Excellent. All right. Good morning, everyone. Welcome to 2025 Jefferies Global Healthcare Conference. My name is Roger Song, one of the senior colleagues at Jefferies. It's my pleasure to have the next fireside chat with Disc Medicine in John. Welcome, John. Yeah, great to be here. Awesome. All right. I think, you know, we had an interview with McCurry yesterday at our conference, and then pretty favorable comment around the rare disease and accelerated approval. We know you have a lead program on the epidural in the EPP space. And then why don't we start from there? Tell us about what has been the FDA interaction on the planned epidural, no, the NDA submission for EPP, and then anything changed before and after the new administration? Yeah, that's a great question. It's been obviously a hot topic, a lot of noise around changes at the FDA. Our experience has been actually very consistent, very positive interactions starting last fall with our end of phase two meeting, where we essentially reached alignment that protoporphyrin IX could serve as a surrogate endpoint to support accelerated approval. Following that, we had a type C meeting where there was alignment around the design for our confirmatory trial, what we call the APOLLO trial, which is, by the way, now up and running and enrolling, with a projection for about a year to get to full enrollment on that. I will say because of the noise around FDA dynamics, we've been probably disclosing a lot more about these interactions than we might normally do. You know, we shared that we would have an interaction around our CMC program, essentially the effort to compress what would have been an ordinary course, regular approval timeline down to an accelerated timeline for the CMC program. You know, for those who have been in the industry a long time, you know that these CMC efforts can take a long time. That interaction was very important to frame it in terms of, hey, if we're on an accelerated approval path, there are going to be a few concessions we need in order to be able to meet these timelines. We got all those concessions. Another favorable interaction. We went about scheduling our pre-NDA meeting, a meeting we wouldn't normally talk about, very ministerial in nature, just setting up how we present things in the NDA. That meeting was scheduled on time, no issues. It is on the calendar. We are projecting an NDA filing coming in the second half of the year. All of these interactions have crossed the boundary between the FDA under the prior administration and the FDA under the current administration. We have really seen no change in the staffing, timing, policy, application in all respects have been the same, and I would say generally favorable so far. Very good. All right. High confidence, able to file for accelerated approval for bitopertin EPP, and then also everything on track, the last step before the NDA submission seems to be the pre-NDA meeting, which is more administrative, just, you know, cross the t's and then dot the i's before you can really submit the package. Yep, that's our perception. All right. Very good. All right. This is a very late stage kind of for this program, and then people start to more focus on the commercial opportunity there. I think you give us a lot of the good data points, maybe just to summarize for us, particularly based on the level of the confidence for this market opportunity, because we have different ways to look at this opportunity from the highest end, maybe epidemiology, maybe the genetic, and then all the way to you have another approved drug and then the usage of the drug. How do you think about the range of the market opportunity? What's your level of the confidence for each estimates? Yeah, that's a great question. You know, the genetic data coming from MGH would say there'd be about 20,000 patients with this disease in the U.S. The usage of, to mark out the other extreme, the usage of the one approved agent, Scenesse, which is surgically implanted every two months, you know, that would measure the market as, I don't know, ballpark like 1,000 patients or something. If you look at the claims database, so we've used the Komodo claims database, we see 14,000 patients over the last seven years who've sought treatment that's been coded as EPP treatment. We think that probably measures, you know, interestingly falls between those two extremes, probably gives a pretty good sense. As we plan out our launch, we've looked at the degree of intensity with which these patients are seeking care. You know, one issue with this disease is that by and large, there haven't been great therapeutic solutions. I think most patients get their diagnosis and are advised, well, you just need to live your entire life inside out of the sunlight. They then go back and live their lives accordingly without necessarily seeking out a lot of additional medical care, unless they have, you know, a third of the patients have a liver complication that requires some additional attention. We have these 14,000 patients seeking care per the claims data, and we see about 6,000 of those having a higher degree of engagement with the medical system, meaning more recent claims or a higher number of claims against their EPP code. As we think about our launch, that's kind of our launch population. We're designing our sales force, our MSLs collectively to go after that population and then plan to use more general marketing strategies, you know, advocacy group engagement to try to activate the full 14,000 patient opportunity. Got