Good morning, and welcome to the Disc Medicine 2024 EHA management call. We'll be providing clinical data updates across our entire clinical portfolio of bitopertin, DISC-0974, and DISC-3405. This is John Quisel speaking, CEO here at Disc, and I'll be joined today as well by Will Savage, our Chief Medical Officer. Before we get going, a few preliminaries. We will be making forward-looking statements today, and these should be taken in context of materials that we filed with the SEC and posted on our website. Additionally, bitopertin, DISC-0974, and DISC-3405 are investigational agents and are not approved for use as therapies in any jurisdiction worldwide. All right, so I will begin with some introductory remarks and a summary of the data that we're sharing today at the EHA conference, a very exciting set of updates, and then we'll plunge into each of the programs. So first, bitopertin. We are today providing a summary across the entire Phase 2 program, AURORA and BEACON, and some interesting new analyses of the data. So first of all, as consistent with our top-line overview, we can confirm that the drug is active. We're seeing significant reductions in protoporphyrin IX, or PPIX, phototoxic reactions, clearly reduced relative to placebo, and improvements in quality of life. What we've been doing since the top-line readout is looking carefully at the relationship between these clinical outcomes and the protoporphyrin IX reduction. I think you'll see here today, the time course of phototoxic reactions and the time in light or sunlight exposure are quite remarkable and show greater treatment effect after the PPIX nadir is established. We are also showing that greater protoporphyrin IX reductions are associated with improvements in multiple metrics of light tolerance. And as we've said before, bitopertin has been generally well-tolerated in this patient population, and we see stable hemoglobin levels. Now, DISC-0974, this is our iron-mobilizing program designed broadly to treat anemia of inflammation. And today we're summarizing updated data from our Phase 1b dose-escalating study in patients with anemia of myelofibrosis. Essentially, this is an update or expansion of the dataset we shared at ASH in December last year. We're looking now at well over 20 patients, and we're seeing substantial reduction in hepcidin levels and increase in iron levels, and this is dose proportional, and converting into a very positive impact on hemoglobin and transfusion burden across a broad range of participants with myelofibrosis. These responses, importantly, we're now able to say, are durable, at least in the context of the six-month trial we're running, and again, generally well-tolerated at all evaluated dose levels. For the first time, we're excited to share clinical data from our third program, DISC-3405. This is an antibody to TMPRSS6, designed to restrict iron for the treatment of polycythemia vera, as well as various iron-loading disorders. Today, we're sharing healthy volunteer single ascending dose data. We see substantial increases in hepcidin levels, generally dose proportional. This is converting into sustained reduction in iron levels, well exceeding the 50% decrease in serum iron that's needed here to achieve what we believe will be therapeutic benefits in PV patients. Overall, the package we have is supportive of subcutaneous monthly dosing. One thing we're excited to share that was not clear whether we'd have it in time is actually data on hematologic parameters. So really seeing some nice effect on hematocrit, for example, at the highest dose levels, and this portends quite well for the effects we'll see in patients. Again, this antibody has been generally well-tolerated at all evaluated dose levels. So that's a summary of the data. Now we're gonna move into the section on bitopertin in EPP. I'll say a few preliminary words before we plunge into the clinical data with Will. So a reminder, bitopertin is an investigational oral selective GlyT1 inhibitor. It's been extensively studied by Roche in the clinic, and we know from that work that bitopertin modulates heme biosynthesis by blocking the uptake of glycine in erythrocytes. And, as you know, in EPP patients, the disease is driven by the accumulation of the toxic metabolite protoporphyrin IX, which is shown in the middle of this slide and represents the last metabolite in heme biosynthesis. So erythropoietic protoporphyria, or EPP, it's a rare, debilitating, and lifelong condition characterized by extreme pain, also called phototoxic reaction, and damage to the skin caused by light. It's a genetic condition, caused by defective heme biosynthesis. Typically, it's the last enzyme in heme biosynthesis, called ferrochelatase, that has a reduced function in these patients. It's lifelong, presents early in childhood, and again, is caused by the accumulation of the toxic metabolite protoporphyrin IX. A related form of erythropoietic protoporphyria, called XLP, mechanistically similar, also caused by increase in protoporphyrin IX.... The goal is to study all of these together. So this disease is debilitating and potentially life-threatening. The daily manifestation of the disease for patients is in the skin. There are severe disabling phototoxic reactions that can last days, and also be accompanied by edema and sensations of burning or other extreme pain. And generally, you'll see our Phase 2 program has been aimed at understanding the effect of the drug on the skin symptoms of disease. There are serious complications in with hepatobiliary disease. Almost a third of these patients will have gallstones or other signs of liver dysfunction, potentially gallbladder removal. In somewhere between 2% and 5% of patients, there may be frank liver failure, which requires a liver transplant and can result in mortality, so very serious liver complications. There are effects on the psychosocial