GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - DISC MEDICINE INC

All right. Good morning. And thank you for joining Guggenheim's third annual Healthcare Innovations Conference. I am Devjit, one of the therapeutic analysts, and my privilege to host John Quizzle, CEO of Desk Medicines as our next presenting company. Thank you for making time for us, John. It's great to be here. Well, given that this is your first, you know, Fireside Chat at Guggenheim, maybe let's do a quick intro before we dive into the Q&A. Sure, that's great. Yeah, so DISC, we've been public for a little over three years, and we focus on molecules that modulate fundamental metabolites in red blood cells. So heme and iron have been the focus. We generally focus on clinically validated mechanisms. And at this point, we had a phenomenal phase three readout for our lead program to address rare porphyria. And then we have a pipeline that's also read out with great phase two proof of concept data, all presumably progressing towards phase three trials in the area of myeloproliferative neoplasms. So why don't we start with the Apollo study, obviously hit all primary and secondary endpoints. What does it mean from a patient perspective that they finally actually have a disease-modifying therapy here? It's a big deal. It's the primary experience they have every day is inability to tolerate sunlight. The average is around 30 to 40 minutes before they have excruciating pain attacks. So it's fundamentally life-altering, this disease. These patients end up having to live entirely inside, choose their hobbies, careers, their family life, entirely dictated by inability to be exposed to sunlight. So profound disease, and this will be the first therapy. It's only this, it'll be only the second therapy available, but it's the first mechanism that gets to the underlying cause of the disease, which is a buildup of a toxic chemical. And we're very proud of the way this trial enrolled incredibly rapidly and then succeeded in the statistics with what are fairly tricky endpoints. But what's really gratifying to see is the way the reduction in that fundamental toxic metabolite translated into profound clinical improvement across everything that we measured. Got it. So as we think about the commercial opportunity here, There's debate about how many patients there are and how many have been diagnosed. Could you talk to the epi work that's being done within the company to ensure a good launch in whatever, 12, 16 months from now? Yeah, I think if you're looking for a floor, you could look at the historical academic research, which pegs the number pretty consistently at about one in 100,000, which would lead to an assessment of about three to 4,000 patients. There is a company that has one, the only approved product. They estimated around 4,000 patients. So that's kind of the world we came into. And then we investigated claims data, claims databases, and what we saw in there was about 14,000 with the diagnosis. And we think it's pretty robust because there's a unique ICD-10 code for this disease. And these 14,000 patients all have that, you know, have had care under that code. And we've done a fair amount of effort to scrape out what might be spurious coding events. So we feel pretty good about that. And then what we see in there is about 6,000 patient who appear to be more engaged in their health care around the disease by showing multiple different claim events, whereas there's about 8,000 who we view as disengaged, which is not at all surprising given the limited care that's available to these patients i think you have those 8 000 patients who are getting diagnosed and then confronted with very few care options and simply retreating back to a life of avoiding sunlight so the way we look at the launch is we're launching into what we believe to be about 6 000 engaged patients who we think will be able to access and reach with a sales force of about 24 reps and then there'll be a longer term effort to activate and reach and and make available what we think is an exciting new therapy for those 8,000 disengaged patients. And is there a good predicate that the company is using to model this launch in the first 6,000 and then try to expand into the disengaging 8,00 patients after that? Yeah, I think there are a number of rare diseases where the patient number is similar and can be used as a model system, like HAE, PNH. These have all turned into very substantial rare disease markets. There's a hepatic porphyria, which is a rarer disease, but the launch curve, again, not a bad way to look at it. Got it, and from a pricing perspective, there could be obviously a range of pricing options here. Where do you think is the most logical price point? And again, from the established rare disease pricing models, are there diseases that you think are a good marker? Yeah, so, I mean, rare disease pricing, we have examples of it happening many times a year, new launches, and you can do traditional kind of graphs that show, you know, patient number versus price, and it forms a pretty linear relationship. I think we would fit right onto that graph. But if you want to look at specifics in the porphyria space overall, there's several different kinds of porphyrya. In erythropoietic proto-porphyria, there is one approved drug. It requires surgical implant. It prices around. It works by tanning, so not really getting at the fundamental cause of the disease. And that's priced at around $300,000 a year. If you look in hepatic porphyra, there are one approved product that does get to the root cause of disease. and that's priced closer to $600,000 per year. And again, you can put those on the graph with other rare disease launches and get a fairly good