Welcome to our last day, day three, Jefferies London Healthcare Conference 2024. My name is Roger Song, one of the senior analysts covering EMEA biotech in the US. It's my pleasure to have the fireside chat with our next company, Disc Medicine. Welcome, John. Thank you. Great to be here. Awesome John, So you know, obviously this could be a very exciting time period for the company and then you have very exciting news, very promising news recently. So can you give us some high-level overview of the company and then with the latest, and then we can have a conversation? Sure. Yeah, as a brief overview, Disc Medicine, we're a company focused on red blood cell biology. We have three molecules in the clinic, all of which are designed to modulate either heme or iron metabolism. By affecting those fundamental building blocks of red blood cells, we're aiming to address and improve patient outcomes across a wide range of diseases that arise from red blood cells. The lead program is a molecule called bitopertin that we licensed from Roche, that basically suppresses heme biosynthesis, and we're taking aim at an indication called porphyria, where a defect in heme biosynthesis leads to an accumulation of a toxic metabolite, and the drug is designed to decrease that metabolite. Awesome. Yeah, we're going to spend most of the time talking about the lead program, EPP, and then obviously you have some second program for the anemia in both kind of myelofibrosis and CKD and some other early pipeline. So we're going to tackle one by one. So for the bitopertin, recently you got us a positive surprise, say FDA allows you maybe grant you some accelerated approval pathway. So what are the key evidence you submitted to the FDA and then FDA take a look and say, yeah, that's probably will qualify the accelerated approval? Yes, we've run two phase 2 trials in this population of EPP patients, porphyria patients, a total of about 100 patients across the two studies, and our primary endpoint was reduction of the toxic metabolite called protoporphyrin IX or PPIX and that reduction, we hit that stat sig very easily in both studies, and then we also had an effect on a whole series of what are called clinically meaningful endpoints, and so the data package we came to the FDA with was showing, first of all, protoporphyrin IX is the toxic metabolite that drives the entire disease state, and we're showing meaningful reductions in that. Moreover, we were able to show across a whole series of clinically meaningful endpoints, including how long these patients can spend in light, the rate at which they have phototoxic reactions, their general impression of their disease status, all of these improving on therapy, and all of these improving in a way that was related to the decrease in protoporphyrin IX. I think that was a key part of getting this kind of open door to accelerated approval was showing that we have a surrogate biomarker of this protoporphyrin IX that has real meaning in the disease itself and then consistent association between the reduction in PP9 and improvement across a whole range of clinical outcomes. Basically the correlation between the PP IX and the clinical endpoint, FDA look at it. That makes sense for using the PP IX as the biomarker to the PD marker to get the. And so understanding you are also designing a phase three, now become a potentially confirmatory study, and then you will have another formal end of phase two meeting with the FDA first quarter next year. So what will be the key topics for that meeting, and then what are you going to update the street in terms of the outcome from that discussion? Right yeah! So the end of phase two meeting we had, the first topic was this question of can Pp IX serve as a surrogate endpoint in support of accelerated approval. The remaining topics of the discussion were all around the design of our trial, of the next trial, which we're calling the Apollo trial. So we went through what's the right primary endpoint, is it clinically meaningful, what's the right dose, we're using the high dose, what's the duration, six months, patient population, we're allowed to include adolescents. But it was really just going through these basic attributes, about six different fundamental components of what a trial would look like. At the end of the meeting, the FDA said okay, this all looks good, please request another meeting where we would like to see a detailed protocol for a confirmatory trial so that we can discuss essentially the statistics and detailed design of that trial. That's the purpose of the next FDA interaction. Really the only topic that's been outlined for that meeting is really just discussing and finalizing the details of the confirmatory Apollo trial. Got it. Yeah, some of the details that you're going to tell us. And then will that be a part of the topic in terms of how much confirmatory study enrollment needs to be underway before you can file for accelerated approval? I think different companies seem to get flexibility from the FDA in terms of you only need to start the enrollment, some of them they need to be well underway, or some of them even need to take an early look at the confirmatory study data. So what's your expectation for the confirmatory study timeline versus your accelerated approval NDA submission? Right, so we've guided that we should get the Apollo trial running by mid-year next year in 2025. That'll be well ahead of any potential approval for the drug. The way the accelerated approval regulations are written, they require that the company have the confirmatory trial running before the approval date, so an NDA can be filed before the trial is running, and then I think in recent years, there's been more discussion at the FDA about does the trial just have to literally be open, or is there a certain degree of enrollment that should have happened. In our case, I think if we're able to get the trial up and running by the middle of next