All right. Welcome, everyone, to Jefferies Global Healthcare Conference 2026. My name is Roger Song, Senior Analyst covers SMID-Cap Biotech. It is my pleasure to have the fireside chat with our next company, Disc Medicine, and then we have our CEO, John Quisel. Thanks, Roger. Great to be here. Awesome. All righty. Before we dive into the questions, why not you give us some high-level overview of Disc, where you are right now, and then also a little bit forward-looking and then what we should expect for the rest of the year and then coming years. Right. We are at a very exciting moment of the company, headed towards the end of the year where our lead program, bitopertin, will read out from its phase II trial. That is obviously a highly anticipated event. We have two phase II programs in progress. The second one is in the anemia of myelofibrosis. Just had an oral presentation of ASCO with some really exciting interim data, and expect to have a readout from our end of phase II meeting with the FDA later this year, and progress that program to phase II next year. The third program in polycythemia vera, where we expect to have our first phase II proof of concept data by the end of the year. If that all goes well, it could also be progressing to phase II next year. Big step forward as we come into the second half of the year. Awesome. All right. We have a lot to talk about today. Maybe since we're just right after the ASCO, why don't you give us some highlights of the ASCO data from the myelofibrosis anemia. Understanding this a little bit, more recent data cuts and a little bit more patients, what are the methods there, and anything change on the profile before you can have the end of phase II meeting? Right, yeah. This very severe anemia in these myelofibrosis patients, there is no drug approved to manage that, and really none in development other than DISC-0974 at this point. The data we showed at ASH last year already looked very promising. We've broken the patients into three categories based on their baseline transfusion levels. About 50%-60% of these patients will be what's so-called non-transfusion dependent, meaning there are no transfusions during the baseline 12-week period. We have the low transfusion burden, where there's one or two units transfused during that baseline period, and then the high transfusion, which is three units or more. At ASH last year, we showed unprecedented good response rates in the non-transfused and the low transfusion burden patients, but quite unclear in the high transfusion burden group. At ASCO, actually similar presentation coming at the European Hematology Association in just a week or so, we're showing great responses across all 3 categories of patients. The other important message and important data is that about more than half of these patients are being treated with a JAK inhibitor to manage spleen size and symptoms. One question was whether the drug would work on top of those JAK inhibitors, which do affect erythropoiesis. The answer is unambiguously, the drug clearly works in combination with essentially any of the JAK inhibitors that these patients might be on. I think the message now very clearly, and this is how we're planning for our end of phase II meeting and our phase II trial design now, the drug is working essentially for anyone who's anemic with myelofibrosis. We're designing a trial program that should address all of these patients and try to make the drug available to address anemia in the maximum number of patients possible. Mm-hmm. Yeah. Great. I think last ASH saw the transfusion dependent high population, you have fewer patients, and then shorter duration. This time you have more patients, and then that seems the response rate also going pretty close to what other subgroup was doing. That's probably the key message here. They're all responding. All these subgroups were getting response rates in the 50%-60% rate. Yeah. It just looks really consistent, which makes us feel more comfortable about the data overall. Yeah, got it. In terms of the EHA coming week, would that be the same data cuts or you will have some other? Yeah, the main body, the main figures will be the same data. There may be some additional analyses that we provide. Yeah, basically the same aspects. Got it. Okay. Later this year, you're going to give us the full phase II data readout, the dataset, and then you're going to talk with the FDA by the end of the year for the end of phase II meeting. I believe you designed the study 30 patient per cohort. Do you expect to get the full enrollment by the time and give us the data with the sufficient follow-up six months? It depends on the enrollment. You don't need a full dataset before you have the conversation. Yes, one of the learnings was that the number of high transfusion burden patients, and really transfused patients overall, has been decreasing due to just improved management. Those cohorts enrolled slower than expected. We've actually ended up opening some additional sites to try to round out that enrollment. Meanwhile, the