it. Okay. Yeah, that's very helpful. So it's basically you have the boundary and then also relatively high confidence of what will be the initial early adopter. And then given this is a rare disease, probably, you know, assuming you'll get approval, you will price at a rare disease pricing based on your payer and then physician, the market research. How do you think about the launch trajectory going to look like? Are you going to be slow or this community is very engaged and then they're really looking for some new transformative therapy like epidural? Yeah, I mean, I think we have done some preliminary modeling and, you know, give us a little more time before we come to give some real guidance around the shape of the launch curve. Broadly speaking, I'd say if you map out other successful rare disease launches, we'd expect a similar kind of launch curve to those. Because to your point, there is a high degree of patient engagement and awareness. There are advocacy groups in place. You know, we will have, we expect roughly 150 patients on trial from our APOLLO + Helios long-term extension rollover trial as of launch. There are lots of tools we have that give us a feeling of confidence as we head into the launch. Yeah, got it. One of the unique perspectives for the epidural is you are addressing the underlying disease, right? It is really disease-modifying therapy. You got a green light from the FDA to use that as the endpoint for the initial accelerated approval and also the co-primary for the confirmatory study. Tell us about that PPIX reduction, how important that is for patients, physicians, would that change the launch trajectory in your market research? Yeah, it's interesting. I mean, PPIX is the entire disease, right? It's the toxin that's produced that drives both the skin reactions, the pain, and the liver damage as well. You know, it's there in the name, Erythropoietic protoporphyria, right? Protoporphyrin IX is in the name of the disease. It is a disease of excess PPIX. As a surrogate endpoint, it's very robust, right? If you go and talk to KOLs, everyone wants to simply reduce PPIX levels in these patients and sees that as essentially an adequate basis to understand that the drug is working. We were delighted that the FDA was willing to see it that way also and use that as the basis for surrogate approval. It was actually, you know, in some ways their recommendation to elevate that into the primary endpoint for the confirmatory trial, the APOLLO trial's co-primary PPIX reduction, as well as the more conventional time in light type of metric. Yeah, that's great. We are very happy for the patient can get this therapy really addressing the underlying disease versus the other current approval of the drug. Some of the pipeline, they are trying to just address the symptoms in terms of how to make those people can expose more to the sunlight. In terms of maybe just tell us about, because this accelerated approval passed, you're running, you just started a confirmatory study, and then you say that you normally do one year. How should we think about the timeline of the full approval? Do you, if you factor that into consideration, how this will impact the sales launch, assuming you get an initial approval? Yeah, so I mean, we haven't provided, you know, precise guidance on when the APOLLO trial will wrap up, but if you, you know, estimate a year of enrollment and then six months to the primary endpoint and a little bit of time to clean and analyze the data, you know, it points to kind of end of next year type of timeline to get that information. I think, you know, a positive readout there is expected and, you know, would add further weight of evidence as we're, you know, marketing this drug and educating physicians and patients about the potential benefits. I think, you know, the data set we have now already shows marked reduction in protoporphyrin IX. That is by itself a source for tremendous enthusiasm. You know, we were statistically significant on reduction in phototoxic reactions, you know, about 75% at our top dose level. You know, after protoporphyrin IX went down, there were literally no phototoxic reactions in the Aurora trial, which would be enormously impactful if we're able to reproduce that in the larger APOLLO trial. I think seeing if we're able to show that, it would be remarkably powerful evidence. Yeah, no, I totally agree. Okay, I think we probably should talk a lot more about your other pipeline because there's also a very big opportunity there. Before we do that, for the EPP, what's upcoming? We take a look at the landscape, seems not many activity there, which makes sense. It's a rare disease and not easy to address underlying disease. Anything really you will keep eye on to watch? Anything you want to mention to investors to say, okay, this is something we should pay attention? I mean, as you mentioned, there's some dersimelagon in development running their second phase three, having failed the first phase three trial. That is being run by Mitsubishi Tanabe. We'll see where that goes. Works by a tanning mechanism, so very similar to the already approved agent that's out there. We're aware of one other early clinical stage asset that's taking aim in a slightly different way at not reducing overall PPIX, but trying to kind of work on a theory of keeping PPIX trapped in the red blood cell. We'll see how that plays out as we go forward. Do we have any updates from that program? Because we, you know, we keep looking at the clinicaltrials.gov. It seems