Good day, and thank you for standing by. Welcome to this Disc Medicine Investor event at 2023 ASH. At this time, all participants are in 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. 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. It is now my pleasure to hand you over to Mr. John Quisel, CEO of Disc Medicine. Please go ahead, sir. Hello, and welcome to the Disc Medicine 2023 ASH Management Call. This is John Quisel speaking, CEO here at Disc Medicine, and we've put together a presentation today to review all the data that we've been through at the ASH conference here today in San Diego. We've also added a few extra elements to the presentation today. We'll walk through some additional data from the DISC-0974 program, some additional information about the commercial opportunity for bitopertin, and we're delighted to have a guest speaker with us today, Dr. Bruce Wang from UCSF. So that's the menu. I'll start by noting that there will be forward-looking statements, and these should be taken in context with materials that we file with the SEC and that can be found on our website. I should also note that bitopertin and DISC-0974 are both investigational agents and are not approved for use as therapies in any jurisdiction worldwide. So I've been through the agenda briefly, and we'll move into a summary of the data that we presented here at ASH. We had an oral presentation of data from our phase 2 BEACON trial of bitopertin in patients with erythropoietic protoporphyria. Our objective coming into this conference was to present data of equivalent impact and importance of that that we showed at the European Hematology Meeting in June, but now extended to a larger group of patients and with some insights on additional endpoints. We've achieved all of that. We're just delighted to have the data that we're showing now with significant dose-dependent reductions in protoporphyrin IX or PpIX, that key toxin that drives the disease. We're really seeing a meaningful reduction of that with bitopertin therapy, and it's dose-dependent as well. This is translating into significant increases in sunlight tolerance, and we're seeing that result in improved patients' reported quality of life. And on top of that, generally, bitopertin remains well tolerated in these patients, and there's been a lot of interest in whether there'd be an impact on hemoglobin. And yet again, we see no meaningful effects on hemoglobin. So we're really hitting all the key points for what we wanted to get out of this open label study being conducted in Australia, and we're delighted with the results so far. With respect to DISC-0974, we presented, of course, in 2022, excellent phase 1 healthy volunteer data with this molecule, which, as you know, is designed to suppress hepcidin and mobilize iron, and generally is positioned as a treatment for anemias of inflammation. Here at this ASH conference, we're for the first time presenting data from trials in patients, so phase 1b studies in patients with myelofibrosis. And also, now at this presentation, we'll share a small amount of data from our study in patients with chronic kidney disease. So in these datasets, we are seeing across the board substantial reductions in hepcidin levels. And this is not surprising, but we are, you know, delighted with the depth and persistence of that drug effect on hepcidin levels. And that has translated into very substantial increases in iron levels, and you'll see that happening at relatively low doses in the myelofibrosis trial. And then in those myelofibrosis patients, where we've had a bit more time to run the study, we've had some more experience with those patients, more duration of therapy. We're able now, and at this conference, we've been able to share some hematologic data for the first time, and we're seeing positive impacts on, hematologic parameters across a broad range of MF patients. So the different subcategories that people have tended to divide these patients into, we're seeing responses, hematologic responses, across all of those categories. And we think that's really unique and important and, and was something we always expected to be part of the profile for this drug, and it's great to see that materializing now in this early dataset. And then, of course, the DISC-0974 is generally well tolerated at all of the evaluated dose levels. So once again, we're hitting each of the key points that we wanted to achieve, in this early first look from these two patient studies. With that, I'll hand it over to Dr. Wang to give us an introduction to bitopertin in EPP. Thanks, John. Hi, everyone. I'm Bruce Wang. I'm an associate professor in the Department of Medicine in the Division of Gastroenterology at UCSF. I am one of the principal investigators in the NIH-funded Porphyrias Consortium here in the US. And here are my disclosures shown here.... So, we're talking about erythropoietic protoporphyria or EPP. EPP are genetic disorders related to the production of heme. And heme is a molecule that is made in every single cell in the body, but red blood cells are the cells that make the most heme, primarily for the production of hemoglobin. You can see here on the right, the biosynthetic pathway of heme, where you start from starting material of glycine and succinyl-CoA, and eventually end up with heme after eight enzymatic steps. Shown in here in purple are the eight genes that encode for the eight enzymatic steps that will eventually make heme. In EPP, most patients with EPP have inherited mutations that lead to defective function of the eighth and last enzyme of heme biosynthesis in ferrochelatase. As a result, this produces a bottleneck, and you have an abnormal accumulation of the pathway intermediate sort of made prior to ferrochelatase, which are the porphyrins, protoporphyrin IX. Protoporphyrin IX then accumulates initially in red blood cells, but then eventually spills over into the plasma, into the skin, as well as in the liver, and leading to its multiple effects. A small number of patients with EPP have a separate mutation, a gain-of-function mutation in the first step of the heme biosynthesis pathway in red blood cells, in the ALAS2. This gene is encoded in the X chromosome, and patients with that condition have XLP. But increased activity of ALAS2 eventually actually