Ladies and gentlemen, thank you for standing by. Welcome to the Disc Medicine Corporate Call at EHA 2026. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question- and- answer session. To ask a question during the session, you will need to press star one one on your telephone, and you will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to John Quisel, Chief Executive Officer. Please go ahead. Good morning. Welcome to the Disc Medicine management call. This is John Quisel speaking, CEO here at Disc. I will be joined by Will Savage, our Chief Medical Officer, and Jonathan Yu, our Chief Operating Officer, to review the data presented at the European Hematology Association conference in Stockholm this past weekend, as well as data from our oral presentation at ASCO earlier in the month. Before we get started, I will cover a few preliminaries. We will be making forward-looking statements. 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. Turning to the agenda, I will give a brief introduction and provide a status update on bitopertin, reviewing the results of our Type A meeting with the FDA. We will get into the EHA updates. Will present updated data from HELIOS, the open-label extension study for bitopertin in EPP, as well as an updated data cut from our phase II RALLY-MF study of DISC-0974, which now has an approved non-proprietary name, selcodebart. This trial is in patients with anemia of myelofibrosis. We are very excited about these data because, as you will see, the results continue to indicate that selcodebart is a potentially transformative treatment for patients with anemia of MF. Jonathan will provide some commercial perspectives on the MF anemia market. Finally, Will discuss our third program, DISC-3405, providing an overview of our vision in iron restriction and study designs for the first two inpatient studies in polycythemia vera and sickle cell disease, for which we will present data later this year. I will close with a review of the company's catalysts for the rest of 2026. Here is a quick reminder of our pipeline, which most of you are familiar with. We have bitopertin, which is in a phase III study for patients with EPP. Our second program, selcodebart, or DISC-0974, is targeting anemias of inflammation generally. We have ongoing studies in anemia of myelofibrosis and anemia of inflammatory bowel disease. Our third program, DISC-3405, is an anti-TMPRSS6 antibody, which we are currently studying in polycythemia vera and sickle cell disease. Here are some of the key messages for today's call. For bitopertin, as we shared a few days ago, we successfully completed our Type A meeting with the FDA to review the CRL. We're happy to say that the FDA is aligned that the results of the phase III APOLLO study can serve as the basis for our CRL resubmission, which we expect to happen by the end of this year. We also shared an update at EHA from the HELIOS open-label extension study of bitopertin, which continued to show sustained reductions in protoporphyrin IX for over one year, which translated to sustained and significant improvements in light tolerance measures, all with a favorable safety profile. For selcodebart, we shared updated data from our phase II RALLY-MF study showing meaningful, durable overall anemia responses across all patient subgroups, regardless of baseline transfusion status and independent of concomitant JAK inhibitor use. We also saw evidence of symptom improvement on several PROs, including FACIT-Fatigue and TSS50. We find this very encouraging and feel it supports the potential of selcodebart to treat a broad range of anemic MF patients. Finally, for DISC-3405, our clinical trials in PV and sickle cell are ongoing, with initial data to be shared in Q4. We'll go into details around these updates, starting with bitopertin. As I mentioned, we are happy to share that we had a productive Type A meeting with the FDA. In this meeting, we confirmed alignment that APOLLO can serve as the basis for our CRL response. If all goes well, we would now be looking at a traditional approval rather than an accelerated approval. As a reminder, we completed enrollment of APOLLO in March and expect to share the top-line data from the study in Q4. Then we will use that data to support our CRL resubmission by the end of the year. In the meantime, we have also launched an expanded access program for bitopertin and are continuing our commercial preparations to be ready for a potential launch in the middle of next year. I'll now hand it over to Will to walk through the HELIOS data presented at EHA. Thanks, John. As a reminder, HELIOS is our open-label extension study for bitopertin. We will be sharing data here from the 86 patients who rolled over into HELIOS from the phase II BEACON and AURORA studies. Looking at the PP9 data, we see that PP9 reductions seen with bitopertin treatment are sustained for the duration of HELIOS, including patients who now have over one year of follow-up. As a reminder, the start of the HELIOS study includes patients on a mix of 20 and 60 mg doses. Then ultimately patients transition to 60 mg, which is a reason there's a slower decrease in PP9 compared to those who are on 60 mg for the full study. What is notable here across all patients is the durability of the PP9 reduction, which we are now showing is maintained for over one year. We also, for the first time, shared light tolerance data for the HELIOS study. The frame of reference for light tolerance is the first day of HELIOS. Note that some placebo patients had already started bitopertin in an inbuilt extension in AURORA. Importantly, all patients continued to experience significant improvements in light tolerance, those previously on bitopertin and those previously on placebo. This shows that the sustained reductions in PP9 with bitopertin continue to translate into