idea of the ranges that might be applicable here. And you talked about the ICD codes. Do you at this point know where these patients are housed, both the 6,000 who are actively seeking treatment and the 8,000 whom are disengaged? Yeah, so if you break that group down even further in a way that a sales force can go at it, we see at the top 100 sites about 1,600 patients, and we can account for the majority of those at this point through in-person contacts to the doctors. And then you kind of get the balance of the 6,000 at another larger group of doctors. And we've started to accumulate some patients who fit in that category. And then even amongst the 8,000, we actually have essentially a call center approach to just try to reach out broadly. And that effort will probably continue for years and has already started to accumulate some patients there as well. So you can kind of see kind of three different ramps developing in our own efforts. One is the top centers in 1600 patients where it's ramping very fast in terms of our ability to get to know those doctors and have confidence around those patients and a somewhat slower ramp to get into the next 4000-ish patients and then a slower ramp still to get into the 8,000 so-called disengaged patients. Got it. And are you likely to pursue the ex-US markets yourself? We are, yeah. I mean, I think the primary, due to the genetic distribution of the disease, the primary ex-U.S. market is Europe, where there's probably proportionally the same number of patients, meaning the total number of patients in Europe is higher. Price points, of course, will tend to be lower. But we think that we can create a very lean and efficient model for accessing certainly the top countries in Europe. Does MFN concern you, given what could be a change in political landscape very soon? Yeah, I mean, I think the MF N approach certainly has impacted European launches. I think in the rare disease space, there's greater ability to kind of bridge that gap and launch successfully in Europe with minimal impact in the U.S. So I think that's the approach we're going to take. Harpreet Sahota- Well, let's switch to MFN, but obviously, the initial data looks very, very promising, kind of head and shoulders above where your potential competition is, and it's kind of a broad efficacy profile. So what do you think are the next steps there, both with, you know, upcoming data readouts and how are you thinking about your registration study? Yeah, thank you. This program, we're incredibly excited about. The phase two data have been excellent, showing from a clinician point of view, 70 to 80 percent response rates. From a regulatory point of you, the most stringent response rate calculation puts us around 50 percent. As you said, all of those are well above what little competition there is. And I think this program gets very little attention because there essentially is no competition at this point. We're kind of alone in trying to provide an anemia therapy to this group of patients. And so it's actually an incredibly exciting opportunity. So what we're doing right now is in the process of having our end of phase two meeting with the FDA to define the phase three path. Our goal is to study the drug in pivotal trials across the full range of patients. So there's roughly 22,000 US myelofibrosis patients who are anemic, all of whom based on our phase two trial should be candidates for our therapy, none of whom have adequate therapy today. There's no, literally not an approved drug to treat anemia in this patient group. So we're looking for a comprehensive pivotal trial design that would allow us to access that full market. And that's never been done before. So that's what makes the end of phase two meeting interesting is we have to kind of discuss with the FDA exactly what the end points will look like and treatment duration and issues like that. So our goal is to come to ASH and share at our corporate call associated with ASH the details of that meeting, what kind of phase three trial design we've been able to align on. That will allow us then give some guidance as to exactly when next year we expect the trial to start, and some sense, at least an estimate, of how long it'll take to enroll. Got it, and would you, or how would the stats work out here? Would every subset be analyzed separately, or would it be sort of a big homogeneous study? Yeah, that's, I mean, it's a very interesting question. Broadly speaking, there's probably two categories of patients. There are those who receive transfusions at baseline, the more severe patients, and those who are not yet receiving transfusions, but are quite anemic, but have symptomatic anemia, fatigue, and other sequelae of the disease. And those probably require different endpoints. Typically in the transfused population, in other diseases, it's well-precedented that you would look at a reduction in transfusion burden, and that's typically viewed as clinically meaningful. In the non-transfused population it's less well- precedented, but there have been examples recently, for example, Agios was able to study their drug in beta-thal, patients who were not transfused, and used a system of reducing, improving hemoglobin, plus a metric of quality of life, like a fatigue PRO. And so that's a pretty reasonable, that at least shows you a precedent and framework for a way of studying the non-transfused population. So in the non transfused group, then you think, say, let's call it a 1.5 grams per deciliter. Would that be a good benchmark to think about? yeah that's certainly in the myelofibrosis field 1.5 grams appears to be well accepted both among clinicians and at the fda as a as a meaningful improvement now clinicians do that as clinically