also leads to a bottleneck step at ferrochelatase, because ferrochelatase cannot handle the increased influx of pathway intermediates. And patients with XLP also have abnormal accumulation of protoporphyrin IX, and they have identical symptoms as those who have loss-of-function mutation in ferrochelatase. So what's the problem with having high levels of protoporphyrin IX in the body? Well, protoporphyrin IX is a highly toxic, and it's a photoreactive metabolite. The chemical structure of protoporphyrin IX, which we'll show in the next slide, is actually very similar to chlorophyll, and it's a molecule that can absorb light radiation. After absorption of light, protoporphyrin IX then releases that extra energy, and that causes the extra energy to be transferred to oxygen molecules, which results in reactive oxygen species. This leads to cell death and tissue damage from a variety of mechanisms, including membrane lipid peroxidation, and eventually leading to complement activation, mast cell degranulation. And protoporphyrin IX by itself may be highly toxic, independent of photosensitizing reactions. This is particularly true in the liver, where high amounts of protoporphyrin IX can form crystals, and that can cause cholestatic liver injury. So what are some of the symptoms that accumulation of protoporphyrin IX causes? The first organ that develops problems is in the skin. Protoporphyrin IX absorption of sunlight can then emits that absorbed energy, resulting in energy and heat and oxidative damage. This results in pain, burning sensations, swelling, inflammation, and eventually chronic skin lesions on the parts of the skin that are exposed to sunlight. Mention that excess amounts of protoporphyrin IX can accumulate in the liver, and they can form crystals that can block bile canaliculi. This results in cholestasis. It can manifest as a rapidly progressive liver disease that can develop into advanced fibrosis and cirrhosis within months to a year, and is generally incurable unless a patient undergoes a liver transplant. There may be other complications, as well, related to the psychosocial impact of this disease. As a result of the sunlight sensitivity on their skin, patients spend most of their time avoiding sunlight exposure. These patients oftentimes will have issues with focus, concentration. They have difficulty sleeping. They suffer from both physical and social isolation and require significant modifications of their lifestyle, leading to mental health symptoms and issues. These other psychosocial aspects can also lead to other complications, including nutritional deficiencies because of a lack of sunlight exposure, resulting in osteoporosis, increased propensity for fractures. There's also chronic alterations in skin, and patients can develop mild anemia. Of all these symptoms that I just described, the primary manifestation is photosensitivity, and this can result in debilitating pain. These symptoms develop very young in patients with EPP. For in some patients, seconds or minutes of sunlight exposure, EPP patients experience disabling pain attacks, and these pain attacks can last for days, and there are very few modalities that can alleviate the pain. And patients essentially just have to wait it out. These attacks can cause burning sensations, swelling, itching, erythema. You can see some of these in the images shown here of this young child. Oftentimes, actually, the skin manifestations are not very visible, and they're typically far out of proportion to the amount of pain that the patients are feeling. But in here, you can see a little bit of the facial swelling. You can see in this child, you can see in the back of the hands here, some erythema and swelling. Over time, this can lead to chronic skin lesions and scarring, shown here in these bottom two images. As a result of the sunlight sensitivity, EPP patients end up taking very extreme measures just to avoid sunlight exposure. They spend most of their time indoors, avoiding sunlight. This causes them to miss many daily activities and is especially impactful on young children. When the patients do have to go outside, they have to completely cover their skin. Shown here are two images of two kids who have learned to adapt that when they go outside, they have to completely cover their skin to avoid direct sunlight exposure. So now I'm going to hand it over to Will Savage, who will tell you more about bitopertin. Bitopertin is an orally administered inhibitor of glycine transporter one or GlyT1. In erythroid cells, GlyT1 supplies glycine for the initial step of heme biosynthesis that Dr. Wang just reviewed. Bitopertin was previously studied in other indications in clinical trials that enrolled over 4,000 individuals. By inhibiting GlyT1, we think that bitopertin can decrease the amount of glycine uptake into red blood cells and modulate heme synthesis to decrease PpIX. Data in the literature suggests that reductions of PpIX of greater than 30%, as seen during pregnancy, for example, can improve light tolerance in EPP. As a result, we initiated the BEACON trial to evaluate safety and efficacy of bitopertin in individuals with EPP. So that's the focus of today's data discussion, the BEACON trial, shown on the left. We also have a randomized placebo-controlled trial of the same two doses used in BEACON, but with the addition of a placebo group in the AURORA trial, in which data is expected early in 2024. The trial endpoints for both of these studies include changes in blood PpIX levels, various measures of light tolerance, including time to prodromal symptom, and a number of measures of safety, tolerability, PK, and patient-reported outcomes. As of the data cutoff, the study was fully enrolled with 22 participants, including 17 who had completed 4 months on study and 14 participants who had completed all 6 months on the study treated with bitopertin. The primary endpoint for the trial is the% change in PpIX. Treatment with bitopertin, shown by the dark blue line, resulted in a significant mean decrease in PpIX of more than 40%, collectively across both dose groups. The reductions in PpIX were dose-dependent and more pronounced in the 60 mg group as compared to the 20 mg group. The reductions were also observed across a broad range of baseline PpIX levels. Marked improvements in