improvements in EPP symptoms over the long term. We are also encouraged that the safety profile of bitopertin continues to be favorable, with over two and a half years of drug exposure in some patients. All SAEs and TEAEs were reported as unrelated to study drug. All other TEAEs were mild or moderate in severity. We also saw the rate of dizziness decrease in HELIOS as compared to AURORA, adding to the evidence that any dizziness side effect tends to be transient. Overall, a great data set coming out of HELIOS on long-term use of bitopertin, with sustained reductions in PP9 and improvements in light tolerance, all with a favorable safety profile. As John mentioned, we are also currently conducting our phase III APOLLO study, which we expect to serve as the basis for our CRL resubmission. A reminder, this study is being conducted in the U.S., Canada, U.K., Europe, and Australia, with primary endpoints of PP9 reduction and average total monthly time in light at the end of study. We designed the study with an initial sample size of 150 patients, providing 80% power with conservative assumptions. Now that we have expanded the sample to 183 patients, it has even greater power, it is really a robust study. We completed enrollment for this study in March of this year and expect top-line data in Q4 this year. Now that the study is fully enrolled, we also wanted to share the baseline characteristics for patients in our APOLLO study. You can see we have strong adolescent representation with 34 of our 183 patients being under the age of 18, which we think emphasizes the level of unmet need in these younger EPP patients. In terms of baseline light tolerance measured as time to prodrome, the patients are split evenly between those with a baseline time to prodrome of above or below 30 minutes. Geographically, we have good global representation with 45% of patients coming from the U.S. and 55% ex-U.S., with 72% located in northern sites and 28% at southern ones. We also had fairly even distribution of seasons in which patients entered the APOLLO study, with the greatest number of patients randomized in the winter and spring. Overall, these baseline characteristics are typical of the EPP patient population and are similar to those in our phase II studies. Now I'll hand it back to John to talk about bitopertin. Thanks, Will. We're excited to share these updates on bitopertin, and we know this program is on a lot of folks' minds, and so we'll have the APOLLO data in a few short months in Q4. I think our biggest update today is actually in our RALLY-MF trial with selcodebart. Selcodebart is our monoclonal antibody that suppresses hepcidin, which as a reminder, is a master regulator of iron. We are exploring this drug across a broad range of anemias, leading with the RALLY-MF phase II trial in anemia of myelofibrosis. We presented initial data from RALLY-MF at ASCO last year, which showed anemia response rates that are unprecedented in this population. Anemia in myelofibrosis is a severe consequence of the disease that has no approved therapy and has been resistant to treatment despite decades of research. The emerging profile of selcodebart in the RALLY-MF trial suggests that we may finally have a meaningful impact on this form of anemia. The trial is progressing well. As we presented at ASCO a couple weeks ago and at EHA this past weekend, we are encouraged to share that the anemia response signal has been strengthened and solidified with additional enrollment and longer follow-up. I'll hand it over to Will to go through the details. In this update, we are looking at data through April on 61 patients across the non-transfusion dependent, or NTD, TD low, and TD high cohorts. I'll call out in particular the TD high cohort, which had only three evaluable patients at the last data cut. Today's update is a meaningful update for that group. Looking at the pharmacodynamics, as expected and consistent with prior results, we see significant decreases in hepcidin and increases in serum iron. This translates into remarkable hematologic response across all cohorts With 50%, 56% of all patients achieving a major response and 72% achieving an overall response. Going cohort by cohort, I'll start with non-transfused patients. On the right-hand panel, you can see there were early, meaningful, and durable hemoglobin increases. This translated into major response rate of 55%, defined as a 1.5 g/dL increase in hemoglobin maintained for 12 weeks, and an overall response rate of 68%, defined as a 1 g/dL hemoglobin increase over 12 weeks. For TD low patients who tended to have a lower baseline hemoglobin, the hemoglobin increases were strong and durable across the board. 64% of patients achieved a major response of transfusion independence over a period of 16 weeks, and 73% reduced their transfusion burden by 50% or more. Finally, for the most heavily transfused patients, 50% achieved transfusion independence over 12 weeks and 88% achieved a transfusion burden reduction of 50% or greater. We also looked at several patient-reported outcomes to further characterize the clinical benefit of anemia improvement. We saw marked improvement in the FACIT-Fatigue score in the NTD and TD low groups, which was correlated with hemoglobin change. An increase of three points on FACIT-Fatigue is considered the threshold for clinical significance. Among NTD and TD low major responders, 50% of patients achieved a 50% decrease in the MPN-SAF total symptom score. Hemoglobin improvement was also tightly correlated with improvement in patient global impression of severity. Importantly, we permitted patients to enroll who were not taking a JAK inhibitor or who were on a stable dose of any JAK inhibitor. The pharmacodynamics and hematological response remain consistent across all background therapies, positioning selcodebart for broad potential