well-being caused by just the general change in lifestyle and anxiety that comes with having pain attacks in reaction to sunlight. There is currently no cure or disease-modifying treatment. Patients generally just behavior modify, design their entire lives around avoiding sunlight. There is one FDA-approved agent called afamelanotide. It's a surgically implanted drug that works by causing tanning and has not been widely adopted in the patient population. So again, the rationale here is to reduce the level of disease-causing protoporphyrin, so getting at the fundamental root cause of the disease. On the left-hand panel, you can see the heme biosynthetic pathway running from glycine through a number of enzymatic steps to arrive at heme. This is a pathway that's functioning at a very high rate in newly forming red blood cells. There are two mutations known to cause EPP and XLP. EPP, the primary group of patients have mutations in that last enzyme called ferrochelatase or FECH. When you decrease the function of that enzyme, it slows down the processing of protoporphyrin IX into heme and results in massive accumulations of protoporphyrin IX in the body. In a handful of patients who have XLP, it's actually a gain-of-function mutation in ALAS2, which is the first enzyme. That gain-of-function ends up driving excess metabolite through the pathway, which again overloads the FECH enzyme and results in protoporphyrin IX accumulation. So that's the mechanistic cause of the disease. Our treatment, bitopertin, reduces the uptake of glycine at the top of the pathway. And as we've shown in mouse and cellular models, as well as top-line clinical data, what bitopertin will do is reduce the flow of glycine into that pathway and markedly reduce protoporphyrin IX levels. Clinical literature would suggest that reductions in protoporphyrin IX levels of greater than 30% can have a major impact on photosensitivity in patients. And before we get into the clinical data, we thought it would be a good time to share an intriguing new mouse experiment that really supports this premise. So we've used a research-grade GlyT1 inhibitor, and we've dosed it at levels in EPP mouse models that reduce protoporphyrin IX levels by about 40%, and that's shown in the left-hand panel. And in the far right-hand panel, you can see visually just how horrible this disease model can be. You know, modest UV exposure in untreated animals or vehicle-treated animals leads to really significant burning caused by the photoreaction of that protoporphyrin IX compound. And animals that have been treated with our GlyT1 inhibitor show dramatic reduction in that symptomology. And in the middle panel, you can see a correlation looking at the skin lesion area on the Y-axis versus the level of protoporphyrin IX reduction. And you see really a remarkably clean correlation pointing directly at about a 40% reduction. So, we can see here that at least in the highly controlled setting of a mouse experiment, a 40% reduction in protoporphyrin IX does largely eliminate photosensitivity in this mouse model. We share that because now I'm going to hand it over to Will as we go, turn to clinical data, which is, of course, less controlled, but I think there's a lot of exciting insights that emerge from our current analysis. So Will, over to you. Thanks, John. We conducted two Phase 2 trials of bitopertin in EPP. The open-label, six-month BEACON trial enrolled 22 adults with EPP or XLP in Australia. We previously reported data in December, when most of the subjects had completed the study. Complete data on all adult subjects is presented at this EHA conference and is available on our website. The focus of today's presentation is the double-blind, randomized, placebo-controlled AURORA trial. The study compares 20 milligrams and 60 milligrams of bitopertin to placebo over a 17-week double-blind period. 75 patients enrolled in the study, and we had 3 discontinuations, one of which discontinued due to an AE that developed prior to dose initiation. Baseline demographics were comparable across treatment groups in terms of baseline time to prodrome, geography, and seasonality of enrollment. Baseline PPIX was slightly higher in the 60 milligram group. The primary endpoint was achieved with a 21% reduction in PPIX in the 20 milligram group, and 40% reduction in the 60 milligram group, as compared to an 8% increase in the placebo group. The differences between bitopertin dose groups and placebo are highly statistically significant. The key secondary endpoint is the total time in sunlight on days without pain. The bitopertin treatment effect was similar to what was observed in the BEACON study on a prorated basis, but was not dose-dependent or statistically significant, in part due to the strong performance of the placebo arm. Sensitivity analyses evaluating the effect of baseline PPIX level, seasonality of enrollment, and geographic location show similar relationships of active arms versus placebo. This endpoint measures time as a single total per patient and does not account for patients' baseline time in light, nor does it measure improvements over time. This figure plots a longitudinal analysis of two-week intervals of time in sunlight on days without pain over the course of the study, adjusted for baseline time in sunlight. So rather than looking at time as a single total, as was done in a previous pivotal trial, we are looking at two-week intervals of time in sunlight over the course of the study. When time in light is looked at longitudinally and the baseline time in light is accounted for, we make two observations. First, while all groups show improvement in the first month, the placebo response that is evident in that first month on study wanes thereafter. Second, when the baseline time in light is accounted for, the treatment effect becomes more apparent, particularly at the end of the study, showing