% with the Disc drug; luspatercept, 26% in the rux combination cohort. Remember, that's the one that looked the best and the one that BMS took forward into the Phase III, the monotherapy giving you 10% there. Elritercept, 24%. And then moving on to hemoglobin improvement. So this is not your transfusion-dependent patients. These are non-transfusion-dependent patients, talking about hemoglobin improvement. And also here, one needs to be really careful because as you look at different abstracts, different articles, you've got to really focus on how these improvements are defined. So in the spirit of fairness, on this slide, we're really looking at the mean hemoglobin increase. So not an increase at every time point necessarily, but a mean hemoglobin increase over 12 weeks of 1.5 grams at least, right? So by that parameter, 50% for Disc and then 43% in the rux stable-dose patients for luspatercept, 23% for luspatercept on its own and 21% for elritercept. Well, then that brings me to the end of my portion of this presentation today. So just to summarize the stuff that we went over, we have four JAK inhibitors approved. The strength of these drugs mostly lie in managing splenomegaly and symptoms. Of course, momelotinib is approved for myelofibrosis with anemia and certainly is a good drug for anemia. However, ruxolitinib is by far the most commonly used, is, in my view, the most potent of the JAK inhibitors in terms of spleen and symptom benefit, also has a demonstrated survival benefit, which may be a class effect, but it has not been shown with the other agents. And ruxolitinib is a dose-dependent drug as we've been talking about. And in order to optimize the benefits of this drug, it is really important to be able to counteract the anemia that it causes and certainly does not help with an anemia-specific agent. And we've discussed that we today have a few of these, nothing approved, but we have a few options that are all somewhat effective, but have their limitations in terms of toxicities or durability of response and also just the response rate. So clearly, there remains an unmet need for new anemia therapies that can work on their own, be combined with any JAK inhibitor, help maintain the dose intensity of the JAK inhibitor, be well tolerated and obviously be effective for anemia. So all of that certainly are what we are striving for. And on the horizon, currently, we have three agents, the DISC-0974 that is the topic of today's discussion and then the EMAs, the activin receptor-ligand traps, luspatercept and elritercept. Thank you.

Excellent. Thank you, Dr. Bose. That concludes our KOL discussion. And Dr. Gerds and Dr. Bose will both be available at the end of the call for Q&A. Thank you both for joining and sharing your expertise. I'll now hand it over to Will to discuss the DISC-0974 clinical program.