they are running a phase one, but we haven't seen any data, any intel you can tell us? Yeah, no, I have no further information beyond the public sources. Yeah, okay, very good. Understandable. Okay, so let's move on to your anemia program, 0974. So you have a, this is anemia associated with chronic inflammation, right? So you have two lead indications, which one is the myelofibrosis, the other one is CKD. Maybe we talk about the MF first, but you recently hosted a KOL event, which I found very informative. Maybe just give us some highlights from that event. What's the key MF need, what people are looking for from the 0974, and then we can talk about more details. Yeah, yeah, that's great. Yeah, that was a really helpful day for us as well. It's fantastic to have some KOLs come in and talk about the unmet need for anemia. I think that, you know, the simplest way to think about it is that there are many, there are several approved drugs that are used to treat myelofibrosis patients. Those approved drugs take aim at the spleen size and the symptom score for these patients, which are of course very important things to control and benefit patients on. The other third morbidity of this disease that has no approved therapy yet is the anemia. It's a direct consequence of the progressive bone marrow fibrosis that goes on and the intense inflammatory state in these patients. It leads to poor quality of life. I think actually one thing that was really helpful at this meeting was the reminder that it's also associated with poor outcomes in this disease. It has always been, I think, a high desire for KOLs to manage anemia alongside the spleen and symptoms that you get with the JAK inhibitor class of drugs. I think what should have come out of that is that there's a high unmet need for any way of managing anemia in these patients. There's no approved therapy for that. The only two therapies under investigation to manage anemia in these patients are DISC-0974 and then luspatercept, which is of course in a pivotal trial looking at a subgroup of patients who are both highly transfused and being treated with Jakafi. Yeah, got it. Yes, I think 0975 is also again uniquely kind of positioned in this population. Then you maybe just talk us a little bit about the upcoming data readouts. One is the EHI, you probably have some a little bit longer follow-up from the phase one portion. What should we expect there? Then also later this year, you're going to give us a phase two portion of the initial data, likely going to be ASH. Tell us about what should we focus on for those two data readouts and then for you to be able to make the next step decision. Yeah, so EHI just around the corner, we have not billed that as a major catalyst. But for both bitopagen and for 0974, we'll have a look at long-term extension data, which, you know, is actually quite important in both anemia and EPP. You want to show that your drug is durable, that, you know, for 0974, you're increasing hemoglobin and you're able to keep it elevated for a meaningful period of time. We'll have a look at that data, but it's just the same 35 patients that we saw at ASH now rolled out longer. As we come in towards the end of the year, we'll be able to provide data from our chronic kidney disease study with 0974. Should be, you know, kind of a complete set of single ascending dose, multiple dose work that we've done there. For myelofibrosis, like you say, we have our 90-patient phase two trial underway. It is open label, so we will be able to take a slice of the data such as it is ahead of that conference and present a snapshot of essentially the progress of the trial with top-line data anticipated in 2026. Got it. I understand that, you know, it really depends on the enrollment and then depends on the follow-up. How much data should we expect for later this year, the phase two update, and then just help us to interpret the data. Yeah, yeah. So, you know, we haven't guided much to enrollment yet. You know, it'll be some kind of slice of it. Although I think one interesting thing that we did share on the MF KOL day call was we have an exploratory cohort for combination on top of momelotinib or pacritinib. It was fascinating to see that that cohort enrolled very fast. There is clearly, at least at our sites, a very high demand for an agent like 0974 to help manage anemia in patients who are nonetheless on momelotinib or pacritinib. We thought that was fascinating. Given the rapid enrollment into that cohort, we have pretty good confidence that you'll get data on that topic, at least at ASH. I think that's important because our core thesis for this drug is that any patient with anemia in myelofibrosis should benefit from our therapy. That would be about 22,000 patients in the U.S. I think one question mark in that hypothesis is, you know, will patients who are on momelotinib need an anemia therapy? I think the answer is starting to look like yes. Part two is, will our drug work on top of that? I think a high degree of confidence that we'll have some type of answer to that question by the end of the year. Excellent. Yeah, that's literally my next question. Because also during the KOL event, I believe I asked that question as well. See, doctor, if you think the momelotinib become, you know, potential standard of care in the future, maybe used more broadly, do you think they can enough to address the anemia? Because in the label, they do have some anemia data. Maybe just remind us what's their anemia efficacy and then what percentage of the