non-transfused patients enrolled very rapidly and represent, as I said, the majority of patients. That cohort, the non-transfused, is closed at this point. The others we're still completing. As we come into the end of the year, each year we typically submit abstracts to ASH. We typically are accepted and have a presentation there. I think that cadence should continue. What's different this year is now we feel like we've got the critical mass of data to go have an end of phase II meeting with the FDA. I think there will be one more data cut that will then be used to form the basis for our phase III proposal to the FDA. We're anticipating that end of phase II meeting to happen somewhere near the end of the year, hopefully, but no guarantee. It can come such that we're able to share the output from that meeting roughly around the time of ASH as well. The presentation we'd have at ASH would probably be that exact same data cut. It may not be the full top-line data, but it would be whatever we took to the regulators for the end of Phase II discussion. Got it. Okay. All right. You have a sequence of the data release before the year end. That's good. In terms of the end of phase II meeting, the phase III pivotal design, understand some of the subpopulation, you have a more defined regulatory kind of path. Some of them you maybe still need to discuss with the FDA. I do notice outside of the transfusion or the hemoglobin endpoint, you also have some PRO and the fatigue score, which are trending towards the right direction. How should we think about among those three subgroups, and then what is the more certain registration path versus the other ones, and what's your approach to get to the pivotal design? Yeah. It appears generally precedented that if a patient has a transfusion rate at baseline, you can use some kind of transfusion-based endpoint for an approval endpoint. Typically, it's so-called transfusion independence, which means for some period of time, either 12 weeks, 16 weeks, 24 weeks, you make them transfusion-free. You count the responders, if you're statistically significant over placebo on your response rate. Yep. that can form the basis for approval in a transfused population. In a non-transfused population, typically, the FDA doesn't allow you to use a transfusion rate basis. Hemoglobin is the most reliable metric, but they also don't allow. Outside the U.S., typically, you can get approval on hemoglobin. Inside the U.S., you need to augment that with something that's viewed as clinically meaningful. In that domain, actually just recently, Agios had a study in beta thalassemia where they broke it into two studies, the non-transfused and the transfused, used the transfusion independence for the transfused, and in the non-transfused population used a hemoglobin primary with a fatigue score as the secondary. That's a reasonably common approach in anemias, because one of the obvious and easily measured clinical consequences of anemia is fatigue. That's why you'll see in our ASCO and EHA presentations, we're showing fatigue score data that looks quite good. In fact, even correlates with the hemoglobin increase. We feel good that that could be the way we design our phase III program for the non-transfused population. We're also scoring well on other PROs, remarkably, the so-called total symptom score. 50% responder analysis, we're hitting on that almost as well as JAK inhibitors, which is where that score was designed for. We have a lot of options about how we want to demonstrate clinical benefit in the non-transfused population, and we'll finalize that after the end of phase II meeting. Got it. You do expect you can get alignment with the FDA among all of those three subpopulation? If you have some work to be done with the FDA, you can start with some of the subgroup in parallel or in sequence in terms of the phase III studies? Yeah, that's right. The goal is to present the whole program. Ideally, we get alignment on the whole protocol system in that one end of phase II meeting and be able to start both those trials simultaneously next year, or hopefully early next year. You can't rule out that they might have more questions about one population than another. There could be some staggering. It's hard to know, hard to predict till you get there. Yeah. At least I think it's totally plausible you can get a pivotal study with certain subpopulation and even get approval, even if the other subpopulation- Oh, yeah. .. may not. Yeah. Yeah. This is rare disease, so if, for example, we end up doing two studies, each one would presumably support a label for that population by itself. It's not a situation where you need two studies to support approval. Okay. Got it. Okay, great. Before we move on to the bitopertin for the EPP and then for the DISC-0974, you have other indication also planned, right? The IBD and et c. CKD, you already have some data earlier last year. Among all the indications, what's the thought process to prioritize or to think about the likelihood of success for those indication expansion? Right. The