use in any patient with MF and anemia. Note that the pacritinib line in yellow represents one patient who held drug due to normalization of hemoglobin, and that's why the curves are variable. Finally, looking at safety, selcodebart continues to be generally well-tolerated with no serious treatment-related AEs. Overall, we are very excited about this data set, where selcodebart continues to show strong responses across a broad range of patient types with anemia of MF. Now I'll hand it over to Jonathan to review the MF anemia market. Thanks, Will. Based on the strength of this data update and the significant need for treatments for anemia of MF, we believe selcodebart represents a blockbuster opportunity in this indication. To give you a sense of the magnitude of today's market, current sales of JAK inhibitors in the U.S. for myelofibrosis comprise around $2 billion annually and continue to grow. This reflects patients who are presently receiving treatment with these agents. It's important to remember that while JAK inhibitors are a mainstay of treatment to control symptoms and reduce spleen size in MF patients, they do not treat the anemia. In fact, this class of drugs is often associated with worsening anemia. Beyond these patients is a large prevalent segment of MF patients who are also anemic but not receiving JAK inhibitors. This can be due to a variety of reasons, but often it is because their anemia precludes them from treatment with these agents. Our data suggests that selcodebart has the potential to address both these groups, anemic patients on or off JAK inhibitors, which combined represent about 22,000 addressable anemic MF patients in the U.S. alone. When you consider the severity and difficulty of treating anemia in MF, we believe this implies a total addressable market potential greater than $4 billion for just the U.S. So this is a very meaningful commercial opportunity, and we believe selcodebart could become a preferred option for these patients. If we move to the next slide, we believe that is because our emerging product profile continues to check all the boxes for meeting the key needs in anemia therapy. We think of this along three critical dimensions. First is selcodebart's potential utility across patients independent of whether they are non-transfused, lightly transfused, or heavily transfused. This update shows that we are seeing strong, similar rates of hematologic responses across each of these different groups. Second is its potential utility across patients independent of background therapy. Again, we are seeing strong similar rates for selcodebart as both monotherapy and in combination with JAK inhibitors. Because JAK inhibitors can worsen anemia to the point of requiring dose reduction or even discontinuation, addressing the anemia with selcodebart could enable optimal treatment with JAK inhibitor therapy. This breadth of activity is a differentiating attribute of selcodebart, and we believe will enable its use across the spectrum of MF patients with anemia, including in the frontline setting, together with the current standard of care of ruxolitinib. Finally, even with a larger data set and longer treatment duration, we continue to see very high hematologic response rates, major responses of 50%-68%, and overall responses of 64%-88%. The magnitude and quality of the responses, together with the fact that this improvement is palpable for patients, is extremely encouraging and we think will set the bar for efficacy in treating anemia in these patients. Now I'll turn it back over to John to discuss how we are thinking about applications beyond MF. There's a lot to be excited for on the MF front as this data set evolves. I want to remind everyone that we view this mechanism as potentially broadly applicable across a range of anemias of inflammation driven by high hepcidin. In a mouse model of inflammatory bowel disease, we saw that selcodebart suppresses hepcidin and increased iron and hemoglobin, and we even saw signs of disease modification and anti-inflammatory activity in this model. Based on this data, we initiated a phase II trial in anemia IBD earlier this year. We've started dosing patients, and we expect to present some initial results next year, which will be an exciting indicator of the broader selcodebart opportunity. To recap, we expect to bring the RALLY-MF data to the FDA by the end of this year in preparation for pivotal trial initiation in the first half of 2027. Meanwhile, we are advancing in the clinic in IBD, continuing to explore ideas around next indications, and in the background, we're progressing a long-acting anti-hemojuvelin antibody towards IND. Lastly, I want to touch on our third program, DISC-3405, which will have some exciting updates as we come into the end of the year. As a reminder, DISC-3405 is an anti-TMPRSS6 antibody, which increases hepcidin and limits iron availability. This has therapeutic applications in diseases associated with excess red blood cell production, like polycythemia vera, and also potentially in the treatment of sickle cell disease, as well as other indications where iron overload may be an issue for patients. We presented healthy volunteer data at ASH last year, which showed this mechanism is working as expected, and we have now advanced into two inpatient studies in PV and sickle cell disease. We have also explored DISC-3405's potential role in treating conditions of iron overload, as shown in our iron pulse study presented last year, and we are continuing preclinical work in some of these indications. This slide is a brief reminder of our healthy volunteer data for DISC-3405, which demonstrated the drug's ability to significantly increase hepcidin and decrease iron availability. This led to decreases in hemoglobin and hematocrit, which are expected to be beneficial in conditions like