people, patients, they on the momelotinib still need anemia, additional anemia drug like 0974. Yeah, so I think the label actually reflects what I think is playing out in the market now. Of course, we'll have to wait for more data. The label is written as, you know, momelotinib is approved for treating myelofibrosis in patients who are anemic, right? It's not written as a treatment for anemia. I think that's important because that, I think, is matching the physician experience, which is that patients who go on to momelotinib, it certainly does not exacerbate their anemia, right? The other JAK inhibitor, Jakafi, well-known side effect is that it exacerbates anemia. While it may be the best JAK inhibitor, you have to manage that side effect profile. Momelotinib is a tool to allow some degree of JAK inhibition in patients where anemia may be prohibitive for use of Jakafi. I think the data, the pivotal data basically bears that out. You see evidence of some improvement in transfusion burden in patients on momelotinib, but I think it's unclear whether it really provides a solution to the anemia. I think that's the kind of feedback you heard from the KOLs and the kind of feedback we're experiencing in our clinical trial enrollment is that, yeah, it may be sparing of anemia, but it's not fixing it. Yeah, yeah. Do you have some numbers, you know, how many patients on momelotinib, they still, you know, still need some anemia? I believe I heard the KOL say at some point they eventually are going to need additional anemia, but in terms of the percentage, how many of them are well controlled for the anemia and then how many of them are at some point they need additional anemia therapy? Yeah, yeah. In the approval study that they ran, there was a secondary endpoint looking at the transfusion burden of the patients at baseline and then at the end of the study. I forget the exact numbers, but ballpark, you know, the burden was around 30% at the start of the study and around 20% at the end of the study. Suggesting that about 10% of the patient population, you know, showed meaningful improvement in their transfusion burden. Okay, so it's not a lot of patients get addressed by the momelotinib and for anemia portion. We expect, you know, anemia to remain a significant problem. Yeah, got it. Okay, very good. The value proposition for 0974 for anemia is really used on top of the standard of care for MF because they are not really addressing anemia. How about the luspatercept? They are running, as you said, only on one subgroup, just remind us which group. Also, how do you think about in the future you're going to use, you know, along with the luspatercept? Yeah, yeah. Right, so luspatercept is the one therapy aimed specifically at anemia that is in development in myelofibrosis other than ours. They're in a phase three trial looking at the most highly transfused patients, so four units or more per 12-week interval. On Jakafi, because for reasons that are not particularly clear, the phase two data showed that luspatercept does not work particularly well unless you're also on Jakafi. Not sure what that's about. That trial is, from what we understand, due to readout this year in that subset of patients. We think that the highly transfused patient population represents about a quarter of the myelofibrosis patient population and those who are on Jakafi, some smaller subset than that. You know, I think the subset of patients that Luspatercept is going to provide clear trial evidence on is going to be, you know, restricted to, call it, 10-20% of the MF patient population. I'm not sure it has a huge effect on the competitive dynamics. Again, our aspiration is that we'll be able to show data across the whole spectrum of anemic patients. I think by getting to the less severe patients and showing that we have a benefit for those, which is where our data has been the most robust so far, means that we're hoping to be able to position this as the kind of the first line anemia therapy for these patients. Yep, got it. Yeah, so I think seems this is a Luspatercept potentially can save to more severe, maybe very niche population versus the 0974 is really can be broadly used as a first-line treatment for anemia with MF. Yeah, yeah, that's the vision. Obviously, we need more data. Yeah, obviously. Yes. And then so now we fast forward to you with the phase two data, initial snapshot, the data this year and then top-line next year, that's phase two. And then what have been the interaction with FDA regarding the registration? Because I think luspatercept provides a precedent for the transfusion dependent. But I believe you have some definition, some changing definition on the transfusion dependence, heavy, low. And then how about the non-transfusion dependent population? What's the potential registration path for that? Yeah, yeah. Yeah, there's been a lot of flux in how both regulators and clinicians want to try to study anemia and myelofibrosis. What we learned at our end of phase one meeting last fall was that the FDA is now wanting to look at these patients in three groups: those who are not transfused, those who are lightly transfused, and those who are more heavily transfused. So NTD, LTD, and HTD. They have in mind, or we now know that there are endpoints that would be acceptable for all three of those categories. We've implemented those. We essentially presented that data at our ASH presentation at the end of last year. Once we learned that from the FDA, we applied those endpoints to our phase one B data and