light tolerance were observed in every patient, and PpIX reduction was associated with the degree of improvement. The greatest increases in weekly averages of total time in sunlight were observed in the participants who experienced reductions of PpIX of at least 30%, the level that the literature would predict would lead to marked and potentially life-changing improvements in light tolerance. Bitopertin improved other measures of light tolerance as well, as seen in the secondary endpoint, time to prodrome. These are data from weekly sun exposure challenges in which participants attempt to elicit a prodrome. A prodrome or early warning, symptom happens in everyone with EPP. Patients usually experience burning or tingling before a full phototoxic reaction occurs, and importantly, patients can avert a full reaction if they extract themselves from the sun when the symptoms start. We take advantage of this phenomenon to measure how much time in sunlight can be tolerated until they get these prodromes. Shown here are the mean changes from baseline for time to prodrome data averaged over two-week periods. Bitopertin resulted in significant time-dependent improvements, with threefold increases in time to prodrome relative to baseline after six months of treatment. Other measures of light tolerance were also assessed in the study. Overall, there was a 92% reduction in the rate of patient-reported full phototoxic reactions. On the left, we are looking at daily diary data and the proportion of symptom-free days, with patients going from a minority of days that are symptom-free to a vast majority of days without EPP symptoms. On the right, we're looking at data from the weekly sunlight challenges, where the time to prodrome is assessed. Only 7% of sunlight challenges did not have a prodrome at baseline, whereas over half the challenges while taking bitopertin did not have a prodrome. This means that most of the time, patients cannot elicit symptoms of their disease when they went into the sun, no matter how much time they spent in the challenge. This graph represents all of the sunlight challenges on study. The proportion of sunlight challenges that were prodrome-free actually increased during the course of the study. Participants receiving bitopertin also reported improvements in quality of life measures. Nearly all participants reported that their EPP was much better or a little better, and that their EPP was mild or not at all severe, and further, that EPP had little or no impact on their quality of life at the end of the study. The key secondary endpoint of the study was cumulative time in light on days without pain. This is a precedented pivotal endpoint as used by the afamelanotide development program. Over the six-month course of the study, the total time in sunlight, according to this endpoint, was a mean of 222 hours, which represents a threefold increase relative to historical control, which is a placebo group from the afamelanotide U.S. phase 3 trial. With regards to safety, no serious adverse events have occurred, hemoglobin has been stable, and no anemia AEs have been reported. The treatment-emergent adverse events reported in more than one subject included dizziness, lightheadedness, headache, and nausea. Thus, bitopertin safety profile on EPP is consistent with prior studies and other indications in over 38 clinical trials. Moreover, the observed safety profile observed to date has supported the inclusion of adolescents in the BEACON study. So the key takeaways from the updated BEACON data that we present here further confirm the establishment of proof of concept. Significant reductions in PpIX were observed at both low and high dose levels of bitopertin. As far as functional outcomes, there's significant improvement in sunlight tolerance, including the precedented pivotal endpoint of total time in sunlight. As far as impact on quality of life, patients reported across a number of metrics, improved quality of life. And with regards to safety, bitopertin is well-tolerated, with no meaningful change in hemoglobin while taking bitopertin. Now, I'd like to hand it over to Jonathan Yu, our Chief Business Officer, to go over the EPP commercial opportunity. Thank you, Will. With the first presentation of our bitopertin data in June, we began the next phase of commercial planning, and that includes understanding the size of the EPP opportunity at a more granular level, which we are sharing today. In terms of prevalence, if you go to slide 25, historically, what has been accepted is around 1 in 100,000 patients. That works out to be about 3,000 addressable patients in the U.S. and 7,000-8,000 combined in U.S. and Europe. These are the numbers that we provided in the past. However, we've always suspected that this figure underrepresented what the true prevalence of EPP was. This is generally true for most orphan diseases, where prevalence grows when an effective treatment becomes available. But specifically for EPP, we felt this was the case because we know that there are reports of higher prevalence in the figure in the literature, anywhere from 2-5 times as high as the canonical figure of 1 in 100,000. We also know that in most cases, the methodology was not comprehensive, as estimates were based on a nose count of patients identified at either only a single center or a few centers. And lastly, we know from our discussions with patients that there's a significant pool of patients who may already have a diagnosis but no longer interact with the healthcare system because there is no available treatment. Now, one of the distinguishing features of EPP is that unlike some other rare diseases, there is already an ICD-10 code for the diagnosis of EPP. What this enabled us to do was to conduct an analysis of real-world claim data to better understand how many patients there are in the U.S. in a systematic and comprehensive way, where these patients are located, and lastly, other patterns of the disease, such as comorbidities and utilization of healthcare resources. The results of this analysis confirmed that the prevalence of addressable patients in the U.S. is indeed higher. Based on the claims data, we estimate that the range of patients in the U.S. is closer to 3,000-6,000 patients, as opposed to just 3,000. This analysis was based on a combination