a nominally statistically significant improvement. Overall, bitopertin treatment resulted in an approximately twofold increase in time in light at the end of study as compared to baseline. This figure subtracts out the placebo time in light over the same time course as in the previous figure and looks at the placebo-adjusted time in sunlight, as well as the reduction in PPIX for the 60 milligram group in the same time course. What is apparent is that the improvement in time in light after the period of placebo effect corresponds to the time when maximal reduction of PPIX is being achieved. Phototoxic reactions are the hallmark and most debilitating pain aspect of EPP. We observed a dose-dependent decrease in the rate of phototoxic reactions that was statistically significant at the 60 milligram dose level, with a 60% reduction at 20 milligrams and 75% reduction at 60 milligrams. We did see a similar effect in the BEACON study, with an approximately 90% reduction in phototoxic reactions. The proportion of participants' experience of phototoxic reaction on study also showed a dose-dependent reduction from 46% in the placebo group to 19% in the 20 mg group and 12% in the 60 mg group. The maximal pain rating of phototoxic reactions showed a dose-dependent decrease. Here we are looking at the patients who had phototoxic reactions while on study, with most of these being in the placebo group and the fewest being in the 60 mg group. When we look more closely at the timing of when the phototoxic reactions occurred on study, we see that most phototoxic reactions occur in the bitopertin treatment groups during the period while PPIX is being reduced. After the first two months, when PPIX has reached its nadir, phototoxic reactions are markedly reduced in the bitopertin treatment groups, as shown in the blue region on the right of the figure, and reaching zero reactions in the 60 mg group. There was a dose-dependent improvement in the Patient Global Impression of Change, or PGIC, reaching statistical significance in the 60 mg dose group. This improvement was on top of a notable improvement in the placebo group. A pre-specified analysis that correlated PGIC with changes in PPIX shows that greater improvement in EPP disease status is associated with greater reductions in PPIX. PPIX change was correlated with multiple measures of light tolerance. Overall, greater PPIX reductions were seen in bitopertin patients who did not have phototoxic reactions versus those who did. Looking in the table at the association of PPIX changes with improvements in light tolerance, a pre-specified analysis looking at tertiles of PPIX with total time in sunlight, average time in sunlight, and improvement in time to prodrome show an inverse relationship between lowering PPIX and improving measures of light tolerance. Regarding safety, there were no SAEs with bitopertin. Hemoglobin levels were stable and similar in all dose groups. There were 2 TEs leading to discontinuation, both in the 60 milligram dose group, one due to dizziness and one due to rash. Dizziness was more common in the 60 milligram dose group, but most cases were mild and short-lived, with a median duration of 5 days. Now that we have complete analyses of AURORA and BEACON, we see consistency of effect across the two studies with regards to PPIX reduction, significant 2- to 3-fold improvement in sunlight tolerance, 75%-92% reduction in phototoxic reactions, and a significant benefit on how patients report improvement in their disease. Now back to you, John. Thanks, Will. So all in all, a very impactful, Phase 2 program that we've run here with bitopertin. We can see again and again now, bitopertin is reducing that toxic metabolite, protoporphyrin IX. It is resulting in increased light tolerance, decreasing phototoxic reactions, and improving quantity, quality of life. So across the board, you know, the profile of a patient who received bitopertin in one of our trials is actually one of, marked disease improvement, and the burden on us is to design a pivotal trial program that can sort that effect out from, placebo effects. So our next step here is to set up an end of Phase 2 meeting in the second half of 2024, and look to initiate a pivotal study in the first half of 2025. As you've heard today, we have a range of available endpoints that we can bring forward to our regulatory discussions to help us address the placebo effect. Among the options we have are, now we're seeing a longitudinal analysis of time in sunlight. We see that once protoporphyrin IX has been reduced, which takes a month to two months, the improvement in that time in light is marked afterwards. And so analyses that take into account both the baseline conditions and the latter half of the study or latter portion of the study appear to provide a very strong separation between treatment group and placebo. And so that's an endpoint we can consider. It also has great similarity to the precedented endpoint as well. Phototoxic pain reactions have been a very robust endpoint for the program. As well noted, these performed markedly in both the BEACON open label and in the AURORA placebo-controlled study. So that has always represented a good endpoint for us, and one that clearly the patients care tremendously about. We also have protoporphyrin IX itself, though it faces some challenges typically associated with a surrogate endpoint, and then we have the option to create composites of multiple endpoints. So what we hope to leave you with today is a message that there's very strong evidence in this Phase 2 program that bitopertin is, in fact, improving many aspects of the disease for these patients, and markedly so. And moreover, that we have numerous endpoints we can use in a pivotal study to provide what we hope is definitive clinical evidence of this patient benefit. All right, so from there, we'll move into the DISC-0974 