All right, I think we'll get started here with our next buyer-side discussion. My name is Derek Archila. I'm one of the senior biotech analysts here at Wells. Very excited to have our next company, Disc Medicine. From the company, we have John Quisel. He's President and CEO. John, thanks so much for joining us
Thanks. Great to be here.
All right. Well, maybe just to start off, it'd be great to just kind of give a little bit of background about, you know, Disc Medicine and what you're working on, and then we can kind of dig into some of the Q&A.
Yeah, absolutely. So Disc Medicine, we flipped public at the end of last year through a reverse merger into Gemini Therapeutics. That provided a great financing route and also provided us access to the public markets. We're a benign hematology company. Everything we do focuses on the concept of manipulating heme and iron metabolism to affect serious hematologic disorders, and we've designed the company to have a lot of clinical programs. We have three ongoing programs with some initial data readout that came just this past June and a host of other data readouts coming at the end of this year and early next year as well.
Got it. So maybe you can, you know, just provide a little bit of background and context around bitopertin and kind of one of the lead assets and, you know, the indications that you're developing for.
Right. Right. Yeah, so bitopertin is the lead program of the company. We in-license it from Roche. It's an oral drug, very well-behaved. You take it once a day. It inhibits glycine uptake into newly forming red blood cells, and the effect of that is to suppress the heme biosynthetic pathway. So in a normal person, that's not necessarily desirable to suppress heme biosynthesis, but in a variety of diseases, it turns out the heme biosynthetic pathway actually drives the disease, and the poster child for that is a set of diseases called the porphyrias.
These are genetic defects in heme biosynthesis that result in the buildup of toxic metabolites, and so if you can suppress the flow through that heme biosynthetic pathway, the concept is you can decrease the buildup of these toxic metabolites in these porphyria patients and have what is intended to be a disease-modifying effect. So our first phase 2 trials with this bitopertin molecule are in a disease called erythropoietic protoporphyria. So again, this is a genetic defect in heme biosynthesis. It arises in the red cell compartment, where most of the heme in your body is being made, and that toxic metabolite that comes out of these in these patients leads to an extreme phototoxicity. So these patients cannot go out into the sunlight for more than a few minutes without experiencing excruciating pain that can last for days to weeks.
So it's a very severe disease, and the concept is that toxic metabolite, which is called protoporphyrin IX, or PPIX, can be reduced with bitopertin. And we showed that in cellular models and mouse models of the disease, and then we opened up an open-label study in Australia called the BEACON trial, as well as a placebo-controlled trial in the U.S. called AURORA. At the European Hematology meeting just this past June, we presented the first data from that open-label BEACON trial, and the data were remarkable. We showed data from the first 15 patients. Two of those patients had been through essentially six months of treatment, and there was really no longer any trace of disease left in these patients, right?
They were able to go out into the sun for more than 6 hours when they started off only being able to spend a few minutes in the sun. They reported their quality of life had improved dramatically. They were reporting no longer any impact of the disease, and the safety profile was excellent as well. So, that was kind of the lead two patients. There was a general trend in the other 13 patients who were earlier in their study. They were going in the same direction, and so that data, I think, really made a splash, both in the scientific community as well as, the investor community, and we're looking forward to sharing data from, all the patients on that open- label trial by the end of this year, and then we'll have a placebo-controlled trial reading out early next year.
That's great. Maybe two things. Just, you know, first off, just kind of what are kind of expectations going into, you know, the remaining data or remaining patients the end of this year? What, what, you know, what would you kind of expect to see? Maybe consistency or, you know, better. And then second, just on the regulatory path and this indication for EPP, can you just talk about, like, are there precedents there, and, and how we should be kind of thinking about, you know, kind of how you've designed the trial and all that sort of stuff?
Right. Right. Yeah, so, the primary endpoint for both our trials, BEACON and AURORA, is a reduction in protoporphyrin IX, right? So we're, as the primary endpoint, we're just trying to reduce the level of that toxic metabolite. Literature would suggest, and our own data would suggest, that if you decrease that by more than 30%, you will have a profound impact on the disease in these patients. Our key secondary endpoint and the ultimate regulatory endpoint is a measure of how much time these patients are able to spend in sunlight over the course of an entire study, and without experiencing pain.