year, we would anticipate that we'd have substantial enrollment already done before we'd get to any approval date, so we don't really see that being a rate-limiting step. Got it. Got it. Okay, very good. And then so now you're entering the really late stage and the NDA filing and the confirmatory study, and then we should think a little bit about the commercial opportunity as well. So EPP, right now we only have one approved drug, which is a surgical implant. Also, it's not disease-modifying mechanism. So the commercial market is not well established yet. So, understanding, maybe you can go through some of the high-level epidemiology, the data points, but how do you really think this market can be in terms of pricing, penetration, what's the real unmet need for those patients, how many patients will really get on the drug, for example, for bitopertin if approved? Right, right. Yeah, no, it's a very helpful way that you set it up because I think the market is not well established yet. So we're doing work to sort all that out. So there's several different markers out there in the literature, right? So there's a body of academic literature that's essentially based on physicians looking around their clinic and saying, how many patients do I have here? And extrapolating that to form a number based on a countrywide level. And roughly speaking, that data will get you a number of around one in 100,000. So that would point to roughly 3,500 patients in the U.S. Then at MGH, they did a study based on the genetics and looked at in the UK Biobank, what would be the predicted number of patients with the genotype for this disease, extrapolate that to the U.S., you get a number of actually 20,000, right? So there's a very big gap between 3,500 and 20,000, what's going on there? So to try to address that gap, we went in and did some extensive claims database research in the U.S. What that showed actually is a total of 14,000 people in the past seven years making claims against the ICD-10 code for EPP. And that code has existed for seven years. So that's why we use a seven-year look back. So that tells us actually there are quite a few patients, the genetic, I think prediction is probably closer to the truth. Then what we saw is that there are about three to five thousand patients who are making multiple claims again and again against that code. That tells us that the one in 100,000 number that you see in the academic literature is probably pointing to the most engaged patients, the ones that the physicians are seeing on a regular basis. The way we look at it is the total opportunity in the US market is about 14,000 patients, of whom about three to five thousand are heavily engaged with the healthcare system and should be very straightforward to launch into. Then there'll be some work that we have to do to establish the remainder of that market. So any additional hurdle for those patients, engaged patients to get on the new therapy? We know the current therapy is just not that convenient and maybe the efficacy is also not good. What's the target product profile maybe can drive those patients engaging the healthcare system can get on the novel therapy if approved? Yeah I mean the current one, the one approved drug, does have to be surgically implanted every two months, requires travel, extensive medical intervention. So, not surprised, it's not broadly used. So, we don't see this isn't really a big conversion project, right? There's just not a lot of people on the Scenesse therapy. And I think as soon as we come forward with a simple once-daily oral pill that you can take, that'll be broadly accepted. And I think the fact that we're lowering this protoporphyrin IX marker, that is something that the KOLs and the patient groups are extremely excited about. Everybody understands that is what that is essentially the disease. And so I think as soon as we're able to get approval and provide people with access to this, given that it's a very simple modality, we would expect pretty rapid uptake. Got it. And then how about the clinical endpoint in terms of the sunlight exposure, make a phototoxic kind of attack? So what will be the clinically meaningful treatment effect the physician and the patient are looking for to be able to say, okay, this drug is really helping me, so I want to get on the drug? Right, right. Yeah it's interesting. There's actually a kind of a separation between the perspective you have from physicians and patients versus the regulators, right? Physicians and patients are looking at this and saying, if you're lowering PpIX, we know that's going to be good for us. And we're very happy to see that, that's enough. So essentially the treater and patient community is just excited about seeing that effect. Regulators, of course, need to see a clinically meaningful stat sig number, right? So they're looking for some way of quantitatively demonstrating that effect. And that's why we've now ended up in this area of measuring, keeping diaries of the time patients spend in light, establishing that and building an endpoint around that, where we can prove out in a quantitative sense that the drug is helping patients. Got it. So, understanding you are powering the study to show the clinical effect, but in terms of the treatment effect, how much you can improve on top of the placebo. So, what is the patient, physician, or your advisor tell you, say, okay, how much longer the sunlight exposure and the phototoxic attack and reduction will be very meaningful to them? Right. Well, I guess that's sort of my point is that when you tell someone, well, you used to spend 150 hours in light between the hours of 10 and 6 over a year, and now you can spend, people are spending 250 hours. People don't really know what to do with that information, right? That's more of a numerical just way of showing, measuring the benefit. As normal people, we don't even know. No, we don't even know right? Exactly. So that doesn't