program. Again, this is an antibody against hemojuvelin, designed to reduce hepcidin, increase iron, and enable red blood cell production in the setting of anemias of inflammatory disease. And Will, I'll hand it over to you here. Thanks, John. So hepcidin is a key driver of anemia in MF. First of all, there are a large number of patients with MF, estimated at 25,000, almost all of whom are anemic, to a degree that is considered severe and requiring transfusion in a majority of them. The etiology of the anemia is complex, but certainly high hepcidin from inflammation is a consistent driver of anemia across patients. And there's an unmet need here, as this anemia is severe and difficult to treat. Transfusions are an undesirable intervention that have their own risks associated with it, and there is no approved or effective specific therapy for anemia. Shown on the right are hepcidin levels in the disease, showing that at every grade of MF, from low risk to high risk, there is a one to two orders of magnitude increase in hepcidin as compared to controls, underscoring the importance of the hepcidin elevation in this disease. The DISC-0974 MF anemia study is ongoing, and as of this data cut, 34 patients have been enrolled. The enrollment reflects a combination of dose escalation and backfill of enrollment into active dose levels. 10 patients were on concomitant JAK inhibition therapy. Most patients were not transfusion-dependent, which means that they had 0-5 units of blood transfused in the 12 weeks prior to screening. 4 transfusion-dependent patients enrolled, but for 2 of these patients, there is not yet sufficient follow-up to assess for a response. DISC-0974 reduced hepcidin and increased iron in a dose-dependent manner. The hepcidin reduction, shown on the left, was maximal and persistent throughout the dosing period at the 50-mg dose level and above. This persistent deep suppression of hepcidin leads to persistent iron mobilization that is required for all hematologic responses. On the left are mean hemoglobin levels in all patients on study, showing meaningful and durable increases. On the right are shown patients who had transfusions during the baseline period. The frequency of transfusion decreased in all patients, with one of the two evaluable transfusion-dependent patients achieving transfusion independence. Looking at hemoglobin responses across the 28- to 100-mg dose groups, on the left, we see that 68% of patients achieved an improvement of 1.5 grams per deciliter in hemoglobin. On the right, we are looking at the durable 12-week, 1.5 g/dL responses in patients who had at least 16 weeks of follow-up. We see that 60% of patients achieved a mean 1.5 g/dL hemoglobin increase for 12 weeks. Safety continues to look favorable and well-tolerated at all dose levels. Shown here are the AEs at least possibly related to DISC-0974, without any specific pattern emerging. Grade 3 AEs included headache that was not related to DISC-0974 and anemia. There was 1 SAE of arthralgia deemed unrelated to DISC-0974. So DISC-0974 is doing everything that we hoped it would do. It's decreasing hepcidin and increasing iron in a durable and profound way. We have 68% of non-transfusion-dependent patients with a hemoglobin response, and most of those patients showing durability of at least 12 weeks. As far as transfusion, we're recording improvements in transfusion frequency across all transfused patients and one of two TD patients achieving TI. All of this efficacy is seen in the context of a safety and tolerability profile that is very benign. Back to you, John. Great. Thanks, Will. So this data package, we're very excited about, really seeing DISC-0974 deliver improved hemoglobin response and transfusion burden across a broad range of myelofibrosis patients. So, like Will said, really doing everything we wanted it to do, reducing hepcidin, mobilizing iron, that leading to a durable increase in hemoglobin, and in those patients receiving transfusion, generally seeing reduced transfusion burden. So our next steps here, we'll have an end of Phase Ib meeting with regulators in the second half of the year and initiate the Phase II study. This is in the nature of cohort expansion, likely focusing on one cohort in the non-transfusion dependent group and another cohort in the transfusion-dependent group, all at likely a single dose level. So it's great to see this program progressing the way it is. So lastly, we'll turn to DISC-3405. This is our anti-TMPRSS6 antibody designed to induce hepcidin, thereby restricting iron availability. And this is intended to modulate red blood cell production. So in the setting of polycythemia vera, the intention is to decrease hematocrit and red blood cell levels to avoid thromboembolic events in these patients. And in disorders of iron overload, the intention is to just overall reduce the iron burden in patients. So here, I'll hand it over to you, Will. Thanks, John. So the development plans for DISC-3405 start with the Phase I study in healthy volunteers that's ongoing, and we're presenting today. We aim to show proof of mechanism here and then advance into, after a MAD portion of the study, into polycythemia vera patients, where we can demonstrate proof of concept of iron restriction to control hematocrit. We are also looking at additional proof-of-concept studies in the future for a range of indications, including hereditary hemochromatosis, iron overload, and beta thalassemia, as well as myelodysplastic syndromes. Today, we're focusing on the single ascending dose portion of the DISC-3405 study. Baseline characteristics reflect a healthy volunteer population and are just presented here for reference. DISC-3405 exhibited dose-dependent PK and characteristic subcutaneous absorption kinetics. On the right is shown hepcidin induction, which shows the expected dose-related increases in hepcidin. As hepcidin