meaningful per se the fta doesn't view hemoglobin itself as clinically meaningful that's why you end up adding on some of these measures of patient symptomology got it and And beyond MF-associated anemia, what's the next step for the program? Yeah, you know, our mechanism aiming at reducing something called hepcidin, which controls iron in the body, it's well known that that system becomes dysregulated in all kinds of inflammatory disease. So, in fact, the original intent of the program was to go after the whole space of what's called the anemia of inflammation. These tend to be anemias that are not well managed by EPO and are typically associated with inflamed bone marrow conditions. And myelofibrosis has emerged now as kind of the prototype of that kind of anemia, based in large part on the remarkable results we get with our drug. But to your point, there are many other anemies associated with inflammatory disease. And we've essentially followed our preclinical data to decide where to allocate our resources. And we have seen just astonishing positive effects in animal models of inflammatory bowel disease, IBD, where anemia is a persistent issue. Fatigue is one of the most common complaints of patients. It's largely attributed to anemia in that population. And so we have, you know, based on that animal data, started a pilot trial to look at the effect of selcodabart in that patient population. So do you think that whatever pricing lands up, would that support use in these other indications? Because MF-associated anemia is one, but you're going into much different market segments there. Right, right. Yeah, when you look at hemlock, you know, anemia is associated with hemlock. Like, for example, lustpatercept and myelodysplastic syndrome, the price points tend to be in the $200,000 to $300,000 per year range. So that's probably a pretty good parallel for myelofibrosis anemia, where we're headed as our primary indication. When you look At other, some of these larger diseases, the Price point, you Know, it would often be viewed as quite a bit lower. So there's several different ways we could handle that. One would be, it's not clear you need to do chronic dosing. You might be able to do single dose type approaches. But we also have, we're bringing up an extended half-life antibody that I think would be highly appropriate and beneficial to patients who have essentially a less severe disease overall than these MPN patients. And so it might be possible to differentiate in a way that's both patient-friendly and and kind of allows different price points by using two different molecules. Got it. And how are you thinking about scaling the organization? Because you're going to launch in, or better put, call it in the next 16 months-ish. These programs will be fairly mature by then. Right, right. Yeah, I mean, you know, thankfully we're very well financed now with over about $1.1 billion pro forma between cash on the books that we just reported, as well as cash we took in through recent financing. That amount of capital allows us to pursue everything, essentially launching a bit of Purden and then progressing the second and third programs into phase three trials towards approval. We will be adding a commercial team. You know, we're about 170 right now, so we've been able to do everything pretty lean, actually. And then we'll be adding enough of a team to enable all of these larger phase three trials that we'll Be running. And when we talked to docs about, you know, what, what would be the threshold for silica debart in, in MF associated anemia, you're currently at 50%. Overall, the docs seem to believe even if you go down to 30%, this would be a very widely prescribed drug. Where are you guys internally with, you Know, talking to folks and trying to scope out the market? Yeah, no, I think you have it exactly. The bar in myelofibrosis anemia has always been about 30%. That was also true in myelo-dysplastic syndrome. It's kind of a view for all of these refractory serious anemias that are not managed by EPO or other sort of broadly available anemia therapies, getting to about a 30% response rate is viewed as excellent. And so with us sitting at 50%, and I mean, the kind of reactions you can, you can look in our data, you could see some patients where they essentially normalized their hemoglobin. We have one patient who came in at seven grams, normalized back up to their baseline of 14 grams per deciliter. So remarkable results that we're getting, unambiguously clinically meaningful. And the data at ASH, could you sort of lay out the scope of what do you expect to show, both from a follow-up and any new patient? Yeah. So what we'll be showing at ASH is the same data cut that we're bringing to the FDA for our end of phase two meeting. In terms of exact numbers of patients, you know, the total trial when finally fully enrolled will be about 90. And I think at this data cut, we probably have ballpark 60, 60-ish patients who have long enough on drug to be valuable for the purposes of ASH. Got it. So let's pivot to your third program in PV. I mean, that is becoming a slightly more crowded landscape, but you do have an interesting value proposition there. So can you walk us through how you're thinking about that landscape as it evolves? Yeah, I think this is a very exciting area. The fundamental concept is that phlebotomy is used to manage patients with polycythemia vera. The intent of phlebotomy, right, these patients have too many red cells. Phlebotomia, of course, removes blood, but the real point is it's removing iron, and you drive patients into nutritional iron deficiency by removing sufficient blood. And when you arrive at iron deficiency, two things happen. One, red cell production is