And that's the key secondary and regulatory endpoint, and we'll be, for the first time, starting to be able to look at that data from our open-label BEACON trial as we come into the end of the year, and then, of course, that's gonna be evaluated in our AURORA trial as well. So in terms of the data we'll have at the end of the year, again, that's from the BEACON open-label study. The study is designed to have 22 patients enrolled. We already had 15 enrolled as of May. So obviously, we're gonna have the full study data for those 15 patients, and we're projecting that we'll have data from all 22 patients available by the end of the year as well.
And so we'll be looking at the reductions in protoporphyrin IX, where, again, the threshold you want to see is a greater than 30% reduction. And then we'll expect to see that translating into major improvements in the time that these patients are able to spend in sunlight.
Got it. Maybe you can frame for us, like, again, a little bit of the treatment landscape right now and kind of where you think bitopertin kind of fits in, and kind of the overall commercial opportunity.
Right. Right. So there's only one approved therapy in this disease. It's an agent called SCENESSE, or afamelanotide. It's administered by a subcutaneous, surgical implant, minor outpatient surgery, and then the drug is eluted over a two-month period. And this drug works by causing tanning, so the intent is to provide essentially a pigment barrier in the patient's skin to try to prevent the sunlight activation of that toxic metabolite. And it's, you know, it, it's approved, and it showed about, a 50% improvement in patients' tolerance to light. So this drug, you know, because of its modality or a variety of reasons, it's not that widely used in the patient population.
So by and large, most of these patients are getting no therapy at all, and they're just simply adjusting their entire lives to basically live inside, live in the dark, you know, avoid simple things that we all take for granted, like taking your kid to the bus stop or going to the store. Even light coming in through car windows can activate the disease. So, you know, you just have this population of people who are really having a dramatically impacted lifestyle.
Got it. And then just kind of shifting to the phase 3 and, like, you know, the design, you kind of explained it a little bit. How should we think about placebo response in this population? Like, what, what's typically seen, and I guess, you know, how much literature kind of backs that up, in terms of, like, you know, what your expectation is there?
Yeah. So there have been, you know, essentially two or three placebo-controlled trials run in this patient population, and, you know, there's a number of different ways that the light tolerance gets measured, as well as PP IX. So on protoporphyrin IX, the metabolite, there is obviously no placebo effect whatsoever, right? So the data we see from our open-label study should translate directly into the placebo-controlled trial. On the measures of light tolerance, pain, there is a placebo effect, and it comes out at around 20%-30%. And again, the magnitude of effect we saw from that initial data readout, you know, you're talking, depending on which endpoint you're looking at, 4x, 7x, 200x improvements. So we're not really expecting to see a major impact from the placebo effect here.
Gotcha. I guess, like, from, you know, quantifying the opportunity, like, how, again, how many patients, and how do you view this in terms of. I mean, this seems like it's a fairly rare condition, I would suspect.
Yeah.
So, like, how you think about, you know, potential pricing in this market, maybe relative to the current treatment?
Right. Right. Right. So in terms of patient numbers, excuse me, a recent genetic analysis from Mass General Hospital would indicate that in the U.S., there's about 20,000 people carrying the genotype that would cause disease. If you look at the number of patients that are kind of in registries, claims data, projected from various estimates of actual patients diagnosed and seeking therapy, those numbers circle around about 3,000. And then when there have been studies in other healthcare systems of trying to really diagnose patients and make a point, 'cause there's a suspicion that a lot of these patients have an initial diagnostic contact with the healthcare system, but then, seeing that there's no real available therapy, they just kind of disappear from the system.
So when healthcare systems have made a concerted effort to identify patients and find them, they roughly can double the number of patients. So, you know, t hink about it as there's probably 3,000 patients in the healthcare system today in the U.S. alone, about 20,000 people with the genotype. And, you know, if you really make a focus, which is what you do if there's a good therapy, you know, you could see that 3,000 double to 6,000.
I mean, is this an indication where most people get diagnosed, like high diagnosis rate? And who's, you know, the typical, you know, physician? Is it generally hematologist, or is it derm first, or is it kind of a combination of the two?
Yeah, yeah. So the diagnostic journey is challenging, right? So it's somewhere early in childhood, most of these patients will have an experience where they, they go outside with their family for a picnic, trip to the beach, play on the playground, and they suddenly get this excruciating pain, and no one can figure out what's causing it. And, you know, they go to primary care. They go to dermatologists. They go to you know, allergists.