Thanks, John. I'll start by reviewing our MF clinical program to date. A couple of years back, we completed a Phase I trial in healthy volunteers, which established proof of mechanism for reducing hepcidin and mobilizing iron through hemojuvelin inhibition. Then at ASH last December, we first presented the results of our Phase Ib study in MF anemia patients, and that initial proof-of-concept data will be our focus here. At the end of last year, we announced the initiation of a Phase II trial in MF, which is ongoing, and we will share an initial readout from that study in the second half of this year. To touch briefly on the healthy volunteer trial, that was a single ascending dose design. And as shown on the top right, we saw clear pharmacological activity with reduced hepcidin production and increased transferrin saturation or TSAT, which showed us DISC-0974, was behaving as we'd expected. What was surprising is on the bottom right, with even a single dose in healthy volunteers who are not anemic, we saw a hemoglobin improvement at the 56-milligram dose as compared to placebo. This told us that DISC-0974 is a potent suppressor of hepcidin, and that drug activity could strongly translate into clinically meaningful increases in the production of red blood cells and synthesis of hemoglobin. So we then moved into a Phase Ib trial in MF anemia. And as a reminder, here's what the trial looked like. There were 35 patients, all with hemoglobin under 10, and we included a wide range of backgrounds in terms of patients on or not on concomitant JAK inhibitors, and we included the full spectrum of baseline transfusion requirements that included non-transfusion-dependent and transfusion-dependent patients. As with healthy volunteers, we saw pharmacodynamics that were consistent across doses and in line with our expectations based on the drug's mechanism. DISC-0974, drove a greater than 75% reduction in serum hepcidin that was sustained throughout the treatment period. And this translated into sustained increases in serum iron and increases in both reticulocyte hemoglobin and hemoglobin and ultimately into hematologic response and improvement in anemia. Before getting into the details of anemia response data, I want to spend some time on how we defined anemia response for different patient segments. People with MF anemia are typically categorized based on how frequently they require red blood cell transfusions. And we show our data in three groups. NTD or non-transfusion dependent are patients who did not receive any transfusions in the 12 weeks prior to the study. Lightly transfused or TD Low patients had 1 to 2 units transfused over the 12 weeks of baseline and heavily transfused or TD High patients had 3 to 12 transfusions over the 12 weeks prior to baseline. The majority of the evaluable patients in the Phase Ib trial were nTD. And in our Phase II, we are expanding each of these cohorts to have 30 patients per cohort. The anemia response endpoints are based on consensus guidelines, and they also take into account our interactions with the FDA. For nTD, an overall response is a mean increase of at least 1 gram per deciliter sustained for at least 12 weeks and a major response is a mean 1.5 gram per deciliter increase for 12 weeks. For TD High, an overall response is achieving at least a 50% reduction in the number of transfusions required and a major response is achieving transfusion independence or needing no transfusions over a period of 12 weeks. TD Low is the same, except that we look at TI over a 16-week period instead of 12 since the baseline transfusion requirement is lower. Following our Phase II data readout, we expect to have discussions with regulators to align on what would be appropriate registrational endpoints for each of these groups. But for context, the regulatory path in TD patients is precedented and the TI endpoint is well established. For nTD patients, there is no precedented regulatory endpoint. But based on our discussions with regulators to date, the FDA recognizes that treating anemia in symptomatic patients is important regardless of transfusion status. And we expect that a combination of hemoglobin response plus some indicator of clinical benefit, whether it's maintaining transfusion independence or showing improvement on a symptom score like fatigue, which has multiple validated instruments, will be acceptable. And we'll look at data for one of those PROs, the FACIT fatigue score, today. Starting with non-transfusion-dependent patients, 68% saw any hemoglobin response greater than 1.5 gram increase in hemoglobin. 59% achieved an overall response of the -- sustained 1 gram per deciliter increase. And 50% achieved the sustained 1.5 gram per deciliter major response increase. Then on the right, you'll see the FACIT fatigue increased by around 6 points on average by the end of the study. And this is a strong indicator that patients were feeling meaningfully better from a symptom standpoint. Moving on to the TD patients with low transfusion burden. All evaluable patients achieved an overall response of greater than 50% reduction in transfusion requirement, 4 out of 5 or 80% also achieved TI. But we acknowledge that these are small numbers, and we look forward to a more robust data set out of the Phase II cohort. Then for TD high patients, 60% achieved an overall response of greater than a 50% reduction in transfusion requirement and 48% achieved TI. And again, here, the numbers are small, and we're looking forward to the more robust Phase II data that we're generating now. So regardless of baseline transfusion burden, we saw strong hematologic responses translating to clinically meaningful improvements in anemia. As mentioned, we included patients with and without concomitant JAK inhibitor therapy in the trial. There were 13 patients enrolled in the Phase Ib on concomitant JAK inhibitor therapy, and these patients fell into the non-transfusion-dependent and TD High groups. Overall, 54% of patients on JAK therapy achieved a major hematologic response relative to their baseline transfusion status. So DISC-0974 is working well in the JAK-inhibitor treated population and the response rates for non-JAK-inhibitor treated patients were right around the same ballpark. As we heard from our KOLs, it is important to be able to add an anemia treatment onto whatever JAK inhibitor regimen is best controlling the spleen and symptoms for a given patient. And there's also need for anemia treatment in patients who are not yet requiring JAK inhibitors. So efficacy in both monotherapy and in combination is meaningful. Finally, in terms of safety and tolerability, the profile was generally consistent with past datasets. The related AE that occurred in 2 or more patients was diarrhea and was mild. The majority of AEs were deemed non-related. We have already shared the design of our ongoing Phase II trial, but today, we're excited to announce the name of the trial, which is RALLY-MF. This name is intended to reflect what we hope DISC-0974 can accomplish for patients, rallying a comeback to better hemoglobin levels, less fatigue and less overall burden of anemia and also rallying the broad community effort coming together to bring this program forward. We initiated this trial toward the end of last year, and we plan to enroll approximately 90 adults with intermediate-1 to high-risk MF and anemia with or without concomitant JAK-inhibitor treatment. Note that there are 12 patients who are eligible from an analysis perspective to be carried over from the Phase Ib at the Phase II dose, which is 50 milligrams. The Phase II has the same 6-month treatment period and optional continuation of treatment. We are including three cohorts, nTD, TD Low and TD High with 30 patients per cohort. We also have an exploratory cohort of patients on momelotinib or pacritinib and are maintaining flexibility to add additional exploratory cohorts. Interestingly, the fastest enrollment demand we have seen so far has been in the exploratory cohort from patients on momelotinib with anemia. And at this point, there is a wait list for that cohort, which we see as underscoring the outstanding unmet need for anemia-targeted treatments. From an endpoint perspective, the key metric of the study we are looking at in this trial is anemia response, which is defined by cohort and based on our discussions with FDA and updated clinical guidelines. We expect to share initial data from RALLY-MF in the second half of 2025 and top line data in 2026. At that point, we expect to engage with regulators and get a clearer picture of what a registrational study would look like. Based on what we have seen so far, we expect a single Phase III trial addressing the full range of addressable MF anemia patients, but the details will be driven by the RALLY-MF data and regulatory guidance. With that, I'll hand it over to Pamela.

Thanks, Will. As we have discussed throughout this call, anemia and myelofibrosis is a market with significant opportunity. It is a serious condition with 22,000 patients in the U.S. who suffer from severe symptoms that negatively impact their prognosis and quality of life. There is a clear unmet need as patients and physicians contend with a lack of good treatment options for this burdensome disease, and it is well-characterized market with established treatment pathways that make finding patients and connecting with HCPs fairly straightforward. Finally, we expect to have a differentiated product with the ability to address anemia for the full spectrum of these 22,000 patients. As Dr. Gerds and Dr. Bose discussed, JAK inhibitors are the mainstay of treatment for the underlying disease of myelofibrosis. These products have seen great success in the market, generating about $2 billion in sales in the U.S. in 2024, with Jakafi as a long-standing market holder and the new alternative JAKs adding to that business. However, these products have limitations, and there are patients who have either never tried a JAK inhibitor or have tried them and had to discontinue. DISC-0974 is designed to work across all patient types, addressing anemia in those on a JAK, those who have discontinued and those who are JAK naive. So we feel the opportunity for DISC-0974 spreads beyond the reach of JAK inhibitors to address all patient segments, representing a true blockbuster opportunity. Taking a deeper look at the unmet needs in anemia treatment, there are five key issues. First, patients need a treatment that works across anemia severity levels, which DISC-0974 is designed to address as it is being studied across all levels of transfusion dependence and independence. Patients also need a therapy that can work as a monotherapy or on top of their backbone JAK inhibitor with the potential to optimize their JAK inhibitor regimen. DISC-0974 has shown similar strong efficacy as a monotherapy and in combination with a JAK inhibitor and will continue to be studied in patients both on and off JAK inhibitors with a range of JAKs, including momelotinib and pacritinib. Finally, patients need a therapy with high response rates, something that DISC-0974 has demonstrated to date with response rates of 40% to 80%. Market research we have done with MF KOLs and treaters supports the significant remaining unmet need in MF and the strength of the potential DISC-0974 profile. Physicians rated the unmet need very high at a 5.5 out of 7 and highlighted anemia-specific treatments and reducing transfusion burdens as two of the greatest needs. Additionally, they recognize anemia, and the fatigue caused by anemia as two of the top three most burdensome symptoms of MF. When reviewing the DISC-0974 Phase Ib data, physicians rated themselves highly likely to prescribe DISC-0974 for their anemic MF patients, driven by the unique MOA, the strong response rates and the ability to use DISC-0974 across all patient types. So overall, we view anemia of myelofibrosis as a market with blockbuster potential, especially for a product like DISC-0974 that works across all patient segments and is designed to address the key unmet needs for anemia treatment. I'll now pass it back to John to wrap up.