PV. DISC-3405 is an exciting growth driver for Disc, offering a differentiated product profile starting in PV, which has been de-risked to a certain extent and represents an attractive market opportunity. PV is a larger orphan indication with around 150,000 U.S. patients, half of which are treated today, with plenty of room to grow. This is a serious disease with uncontrolled hematocrit leading to significant risk of potentially life-threatening thrombotic events, among other debilitating symptoms. Many patients are not achieving optimal hematocrit control with current treatments. The hepcidin mimetic rusfertide has shown great results in PV, achieving significant phlebotomy-free hematocrit control and improving negative symptoms associated both with the disease itself and with the iron deprivation that is caused by frequent phlebotomy. If this product is approved, it should open up the market for hepcidin-pathway-targeting agents in PV. Then we believe we can improve on that profile with a monoclonal antibody that is dosed less frequently and has shown favorable safety and tolerability and a low rate of injection site reactions to date. Importantly, there is also significant synergy here with our MF program, and this synergy has already benefited both programs in terms of clinical development efficiency. These two programs together form the start of a strong MPN or hem-onc franchise. Here I'll hand it back to Will to discuss our initial phase II PV trial. Here's a look at our phase II PV trial, which we are calling RESTORE-PV. This is an update from what we have shown previously. In the early days of the trial, we saw such strong interest in enrollment that we amended the protocol to increase the siz e to 40 from 20, with 20 patients in cohort A and 20 patients in cohort B. Cohort A has a dose escalation period before moving into maintenance periods, dosing DISC-3405 at 300 mg every two weeks. Cohort B will receive dosing of 300 mg every four weeks for the entire study period. We'll be focusing on safety, PK, hepcidin, iron, hematocrit, and phlebotomy rate, and expect to present initial data in Q4 this year. Enrollment is well underway, and baseline characteristics of the trial population, which you can see on our EHA poster, are generally consistent with comparable PV trials. In addition to PV, we have been investigating other indications in which DISC-3405 could be beneficial. One such indication is sickle cell disease, where there is a growing body of literature supporting the potentially disease-modifying effects of iron restriction, either through phlebotomy or dietary changes. We conducted a preclinical study in Townes mice to test whether iron restriction through weekly doses of DISC-3405 could have a beneficial effect. In our study, we saw that treatment with DISC-3405 led to reductions in red cell hemoglobin S concentration, improvements in markers of inflammation, and improved hemolysis markers. These data are encouraging and open up the possibility of sickle cell disease as an interesting indication for DISC-3405. Here is our phase Ib sickle cell trial design. The main cohort of 12 participants will include patients with hemoglobin SS and hemoglobin SC genotypes. There will be 20 weeks of dose escalation from 75 mg- 300 mg, followed by an optional maintenance period. We're measuring safety, PK, hepcidin, iron, hematologic parameters, and hemolysis markers, and we'll explore additional efficacy endpoints, including PROs and clinical endpoints. We expect to present data in Q4 as well. Now I'll hand it back to John to wrap up. Thanks, Will. Overall, this represents another exciting set of updates at these mid-year conferences of ASCO and EHA for our programs, and with more catalysts to come in the second half of the year. We continue to execute across all three programs and expect a steady cadence of value-driving milestones through the remainder of the year. For bitopertin, we have aligned with the FDA on our CRL response strategy and continue to generate encouraging long-term clinical data. We expect APOLLO top-line results in the fourth quarter ahead of a planned NDA resubmission by year-end. Selcodebart continues to demonstrate strong activity in myelofibrosis with additional data and regulatory interactions anticipated later this year. DISC-3405 advances in both PV and sickle cell disease with initial patient data expected in the fourth quarter. With approximately $730 million in cash and runway into 2029, we are well-positioned to advance our portfolio and deliver on these upcoming milestones. To summarize, we feel we have three strong programs here, each of which has blockbuster potential in the initial indications alone. For bitopertin, we have been pushing forward with our regulatory and commercial activities as I covered today, and we look forward to delivering this potentially transformative therapy to EPP patients soon. For selcodebart, we are continuing to build on our foundation of strong data and progress the program quickly in myelofibrosis, which is, we expect, an over $4 billion opportunity on its own, while also building towards the broader opportunities in other anemias of inflammation. For DISC-3405, we are excited about the opportunities in PV and sickle cell disease, and we look forward to seeing our first inpatient data later this year. A lot of excitement to come as we head into the end of the year. With that, thank you for joining, and I'll hand it back to the operator for Q&A. Thank you. As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. The first question comes from Thomas Smith with Leerink Partners. Your line is open. Hey, guys. Good morning. Thanks for taking the questions and congrats on the data and all the progress here. Just starting with bitopertin. Any additional color you could share from the Type A meeting with FDA on