have any real kind of impact on people other than just saying, well, there's more, right? That's good. The phototoxic reactions, what was remarkable in our phase two data is that after two months on drug at the top dose, the number of phototoxic reactions went to zero, right? So zero out of 25 patients. If we can sustain that kind of effect in a larger study and show that, I mean, that is very intuitively meaningful to anyone, right? Zero is a powerful number. So that kind of rate matters. But otherwise, a lot of these clinical endpoints end up being numbers that people don't know how to relate to. But this idea of, hey, you're lowering PP9, you're lowering the toxin that causes these sunlight reactions in me, that is meaningful. Yeah. So this is still kind of a rare disease. And then those patients are kind of well educated and they know what caused the disease and they know what they really need to treat. So that's maybe the reason they think PpIX is sufficient for them to take the drug. It's a remarkably well educated and organized patient group, yeah, for sure. Got it. And then what are the other factors to help the commercial part in terms of maybe the payer side? And so take a step back, you are pursuing the accelerated approval potentially based on the PpIX, and then you also have the confirmatory study based on the clinical endpoint, how the payer view that, and then maybe how you're going to project the launch trajectory after accelerated approval and then full approval later on. Yeah. So obviously we have engaged in some payer research as is typical for a company at our stage. And I think generally the package that we have finds a sympathetic ear with the payers. There's broad recognition that this is a severe disease and these patients are desperately in need of therapy and that improving their ability to spend time in light and reducing their rate of phototoxic reactions is all viewed as a valuable proposition. So I don't expect, at least as of today, access to be a major issue, but it's something we are paying close attention to and we'll be continuing to build the value package for the program. Got it. Okay. And then at the biotech, always this question, how you think about the commercialization, what's the strategy in terms of the US, Europe, maybe the rest of the world for bitopertin? Yeah, yeah. So the major markets will be the US, Europe, Japan. There's also some ability in some of the other jurisdictions, but those are probably the major places where you find patients. And so we're working on our approach to all those. Our planned Apollo trial will be run in the US and Europe. We are still in the process of interacting with the EMA to figure out the late stage plan there. But we'd expect to launch into European markets as quickly as possible. And then Japan would come along a bit behind that. There certainly are actually, so Europe and the US have similar genetic prevalence of the disease. There's some literature suggesting that in Japan, it's actually quite a bit higher, as much as four-fold higher. We haven't done a lot of testing of that, but that's what you find in the literature. So we think that's a meaningful market as well. And then you expect this will take on the launch in the US, Europe maybe? Oh yeah. So we've hired, I think, a fantastic Chief Commercial Officer, Pamela Stephenson, who was last at Albireo, where they launched their rare disease program simultaneously in the US and Europe quite successfully. So we have built a team with the experience to go execute on that. Because of the rare disease approach, we think a very lean sales organization will be sufficient both for the US and in select European countries. Got it. What's the expectation for the sales force, the size of the team? We haven't guided to that yet, but I think it will be small. Yeah o ka, good. All right. So we spend a fair amount of time on the lead program bitopertin in EPP, but you do have some other also very, very promising pipeline. Maybe we can focus on the DISC-0974 for the anemia. So you reported some early data for myelofibrosis and then the CKD just recently for ASH and the EHA earlier for myelofibrosis, but you will also present some data at ASH for the myelofibrosis. So maybe just give us some preview, how you think about that data, the presentation, understanding this is probably just a full follow-up from those escalation studies. So what should we expect from the ASH presentation? Yeah, we're very excited about this program, DISC-0974, the anti-hemojuvelin antibody to treat anemia of inflammation. Broadly, our most advanced studies in patients with myelofibrosis, right, the HemOnc indication with a significant inflammatory component. So these patients, about 80% of them, are quite anemic. We are now up to about 35 patients that we've dosed for six months. So actually that's starting to approach. We call it a phase 1b trial, but it's actually approaching a meaningful phase 2 data set for this disease area. And the response rate has been excellent. We're in the 50%-60% responders using pretty much the most rigorous IWG standard definition of a hematologic response. At this point, most of the data is in patients who are lightly transfused or not transfused. We have only two patients' data from the heavily transfused population, but the drug appears to be working across essentially all patients with myelofibrosis and anemia. So we're coming into ASH now with basically complete follow-up for all 35 of these patients. We got an oral presentation, which is great. This is pretty much the premier meeting for myelofibrosis KOLs. So really looking forward to that presentation. And we've guided that we'll be starting up a phase two trial before the end of the year. And I think it's actually not going to be that much bigger in the end, right, than what we've got now. The drug pretty clearly is working in the lightly transfused and non-transfused patient populations. And