Thanks, Pamela. To close today, I will emphasize that we view the DISC-0974 program in anemia as a chronic disease, starting with myelofibrosis, as we focused on today, as a key engine of growth here at Disc and is an important part of our mission to bring new therapies to patients with hematologic diseases. Hopefully, in today's discussion, it came across how significant the need is for better anemia treatments for MF patients, how encouraging our initial proof-of-concept data is and how valuable the product profile we are pursuing could be for this community. The 40% to 80% response rates we saw in this early patient trial are a big deal, and we are working to prove out the efficacy in a larger sample in our ongoing Phase II study, the RALLY-MF trial. And we expect eventually to proceed to a pivotal trial. MF is a relatively rare indication with 25,000 patients in the U.S., but the need is clear, and it has been an important testing ground for us to understand how DISC-0974 and hemojuvelin suppression may work in the broader context of anemia driven by high hepcidin and inflammation, which is a complication of many chronic diseases. As we have discussed, we also have a Phase Ib trial ongoing in chronic kidney disease, a much larger indication of 37 million patients in the U.S., about 17% to 50% of whom are anemic. In the single-dose data we shared last year at ASN, we are already again seeing expected drug activity translating to iron mobilization and changes in hematologic parameters. So we're excited to see how that dataset matures with the multiple dose data later this year. Altogether, stay tuned for key readouts this year in our first two indications and look out for more to come in anemias of chronic disease. Now zooming back out to our broader portfolio, I'll remind everyone that we have several other important milestones expected this year. Notably, our planned NDA submission for Bitopertin in EPP in the second half of the year. We'll also be starting the first inpatient study for our third program, DISC-3405 in polycythemia vera in the coming months. And this is another exciting opportunity targeting a clinically-validated pathway. As we gear up for our first potential FDA approval, we are fully funded into 2028 to execute on the Bitopertin launch as well as advance the rest of the pipeline and potentially start to explore the next wave of development for our portfolio. Thank you all for joining today, and I will hand it over to the moderator for Q&A.

Certainly. And our first question comes from the line of Thomas Smith from Leerink Partners.

A question for both clinicians. I was wondering if you could just comment on what percentage of your patients are currently on momelotinib or pacritinib as a function of their anemia. And if you could just describe what proportion of those patients you think could still benefit from another agent like DISC-0974 on top of those agents? How many of the patients, I guess, in your anecdotal clinical experience still have residual anemia that needs addressing?

Tom, this is John Quisel. Thanks for the question. So why don't we hand it over to our panel, Dr. Bose, are you on? And do you want to go first?

Yes, sure. I'm on. Yes. Thanks for the question. So certainly, momelotinib and pacritinib are seeing increasing use. In my personal practice, momelotinib more so for anemia. I think of the two, it does a better job for the anemia. So I think if you're asking across my practice, which obviously means patients in different lines of therapy, right? So there's going to be frontline patients as well as second and third-line patients. I think momelotinib and pacritinib together could make up about 30% to 40%, let's say, with about 50% still ruxolitinib, and maybe 10% or so on fedratinib, I do have some patients on that. And these are my -- of course, only my JAK inhibitor patients. To be clear, there are other patients who don't necessarily need a JAK inhibitor and could be on something for really early MF or something purely for anemia. But coming back to the JAK inhibitor patients. So like I said, say, 50%, ruxolitinib; up to 10%, fedratinib; and then maybe 30%, momelotinib; 10%, pacritinib. Going with that, generally speaking, momelotinib in particular, usually suffices on its own for the anemia. However, as Will pointed out in his presentation, there are absolutely patients on momelotinib that require some more help with their anemia. And for example, in my current practice, I have patients on momelotinib and luspatercept. Same with pacritinib. So it's not always that those drugs in and of themselves are a fix for the anemia. So within the momelotinib and pacritinib patients, I think this was your -- really the second question -- I'm sorry.

Bose, you're okay. Please go ahead.

Okay. Sorry, this e-mail is coming through. I'll close that. So within the momelotinib and pacritinib patients, I would say up to 40% of them would need something else added. And this is, I think, largely because the use of these agents is often in second and later lines, when the disease is worse, the anemia is worse. And so I would say, yes, I would say up to 40% could need an anemia agent as a partner.

Great. Thanks. Dr. Gerds, did you want to add anything to that?

Thank you. It's great to be with all of you today. Thanks, Dr. Bose. That was a great explanation. And I agree that there is a dramatic need for this agent. And I think the fact of the matter is that at some point, even if a patient does have anemia response on pacritinib or momelotinib, at some point that they won't have a response anymore. I even had a patient on SIMPLIFY-2. They were on momelotinib for 8 years. And at that point, all of a sudden, the momelotinib was unable to support their anemia and they needed additional agents. So even if in the short term, there is a response to momelotinib or pacritinib, there will be some point in time where those agents don't support the anemia, and they will need something else. And I think it was brought up in the presentation, we're always trying to maximize JAK inhibition, and a limiting factor is always anemia. And I think an agent like this can help us maximize no matter what the JAK inhibitor is. So you could definitely see this partnering with other agents, other JAK inhibitors, of course, to really maximize that benefit. And I would even think beyond that, right? So there's all this interest now in combination therapies with imetelstat, all these other drugs, too. And a drug like this, the Disc compound here, would play nicely with others given the side effect profile and could be a valuable, say, triplet in combination therapy or in combination even with something like imetelstat that could stave off the anemia in order to deliver more effective therapies.