Yeah.
Right? There's all kinds of theories that will get spawned when you have a patient who suddenly turns up with pain as a kid, right? And it, you know, the only way you get diagnosed is if you continue to have a clinical need and persist in the healthcare system until you find that doctor who says, "Oh, wait, did we check for protoporphyria?" And if someone has that idea, then the diagnostic test is very simple. I mean, the blood will literally glow in a UV light in a way that normal blood doesn't. So that's the diagnostic journey, and in the end, the treating physicians are primarily dermatologists, hematologists, and GI hepatologists because there's a liver complication. So there's significant liver disease management in these patients as well.
Got it. Yeah, maybe you should shift gears to, like. Talk about bitopertin, kind of, of the other opportunities that you're pursuing there, maybe with some of the other anemias that you're.
Yeah. So these porphyrias represent the most straightforward use of the drug, right? A disease that's caused by the accumulation of toxic metabolites from a broken heme biosynthetic pathway. Our drug reduces those metabolites, so porphyrias are the most straightforward place to start, and we're really gratified by the data we're seeing so far. There are other indications in hematology, where the accumulation of heme itself or hemoglobin is implicated in driving disease. So we've opened now a study in collaboration with the NIH, looking at a rare and very severe anemia called Diamond-Blackfan. There, the accumulation of toxic, unpaired heme is thought to drive the ineffective production of red cells. So we have now, for the first time, we're sharing in our corporate deck some of the preclinical data.
Showing that bitopertin has a positive effect on cellular and animal cells from patients and in an animal model. So that study is up and running. First patient enrolled, we just announced that about a month ago. And then there are other indications as well, where the accumulation of, of heme or hemoglobin can lead to toxicities that ultimately drive disease, and we'll be unpacking that more in the future.
Maybe around Diamond-Blackfan, like, how do you think, you know, again, you've the development path, but, like, the regulatory path there? You know, is that.
Yeah.
A s defined as, you know, with EPP?
Yeah. So in Diamond-Blackfan anemia, nothing works. This is a very severe anemia, onset in childhood. People go on corticosteroids. Many people respond to that initially and then lose the responsiveness, and then just go on chronic transfusions and face a greatly decreased lifespan due to the buildup of basically iron toxicity from chronic transfusion. So kind of similar to β-thalassemia in that way. Nothing has ever worked in these patients, and we're really excited to be working with two of the world-leading experts in the field, who have advanced the hypothesis that heme toxicity drives this and have developed all the preclinical data that we've shared. And there's this pool of prevalent patients at the NIH that we're, you know, we're collaborating with, and we're fortunate that they're eager to enroll in this.
So the path here would be, we run this collaborative study with the NIH. I mean, really, NIH runs it. We'll get data probably over the next year or so. And, you know, the beauty of hematology is you can look at the hemoglobin output, and if we see some meaningful increase in even just a handful of patients, I think, you know, we'd be able to take that information and approach the FDA and try to figure out what a registrational study looks like. 'Cause it is quite rare and quite severe. You know, it's probably about 1,000 identified, kind of, in the healthcare system type patients in the U.S. And we have, I think I didn't mention, but we have a safety database of about 4,000 patients from Roche.
So it's the kind of thing where we ought to be able to design a very small and efficient approval pathway in the face of some initial positive data.
Like, how homogeneous is this population? So, I mean, you know, obviously, they're bringing people into that trial, but is it, you know. Again, could those be different than what you ultimately end up with in, like, a, you know, a registration trial? And then, to your point on the, the safety database, you know, what is that comprised of? Is it mostly just normal healthies, or is it, was it broad?
Right.
Where was Roche kind of developing the drug prior to you gaining the asset?
Right. So the Diamond-Blackfan population, it should be reasonably consistent between.
Yeah.
I mean, there are many, many different mutations in ribosomal proteins that lead to it, but the phenotype is pretty consistent. So we wouldn't imagine to see significantly different patients from the IIT to a planned pivotal trial where we were to get there. In terms of the safety, safety database, that is, mostly people who are hematologically normal. Roche was exploring this, for a theoretical effect that, glycine reuptake could have in certain neurological conditions. Those efforts failed for lack of efficacy, but only in phase 3, so that's why they have about 4,000 patients worth of safety data. But they are all hematologically normal.