increases across dose levels, we see decreasing iron that is anticipated, with the greatest reduction at the 300 milligram dose, showing a persistent greater than 50% reduction. As iron is restricted from circulation, ferritin, a storage form of iron, increases, as shown on the right. The iron-restricting effects of DISC-3405 translated into changes in hematologic parameters. Shown for the 300 milligram dose level, hemoglobin content in reticulocytes, overall hemoglobin, and hematocrit all decreased. These are the hematologic effects desired for control of hematocrit in PV. Overall, DISC-3405 was well-tolerated without a dose relationship of AEs. This profile would be expected for a monoclonal antibody modality that targets a gene that is generally silent in humans with loss of function outside of its hematologic effect. Back to you, John. Thanks, Will. So for the first study in man with this antibody, we are very pleased with the results. This single-dose subQ administration demonstrated dose-dependent increases in hepcidin and corresponding reductions in serum iron levels across all dose levels. We reached our target of greater than 50% reduction in serum iron at the 150 milligram and 300 milligram subQ doses. The PK/PD profile is supportive of monthly subQ dosing in PV, as well as in iron overload conditions. The molecule was generally well-tolerated, as expected for an antibody targeting, as Will said, a protein that we know can have loss of function in humans without adverse effect beyond the iron restriction that we're intending here. So our next steps are to conclude our multiple ascending dose work, and we expect to provide readout on that data by the end of the year, and then initiate a Phase 2 study in polycythemia vera, which we're aiming for the first half of 2025. So with that, I'll move into closing remarks. We're really delighted about the package of data that we're putting out here at EHA and also on this call. Again, with bitopertin in EPP, we're showing meaningful improvements on key aspects across both studies, with significant reductions in protoporphyrin IX, twofold improvement in light tolerance relative to baseline, significant reduction in pain, and improvements in quality of life. And so this gives us a range of viable endpoints that we can bring forward to an end of Phase 2 meeting, and then, you know, with positive outcome, progress to a pivotal trial next year. For DISC-0974, our antibody against hemojuvelin, we're seeing decreased hepcidin and increased iron that's sustained for several weeks. This is translating into a durably increased hemoglobin with reduced transfusion burden in those patients who have such intervention, and is generally well-tolerated. And this is just so exciting because for the first time, we feel like we've cracked through on hepcidin reduction and are really showing impressive hemoglobin increases in one form of anemia of inflammation. So we look forward to moving ahead there. And DISC-3405, our hepcidin-inducing agent, healthy volunteers, it's doing what it's supposed to do, increase hepcidin, reduce serum iron levels. We're getting to below the 50% reduction at the top doses, which is exactly what we expect to be needed in PV patients. It's all supportive of subQ monthly dosing, and again, generally well-tolerated. With success now across the entire portfolio, we do have a rich calendar of catalysts coming just in the second half of this year. As I've mentioned, we're expecting to have an end-of-Phase 2 meeting in the second half for bitopertin. We are also still, though we're not talking about today, expecting some initial data in the DBA study. With DISC-0974, as we come into the end of the year, we'll have our final Phase 1b data in myelofibrosis. We expect to have initiated our Phase 2 program, and we will hopefully have Phase 1b data looking at hemoglobin levels in patients treated with the anemia of chronic kidney disease. And then for DISC-3405, as we come into the end of the year, we'll have full Phase 1 data set, including multiple ascending dose data as well. ... And then we'll look forward to next year as we initiate a variety of trials, both pivotal and Phase II across the entire portfolio, and hopefully continue to roll with interesting data updates. So thank you for your attention today, and with that, we'll hand it back to the operator for questions. 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. Please stand by while we compile the Q&A roster. Our first question comes from the line of Thomas Smith from Leerink Partners. Hey, guys. Good morning. Thanks for taking the questions, and, congrats on the updates here. First on bitopertin, provided some great data looking at the time course of the phototoxic reactions. And now that we have some of these patient-level analyses, can you just comment on whether any of the bitopertin patients who reported phototoxic events also had a greater than 30% reduction in PPIX levels, or were these patients who hadn't achieved that threshold? I'm just trying to get a sense of whether there's a greater confidence in the threshold looking at this particular analysis. Yes, John, would you like me to take that? I guess we don't have... We'll wait for John to get on the line, but we did see that the people who had phototoxic reactions had much less reduction in their PPIX than those who did. There was only, you know, one or two patients who did not meet that 30% threshold reduction, who had a reaction. Okay, got it. That's helpful. And then, for DISC-0974, yeah, congrats on these data. Really nice changes in hepcidin, iron mobilization, hemoglobin. Just wondering if you could comment on how you're thinking about potential read-through to the ongoing CKD program. I guess how much read-through there is, both in terms of doses that you expect to evaluate in CKD, and then just mechanistically, how you think some of the