And our next question comes from the line of Roger Song from Jefferies.

Great. Maybe -- my question is a follow-up on the previous question. Understanding the patient, even there a new JAK inhibitor, they may still need anemia agent like Disc compound at some point. My question is, can the doctor -- to give us some sense of what will be considered as a clinical meaning for those different patient segments like a JAK inhibitor naive or those patients on top of different JAK inhibitors, including those first-gen rux and then [ momelotinib? ] That would be helpful.

Thanks, Roger. Dr. Gerds, do you want to start on this one?

Yes, absolutely. So as far as I understand the question, really, it centers around what's the value there. And I think I'm trying to wrestle with exactly what you're saying there. But I think -- again, there's a good value in treating this. I think a lot of times when we have a patient sitting in front of us, we're trying to address everything, right? So kind of part of our brain is looking at the spleen and symptoms. We're thinking JAK inhibitor, clinical trial, what have you. And the other part is like looking at, well, what are the more immediate consequences for the disease like cytopenias. And it's almost like two functions in our mind at once while treating a patient. And sometimes there are agents that can address both, right? Again, we've talked about pacritinib and momelotinib already. But really, there are almost two somewhat, I guess, independent functions. And we know we want to maximize that JAK inhibitor therapy, whether it's first line or second line or third line. But to address the spleen and symptoms with these patients will have, but we also think about anemia. And as I said in an earlier slide, virtually every patient over the course of their disease will develop anemia. And again, the therapies that we have available don't work for everyone, and they don't work indefinitely. So I would say that thinking broadly about this, there's a lot of opportunity there for new and better anemia-focused agents.

Dr. Bose, do you want to add anything?

Actually, could I request the person asking the question to clarify what exactly the question was? I thought it was maybe the added value or lack thereof over the JAK inhibitors. Was that the question?

Yes, I can clarify. Just in terms of different patient population, they are JAK naive or used on top of the current JAK will be the clinically meaningful for anemia efficacy for the Disc compound?

Okay. Okay. Yes. So as Dr. Gerds very nicely pointed out, something to remember in this disease is that we don't -- it's not a cancer that you approach as first line, second line, third line or by stage. In fact, there is no staging. We really focus on the clinical need of the patients. And as Dr. Gerds said, for many of our therapies, we know they do certain things well, but there are certain other things which are equally important that they do not do well or even worsen, right? So like in the context of ruxolitinib, amazing drug for spleen and symptoms, but actually worsens anemia. So I think you need this added efficacy across lines. You need it in frontline patients, but even more so in -- down the line. Now if you're asking what response rate would -- and I think that's how I understood your question, like you're probably wondering what response rate to the Disc compound or another compound for anemia would be clinically meaningful to us. Well, that is -- I think that it's hard to put that in numbers. But again, you obviously want transfusion independence. You probably at least want a hemoglobin of 8 or higher. I mean that's -- higher would be better. And you want to maintain that dose intensity, right, of your JAK inhibitor so that you're getting the maximum spleen response that you can because that is tied to survival. So you want to allow your JAK inhibitor to do what it does best. And obviously, the anemia is a big limiting factor that you're trying to counter with these drugs.

And our next question comes from the line of Kristen Kluska from Cantor Fitzgerald.

I think we spent a lot of our time thinking about how sometimes the current medications for MF tend to make the anemia effects worse. But I'm curious how addressing the impacts of anemia might potentially allow the other MF drugs to do a better job addressing the other symptoms of myelofibrosis that they are more targeted to.

Thanks, Kristen. And Dr. Bose, do you want to start this one?

Yes, sure. That's, actually, I think what I was just talking about, flows nicely into this in the sense that, again, the four JAK inhibitors are somewhat different. They certainly are not all the same in terms of their strengths and weaknesses. I think momelotinib's greatest strength is anemia, whereas with ruxolitinib, it is spleen and symptoms as well as with fedratinib. So the point being that we know with ruxolitinib, which is the most widely used JAK inhibitor, the only one with a demonstrated survival benefit that this drug requires an optimal dose or requires an adequate dose to be able to lead to the best spleen shrinkage, which then correlates with the best survival. So to that end, it is important to be able to deliver an adequate dose of ruxolitinib, which, in my view, is at least 15 twice a day, 20 twice a day, even better. And that is where these drugs, drugs that support -- that help the anemia and combine well with ruxolitinib could really help because, again, you're trying to optimize that efficacy. And also, I should mention that studies have shown that the most common reason for discontinuation of ruxolitinib is anemia. So it's a frequent problem. It is an on-target effect of ruxolitinib. It happens and obviously, it's a problem for the patient. It's a problem for the clinician in terms of transfusions, et cetera. And often ruxolitinib gets stopped or at least dose reduced. And that is impacting the long-term benefit, right? So that is where these drugs can be very good adjuncts.

Great. Thanks. Dr. Gerds, do you want to add anything?

Yes, absolutely. I would love to. A couple of things, kind of going back to the previous question, just to kind of emphasize the point. We have all these endpoints that are designed to capture a benefit in clinical trials. But quite frankly, I think patients benefit well beyond those measures. If a patient has a 30% reduction in their transfusion burden, say, they're coming in every week to get a transfusion. If you drop that to every 2 weeks or maybe even 3 weeks or something like that, although they're not transfusion independent, that is a huge improvement in their quality of life as well as resource utilization for our health care system. So I think there are subtle -- more subtle benefits beyond what our endpoints can capture. And then to pivot over to the benefit of supporting anemia to get other MF therapies in, we have the RR6 model, which shows three things pretty convincingly that if a patient is on 20 milligrams of ruxolitinib twice daily, is transfusion independent and has had a spleen reduction of at least 30%, those patients are going to do tremendously well. And as you start to tick away at those things, survival goes down. And so anemia supportive agent can help us to that end, right? So if we put a patient on, say, ruxolitinib, for example, they become anemic, we have to back off the dose. They might need transfusions. That's 2 of the 3 check -- boxes checked. But if we're able to put them on anemia supportive agent, ramp that rux up to 20 twice daily, get them free of an -- independent of transfusions, you would predict that, that person would do quite well going forward. And so I really think there is a big opportunity there to better our current therapies by adding in a strong performing anemia supportive agent.