APOLLO and what was discussed there, specifically with respect to alignment on the trial size and co-primary endpoint and how you're defining that time and daylight co-primary endpoint? Was there any discussion on a potential to resubmit prior to the APOLLO top-line data? Hey, Tom. Yeah, thanks for the questions. I'll start at the back end of what you asked. As we've been saying for months now, really since the CRL, we're delighted that the APOLLO trial has enrolled as quickly as it did. That means the data is coming pretty soon. I think that creates a situation where getting regulators to agree to approve the drug without the benefit of seeing that data is just impossible. We've been guiding everyone all along, don't count on that, and nothing coming from that Type A meeting would suggest that we'll get approval based on phase II data, essentially reversing the CRL. The path here is really crystal clear. Deliver the APOLLO data and then follow the traditional approval path. In terms of the discussion around the trial design, et cetera, we had thorough discussions with the FDA back when we set that trial up in the end of phase II process. There's nothing. We're just looking to deliver that data essentially as designed in the fourth quarter. Great. That makes sense. If I could just sneak in a quick follow-up here. With respect to the bitopertin expanded access program, just talk about the rationale there. Was the decision to initiate that program driven by patient and clinician inbound interest, or is there anything you can share from the early experience here, perhaps in terms of patient numbers and how you think this could play into the broader commercialization strategy? Thanks so much. Yeah. We're really excited about the expanded access program. I think if you're on social media, the frustration from the patient community around the lack of availability to bitopertin now as was expected was really disappointing. We wanted to try to find a way to make the drug available to as many people as we can for compassionate use. Glad to see regulators also appreciated the importance of that. It's pretty straightforward to set that up and kind of obvious that we should. Just as a bit of a warning, we are also keeping the enrollment criteria for that consistent with the clinical trial, just to make sure we maximize our chances of approval with a clean data set for APOLLO. It's not going to be wide open to everyone, unfortunately. That's going to have to wait until after formal approval. At least we're able to get it to as many people as we can who would otherwise have qualified for the trial. Got it. That makes sense. Thanks, John. Congrats again on all the progress here. Thanks, Tom. Thank you. The next question is going to come from Kristen Kluska with Cantor Fitzgerald. Your line's open. Hi, good morning, everybody, and congrats on all the updates. Going to be a very exciting few months coming up ahead. First on MF anemia, I'm curious about the commercialization aspects. Do you expect that one or a few of the subpopulations is going to lead to the most initial uptake, where that experience could then make physicians more comfortable to expand into others? Do you think from the get-go, there's going to be a little bit of uptake everywhere? Yeah, thanks, Kristen. Based on our clinical trial enrollment, if that's a kind of crude measure of demand and patient need, we're going to see it across the board. It just seems to be something that physicians and patients are looking for, regardless of their status. I think people gravitate to the obvious use case where someone's going to go onto ruxolitinib or another JAK inhibitor that's expected to exacerbate anemia. The idea of either in advance of that or. Okay, thanks. And then, for bitopertin, can you talk a little bit more about the seasonality? We've been getting questions on this, particularly the patients enrolled in regions where it's winter. What do you expect the impact of the sun is in that season? Also, will this mitigate the amount of time spent in sunlight? Yeah, thanks, Kristen. Sorry, I think I accidentally hit the mute button there while I was talking. Will, do you want to handle this question? Yeah, sure. I think the most important thing to note is that the AURORA trial had patients exiting throughout the year, at all seasons, including fall, winter, and starting in fall and winter. The result from there showed no effect on the time in light endpoint in terms of bitopertin always being superior to placebo. It is true that there are fewer daylight hours in winter and the time in light does go down in winter, but it remains greater in the bitopertin group. When we look at APOLLO, we have people in the U.S. exiting at all times of the year. When you look at ex-U.S., those sites got started later. Essentially they all started in the fall and winter, meaning that they are all exiting in spring and summer. Essentially half of the study in the geographies where we did not have experience in AURORA are essentially synced up. Thank you. Thank you. The next question will come from Roger Song with Jefferies. Your line is open. Hi, guys. This is Cha Cha on for Roger. Congrats on all the data and all the updates and thanks for taking our question. Just one question from us on the RALLY-MF data. Just wondering if any of this new data influences anything about your future trial designs for inclusion, especially for TD high patients as you go forward? Yeah, thanks, Cha Cha. Absolutely it does. I think now we have real indication that the drug works across the full spectrum of patients. We're pretty motivated to design a phase III program that will capture and include all of those patients with the goal of getting the broadest possible label and making this drug available to as many patients as possible with this disease. Okay. Wonderful. Thank