Got it. Interesting. Then maybe beyond, so like, you know, maybe going back to an earlier question, kind of the, you know, this is kind of like a pipeline and a product kind of, you know, scenario in these rare, you know, anemias, and I guess, where else can you kind of go within that kind of, you know, spectrum of anemia disease?
Right. So we do view it as a pipeline and a product. We think there is broad applicability of controlling heme biosynthesis. We're starting in the erythropoietic protoporphyria. There is also a set of porphyrias that arise in the liver that may become in scope.
We've mentioned Diamond-Blackfan anemia, which is driven by ribosomal mutations. There are forms of myelodysplastic syndrome, also driven by ribosomal mutations, so that could come in scope. We've talked about, on our slides, sickle cell disease being driven by the concentration of hemoglobin inside the cell, which is something that bitopertin is able to manipulate. And then there's diseases like polycythemia vera, which are simply driven by the excess production of red cells, and we know now, from work by others, that if you're able to restrict iron, you can actually control the accumulation of red cells in PV patients. And it's very reasonable to think that by restricting heme, which is essentially the partner to iron you could accomplish the same thing.
I mean, is there a way to kind of, like, generate proof of concept, like maybe via, like, a basket trial for some of these more rare anemias, or is that not like, you know?
Probably not.
Right.
Unfortunately, each of these indications is a real, clinical case with its own clinical endpoint. So, the way we're going at this is building our conviction through preclinical data and KOLs awareness and feedback. As we get to that level of conviction and obviously, you know, financial support, then we'll plan to open up each sequential trial and really hope to prove out the breadth of the potential therapeutic benefit of the drug.
Got it. Yeah, maybe shift gears to just DISC-0974, and maybe just provide a little bit of background about that program and, and where you guys are in development.
Yeah. So shifting from bitopertin, where we're focused on heme, our other two programs, and particularly DISC-0974, are focused on iron. So DISC-0974 is a genetically defined—it's an antibody against a genetically defined target. Should be the best in class, best ever way of reducing the central regulator of iron, called hepcidin, making iron more available to support erythropoiesis. And so it's broadly aimed at a body of anemias, called anemia of inflammation. So in general, a wide array of chronic diseases, you know, kidney disease, as well as autoimmune diseases, as well as things like myelofibrosis that have a high, highly inflammatory component. These all drive the kind of anemia that results from elevated hepcidin, which restricts iron in the body.
Your body may have iron, but it can't, it can't make it out of the tissues in order to support red cell production. And red cells are voracious consumers of iron, right? About 70% of your body's iron is in your red cells. So, when you have these kind of chronic inflammatory diseases, there's a kind of anemia that sets in that's a very classic, called anemia of inflammation or anemia of chronic disease. So we're taking aim at that with DISC-0974. It's, it's a huge potential market space. Your question about a basket trial would be highly relevant here as well. Again, I think for signal seeking and kind of building, building the case for the drug, you have to start with individual indications.
So we're starting with myelofibrosis, a heme-onc indication, where hepcidin levels are elevated by, you know, more than 10x. And that's been established now with clinical evidence that if you can reduce hepcidin, you can actually reduce the anemia in those patients. So that's one trial we have running now. And the other area where hepcidin was actually discovered is in the area of chronic kidney disease, whereas the kidney fails, actually, hepcidin is eliminated through the kidney. So as the kidney fails, hepcidin naturally accumulates and leads to iron dysregulation in these patients. And the two main drivers, you know, everybody thinks about kidney disease anemia as being EPO, right? Yes, that's true.
But there's also a huge iron component to the anemia in these patients, and a lot of them are EPO resistant because their body's not able to access iron supplies due to this organically elevated hepcidin levels.
Got it.
Two studies we have running right now, one in myelofibrosis patients, the other in pre-dialysis patients with chronic kidney disease, which is a huge patient pool. You know, anybody watching the field would know that there's essentially no therapy for these patients. I mean, there's ESAs, which have a black box warning and are not widely used, and there's IV iron, which are just used as kind of a last resort. Otherwise, all the other therapeutic approaches have fallen apart.