Yes. That's a really helpful discussion. I'll just add, from our perspective here at Disc, interacting with regulators, the sense is that there's a view of anemia as being symptomatic, right? And as long as there's a symptom of the anemia, there's a strong desire to find a therapy for that. And we're seeing the regulators zero in on transfusions essentially as a consequence or symptom of anemia, which -- if that can be addressed, that's a clear endpoint and basis for progressing a program. And then they've also looked at things like fatigue as being a meaningful endpoint for patients who are not on transfusion. So that's been our experience so far with -- from the regulatory point of view.

Our next question comes from the line of Vikram Purohit from Morgan Stanley.

We had two, one for the company and then one for the clinicians. So for the management team, I know you mentioned that 0974, there's data flow in second half of this year and then 2026. Could you help us understand, I guess, the level of difference in the amount of data and the amount of detail we'll be getting from each dataset? And incrementally, how much more do you think the 2026 dataset is going to be able to tell us versus the initial data later this year? And then secondly, picking up on a comment that Dr. Gerds just made on kind of interpreting kind of emerging datasets. I'd be curious to hear from both clinicians, when you review the initial data from 0974 later this year, what specifically will you be looking for? And what are some of the -- I guess, what are the one or two most important takeaways that you kind of hope to walk away from after reviewing that data when it comes out?

Okay. Thanks for the question. So I'll start to walk through our expected data flow, and then I'll hand it over to the KOLs to talk through how to evaluate the data that we present on this program. So starting with data flow, actually, we have EHA just around the corner. We haven't guided to it as a major catalyst for the company, but we -- typically it's been our practice to provide some presentation there. And you can imagine that we won't be recutting the data from the main part of the study that we already presented at ASH, but we do have access to some long-term extension data. I can imagine there might be some presentation around that. Then looking towards the end of the year, where we typically present our MF program at ASH, although again, you can't commit to that until you've had a successful submission and acceptance process. But we'll find some avenue there at the end of the year to present. What we're saying will be just a simple data cut from the open-label ongoing RALLY-MF trial. In terms of exactly the number of patients across the three main cohorts plus the exploratory and full momelotinib cohort, we can't really provide more detail. You could ballpark it as roughly half the study, something like that. And then as we get into next year, that's when we're looking to provide the top line data from the full study cohort, which again is 30 patients in each of the cohorts plus the 10-patient exploratory. So that will be, I think, a very comprehensive dataset for Phase II in this disease. And our intention is that, that data set should form the basis for engaging in an end of Phase II meeting with the FDA and progressing to pivotal trials as long as the data hold up to show the same kind of quality we've seen so far. So with that, I'll hand it over to Dr. Gerds. Do you want to go first and talk about how you would -- I think if the question was, if you remember it after my long speech here, how you're going to evaluate the data from this program when it's released.

Yes. Thanks. That's a great question. And I think what we can always get in the first pass is kind of basically the established response criteria, right? Are we hitting those kind of hemoglobin increases at the predefined endpoints -- time points and just looking for that kind of signal of activity. I kind of was a little negative on some of the established endpoints because I don't think they capture all of the benefit that a drug may have for a given individual patient. But it is a nice shorthand to compare against other agents, right? That's what we're all going to do with human nature, right? We're going to compare this to ESAs, luspatercept, danazol, et cetera, just -- or elritercept, just to kind of get a sense of how is it compared to everything else. But the thing that I'm kind of looking forward to as well is kind of the -- in addition to those basic anemia responses with further -- with the initial data and then further follow-up data, how is it impacting quality of life? Is there any evidence there? And then lastly, in terms of the subsets of patients and how this is performing, right? So there may be with some medications, ESAs, I think, are the classic example wherein patients are just anemic versus not transfusion dependent and then transfusion-dependent to different degrees, there are different response rates. We see that a little bit with luspatercept as well and maybe or maybe not with our elritercept, but are there certain patients where this performs better or worse? Like if a patient is like super heavily transfused, is there still efficacy there? And kind of -- or is there any cutoff anywhere in terms of the degree of anemia that would predict a better or worse response. And so that to me would be kind of interesting as well and something I'm looking forward to seeing off the initial and primary endpoint of the study.

Great. Dr. Bose, do you want to add anything?

Well, I would say that as we try to think of benchmarks, right, like how to know where really to place the drug, that type of thing. Of course, as Dr. Gerds said, we're going to do that using the usual metrics, right, the rates of transfusion independence, the rates of 1.5 gram mean increase, as Dr. Savage was pointing out earlier. We're going to use those metrics, but we are going to maybe keep the luspatercept numbers in mind. Dr. Gerds and some of us published recently the Phase II study of luspatercept. So we have a sense. We have a kind of a ballpark sense of what rates of transfusion independence we have there, right? So I think that is -- that being a contemporary dataset, that is helpful that luspatercept gave you a 26% rate of transfusion independence, for example. And then we have the MOMENTUM trial where the comparator was danazol, the comparator to momelotinib was danazol. And that gives you a 20% rate of transfusion independence. So we've got some numbers there in our heads to use as possible benchmarks. And I think we're going to see -- obviously hope for greater efficacy. And then one other thing that I found interesting in the luspatercept data that, again, that I think we published last year is that there was a proportion of patients that were able to increase their dose of ruxolitinib. And as I was alluding to earlier, I do see that as a benefit. I see that as something that enables a better spleen response, which again is tied to survival. So I'd be interested to see what proportion of patients are, say, able to up their dose of JAK inhibitor because of the support that JAK is giving them.