you. Thanks. Thank you. Our next question is going to come from Tara Bancroft with TD Cowen. Your line's open. Hi. Good morning. I know it's been a pretty busy EHA across the board. I'm curious if you have any updated thoughts on competitive positioning or even plans for expansion of combination cohorts in MF, perhaps even with other investigational drugs. Because there were other updates in the MF space at EHA, especially from CALR, which it does look like it degraded a bit but still looks better than momelotinib. Just curious to hear what you think happened there and how this changes, if at all, the utility of selcodebart. Thank you. Yeah, thanks, Tara. Broadly speaking, I think no. Obviously there is a lot of action. I think we see what I'll call the activin ligand trap class of drugs with luspatercept and sota tercept both reporting data and leaning into efforts to get approval in MF patients. I think there the key points are that there's almost very little overlap between the type of patients they're trying to treat. They're generally taking aim at the very high transfusion burden patients who are also on ruxolitinib. That represents some pretty small fraction of the patients that we're either studying or that even exist in this population. We see those as kind of a sequester set of drugs, and obviously we'll have to see how it all comes together from their safety efficacy profile, given the miss primary on luspatercept. That's that class. CALR, yeah, I mean this is super exciting for patients. It's great to see these antibodies targeting a driver mutation. Here we're talking about a quarter to maybe 30% of MF patients overall, who by the way, are sort of underrepresented in the anemia population because that driver mutation tends to focus its effects in the platelet compartment. Not clear how much that's really going to affect who needs anemia therapy. We see effects on hemoglobin with those drugs in those patients. Again, kind of need to wait and see how it all settles out when you look at response rates, et cetera. My guess is a large number of those patients will still be looking for example, a combination with selcodebart to manage their anemia. Which I guess comes back to where you started about would we run combination trials. Yeah, we'll see. That is entirely possible that we could do some additional sort of small trial work while we're running our phase III program. Yeah, let's get through our end of phase II meeting, then we'll update on those things. Understood. Yeah. Thank you so much. Thanks. Thank you. The next question will come from Evan Segerman with BMO. Your line's open. Hi, Malcolm Hoffman on for Evan, thanks for taking our question. Can you touch again on the importance of the change you saw in that FACIT-Fatigue score for selcodebart? I know you mentioned a three-point change could be clinically significant here. Given the results we saw here for the phase II, how do you think about the importance of FACIT-Fatigue for potential approval if included in the phase III? Thanks. Yeah, thanks. It's certainly a precedented endpoint for anemia studies. Will, do you want to comment further on that? Sure. FACIT-Fatigue is one of the many PROs that we're administering in the phase II. The past experience with FACIT-Fatigue in a number of different settings has shown that an increase in three is a kind of a consensus clinically important difference. There's a spectrum there, the greater the change, the clearer the benefit. People have gotten demonstrated benefit with less than three. We just picked three as the dotted line on the figure to just pick the most commonly cited threshold in the literature. I think at all levels, it's clear that there's benefit on the PRO and for the phase III, I think this is more applicable to the NTD and perhaps TD low groups because the improvement in the FACIT-Fatigue is related to the delta in the improvement in hemoglobin. Those with higher transfusion burdens, it's more about reducing transfusion burden than increasing hemoglobin. Appreciate it. Thanks, guys. Thanks. Thank you. The next question will come from Stephen Willey with Stifel. Hold your lines open. Hello, this is Carolina Ibanez on for Steve. Thank you for taking our questions and I echo the congratulations on all your progress. Related to DISC-3405, post hoc analysis of the phase III VERIFY study show an elevation of platelet counts when the dose of cytoreductive therapy hydroxyurea is reduced in the patients who are receiving rusfertide. What do you think the implications for drugs impacting hepcidin are in clinical practice? Do you think that they can be dosed without hydroxyurea? Thanks for the question. Regarding kind of the effects of rusfertide on platelets, particularly in relationship to hydroxyurea use. Will, do you want to comment on that? Sure. Many patients are managed with their PV without hydroxyurea. It is described that iron restriction can increase platelet count. I think the question is what is an important increase in platelet count? I think what you see with iron restriction approaches that for the vast majority of patients, the increase in platelet count is not considered clinically meaningful. It's measurable, but it doesn't meet a threshold of clinical significance. I think that when you look at the population in all of the PV trials that are going on, I don't think there's a need to change the additional therapies, interferon, hydroxyurea, or phlebotomy alone. I don't think the platelet count changes themselves would change the landscape of PV treatment. Yes, thank you. If I may ask another question on this program. There was also initial data presented in a set of Chinese polycythemia vera, by Jordan Lesser of DISC-3405. Can you confirm if the molecule they use is similar to a very close iteration of DISC-3405? If it is the