way the drug works, it's really addressing what's called the anemia of inflammation or anemia of chronic disease. If you look across the landscape, myelofibrosis is a very good archetype of that, and that's probably why the drug works so well there. We probed chronic kidney disease with mixed results, and what we learned from that is the endogenous EPO level that patients have influences their response to our product. In patients with chronic kidney disease, you get heterogeneity. Some patients have relatively low endogenous EPO levels, and those tended to be poor responders. Now when we think about indications where the drug could be used, it would be anemia of inflammation accompanied by relatively high EPO levels. That actually is pretty much most kinds of anemia. Your body is responding to that by pushing EPO production. Because iron is limited, the body can't really make the red cells. Our drug can make that iron available, and you get a good response. IBD, as you referenced too, that's a disease where there's definitely inflammation. Patient groups are very concerned about fatigue, and we've got that study going now, and they tend to have high EPO levels. I think, beyond that, it would be probably thinking about just baskets of patients who have anemia of chronic disease or inflammatory disease, and looking for those who would benefit from an anemia therapy. Interesting. IBD, I know you have a separate cohort, you are running trial, and then when we're going to see the data for IBD? We should have some initial data by early next year. Early next year. Yeah. Okay. Then you think, the next you'll potentially do some kind of basket trial, then you're going to just, in terms of the patient enrollment, everyone, patient with inflammatory disease and anemia with a relatively high EPO, that's the inclusion criteria? That would be ideal. It is still an idea. That's not one that we've really tested with sites yet, but I think it's precedented in this field that you wouldn't typically continue to do indication after indication after indication. At some point, you'd say, "This biology is pretty consistent. Let's just do a basket type trial. Yeah. Okay. Got it. Yeah, I think, 0974, we really like the mechanism and then also the data so far for MF is pretty strong. A lot of the expansion opportunity. I understand the investors' focus still be the bito because it's a more near-term. Oh, yeah. Bito study, then you just get a PDUFA, the CRL recent. I think the next step is you're having the Type A meeting with the FDA, reaffirm the ongoing APOLLO trial is supportive of the approval. Is that the next step? That is correct, yeah. There's a Type A meeting that you get as a matter of right after a CRL. Then we'll need to wait 30 days after that meeting to get the minutes, at which point then we can talk about the results with the public. I would say our expectation around that meeting is pretty neutral, meaning there's all kinds of things we could talk about in terms of, is there room to reverse the CRL to get approval without the phase III data? Just to confirm that the phase III data should be satisfying and drives a traditional approval path. The truth is, I think all that is already baked. I think because the data is so close, there's no room to reverse the CRL. We've had longstanding alignment with the FDA around the design of that program, and even if you read the CRL, you can see that they're basically saying, "Okay, accelerated approval, we don't think you've shown us the evidence to support that. But if you show us the full phase III readout, that would be the basis for a traditional approval. That's the path we're on. Got it. Just to confirm, clarify, have you had a meeting already or? We can't say. Okay. Got it. Okay. Got it. Okay. Either we haven't had it, or we've had it and we're waiting 30 days for the minutes. Okay. All right. Good. You say enough. Yeah. You have your disclosure obligation there. Okay, got it. That's a kind of a de-risking, but also the base case should be people not expecting too much surprise. That is the base case. That's right. Okay. Got it. All right. Then you're running up APOLLO. You will have the data readout later this year. Just walk us through in terms of the translation from your phase II to phase III. Initially people think, "Okay, you get an accelerated approval," then this has become a, I don't know, it's kind of bonus trial, now it's more critical in terms of people want to handicap before the data readout. How subjective that endpoint you have for the primary endpoint, how confident you are for the translation from phase II to phase III, phase II is positive. Yeah. We're very confident. We ran a good phase II program with 100 patients. We saw very consistent reductions in protoporphyrin IX, and we saw improvements across every clinical endpoint that we measured pretty much. Some of them were statistically significant, some not, none of them powered. We got a very good view of the variability. Notably, an endpoint called the total time in sunlight had a