of how frequently these patients had ICD-10 claims codes, how recently they had these claims codes, and other hallmarks of the disease, such as complications, comorbidities, and exclusions of other diagnoses. This figure of 3,000-6,000 patients is more in line with the higher range of reports in the literature, roughly 1 in 60,000-70,000, from the previous slide. To be clear, we expect that these patients represent an immediately addressable segment. In other words, these are diagnosed, symptomatic patients who are engaged with the healthcare system and seeking treatment, and they will be the initial focus of our commercialization efforts. In addition, the claims data suggests that a number of diagnosed patients and prevalent patients could be as high as 14,000. Now, we need to further qualify this segment of incremental patients, but we believe that these patients reflect the EPP patients who were diagnosed but now have limited interaction with the healthcare system for their disease, given the few treatment options that are available. This is a group that we hope to bring back into the system with the advent of a new therapy. To give you context of what this, these numbers mean, we've mapped on the right side of the slide the prevalence bands, against the prevalence band of EPP, against the prevalence of other rare and ultra-rare diseases, which have supported blockbuster drugs or classes of drugs. What this tells us is that there is already a strong and sizable foundation of existing EPP patients in the healthcare system, the size of which is on the order of markets such as PNH and HAE, and that there is potential for expansion in the long run. In addition, the data set is rich enough that we are able to understand how the patients are geographically distributed and who is managing their care. As you can see, these diagnosed EPP patients are largely concentrated in key porphyria treatment centers in the U.S. This concentration of patients should allow us to have a very focused patient and healthcare professional targeting strategy and enable an efficient field force during the launch for the launch of bitopertin. Lastly, on slide 28, in addition to the number of EPP patients and their concentration at key centers, our claims data analysis also validated the significant burden that EPP places on patients. As Dr. Wang discussed earlier, the phototoxic reactions are the most prominent manifestation of the disease for EPP patients. We also know from reports in the literature and our interactions with patients that EPP is multidimensional and has an impact beyond just photosensitivity. This is borne out in our analysis. For example, we know that as a consequence of the disease, patients spend the majority of their time indoors, leading to isolation and contributing to psychosocial issues. Our analysis indicates that this results in 56% of EPP patients also having a diagnosis of anxiety and/or depression that requires treatment. This data also confirmed another key manifestation of EPP, with 34% of patients having a claim for liver and/or biliary issues. In other words, those hepatobiliary complications requiring some level of medical intervention or consult. And lastly, this analysis revealed that EPP patients have a disproportionately high treatment rate with steroids, narcotics, and prescription vitamin D, and also have a higher rate of ER and hospital admission, underscoring the severity of their disease. So taken together, these data confirm that there is a sizable number of diagnosed, identifiable EPP patients with a significant burden of disease, and that these patients are largely concentrated at a small number of key treatment centers. We feel this supports the significant potential co-commercial opportunity for bitopertin in EPP, which can be achieved with a highly efficient operating model. With that, I will turn it back over to Will. Thanks, Jonathan. Now we'd like to change gears to review the initial data that we presented at this ASH meeting on the anemia of myelofibrosis in our DISC-0974 program. DISC-0974 is an anti-hemojuvelin or HJV monoclonal antibody designed to suppress hepcidin. With the reduction in hepcidin, we expect increases in iron in circulation, which can then be made available to red cell precursors in the bone marrow to enable red cell production and correction of anemia. The target, again, of 0974 is HJV, which is an upstream regulator of hepcidin gene expression. HJV is genetically precedented to lower hepcidin and increase iron in people who have loss-of-function mutations in HJV. That loss of function is tissue-specific and specific to hepcidin and iron metabolism. In 2022, we presented single ascending dose healthy volunteer data that showed robust hepcidin reduction, shown on the left, and robust iron mobilization, shown on the right, particularly at the top dose tested, the 56 mg dose level. In this slide, on the left, we're showing the PK/PD relationship at that 56 mg dose level. The red line shows dose concentration after subcutaneous administration. In blue is the hepcidin reduction, which goes down 75% after drug is given. And then as hepcidin goes down, iron goes up, and here that's measured as transferrin saturation, which more than doubles. On the right was an unexpected finding in this study, and that was a 1 gram per deciliter improvement in hemoglobin as compared to the pooled placebo group. This increase was durable through the end of the study. With these compelling results of the healthy volunteer study, we turned our attention to myelofibrosis. MF is a clonal hematopoietic disease that affects about 18,000 people in the US, and anemia afflicts almost every patient at some point in their disease and is a major unmet need for this population. The cause of anemia is multifactorial, but essentially, all patients have elevated hepcidin from the inflammatory stimulus of the disease. On the right are hepcidin levels in MF patients at progressive stages of disease, and essentially all patients are seen to have an elevated hepcidin with an average of 12-fold increase as compared to controls. The data we're presenting today come from our phase Ib dose escalation portion of our MF trial. Patients in this trial are receiving 6 monthly doses of DISC-0974 at each dose level. Patients may be