curtailed, right? So even the driver mutation that's trying to push excess red cell protection cannot do it in the absence of adequate iron. The second thing that happens with phlebotomy is that people feel terrible, actually. Elimination of iron from the body leads to a lot of sequelae like brain fog, itchiness, restlessness, sleeplessness. It's a very unpleasant feeling. So the remarkable observation is you can give a drug that will restrict the availability of iron, achieve all the benefits of phlebotomy in terms of controlling the red cell production, but allow the patients to live a better life again. They don't have nutritional iron deficiency anymore. So it's, you know, Russ Fertide from Takeda and Protagonist proved this out in their phase three trial. And I think that's really broken open the field. You can see that there's about 50 to 100,000 polycythemia vera patients being managed by phlebotomy in the U.S. today. Arguably, they should all be migrated over to an iron restriction drug to improve both their clinical management of the hematocrit and to improve their quality of life. so uh russ for tide being the first approved product now we have agents like ours targeting tempera six of which there's three uh now in late stage trials and uh our goal we're the only antibody we think it has the ability to provide what we think will be an optimal profile and by optimal profile what i mean is we're all aiming to get 70 to 80 percent elimination of patients where phlebotomy is eliminated and their hematocrit is maintained at a 45% level or below. And in addition to that, our objective is to provide a self-administered auto-injector and minimize the side effect profile. So essentially no injection site reactions, essentially no anemia. I think if we can provide a perfectly safe product with that kind of efficacy level, it should be really the optimal therapy. So the data at by year end, could you sort of lay down the scope of where do you think efficacy has to land up given where the current, you know, bar is with the longer acting versions? Yeah, so efficacy should land up at about 70 to 80% phlebotomy free. And that's what we showed already from our very first data that we shared at Soho in September. That was with a Q2 weeks dosing schedule. I think some people have compared that unfavorably to one of our competitors that's at a Q12 weeks level. So we're going to show now at ASH Q4 weeks, we have an oral presentation. And I think when you can achieve that with an autoinjector, there's no real benefit to having a longer interval between dosing. And in fact, we believe that as you get to longer and longer intervals, the challenge will be that when patients do get overdosed and become anemic, it will be difficult to reverse that anemia. And I think with an antibody on a monthly basis, it'll be, you know, we'll be able to resolve any side effects very quickly by just simply skipping a dose or titrating the next dose. And what do you think is a sweet spot here commercially? You could go 12 weeks, may not be ideal. Um, resveratide is a lot more frequent, um, the Ionis product has issues. So what's the balance between safety and, um you know, elimination of phlebotomy? Yeah, I think, oh, well, like I said, I think we're all going to collect at the same basic phlepotomy free rate. And the key thing is going to be safety and tolerability and ease of patient use. And I think if we can achieve a once monthly dosing at home with an auto-injector plus, you know, as basically the lowest rate of side effects, which we haven't proven yet, we still have to prove that. But if we could achieve that profile, that will be the drug of choice. And given Minrella's approval, you think the endpoint and everything else is completely de-risked right now with what you're trying to do? I believe that will be the precedent. Yes. We have not had yet an end of phase two meeting to confirm that for ourselves. But I think it's a reasonable assumption. And when do you expect to get this pivotal up and running? Next year. Yeah. So I think if you look at our competitors, one of them is up and running kind of because we come in towards the end of the year this year, and then the other one is going to be up and running next year. So, I think we're all very close in timeline. I just want to go back to MF for a second. And in the transfusion-dependent patients, are you thinking about your registration study to be, you know, call it that 30% which the physicians are talking about that's like the minimum threshold when you think about powering that study? Or given the data so far, 30% is an achievable hurdle for you? Oh, yeah. I mean, I think, yeah, that's a reasonable way to power the study. I mean I think pretty straightforward to do it with that. Yeah. You know, to the extent that other endpoints become important as well, like, for example, a fatigue score or what have you, you know, that feels tend to be a little bit more variable. So powering may actually hinge on some of the important secondary endpoints. Got it. And in the last minute or so, you Know, if you were to fast forward 12 months, where do you see disk medicines next year at this time? And yeah, next year at this time, if all goes well, we'll be a commercial company marketing and launching the bit of hurt and product in Porphyria. And then we will have progressed the two phase two assets into phase three studies. And meanwhile, continuing to pursue some of our signal seeking studies in IBD and sickle cell disease. So very exciting moment for the company as we transition essentially everything in our pipeline forward by a major step well appreciate your time today thank you so much John thank you good luck to you guys appreciate it thank you