significant placebo effect in the first two months of that. That would be the precedent endpoint for getting approval for the one drug that's approved in this disease. We decided to modify that endpoint based on those phase II learnings to just look at the time in light in the month six, after the placebo effect has waned. By the way, had we measured that as the endpoint in phase II, it would've been statistically significant post hoc. We used all of that learning from variability, et c, to design and power the phase III trial. In every other respect, we maintained the phase II elements of the trial exactly in phase III, right? The goal was to kind of keep the biology exactly the same and simply treat it as a math problem with adequate powering for phase III. We moved from being 25 patients per arm, we chose our best dose, the 60- milligram dose, to now 75 patients per arm. Effectively tripled the study size. Due to excessive demand at sites, which we're flattered to have, patients really want access to this drug. We ended up over enrolling up to 183 patients. Now we have 90 per group versus phase II, where we had only 25 per group, we feel very good about the powering, we've had a chance to look at a blinded sample size reassessment with 50 completers. We were able to assess the variability, that matched very well with the variability that was seen in phase II. All the assumptions that went into that phase III trial design are bearing out very well so far. Got it. Okay. With a little bit upsize the sample size, and then also the design from phase II to phase III, that's the confidence coming from. Yeah. The other angle is the recent Tanabe, they reported a positive phase III top line, then later we see from the AAD, they gave us detailed data from their drug. That's another kind of a validation, but also we want to highlight the endpoint is slightly different. Yes. How we should think about the read-through from their trial, probably it's most on the placebo arm and then how those patients will behave in this disease, but using slightly different measurement. Yeah. Well, I think their trial shows what we already knew is you can win on these time in light endpoints, right? People worry about the subjectivity, the variability, but it can be measured and we saw numerical and some statistically significant benefit differences in phase II, and it's really just a powering question to turn that into statistically significant for phase III. I think, they showed that similarly that you can do that. Interestingly, the one approved product, SCENESSE, this program, dersimelagon, our program, bitopertin, we're all using slightly different ways of measuring the degree to which patients spend time in light. We're all on this quest because the FDA has told us to. This is what they want, as this is what they seem to think is clinically meaningful. It makes it a little bit more difficult to compare across programs. Roughly speaking, if you look at the one approved product, they had about a 50% increase in their metric of time in light, relative to placebo. We showed at the end of our phase II trial about a doubling, dersimelagon, the oral tanning agent, showed close to a doubling as well. I think that gives you a feel for the time in light endpoints. Interestingly, if our phase II data bear out in phase III, we would seem to have a much more profound effect on phototoxic reactions. We need to prove that out in the phase III trial. Mm-hmm. Yeah. SCENESSE is an implant. We know it's not that convenient, but dersimelagon, which is an oral version of the SCENESSE. How should we think about, now both of you are oral, but on one side if your efficacy is better, they can be preferred maybe on the safety side, and then also from the mechanism side. Why you think for bitopertin, what kind of the profile can win the market and to get more market share compared to dersimelagon? Our approach is going to the root cause of the disease, which is a toxic metabolite called protoporphyrin IX that builds up as a consequence of a genetic mutation in the heme biosynthetic pathway. The entire disease, the light sensitivity, the liver damage, all comes from the buildup of PP9 in the body, and our drug directly reduces that buildup. That's unique. We're the only people with that kind of effect. We believe that that will both result in a reduction in the sunlight damage, but it also, one of the scary complications of this, potentially fatal complications of the disease, is liver failure due to crystals of PP9 precipitating in the hepatobiliary system. We've shown in mouse data that this mechanism, by reducing PP9, you do greatly decrease that liver damage. The epidemiology would say that people with less PP9 in their bodies have less of this kind of liver damage build up. Now we're not able to study that in this program, but eventually we will run some clinical trials that look directly at liver damage in patients who are experiencing that. The expectation is that by reducing PP9, you could have a holistic benefit on every aspect of the disease, and