And our next question comes from the line of Evan Seigerman from BMO Capital Markets.

Malcolm Hoffman on for Evan. Maybe a question for Dr. Gerds. We talked a lot about how anemia demonstrates this clear association with worse outcomes for patients. So it seems well defined that anemia is detrimental to MF patients broadly. I guess my question is, given this clear association, why do you think MF anemia has not been prioritized for drug development to date? Is it because the research is relatively new as far as the association with clinical outcomes? Or is it the availability of existing generics like EPO? Just want to get your thoughts there.

Super. That's a great and insightful question. I think there's a couple of reasons. One is due to the fact that, yes, there are some agents that are already available like EPO. Two, I think there's been -- there is this discovery of how we can manipulate various pathways in these cells to ameliorate anemia in new and creative ways. Now, EPO is kind of just a blunt instrument. And I would argue that danazol is probably the same thing, and that's what we had for the longest time. There was a look at immunomodulatory drugs as well to improve anemia. But none of these really kind of said, well, what are the key pieces that lead to anemia and myelofibrosis. And certainly, one of them is the anemia of inflammation and targeting that makes a whole lot of sense. And now we have the idea that we can target this pathway. We've seen similar -- drugs that are still going after this pathway and different mechanisms or different processes in order to go after this pathway have success. And we can build on that, right? And that's really, I think, the story that's evolving. It's kind of a recent discovery, recent proof of concept that's now parlaying into better agents, certainly not for a lack of desire or want, but there is more focus on this particular topic because I think we have new discoveries that are driving these new therapies to come to the surface.

And our next question comes from the line of David Nierengarten from Wedbush Securities.

I just had one on the nature of the patients in the Phase II. It was mentioned that the exploratory arm had the highest demand. And I was just curious if that's because those patients are perceived to have a higher need. Maybe they're later in their disease and there -- I was just curious if there's some different aspects of that patient population, the exploratory setting compared to the ones in the other arms.

David, this is Will. That -- I mean, we're interested in learning that, too. It's not information that we have. We just -- it's just an enrollment dynamic that has piqued our interest, and we'll have to look at the significance of that as the trial unfolds.

And our next question comes from the line of Frances Dovell from TD Securities.

This is Frances on for Tara Bancroft. So a question for both clinicians. In what ways does DISC-0974 differ from the erythroid maturation agents in development like luspatercept? And if both agents were available, what would you use in your patients? And what would dictate your choice?

Thanks for the question. Dr. Bose, do you want to start?

Yes, I'll take a stab at it. So the two -- I mean, they are mechanistically different, right? So the erythroid maturation agents, luspatercept and then before it, there was sotatercept, which has now gone in a different direction, into a different therapeutic area. And then there's elritercept coming. So these are essentially activin receptor-ligand traps that sequester ligands belonging to the TGF-beta superfamily, which suppress late-stage erythropoiesis, right? So you get rid of those ligands [indiscernible] them from -- to the activin receptor, and that is how you can suppress this -- or remove, I should say, remove the suppression that they would have caused of this -- of the terminal stages of erythropoiesis. So that's the idea there. Now the hepcidin story, I think, in my view, began with momelotinib. And Dr. Gerds was just alluding to this when he was answering the previous question that why all this interest now in anemia and why not earlier? And I think that's because we just understand certain things better now, which is that we learned from momelotinib again that if you block ACVR1, you down-regulate hepcidin. And if you down-regulate hepcidin, then the iron is just more available for the bone marrow to use. Less of the iron is sequestered and trapped somewhere in the reticuloendothelial system, as we call it, and just more of it is available. So that then led to the enthusiasm, I mean, with other agents like Incyte, for example, had developed an ACVR1 inhibitor for a while that they have now actually shut down. Pacritinib, they found that they hit ACVR1 kind of a late finding for that drug. So I think this whole hepcidin story evolves that way. And then coming to our Disc compound, obviously, this is the only one in its class where it's not using ACVR1, but rather hemojuvelin, right? So just a different way of down-regulating hepcidin, ultimately with the same goal. So I think the two classes, the hepcidin drugs and the activin receptor-ligand traps are quite different. But obviously, both are welcome as being new and proven, I think, by now mechanisms of improving anemia.

Thanks. Dr. Gerds, did you want to add anything?

Yes. I think to build on everything that Dr. Bose [indiscernible] here, both of these kind of classes of medications or broadly classes, I suppose, really work on this TGF-beta superfamily pathway, right? And you can actually start to conceptualize in your mind how they might be synergistic, right? So blocking, drugs like Disc and momelotinib blocking that kind of hepcidin pathway, it's actually working on the SMAD 1, 5, 8 pathway, which ultimately translates again into hepcidin transcription. And then on the other side, luspatercept or elritercept, sotatercept, they all work on the -- they're active in ligand traps, but they're on the SMAD 2, 3 pathway. So it's different kind of parts of a similar pathway that interconnect with SMAD 4 in the middle. So conceptually, like even combining these two, working them together, you might get some additive benefit. And then on top of it, if you think about it a little bit differently, too. So if you think about if we lower hepcidin levels, we're making iron available for erythropoiesis, if these maturation agents, if you will, are working on terminal differentiation at the proerythroblast stage, that's when they start needing the iron. That's where the iron is needed. And so you could see like these actually working together and synergistically almost in your mind conceptually. But they are working on different pathway, different subtle bits of the same TGF-beta superfamily pathway, the SMAD pathway. And I think that's what the exciting thing. And as Dr. Bose mentioned, this is all recent and -- relatively recent and new discovery that this is a key piece and part of the anemia story. And now we have therapies that -- the technology is caught up, and we have therapies that can actually get after these individual pathways that we've learned about.

And our next question comes from the line of Rami Katkhuda from LifeSci Capital.