transfusion-dependent or not transfusion-dependent and may be taking any stable dose of MF-directed therapy. The dose escalation has an accelerated titration phase with an escalation of N=1 per cohort until iron mobilization or safety escalation rules are met. Then the dose escalation continues to what's called a BOIN design, which is a kind of flexible 3+3 design that can enroll 3-9 patients per dose level. The study will then move into a phase 2a expansion portion. Below is shown the enrollment as of the October 20 data cutoff, which includes 11 patients. We had 1 accelerated titration cohort of N=1 before moving into the 28-milligram BOIN dose escalation, in which we enrolled 7 patients before escalating to 50 milligrams. The patients were a mix of transfusion-dependent, not transfusion-dependent patients, and were on and off JAK inhibitors. Hepcidin results are shown on this slide. On the left are the hepcidin results for the 28 milligram cohort. They show markedly elevated baseline levels of hepcidin, but regardless of the baseline level, all patients had their hepcidin reduced for several weeks after DISC-0974 dosing, and the reduction continued until the second dose would be given on day 29. On the right is longer-term hepcidin data for both the 14 and 28 milligram dose groups. They show a dose-dependent decrease in hepcidin after each dose, which is indicated by the arrows. As we discussed previously, when hepcidin goes down, iron goes up, and on the left, we see a dose-dependent increase in iron over time. On the right, we are putting together the PK/PD relationship with the drug concentration in purple, hepcidin reduction in black, and iron mobilization in red. These data show a greater than 75% reduction in hepcidin that is durable and a reciprocal greater than 75% increase in serum iron. The consequence of iron mobilization in the setting of anemia and high hepcidin should be an improvement in hemoglobin, to the extent that high hepcidin contributes to that anemia. We divided the evaluable 28 and 50 milligram patients into non-transfusion-dependent and transfusion-dependent groups. On the left are the non-transfusion-dependent patients, in which 4 of 7 had a durable increase in hemoglobin of greater than 1.5 grams per deciliter. Responses occurred both in patients taking and not taking a JAK inhibitor. On the right are the transfusion-dependent patients, and in whom 1 achieved transfusion independence, going 12 weeks without a transfusion in the last 12 weeks of the study. DISC-0974 was well tolerated at all dose levels, and most AEs were not attributable to drug. There was one SAE that was hip pain and deemed not related to drug. We also are conducting a trial in non-dialysis-dependent chronic kidney disease and anemia, and we'd like to share initial data out of this study as well. For some background, non-dialysis-dependent chronic kidney disease affects over 5 million people in the U.S. and has a high prevalence of anemia. Hepcidin contributes to anemia from underlying inflammation and poor clearance of hepcidin, which is excreted by the kidneys. On the right is shown a 20-fold increase in hepcidin versus healthy controls. Most patients are untreated or undertreated for their anemia. Our study is a single ascending dose study of anemic non-dialysis CKD patients, and we are presenting data from the first 28 milligram cohort. This included 6 patients receiving active drug and 2 placebo patients. On the left is shown a meaningful reduction in hepcidin with a single dose of DISC-0974. We anticipate that this reduction will increase as we continue with dose escalation in this study. In the middle panel shows iron response as measured by transferrin saturation and compared to placebo. And on the right is shown the similarity of iron mobilized in the 28 milligram sub-Q dose in this study versus 28 milligram sub-Q in the healthy volunteer study, a dose that did not increase hemoglobin in that healthy volunteer study. Overall, DISC-0974 was well tolerated. There were 2 SAEs that were not related to DISC-0974. So the key takeaways from our initial DISC-0974 data are, again, establishing initial proof of concept.... There is dose-dependent meaningful reductions in hepcidin and increases in iron, and we have a signal of the hematologic response in the more mature MF study. We see improvements in hemoglobin and transfusion burden across a broad range of MF patients. And from a safety perspective, DISC-0974 is well tolerated at all evaluated dose levels. And now I'd like to hand it back to John for closing remarks. Thank you, Will. So across this conference today and at this discussion this evening, hope you've heard some interesting information and new clinical data across these two lead programs at Disc Medicine. To summarize what we shared with bitopertin, our leading heme synthesis modulator, we've demonstrated in this open-label BEACON trial, consistent significant reductions in protoporphyrin IX, with a pooled average of greater than 40% reduction across both dose groups. We've shown significant improvement in sunlight tolerance using multiple different endpoints. Specifically, a greater than threefold increase in time to prodrome, and a greater than threefold increase in cumulative time in light as compared to historical controls. And this, as we've said, is the precedented endpoint, and foundation for approval of the only approved drug, in this space. It's also translated into an increase in symptom-free days and improvements in quality of life, and the drug was generally well tolerated in these patients. Turning to DISC-0974, our hepcidin suppression agent in our phase 1b/2 trial in myelofibrosis patients with anemia. This initial look at data from dose escalation demonstrated a consistent decrease in hepcidin, at serum hepcidin, greater than 75% decrease on average, in fact. And this, of course, translated into meaningful increases in serum iron. And we've been able to show hematologic responses in a broad range of patients. Turning to our phase 1b/2 trial in non-dialysis chronic kidney disease patients with anemia, we've shared data from our initial cohort, a 28 milligram dose group. And in these patients, we've been able to share that at this relatively low dose, we're seeing meaningful reductions in hepcidin and an increase