case, how do you think this Chinese data set can be extrapolated to the ongoing phase II RESTORE trial? Will, you want to take that? Sure. Yeah. The Mabwell poster that was presented is a related molecule. It's the source of the in-license for DISC-3405. We are not co-developing. They're doing their own development path, and their management of PV in China is very different than it is in the U.S. The endpoints are different, we don't really know how those data reflect on management of PV in this country and potential efficacy signals. I think what's most important is waiting for us to present our data later in the year. Got it. Very helpful. Thank you. Great. Thank you. Thank you. The next question will come from Martin Auster with Raymond James. Your line's open. Hi, this is Shaoshang from Marty. Congratulations on the data and progress. On RALLY-MF, we were just curious if you could provide some color around major responses for these different TD status patients on JAK inhibitors, or these details, do you think will be reserved for a future update? I think the second part of our question is just more so on could you at least educate us on the distribution of TD status of these patients when they start on these JAK inhibitors? Thank you. Yeah, sure. Just to refresh, broadly speaking, what we see is that about somewhere between 50% and 60% of these patients would classify as non-transfusion dependent in our study, meaning they have no transfusions in the 12-week run-in period. We'd probably see another, you know, 25% or so, 30% in the low transfusion burden, meaning one to two units in that 12-week run-in. Per our study, the high transfusion burden would be the last 15% or so of patients who are getting three units or more in the 12-week run-in. That's how we've broken it down and how that kind of relates to the way we estimate the population of patients in the U.S., at least in these categories. Now you're asking about the subset of people who are receiving transfusions at baseline who might also be on JAK inhibitors. I think that breakdown, Will, maybe you want to speak to that. I think it's around 50% or so, or a little higher. Yeah, it follows the overall trend. The subset of the subset question we haven't explicitly presented because the trends are basically the same. Over the course, in general, in MF treatment, you get people with more advanced disease tend to be on more JAK inhibitors. I think there's a slight increase in the proportion of TD high, for example, that are on a JAK inhibitor. We see responses both on and off JAK inhibitors in all transfusion cohorts. Okay. That's appreciated. Thank you. Thanks. Thank you. The next question will come from Douglas Tsao with H.C. Wainwright. Your line's open. Hi. Good morning. Thanks for taking the question and congrats on the progress. We're just curious, in terms of interest or I guess as we see reflected in enrollment in RALLY-MF, as you've released data, have you seen sort of an increase in any particular populations? I'm just curious in particular what you're seeing in terms of interest in terms of patients on JAK inhibitors and continuing to see sort of strong demand from patients who are on momelotinib. Yeah. Right. Good question. I think if I heard you right, just looking at the enrollment in the RALLY-MF trial, have we seen trends of certain kinds of patients who seem particularly in need of anemia therapy? Yeah. Yeah. As we see more data coming out, I guess, you have access to an option that these patients are on and just what you're seeing today, just given the updates that you've given over the last few months. Right. One thing we've definitely said is we've been surprised and I guess interested by the number of people who have been on momelotinib who've come into our study. That data we've continued to present. We presented some of that at ASH. A lot of patients who are getting momelotinib, while it may be anemia-sparing, we see a lot of people still in need of actually improving their hemoglobin and that DISC-0974, selcodebart, seems to deliver that effect very well in combination with momelotinib. It's also pretty clear that at least those patients coming into our study, their hepcidin has not been managed on that therapy. In fact, their baseline hepcidin is about the same. That's been a kind of an interesting little subgroup for us to be looking at and confirms the overall view that regardless of the underlying MF therapy people might be on, there's still a need to manage anemia and DISC-0974 can manage that. The other point I'll make, just so as enrollment continues here, hopefully closing out pretty quickly now, we have actually stopped enrollment on NTD patients, so you won't see any more accumulation of those patients in the study. It's going to be focused entirely on the somewhat harder-to-find transfusion-dependent patients. As you see those numbers increase, while the NTD doesn't increase, it doesn't mean that there's a different demand or unmet need. It's simply the dynamics of how we're enrolling the study. Maybe I'll pause and, Will, if there's any further commentary on these points? No, I think that covers it. I guess the only thing to note is that. That's the answer I got for you. Just as a quick follow-up now, just when we think about a phase III design, do you anticipate, just given what you've seen, enriching for certain populations in particular? Sorry, can you say that again, the design of the phase III trial? For phase III, do you plan on having sort of enrichment to just ensure you have sufficient numbers of certain types of patients, just given your interest in having as broad a label as possible, and sort of how you're thinking about what those groups might be? Well, it's very clear ruxolitinib is the backbone therapy for these patients, and it will continue and maybe even become