Two from my end. I guess given the multifactorial pathogenesis of anemia and MF, is it known what percentage of patients have their low hemoglobin primarily driven by high hepcidin?

That's a great question. And I don't know if Dr. Bose knows any different, but to the best of my knowledge, there's no clear reason what the percentage is. Hepcidin is actually somewhat difficult to measure clinically. But ultimately, every patient's anemia is a little bit different, right? And that's why we need multiple agents kind of targeting different pathways, either working the best for that individual or in concert with others to improve one's anemia.

Yes, I completely agree. I am not aware of any percentage that one can quote as to how -- what percent they are dependent on hepcidin. But clearly, it's multifactorial. We know that. There's multiple reasons for anemia in MF. And certainly, it's only welcome to have different MOAs.

Makes a lot of sense. And I guess going off a previous question, we've seen the discontinuation of development for a couple of ALK2 inhibitors in MF anemia. I guess, can you touch on the mechanistic differences or maybe benefits [indiscernible] hemojuvelin just given that the two targets somewhat function along the same axis as you mentioned?

So yes, Rami, thanks for the question. Obviously, the Disc perspective on that, I'll provide our view and then look to our panel to provide some perspective as well. But we got into this with hemojuvelin because of the mouse and human genetics of this target where in both species, there are loss of function mutations where really the only phenotype is a severe or very substantial loss of hepcidin production that leads to a markedly increased availability of iron in the blood and then ultimately, over time, an iron overload disorder. So if you look at that pharmacologically, an antibody against that target should have a very selective and powerful effect in lowering hepcidin and leading to the mobilization of iron. And that's more or less what we've seen in the clinic to date. And in fact, just going back to your prior question, I think we view it as the answer to the question of how much of anemia and MF is caused by hepcidin, I think scientifically can be answered with our drug. It's highly selective, causes a dramatic reduction in hepcidin, probably whatever the response rates you see with the contribution of hemoglobin you see with our drug is going to pretty much tell you that is the contribution of hepcidin to anemia in this patient. So there's like an interesting scientific question there as our data matures further. But -- so that's our perspective, and I know you and many of the listeners know that very well. I don't know if Dr. Gerds, Dr. Bose, if either of you want to comment further on that.

Well, I think it's a great question. And I don't think I can answer precisely why hemojuvelin would be a better target than ACVR1 any more than what was just mentioned. And I do acknowledge that, for example, the Incyte ACVR1 inhibitor, a very potent drug, at least preclinically, was discontinued for relative lack of efficacy or somewhat disappointing efficacy. But I think maybe a little bit tangentially to that, I will say that the disappointment around that drug has led to some speculation around the efficacy of momelotinib. We have generally attributed the anemia benefits of momelotinib, which are undeniable to its ACVR1 inhibition, right? And the "failure" of the Incyte drug has led folks to wonder if momelotinib has benefit beyond ACVR1 that explain its efficacy. So I think it's all the more I welcome for a different mechanism to down-regulate hepcidin to be explored as we are looking at here.

And our next question comes from the line of Douglas Tsao from H.C. Wainwright.

I'm just curious, two questions for the clinicians. First, obviously, anemia is a reason why patients often have suboptimal treatment. Has that been quantified in any way in terms of what the impact or sort of how -- to the degree that outcomes are worsened? And then obviously, I think you mentioned sort of the different mechanisms that are now being under development and how luspatercept uses a different mechanism than 974. I'm just curious, you said they could potentially be used synergistically. But that said, if they're not, are there ways that you would think one mechanism might be better for certain patients and the other better for other patients?

Dr. Gerds, do you want to start?

Yes. Thank you for that question. A great insightful question. So thinking about the impact of cytopenias on delivery of JAK inhibitor, I think it's pretty significant. So we quote lots of stuff from the COMFORT study. And one of the examples is the median duration of therapy in the COMFORT study is, what, 3.2 years. When we look at some real-world analysis, it's much shorter. We did one particular pharmacy database analysis and found that the median duration of therapy was around 6.5 months for ruxolitinib. And in that particular analysis, we found that the doses of ruxolitinib were incredibly low. Most patients receiving 10 milligrams twice daily or less, I think it was roughly almost 60% of patients were on that low of a dose of ruxolitinib. So we know that anemia really contributes the biggest thing there. We've taken a look at a couple of other studies on that in particular. It's kind of tough without a well-linked database because you're linking pharmacy as well as lab records together. But another one we did with Cardinal Health, we did see that the most common reason for low dose -- lower doses of ruxolitinib was, in fact, cytopenias. Anemia, at least it was listed as -- and so certainly, there is a direct correlation there. And as Dr. Bose mentioned earlier, the lower the dose of the ruxolitinib, the less response that we get. And so it is a major limiting factor.

And our next question comes from the line of Greg Harrison from Scotiabank.

This is Teraesa Vitelli on for Greg Harrison. I have another one for the clinicians. Just wanted to know if you had an idea of what the average time to transfusion dependence is after non-transfusion-dependent patients are diagnosed. And given the data that we've seen thus far for DISC-0974, what sort of impact do you think it could potentially have on delaying disease progression as both a monotherapy and in combination with the JAKi?

Dr. Bose, do you want to start with that?