in serum iron, with a similar overall PK/PD effect as seen in our healthy volunteer study. The drug was generally well tolerated in these patients, and so we look forward to escalating through higher doses, where we'll be looking to see this translate into potential hematologic benefits. So here we are in December. It's been a remarkable year at Disc Medicine, and we're really continuing our strong growth trajectory as we work to build what we hope to be a leading hematology company. We've made significant accomplishments in 2023. On bitopertin, we've now been able to share positive initial phase 2 data from our open label study with the second program, DISC-0974. Now, at this meeting, we've been able to share the initial proof of concept in anemia of myelofibrosis and some initial data in our chronic kidney disease trial. And not mentioned today, but we've also, this year, acquired rights to our third clinical stage program, DISC-3405, and in fact, initiated a phase 1 healthy volunteer study just a couple months ago. So this sets us up for what we hope to be a very exciting year in 2024, with many strong catalysts to come. First and foremost, in the bitopertin program, we'll have the readout of our double-blind placebo-controlled trial, AURORA, projected for early 2024, and that will lead to, what we think will be meaningful regulatory interactions and, hopefully, preparation for a phase 3 trial. We also look forward to sharing proof of concept data in our study in patients with Diamond-Blackfan anemia. In DISC-0974, as we continue these studies in myelofibrosis and chronic kidney disease anemia, we'll be able to strengthen the POC data in myelofibrosis and hopefully achieve that kind of POC in CKD. And then we are continuing our efforts on preclinical models to establish potential additional indications across this broad space of anemia of inflammation, where this drug may be useful. And for DISC-3405, we'll be sharing our initial healthy volunteer data in 2024 and zeroing in on polycythemia vera as our first indication. And all this is supported by a strong cash position with a runway projected well into 2026, and that's assuming, you know, all success across all of these programs. So thank you for your attention today, and we're, you know, excited with everything that's happened in 2023 at Disc Medicine and looking forward to 2024. Thank you for your attention today, and now we'll open the lines for questions. ... Thank you. We will now begin the question-and-answer session. As a reminder, to ask a question, please press star one one on your telephone keypad 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. Once again, that's star one one for questions. Our first question comes from the line of Jeff Hung from Morgan Stanley. Please ask your question, Jeff. Congratulations on the updates, and thanks for taking my question. For 0974 and MF, what level of hepcidin reduction is needed to show clinically meaningful benefits on anemia? And how long does hepcidin reduction take to translate to benefit in patients? And then I have a follow-up. Hey, Jeff. Yeah, great. Thanks for the question, and, Will, answer that. Sure. So the key to improving hemoglobin is making iron available, and so there's not necessarily a specific threshold of reduction in hepcidin that is needed. You just need to see the iron mobilization go up. In our... You know, we now have hemoglobin response data that show that we need to get greater than 75% reduction to get the iron mobilization that's needed to get these initial responses. Okay. And then, can you just talk about the hemoglobin change from baseline in the two transfusion-dependent patients? And do you have a sense for the treatment duration needed to have an impact on transfusion dependence? Thanks. Yeah. Well, it's shown in the figure. It's more of a visual representation, you know, seeing the transfusion reduction over time in the one responder. For a response, for a transfusion reduction or a transfusion-independent response, changes in hemoglobin are not necessarily needed to be robust. You just need to stabilize at a hemoglobin that's higher than their baseline. So, you know, we have in the one patient shown a, you know, had an increase in hemoglobin that was sufficient to ward off a lot of transfusions as compared to baseline. Thank you. Thank you, Jeff. Our next question comes from the line of Thomas Smith from Leerink Partners. Please ask your question, Thomas. Hey, guys. Good evening. Thanks for taking the questions, and, congrats on the strong data. Just, two on bitopertin, if I could. I guess first, when you look at the individual patient-level PpIX data, could you just elaborate on, some of the patient-to-patient variability you're seeing and how that compares versus your expectations? I know it's a limited number of patients, but, are you seeing any common characteristics across patients that suggests, either very deep kind of super responders, or was there anything notable in the two patients who didn't achieve at least the 30% reduction? So I think the data are not yet mature, to make a comment about things like, you know, genotype or adherence in the trial, to make a statement on that. There's not any characteristic thus far that we see. I mean, in part because, most patients are getting great reductions in PpIX. So, I mean, it's something we'll continue to look at as the dataset, matures, though. Got it. That makes sense. And then just a question for Dr. Wang. I was just wondering if you could help put some of the clinical improvements into context. Things like the improvements in daylight tolerance, symptom-free days, some of the patient-reported outcomes data. Would just love to get your view on the efficacy and how meaningful you think this is, this treatment effect would be for patients. Thanks. Sure. You know, as it was mentioned by Will, the increase in total amount of time to light before patients develop burning pain was, I would say, pretty actually, you know, relative to the historical controls in the afamelanotide study, patients in the BEACON study did a little bit better. In terms of the time to prodrome, which is a more recent endpoint and was also the endpoint that has been used in the more recent dersimelagon study, I think the 3-time increase over the patient's baseline