that's going to be distinct from the way these tanning mechanisms work. Yeah. I think, I would treat bito as the disease modifying, because you're targeting the root cause of the disease. One clarification, maybe also a confusion from investor is the PP9 in whole blood level or the plasma level, because we know another company is also targeting PP9, but seems they're only targeting one compartment of the PP9- Right. ... not the whole blood. Yeah. Yeah. Essentially all of the PP9 that builds up in your body is in the blood. Right? From there it gets cleared through the liver and out. In the blood, about 90% of it is in the red blood cells, and about 10% is in the plasma. We're measuring the whole blood. That's what's typically been measured, that or it doesn't really make much difference, right? The cellular compartment 90%, the whole blood 100%. If you want to measure the plasma compartment, which yeah, we have one competitor working on that's quite distinct. It's a very volatile compartment. The clinical meaning of doing that has not really been established yet. Our approach has been, again, to kind of reduce the PP9 that builds up in the blood, which is essentially reflecting that we're reducing the whole body PP9 levels. Yeah. Okay. Yeah. I like that approach, you address the whole PP9 versus you sequence the PP9 in the plasma. The question is, what if you stop dosing or you have an issue, it release the PP9 from the other compartment, and it will causing the issue continue. Right. Sure. Yeah. Okay, good. Now we have a pivotal data lining up for the fourth quarter later this year, and then approval submission next year. How should we think about the pre-commercial activity, understanding you were accelerating that because you were under CNPV. Now you're kind of relaxed a little bit, I don't believe you are kind of slowing down anyway. Yeah. Yeah. Certainly, we have PTSD from this kind of run into the CNPV. We hired a full team to go launch the drug. Very sadly, had to lay off a portion of that team. We did retain a small sales team, and an MSL team, who are able to go out and call on accounts. We have claims data suggesting 14,000 patients, and that claims data comes with physicians who are providing care to these patients. The goal is to have the reps go visit those accounts, build a relationship, start to understand, are the patients really there? Is the claims data telling us the truth, or are they maybe getting their care elsewhere and tracking down. Essentially mapping the world of EPP patients and where their care is happening. In the process, hoping to raise awareness of the disease. Despite the fact that there is one approved product, there's probably more patients in clinical trials than there are on that product. It's a very undeveloped market overall, and therefore, the importance of having people out there, as well as the advocacy groups out there, raising awareness of the disease, so that when a product does become available, we can quickly turn the switch and have doctors alerting their patients to new therapeutic options that come along. Yeah. Honestly, when you're under CNPV, honestly, we are a little bit worried about the early launch because you're not fully ready. You're not even having the full sales team. Now it's kind of opposite. You have a lot of time, when you're going to start to rebuild the sales team and then get ready, how we should think about the early launch if they get approval next year? Right. Well, we will certainly be ready. We were ready in practice as of February. Now we have a lot of time to really understand this much better. We'll, based on the data we generate, kind of recalculate our launch team needs. How many reps do we really need given the distribution of patients and the number of accounts they need to call on? I think we'll be well prepared. It's already apparent that there's quite a bit of concentration of patients at top centers and then quite a bit of dispersity, quite diffuse outside of that. I think that makes the near-term launch relatively straightforward. Long-term, the challenge is creating awareness of treatment options for patients who probably, in large part, have given up hope. They got their diagnosis, they found out there wasn't much to do for it, and they've kind of ceased to get medical care, and we need to try to figure out how to make them aware and provide the care that they can get now. Awesome. All righty. I hope your sales team is not PTSD and they're waiting to coming back and then when you're ready. It's unbelievably motivating to try to treat these patients. There are all these anecdotes out there in the media now because the patient groups were really frustrated about the CRL and really wanted this drug to be available. I think they became much more active. If you read these accounts, it's truly moving. People, just the way their lives have changed, for those of us working on the product, it's motivating. I can tell you the sales teams feel that same motivation. Excellent. Okay. All right. Our time's up and thank you so-