Sure. So in terms of disease progression, I'm not sure I think of DISC-0974 as truly delaying disease progression, but one has to be careful as to what one means by that, right? So for me, disease progression is the -- let's say, the blast increasing, the spleen getting larger, the disease sort of pursuing a trajectory towards accelerated and blast phase or AML, stuff like that, which I do not expect this agent to address. But going back to the anemia topic, if this were used preemptively, right, like, let's say, you were asking what's the time to transfusion dependence when a newly diagnosed patient, let's say, get started on therapy. So let's take ruxolitinib, again, till today -- till date, the most commonly used frontline JAK inhibitor, so that certainly gives you anemia very quickly in that 8- to 16-week time frame, that it's worse, sometimes once we say 12 to 24. But essentially, in that 3- to 6-month phase, the first 3 to 6 months, you get the nadir, and people can need a transfusion right then based on where they started, where their baseline was. Now if they started above 12, well, they probably will not get down that low, but if they started at 9 or 10, they well might. So one concept is to like preemptively treat with anemia drugs, like just start off the bat with rux and an anemia drug. So in that sense, something like DISC-0974 could absolutely very significantly delay the need for transfusion because there is disease-induced anemia and there is drug-induced anemia. So -- and those two are different, right? So the disease-induced anemia will occur at some point. But obviously, if you're supporting it with an anemia drug that will probably happen later. But the drug-induced anemia from rux would be easier, in my view, to reverse and prevent from becoming a problem.

Thanks. Dr. Gerds, do you want to add anything?

I think that's a fantastic explanation. I don't think I have anything else to add.

Our next question comes from the line of Stephen Willey from Stifel.

Just curious, I guess, of the 22,000 prevalent anemic MF patients that was referenced earlier, do we know what proportion of those patients kind of fall into that TD High or higher bucket that is currently being targeted right now in the INDEPENDENCE trial via luspatercept? And I just have a follow-up.

Yes. I'll start briefly and then Pamela can chime in. But we have a general sense of the percentage of patients that are receiving some degree of transfusion. It's always a little tricky to kind of cut that down to the precision of a clinical enrollment criteria. I believe that study with luspatercept is using 4 units in 12 weeks as a cutoff for entry. I think our general assessment is that that's a smaller portion of the patients who are receiving some degree of transfusion. I don't know -- maybe actually I'll ask the KOLs whether you have any perspective on that from the patients that you see once people start needing transfusion, are most of them being heavily transfused? Or do a lot of them sit in the kind of occasional transfusion status?

Yes. I would say that most of them kind of sit in that occasional transfusion range, especially -- I don't have any data to support this, but it certainly is a clinical anecdote that seems that patients who are started on a JAK inhibitor and have relatively soon the development of a need for transfusions. It's kind of this -- that state. The heavily transfused patients typically as someone who has received one or two lines of therapy already of JAK inhibitors and have a longer time from diagnosis where their bone marrow is more dysfunctional. I would also kind of go out on a limb there, there is this kind of developed idea of cytopenic myelofibrosis where that's a population of patients that have lower driver mutation alleles. They have higher numbers of second and third and fourth mutations, often more likely the primary myelofibrosis versus secondary myelofibrosis. I would say those patients are much more heavily transfused than someone who has a more simpler disease like maybe just a single driver mutation with no other mutations, maybe a post-PV, post-ET myelofibrosis patient as well. So there's certainly a flavor to those things. But I really don't have a good sense on like a larger epidemiologic scale, the proportion of patients that are heavily transfused per the inclusion criteria. I think the other shred of evidence that it's probably a smaller proportion than the occasionally transfused or less transfused is the fact that it's taken INDEPENDENCE quite some time to enroll patients, finding the right patients for that. So again, it's a mix of things. And when you add in the longitudinal aspect of the disease that every patient who is getting some transfusions will eventually be fully and heavily transfusion dependent unless they get a transplant, I think the need is still there to treat those patients.

Great. Thanks. Dr. Bose, do you have any additional perspective?

I just want to emphasize that this is extremely heterogeneous, right? So now if you look at INDEPENDENCE that was mentioned in the question, I'm sure the INDEPENDENCE population reflects both drug-induced and disease-induced anemia, right? So I think both pieces are operating there because they require patients to be on a JAK inhibitor stable dose, mostly ruxolitinib or fedratinib, I believe, and require transfusion. So there is the aspect of the drug, which I consider a more artificial anemia and also the real disease-induced anemia. And then also, as Dr. Gerds said towards the end, preliminary [indiscernible], there is a report that says that 50% become transfusion dependent within a year. Now that's a high number. I was a bit surprised by that number. I didn't think it was that high. But there is a report out there, a large dataset that says that. But then post-PV and post-ET MF are quite different, and they are not going to become as transfusion dependent. So there are many pieces, moving parts to this.

Okay. That's helpful. And then just curious, I don't know if the clinicians or the company wants to chime in on this, but what do we know about the role of hepcidin in low-risk MDS. And I know the biology is a little bit messy. I think some of these patients who have these splicing mutations might already be hepcidin suppressed. But just curious if you think that there might be a role for this drug in low-risk MDS in terms of addressing anemia.

Yes, it's a great question. So actually, there is an open cohort of patients to explore the effect of this drug in MDS patients. What you're saying about the relative hepcidin levels, it's generally been reported that patients with SF3B1 mutations who are commonly called ring sideroblasts-positive patients tend to have a lower hepcidin level and therefore, on its molecular face, you might guess a less advantageous target for a drug like DISC-0974. That's probably why we started in myelofibrosis because we know if the disease is generally high hepcidin where our drug would be correcting a part of the molecular pathology of the disease. But MDS is quite heterogeneous and there are patients who do exhibit elevated hepcidin. And there are also patients who have kind of a mixed myelofibrosis, MDS genotype and disease characteristics that may also be an interesting target for the drug. So I think we'll get some data out of that cohort over time. We haven't made any commitments around when that data will become available. I don't know -- Will, did you want to add anything to that? Or does that cover everything?

No, I think that covered everything.

Okay. Great.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to John Quisel further remarks.

All right. Thank you. Well, a huge thank you to our two panelists today, Dr. Gerds and Dr. Bose. Really appreciate the time you spent to help educate all of us on these topics. And thank you also to those of you listening and joining in and asking questions. I hope this was an informative program for everyone, and we look forward to providing data. As we said, perhaps coming up soon at EHA and certainly as we come in towards the end of the year, hopefully, at ASH and on to next year. So thanks again for your attention, everyone.

Thank you.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.