is also in line with what has been published in the phase 2 study for dersimelagon. I can, you know, I can say that from my experience with my patients, who have been on afamelanotide, really for the EPP patients, really, any significant increase in the amount of time that they can spend in the sun, leads to a really significant improvement in quality of life. And so I think the quality-of-life data that's shown in the BEACON data is consistent with what I've seen, in EPP patients. And I do think that this is really clinically significant for them. Got it. That's super helpful. Thanks for taking the questions, and, congrats again on the data, guys. Thank you, Tom. Thank you, Thomas. Our next question comes from the line of Ben Burnett from Stifel. Please ask your question, Ben. Great, thank you, and I'll add my congrats to the data. Great update. I want to ask about the bitopertin data. Is there any color you can provide on the headaches and lightheadedness that we're seeing? Like, were these more or less first dose effects? And I guess how persistent were they? ... Sure. So, you know, when we presented data in mid-year, we mentioned that these headaches and lightheadedness followed the same course that was observed in the previous Roche development, and that is that they are-- they occur generally early on upon initiation of dosing, and they're transient and mild and seldom need dose reduction. So that continues to be the case here. Okay, that's very helpful. I also wanted to ask about some of the claims data that you highlighted as, as illuminating, I guess, potentially bigger market opportunity in EPP. I guess, if you could just maybe walk us through that analysis, and maybe just give us a sense for what's behind it, sort of rather wide range. I think it's, it was like 3,000-6,000 was sort of the initial kind of target population. Just curious if you could give me color on why the range. Yeah, sure. I mean, I think just to be clear, Ben, so this is Jonathan. Thanks for the question. Just to be clear, these numbers that we gave, this 3-6,000 and also the 14,000, these represent actual individual patients with claims for the ICD-10 code for EPP. We decided to triage this a little bit. When we talk about the 3-6,000 patients in the U.S., we put some pretty strict filters on that. So these are patients who have very recent, very frequent diagnoses of ICD-10 of EPP. They have complications associated with it, that are hallmarks of EPP, and they see specialists who treat EPP, so we feel very confident about the 3-6,000. The 14,000 patients represents those who may be less frequent. We feel that those that have less frequent or less recent ICD-10 claims for EPP, and we think that represents the patient population who they do have EPP, they are symptomatic, they are trying to seek treatment for it in the healthcare system, but they sort of, broadly speaking, have sort of excluded themselves and sort of need to sort of become back to the system and will, once there's a treatment that's available then, and effective. Got it. Okay, so that range is just sort of the kind of degree of filter that you're putting on those claims data? Exactly. Exactly. Okay. The 3,000-6,000, sort of like, they call it day one, kind of available. We know that these are patients who are actively seeking treatment. And then as over time, as the drug becomes available, it potentially grow to the 14,000. Understood. Okay. And if I could just squeeze one quickly in for DISC-0974 myelofibrosis. Very interesting data. I, I think we were kind of assuming or expecting that a lot of those patients would be on, on background, like JAK inhibitor therapy. You actually enrolled a fair number of patients who weren't on concomitant JAK treatment. Is this what you were expecting? And I guess maybe going forward, as the program matures, would you expect more patients to be on concomitant JAK inhibition therapy? Yeah, I think over, you know, looking at a population of MF patients, you'd expect most majority to be on JAK inhibitors. You know, our inclusion criteria are open to people on or off JAK inhibitors. You know, as we do have plans later on in this study to ensure that we enroll sufficient numbers of patients who are on or off, so that we are able to make a statement about each population. I will, you know... That said, we think our mechanism is independent of a JAK-related efficacy, and so we think it can work in both populations, but nevertheless, we'll evaluate it in both. Okay, awesome. Thanks so much. Thank you, Ben. Our next question comes from the line of Danielle Brill from Raymond James. Please ask your question, Danielle. Hey, guys, this is Alex on for Danielle. Let us also extend our congratulations on the data update. Just another question on vitiligo. It seems like baseline light tolerance for these precedent EPP studies are a bit variable, with the baseline tolerance here in BEACON falling a little bit towards the higher end, in our view. So the question from us first is, what is the upper bound light tolerance in your mind for an untreated EPP population? And then, if you do get a population in AURORA with a high baseline light tolerance from a powering perspective, is there a sufficient window, from baseline tolerance to maximum time people are willing to stay out in the sun to visualize a statistical sig- difference and moreover, a differentiated profile, versus Scenesse? So to answer your first question, I think that the baseline light tolerance is rather representative, and when you look across development programs, it's pretty aligned with the epidemiologic data of a median time of half an hour of light tolerance, with some people ranging from, you know, minutes, and, you know, essentially, most people having only up to 2 hours of light tolerance. So that's, you know, the population that was included in BEACON and is seen in other studies as well. So, you know, it, it is, you know, just a, and well, I should say that those who have—because the median is 30 minutes, those who have longer periods of light tolerance are a smaller number of smaller proportion of the EPP population. you know, their contribution to a larger trial in terms of the amount of increase in light, it is true, there's only so many hours of the day to be in sunlight, but they still have