more so as it trends towards potentially becoming generic. We'll definitely want to make sure that our phase III program has adequate experience in that group of patients, which, by the way, we're getting a lot of experience now, and the data looks great. Other groups, they're going to be smaller fractions of patients, and I'd be surprised if we're going to have sort of enrollment criteria for those, whereas we might for ruxolitinib to ensure that there's a minimum number of patients. We're going to have an interaction with the FDA in Q4, at least that's the plan, and we'll be able to provide more details after that. Okay, great. Thank you so much. Thanks. Thank you. The next question will come from Rami Katkhuda with LifeSci Capital. Your line's open. Hey, guys. Wanted to pass along my congrats on all the updates, and thanks for taking my questions as well. I guess for patients who switched from placebo to bitopertin in HELIOS, can you just remind us, do the kinetics and magnitude of clinical benefit ultimately mirror what was seen in earlier studies? Why was there so much variability in light tolerance at the week 12 and 16 x points? Yeah, thanks. Big picture, the way to look at this data is really kind of patients who've been on bitopertin for a long time, how are they doing? By and large, how they're doing is their PP9 has come down and in a sustained way. There's no sign of tachyphylaxis there. And what we see is that people are increasingly taking advantage of their ability to spend time in light, and that's true whether you were a crossover patient or just continuing on bitopertin. That's the best way to kind of really look at the data we presented at EHA. To get into the weeds a little bit, the way the studies were designed, and there was a lot of operational complexity to this, we designed both the phase II trials, AURORA and BEACON, to have what are called inbuilt extensions, meaning patients would go through their either six or four-month treatment period in study, and then they would actually, many of them, first rolled onto a crossover or extension study inside that study. Then a little bit later, we got the HELIOS extension study formally open, and we were able to cross people onto that. When you look at people starting the HELIOS study, some of them had already crossed over into extension, and some of them had not. When you use that as your cut point, it creates a lot of variability in the baseline conditions because some of them have already started on bitopertin, where they may have been on placebo before. The other complexity is here in the U.S., initially, we needed to get permission from the FDA to put people on the 60 mg dose after the first four months. Some people crossed onto 20 and then were able to bounce back up to 60 later once we'd done the necessary regulatory rigmarole. Anyway, the transition point between the BEACON and AURORA studies and then onto HELIOS was a little bit choppy, right? It really wasn't designed to be a clean crossover-type study design, That's why you get some noise in the baseline data when you look at the HELIOS start. That's how I started the conversation, is really just look at this data as a snapshot of patients who've been on drug a long time and take it as a view of how patients on bitopertin are performing after a long time, They're really performing great. We would love to see this kind of effect for any patient with this disease. That's the right way to look at the data. Got it. How are you guys thinking about the regulatory and commercial path forward in Europe? Do you think the EPP light results there will help with ultimate access? Yeah, I think so. We're doing a lot of work to look at some of the pharmacoeconomic pieces that perhaps have a greater significance in the European system. We're certainly all signals go on driving towards approval in the European region. That, of course, will require the APOLLO data. Our cadence is probably first get our response to the CRL in, push for availability in the U.S. as quickly as possible. Our team can also work simultaneously on getting those European regulatory filings done as well. You'll notice the AP is also opening up in various European countries. We're doing our best to make the drug available to people there as well. Thank you. Thanks. Thank you. The next question is going to come from Derek Archila with Wells Fargo. Your line's open. Hello, good morning. This is Jacob, watching for Derek. Thanks for taking our question, and congrats on all the updates. Just a quick one from us on RALLY-MF. Just in terms of the mutational status, could you speak to what responses look like across JAK, CALR, and MPL driver mutations? Is there any expectation that there would be any differences? There's no reason why it would be different, we didn't design the study to meticulously sort out driver mutations and attach that by response rate. As I mentioned earlier, the CALR population tends to be less anemic. When we say 80% of MF patients are anemic, I think the number is more like 60% for that CALR group. Will, are you on and able to answer now? Yeah. I don't know if you can hear me, John. Yes, I can now. Yep. Yeah, we are doing that sequencing. It's being done in batch at the end of the study because we did not have a reason to think it would make a difference, both in terms of the biology of the anemia and the interaction with selcodebart. We will look at it formally, but I think the responses we're seeing, even just in a casual way, looking at people's past history, not from of their mutational status on our own record, but we're seeing responses across the board. All right. Thank you. Thank you. There are no more questions in the queue at this time. This will conclude today's Q&A session and today's conference call. Thank you for your participation, and you may now disconnect.