of course, it's working fine in the two heavily transfused patients that we've dosed so far. We'll have, I think, part of what we're doing at ASH, as well as a company, is starting to put the pieces of this market together for people, right? It's understood that you have patients ranging from lightly transfused to heavily transfused. There's regulatory precedent for endpoints of clinically meaningful endpoints in the heavily transfused population. What hasn't yet been precedented is what are the endpoints for the lightly transfused population? I think we've now had some interactions with the FDA. We'll be able to provide some guidance at ASH around how we're designing that phase 2 program and what are the kinds of endpoints that will drive us towards registration across that whole range of patients. Got it. Yeah, so look forward to the ASH and then the phase two guidance, and then so I think we have quite a few drugs in the myelofibrosis, maybe even with anemia, but we don't have a specific drug really targeting anemia due to the myelofibrosis, so what's the real target profile you try to get to address that specific population? Yeah, that's exactly right. So when a physician is treating a patient with myelofibrosis, they're typically managing three different symptom domains: enlarged spleen, kind of inflammatory disease symptoms, a general feeling of sickness, which is measured as a symptom score, and then anemia, right? So about 80% of these patients will have anemia. And while there are many drugs that have been approved, most notably Jakafi to try to manage spleen size and symptom score, there are no approved therapies specifically to manage the anemia. So EPO is used off-label, a drug called Danazol is used, neither with great efficacy. So the profile of drug we're looking for is really a simple mechanism that can be combined broadly with all the other drugs that might be used managing spleen size, symptom score, things like that. And we think our modality and antibody that's simply mobilizing iron has a lot of potential to be a simple add-on to whatever underlying regimen these patients are on. And that's been the experience so far. So for example, patients on Jakafi, we have about 10 patients in our study on Jakafi. You put 974 on top of that, it works just fine. It works just as well as in the patients who are not on Jakafi. Awesome. So basically in the future, when a physician manages the myelofibrosis patient, they can use addressing some of the other symptoms and then use the DISC-0974 to address the anemia specifically because you can use a combination with the other standard of care. Exactly. And I guess I should add, it's a highly active antibody, active at doses under one mg per kg. So we're able to do it sub-Q on a monthly basis. So it's the kind of thing that can be done very routinely in the doctor's office. It's not going to require an infusion center or anything like that. Got it. Okay. Very helpful. And then so also this is because it's an iron mobilizer, so they can address multiple different underlying diseases causing the anemia. You do have some data from the CKD. And then recently, I think for the ACR, you have some data around the, I know maybe the ASH around the IBD, right? So that's the broad application. So how should we think about the CKD? How you compare the CKD opportunity versus myelofibrosis and then some other chronic disease? Yeah. So from the very beginning, the intention of this program was to address the whole range of people suffering from anemia of inflammation, which is a very broad range of causes, right? So myelofibrosis is probably the narrowest hem/onc application of the drug. Chronic kidney disease is the area where hepcidin and iron metabolism was really first discovered because it is elevated hepcidin and is so prevalent in these patients. But then there's a whole suite of autoimmune type inflammatory diseases where hepcidin and iron restriction are contributing to anemia. And then other areas like anemias of cancer where this could apply. So we believe now that we're seeing very nice activity in myelofibrosis, good, but admittedly early single dose activity in the chronic kidney disease patients, it tells us this drug, this mechanism is kind of pointing at this much broader opportunity. We've started to do a lot of the preclinical models to just try to validate other indications as well. And one of the first of those to read out now at ASH is our very standard mouse model of IBD. People study it all the time when they're looking at kind of anti-inflammatory agents. We looked at it through the lens of anemia. These mice actually do get a very severe anemia that's driven by hepcidin and partly by bleeding, by blood loss. And on our drug, we saw a profound increase in hemoglobin to 15 grams per deciliter. And actually we saw somewhat surprisingly, but interestingly, a pretty good anti-inflammatory effect as well, which there is a growing hypothesis now that manipulating iron loading in macrophages may have some benefit on the inflammatory front as well. So we're very excited about that preclinical package, but kind of looking now to think about signal seeking studies that we can set up to start establishing the full breadth of applicability for this drug. Excellent. So I think our time is up. Maybe we can save the last program or maybe some other early pipeline for the next time, but just lastly, cash position and then what's the runway look like for DISC? Sure. Great. So at the end of quarter three, we had $487 million. That gave us runway well into 2027. We since did a debt transaction that gives us access to an additional $200 million should we want it. We took $30 million at the front end of that. So we're very well funded to execute on essentially the full bitopertin program plus all of these phase two trials that we've been talking about. Excellent. Thank you, John. All right. Thank you very much. Yeah. Thank you, everyone.