an opportunity to improve, but that proportion of the population is gonna, you know, be a small minority contributing to a light tolerance endpoint. It may be worth elaborating also on how we did the stratification in the AURORA trial. Sure. So both in BEACON and AURORA, we stratified patients into the arms by ±30 minutes of light tolerance at baseline to make sure we get an even distribution of those with shorter and relatively longer times of tolerance. Great. That's very helpful. Thanks. Thanks. Thank you, Alex. Our next question comes from the line of Malcolm Hoffman from BMO. Please ask your question, Malcolm. Hi, guys. Malcolm on for Evan Seigerman. I wanted to first start by saying congrats on the data for both DISC-0974 and bitopertin, and thank you for taking my question. So for my question, I wanted to ask about the patients in the MF anemia study who were treated with JAK inhibitors. Did you guys notice any variability in anemia improvement trends for patients across different JAKs used, either previously or concomitantly? The reason I'm asking is I'm just trying to get a sense whether anemia responses may be different with new JAK inhibitors like momelotinib, which have been shown to have an improved anemia profile in some patients. So thanks again for taking my question. Sure. So I think, you know, the numbers are still small, and we're still escalating. I think it's an analysis that we will look at as we get, you know, more data. I think, you know, we are transparent about the responses. You can look at those who are on a JAK inhibitor and look at the stability of their hemoglobin following the individual curves. I think at this point, you know, we haven't seen JAK inhibitors other than Jakafi in patients on our study at this point. Yes, but all comers are allowed in the study. Yeah. Right. Right. Gotcha. Appreciate it, guys. Thank you. Thank you. Thank you. you. Thank you. Our next question comes from the line of Douglas Tsao from H.C. Wainwright. Please ask your question, Douglas. Hi, good evening. Thanks for taking my question. Just maybe starting with bitopertin, obviously there were two patients who did not achieve the 30% reduction in terms of their PpIX levels. I'm just curious if you have a sense of what might have contributed to that, because obviously they had a fair amount of exposure to the drug, or is it just simply a function, some patients may not be fully responsive to this treatment? Yeah. So we, you know, I think the first point to make is that the 30% threshold is really to achieve, is where you achieve those life-changing improvements in light tolerance. The less than 30% is still associated with marked improvement in light tolerance. But, you know, as I mentioned before, you know, we, we don't have analysis yet of treatment adherence. We will look at genotype. You know, there's no expectation that genotype matters, here. You know, it, it'll be something we, you know, we look into, but we don't have an answer for that now. But nevertheless, they still are showing marked improvement. Okay. And then just in DISC-0974, when we look at the patients and the hemoglobin increase, it seems to occur fairly rapidly for those who do experience a response. And so would your expectation be that for the most part, patients will sort of see the improvement that they're gonna see within 30-60 days? Well, that's what the data are looking like so far, but, you know, we don't know, or we will find out how representative that is. I mean, there's, you know, there's gonna be varying levels of marrow fibrosis, splenomegaly, you know, in the background here, and there may be, you know, some patients in whom it takes longer to manifest, a hemoglobin improvement. So you know, I, I, I'm remain open-minded to responses, you know, up to six months, which is why we designed the study that way. And I think that's a range that's clinically, you know, meaningful in clinical practice to be on treatment for a while and, and await a response. Okay, great. Thank you so much. Thank you, Douglas. Our next question comes from the line of Kristen Kluska from Cantor Fitzgerald. Please ask your question, Kristen. Hi, everyone. Let me also add my congratulations on all the updates you shared today. So one on bitopertin, just looking at the prodromal symptoms and the phototoxic reactions, are you seeing any change to the degree or severity or, of pain or symptoms that emerge when it does happen, considering that these patients are, you know, benefiting from the therapy in general? Yeah, so that's something we haven't fully analyzed yet. I mean, early indicators are yes, but we don't have that quantitatively yet. Thank you. ... Thank you. Great. Thanks, Kristen. Our next question comes from the line of Rami Katkhuda from LifeSci Capital. Please ask your question, Rami. Hey, guys. Just wanted to pass along my congrats on the updates as well. I guess, given that the greatest improvements in light tolerance have been observed in patients with PpIX reductions greater than 30%, do you still expect to advance both the 20 and 60 mg doses of bitopertin in future studies based on the PD data that you've observed thus far? And then maybe could you introduce a dose titration schedule based on a patient's PpIX reductions in a pivotal study? So, I mean, we remain open-minded. You know, as you know, we have the AURORA data, which are really gonna be, you know, three times as many patients and in a double-blind setting. So that's gonna be a compelling data set from which to evaluate the dosing strategy for phase 3. So we really haven't started forming an opinion yet. Both 20 and 60 are tolerated, and they're doing well in terms of light tolerance and achieving that 30% threshold. So there's really, you know, nothing discriminating right now, nor is there urgency, you know, ahead of the AURORA data readout. Makes sense. Thank you. Thank you, Rami. We have reached the end of the question and answer session. Thank you very much for all your questions. I'll now turn the conference back to John for any additional closing comments. Well, thank you all for your attention tonight. Really appreciate the questions, and we'll connect further at another date. Thank you. Good night. That concludes today's conference call. Thank you for participating. You may now disconnect.