presented that data to ASH. You saw average hemoglobin increase sustained for 12 weeks. That's the endpoint for the non-transfusion dependent patients. Plus, you're going to have to show some kind of symptom improvement, most likely something like fatigue, but we'll figure that out in phase two. But the fatigue score looked excellent in that patient population. So that's the non-transfused population. The lightly transfused population, you're looking at just a long period of no transfusions. Right now, we're looking at a 16-week period, could even go longer and probably be good as an endpoint. And then in the most highly transfused patients, that's where you have the precedent set by Luspatercept. A period of 12 weeks without transfusion would be viewed as a responder analysis. So the good news is we have, I think, already a view to what would be a regulatory path for the full breadth of myelofibrosis patients. You know, we need to do our phase two data, form that into an idea of how we want to run our pivotal trial. In the end, discuss that with the FDA. Obviously, we do not know exactly what those trials will look like, and we may even be able to create simpler designs that can be used to get a broad approval here. Excellent. Okay, great. It seems the registration path is also more clear than before, right? The new definition and then the endpoint. You designed the phase two with those endpoints. We're going to see the preview for the phase three. Exactly, exactly. All right. Let's quickly move on to the CKD. Non-dialysis dependent, NDD, CKD. You say you will have data later this year as well, but that's a phase one set in the map. You know, I think last time you gave us some single dose data, but this time it's a multi-dose data. Last time, I think data is good, but you know, it seems you are still having room to improve in terms of the hemoglobin increase. Tell us what's the expectation there, what you want to see for you to say, okay, I can move into the phase two for CKD. Yeah, yeah. This is a, I mean, a huge indication with an estimated six million anemic patients with non-dialysis chronic kidney disease in this country alone. I think there's a couple different ways we can win here. Generally speaking, the bar for efficacy in this population appears to be somewhere between 0.8 and 1 grams per deciliter increase in hemoglobin. You want to see that sustained for a reasonable amount of time. What we showed in just our first few cohorts last year at ASN Kidney Week was at the 40 and 60 milligram dose groups, you know, you're getting up towards about a third of the patients achieving that at least at some moment in time. That was single dose, so it's hard to really show a sustained effect. That's not bad. You know, what we're looking for now as we go to multiple dosing, potentially higher doses, is to get, you know, a larger percentage of the patients achieving that target, hopefully in a sustained way. The other way we can win is let's just say it's only a third of the patients who ever show response. If we're able to kind of define that as a particular set of those patients, that's also a perfectly legitimate way to approach this development plan. It's just narrow down the appropriate addressable patient population. Let's say it's a third, six million to two million, that's still a great development plan. That would be the other way we can win. I say that not because we know what the answer is yet, we're still in the middle of gathering all this data, but just, you know, to say we don't need to show everybody responding in order to get to a place where we feel like we have a really high potential program here. Would you be able to screen or identify those patients as a responder or a high responder before, you know, you can identify those ones that are the patients? Right, so that would be the questions. Are we able to figure out, okay, here's a group of patients who look like they respond really well? Yeah. What could be the potential driver for that? I know, you know, some of the... Yeah, yeah. So, you know, interestingly, iron is a serious issue for these patients. Many of them are frankly iron deficient, right? There is the one agent that gets used a lot is IV iron that works well in patients who are iron deficient. Maybe that's the appropriate therapy, and we may not be the appropriate therapy for iron deficient patients. You can assess that by looking at ferritin levels, right? By contrast, I think there are many patients who have ferritin levels that are normal or above, and our drug presumably would be a better choice for those patients. So, you know, baseline ferritin levels may be a way you stratify these patients. There's also EPO, right? Some of these patients have quite low EPO. Those are generally expected to be good responders to an ESA type agent. There are also many of these patients whose EPO levels are normal. That is where you'd say, why would you use EPO in that population? That is actually where that type of therapy ran into safety issues, right? Maybe there is a normal to high EPO population who would be a good responder to our drug. On the other hand, we may see pretty good responses across the entire population. There are lots of things to learn yet as we kind of plug through our phase one B data here. Excellent. I think that's something I really knew I learned. Thank you for giving us this information. I think we're on top of 30 minutes, and I very appreciate the time with us this morning. I thank you everyone for listening. Yeah, thank you.