signals you're seeing now in myelofibrosis could translate into that indication. Yeah. Well, I have high confidence on the read-through here. I mean, as John mentioned in the presentation, you know, we have very profound hepcidin reduction in the setting of a disease that has very high hepcidin, and we can essentially make flatline hepcidin into the low normal range with the appropriate dose. So I think there's nothing about CKD that would or any other inflammatory disease, that I think would dampen the expectation that we couldn't that we could reduce hepcidin to these levels as well. You know, there. When we talk about at what dose level that is in CKD, when we look at the at ASH last year, we presented the iron mobilization from the first cohort in CKD. They behaved more like healthy volunteers, in which we needed to go up to the 56 milligram dose level in order to see a hemoglobin effect. MF, obviously, we're seeing a hemoglobin effect at lower dose levels, so I would expect that, we'll need to escalate higher in CKD than MF, but we'll see what the data show. Got it. That makes sense. All right, guys, thanks for taking the questions. Congrats again on the data updates. Yeah. Thank you. Thanks, Tom. Thank you. One moment for our next question. Our next question comes from the line of Evan Seigerman from BMO Capital Markets. Hi, guys. Thank you so much for the really comprehensive data update. I wanted to touch on two things. One, can you just talk about maybe kind of the decision to initially stratify patients by time to prodrome? And then, you know, as we pivot away from this, maybe kind of help us understand just why this makes sense and, you know, what you hope to achieve with your meeting with the FDA. And then I just wondered, maybe, Will, if you could kind of compare and contrast, how you think about your DISC-0974 data, in comparison to some of the data we've seen with luspatercept in, MF recently. Thank you so much. Yeah, thanks for the questions, Evan. And just confirming, Will, are you able to hear me? Yes. Great. Yeah, you go ahead and address Evan's questions. Perfect. Sure. So time to prodrome was our stratification factor in both BEACON and AURORA, just to make sure that the severity of disease in terms of light tolerance was balanced between dose groups. I think what we saw with the time to prodrome data is that it is heavily influenced by a placebo effect, and, you know, it's also not a binary stratification factor above or below 30 minutes. And when we move to the more quantitative time in light which captures more of a spectrum, and it is as an endpoint being captured. It doesn't rely on the prodrome as the data entry is less susceptible itself to the placebo effect. That's when we start seeing the important dose differences. So we've learned something about time to prodrome as an endpoint over the course of the AURORA trial. Regarding the DISC-0974 data and luspatercept, you know, there was a recent publication of the Phase 2 data that an apples-to-apples comparison is looking at one of the secondary endpoints in the non-transfusion-dependent group. We have a mean 1.5 gram per deciliter increase in hemoglobin, durable for 12 weeks, and in aggregate, there's roughly a 30% response rate on that endpoint. We're at about 60%, you know, with a smaller N, but encouraging nonetheless. Great. Thank you. Thanks, Evan. Thank you. One moment for our next question. Our next question comes from the line of Ben Burnett from Stifel. Hi, good morning. This is Carolina Ibanez-Ventoso for Ben Burnett. Thank you for taking our questions, and congratulations on all the progress. My apologies, I joined a little bit later to the call. What exactly are you planning to propose to the FDA in terms of next steps on the bitopertin study? Yeah, hi, and thanks for the call. I have a question. Yeah, I'll take that one. So, what we're sharing today are analyses that show that time in light, assessed on a longitudinal basis, is performing actually very well in the AURORA dataset. And so that represents a possible pivotal trial endpoint that we could discuss with the FDA. And it has the benefit of being quite close in nature or essentially almost the same as the precedented endpoint. But we also have the rate of phototoxic reactions as a potential endpoint, and that endpoint has performed exceptionally well across both the open label study, where we saw over 90% reduction in phototoxic reactions relative to baseline, and in the placebo-controlled trial, where we saw roughly 75% reduction that was statistically significant relative to placebo. So we have these, you know, probably these two endpoints that look the most promising, and our basic plan is, you know, we'll build our proposal to the FDA, have that discussion, and then come out with to all our stakeholders with the pivotal trial plan, and that's projected for the second half of this year. Okay. Understood. And then, if I may ask a follow-up question on your CKD program. What should we expect from in the next update, just in terms of patients and those cohorts and do you know, at this point, which endpoints do you plan to share? Yeah. So looking ahead to the second half of the year, we'll have, as you suggested, data from our trial in the patients with anemia of chronic kidney disease who are not dialysis-dependent. We shared just a tiny bit of the first cohort of data at ASH in December, where we were at a dose that was, you know, not effective in the healthy volunteers and not yet effective in the CKD patients, though we're seeing early signs of iron mobilization. So we're projecting to share additional data from that study in the second half of the year, and, you know, where we're aiming for is to share that at the ASN meeting near the end of October. Although again, no guarantees yet as to the forum. In terms of the nature of the data, the study is designed as a single-ascending dose, looking at dose levels of 28 milligrams, 40, 60, and 90. We're progressing through those, as we speak, and, you know, hopefully, we'll have a package across, all or most of those, dose cohorts by that second half year disclosure. Okay, got it. Thank you so much. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley. Thanks for taking my questions. In the AURORA time course of individual phototoxic reactions, I understand the placebo patients having more reactions in the last 60 days, but what is your thinking behind why patients on placebo seem to have fewer reactions than bitopertin patients in the first 30 days? And then I have a follow-up. Yeah, thanks for the question, Jeff. Will, this one sounds for you. Sure. So when you look at the baseline, phototoxic reaction rate, they were actually lower in the placebo group than in either of the bitopertin groups. So I think the first 30 days is more a reflection of the phototoxic reaction rate that was in the period closer to baseline. And then, you know, I think that while the trend for on bitopertin starts with a higher rate and then goes down, while there's a slight uptick in the placebo group, you know, while there's a slight uptick in the placebo group, I think has to do with the fact that there is a placebo effect, and people do spend more time in light, and it's over the course of the study that it catches up with people, and they have more phototoxic reactions. ... Okay, great. And then for DISC-0974, how are you thinking about the hemoglobin change being similar for the 28-mg and 100-mg doses, while changes with the 50- and 75-mg doses seem greater? Sure. So for- Go ahead, Will. Oh, yeah, thanks. So, for full transparency, we presented all hemoglobin data. There are some transfusion-dependent patients in that graph. You know, so that is decreasing the hemoglobin response, where in transfusion-dependent patients, you're not necessarily expecting an increase in hemoglobin, just a stabilization of hemoglobin to show transfusion reduction. I think the other thing is, we know that people with MF have multiple causes that contribute to their anemia. In particular, the splenomegaly and bone marrow fibrosis are not quantifiable in terms of how much they contribute to anemia. And in fact, that's baked into the response rates of, you know, expecting that not everybody's gonna have a response. And I think there is some with these, small N, particularly in the 100-milligram group, that just distribution of patients who, you know, have a stronger contribution of spleen or marrow to their anemia than, hepcidin is, you know, what's being reflected there. When you look at hepcidin and iron, I mean, they're overlapping with, 50 and 75 milligrams, so I think it's, due to something separate from our mechanism. Great. Thanks so much. Thanks, Joe. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Kristen Kluska from Cantor Fitzgerald. Hi, good morning, and let me also add my congrats on the data. So for bitopertin, it sounds like there are a number of options to include for a primary in Phase 3. What can you share to us about what would be at the top of your wish list to present? And then, while these can all potentially address the placebo response, how would you consider things like patient numbers as well as length of trial to further mitigate this risk, of course, depending on the endpoint? Thank you. Yeah, thanks for the question, Kristen. Yeah, I mean, as to the pivotal endpoints, the plan here is to probably focus on the two that are performing the best at this point and show a lot of reason to believe they're clinically meaningful. So we have this longitudinal assessment of time in light, which is exceptionally close to the precedented primary endpoint that's been used to approve the one drug in this space. So that's a compelling endpoint, and then we have the phototoxic reactions, which, as I've said, has, have performed very well across these studies. So we're not committing today to which one, you know, we're gonna focus on as our primary. You can assume both will be in any future study. Your other question about trial design, as you can see from the data, you know, the 60-milligram dose group is performing very well, really, providing good protoporphyrin IX reduction. That's, of course, the key to the whole disease. So that's an attractive dose. The safety looked good and not appreciably different from the 20. So if we're able to progress with a single dose level, that, of course, allows us to create a much more robust study, even with relatively few patients, right? Because even if you had 100 patients, you'd have 50 in a group, which is double the size, basically per arm, as we had in our AURORA study. So, you know, it feels really good seeing statistical significance in a pre-specified way on phototoxic reactions, in a post-hoc way anyway, but very reasonable analysis in the time in light. And that's coming in a study where, as a reminder, is 25 patients per arm. And, you know, a lot of the pivotal programs in this disease space are somewhere in the range of 100 to 200 patients, which can enroll, we think, quite reasonably. So that's how we're thinking about all that. Okay, appreciate it. And then for slide 20, the phototoxic reactions pain, it's very clear that once the PPIX reductions exceed that 30% or higher level of reduction and become more robust, the number of reactions decline. But what is your thoughts specific to the pattern of placebo for the first 30 days that you saw? Yeah, thanks. Yeah, I mean, I'll just say, and it's an important reminder when you look at this figure, the other patients who had no phototoxic reactions are not shown. So if you look at that 60-milligram group, literally zero of the 25 patients in that cohort had a phototoxic reaction after 2 months on study, which we think is quite, quite remarkable in this time course. And I think, you know, Will spoke about the placebo rate early. It appears that, you know, that's sort of a flow-through from the baseline state, and they seem to accumulate a few more reactions at the end of the study, possibly as a result of, frankly, spending time in light, on the premise that they might be on drug and then, and then unfortunately having adverse reactions from that. All right. Thank you. Congrats again. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Douglas Tsao from H.C. Wainwright. Douglas, your line is now open. Please proceed. One moment for our next question. Our next question comes from the line of Danielle Brill from Raymond James. Hey, guys. This is Alex on for Danielle. Thanks for taking our question. Just looking at enrollment in DISC-0974 myelofibrosis, do you have to do anything differently on inclusion/exclusion criteria to capture more TD patients in further analyses? And are you confident that you can extrapolate these data to the transfusion-dependent population, or is the data in the infrequently transfused NTD population sufficient to demonstrate efficacy on reducing transfusion burden in your eyes? Thanks so much. Yeah, thanks for the question, Alex. Will, do you want to take that one? Sure. So, I don't think we have to do anything to inclusion or exclusion criteria to include more patients. You know, we opened this dose escalation part to both NTD and TD patients. TD patients tend to be a group who are in greater need of MF-directed therapy, and what investigators have told us is that, you know, at this point, they're those patients are going on to MF-directed therapy trials, but once we get a Phase 2 dose, that then they will direct TD patients into our study. So and conversely, NTD patients who are not yet in need of a JAK inhibitor or who have failed a JAK inhibitor are and not going on other MF-directed therapies, yet are still anemic, are being enriched for this trial in terms of enrollment early on. So I think the patients are out there. We just, you know, as we saw the rapid uptick in enrollment with our—after our early success, in that we presented in December, you know, we'll see the next wave of that to get the TD patients in the Phase 2 portion, which will start by the end of the year. Regarding the read-through on the efficacy from NTD to TD, I think we have to... I, I think it does. There's no reason that the hepcidin and iron effects that we're seeing in NTD are any different than in TD patients. And, you know, the pathophysiology is the same, and it's really an arbitrary clinical distinction to define TD and NTD. I mean, these are the same patients in both dose groups. They, you know, they can actually flip-flop even from one classification to the other. So, you know, we do need to prove that out in Phase 2, and we'll get those patients and do that. Great. Thanks so much. Thanks. Thank you. One moment for our next question. Our next question comes from the line of Rami Katkhouda from LifeSci Capital. Hi, guys. Thanks for taking my question as well, and congrats on the data. I guess it's a bit hard to see on the graph. Are you guys observing big differences in the decreases in serum hepcidin with the higher doses of DISC-0974, or is there a point at which-- or is there a dose, rather, at which the efficacy kind of plateaus? Yeah, thanks for the question. Will, you want to speak to that? Sure. In terms of the PD effect of reducing hepcidin, it is true that at 50, 75, and 100, it's hard to see a meaningful difference. They are overlapped in the low normal range, you know, with some values being below the limit of quantification. So, you know, we wouldn't expect much difference in iron effect or the consequent anemia benefit across those dose levels. Got it. I guess based on the data thus far, do you have any expectations as to what the dose will be for the future studies with DISC-0974 in this indication? Yeah. So we're in the process of finalizing that now. I think we have sufficient data here to determine a Phase 2 dose. And, you know, when we start the Phase 2, and we'll be able to present that. Fair enough. And then quickly on 3405, I guess, can you remind us of the benefits of the monoclonal antibody approach, I guess, against TMPRSS6 versus some of the other siRNA or ASO approaches against the same target? Yeah. It's a good question. Clearly competitive space. There are many folks targeting TMPRSS6 because I think it shows a lot of exciting potential. And I'll, I'll just note, while our, our focus is on PV, there's a lot of work in the space, looking at a variety of other indications across, for example, iron loading and liver iron in beta thalassemia patients, in sickle cell disease, and then there's been some work in hereditary hemochromatosis. So we're really excited about the breadth of this mechanism. In terms of why we like our antibody approach, we think an antibody represents a very well-understood, well-validated framework or category of, of therapy. And we're seeing that we should be able to dose this on a, let's call it, once monthly basis. Could be a little less, could be a little more, and it should be highly titratable. We think all those features are gonna be really helpful in trying to manage iron levels in patients. You know, I just don't think we know as well about how other approaches, you know, primarily nucleic acid approaches, how easy it will be to titrate and achieve optimal levels for patients. But, you know, that's something that will emerge in the clinical data. Makes sense. Congrats again, and thanks. Thanks, Rami. Thank you. At this time, I would now like to turn the conference back over to John Quisel for closing remarks. All right. Well, thank you everyone for your attention today. As I said, we're very excited about the data across all three of our programs and moving them ahead across the year. So thanks again, and goodbye.