How are you evaluating, when I've done before, you know, in myelofibrosis, is it on top, like, on top of Rux or, you know, is this, y ou know, in place of Rux?
Yeah, it's a good question, right? So Rux is the mainstay therapy. We anticipate the drug will work in combination with Rux as well as without Rux. Either way, it shouldn't matter.
Okay.
We are right now in a dose-escalating kind of phase 1b/2 study, just kind of rapidly trying to get to the right dose and then expand. That's the data set we expect to provide by the end of the year. It's designed to be an all-comers type of trial. It's a fairly heterogeneous patient population. You have people who are on transfusion, people who are not on transfusion. People who are on Rux, people who are not on Rux. Right now, we're taking all comers, and then we'll sort it out and see where the drug really performs.
I mean, myelofibrosis is, you know, I guess, quickly starting to evolve into a more competitive area. So I guess in terms of some of these newer treatments that, you know, whether some of them are JAKs, like pacritinib or momelotinib, that some of them have, you know, better data on anemia or, you know, or reducing transfusions. You got ALK2 that. So, like, how do you think this kind of fits? And ultimately, how are you guys viewing that kind of, you know, evolving landscape there?
Yeah. So there's a whole body of new therapies, you mentioned BET inhibitors that I think are aimed at the underlying disease state, which is, you know, you're trying to control the symptom score, trying to control the spleen size, trying to control the fibrotic scarring that's happening in the bone marrow. All those drugs, you know, if they work, they're not really going to be therapies for anemia in these patients. And anemia is one of the key unmet needs and morbidities that these patients have. So there's very much a strong KOLs interest in having a selective therapy to treat anemia. In that space, there's really only a handful of competitors. So there's luspatercept, a drug I know well. I spent 14 years at Acceleron, and that's in a phase 3 trial for anemia of these patients.
Some recent literature would suggest it's not performing that well in this patient population, but we'll see. And then the rest of the mechanisms that are out there are hepcidin-focused. So you mentioned ALK2 inhibitors. Incyte has the leading ALK2 inhibitor. They're probably our primary on-mechanism competition. They have a small molecule. So by inhibiting ALK2, that's essentially one of the key BMP receptors that controls hepcidin production. It does also control BMP signaling in a whole host of other tissue types. So I think, you know, the key question for them is how deep a hepcidin suppression can you actually get without triggering some kind of off-target effects? Whereas our approach, you know, what I think is genetically defined about it is our target, hemojuvelin, you can knock that target out.
And it will have a profound effect on hepcidin, but no other effects. Right, and that's why and it's also controlling that, the BMP signaling pathway that regulates hepcidin.
Got it. Interesting. So in terms of where you are, so yeah, you're not the dose escalation, when should we kind of get an update there in terms of additional data? And again, how do you think about, you know, expansion cohorts? And again, will you look at different— I know you said all comers, but like, you know, would you look, you know, obviously, naive patients, post-Rux, maybe, you know, other types of, you know, phenotypes of the patient population?
Yeah. So our projections, by the end of the year, we'll have a body of data that we can share, expected to be, you know, more than 10 patients, and, you know, multiple doses. So there'll probably be some doses where, we're not seeing a lot of activity, then you get into the active range. Dose escalation is really driven by, looking at the iron effects. So what I think we would hope to be able to show is that we're having a profound suppression of hepcidin, very substantial and sustained increases in serum iron, which is the iron that's available to support erythropoiesis. And then, you know, in these early days, and, a handful of patients, we would hope to have then maybe some case histories where we're showing the effect on hemoglobin or transfusion burden.
Got it. And then, yeah, just a couple of comments on CKD, again, how you can, again, elaborate on that opportunity. And I guess, I think that's a much larger patient population, potentially. So, like, how are you guys. Is this, like, a partnership opportunity for you after proof of concept? Like, again, how do you think about the future development there?
Yeah. So I think it's fairly straightforward for us to run the studies that get to proof of concept. As you say, it's literally millions of patients in the U.S. alone, that have chronic kidney disease and have anemia as a consequence that's not being managed appropriately. But because hemoglobin is really the endpoint, right? The expectation is if you can show a gram per deciliter increase in hemoglobin without excursions higher than that, which creates safety issues, that should be satisfactory from an efficacy point of view. But traditionally, you do have to run large studies in this patient group to establish the safety to the satisfaction of the FDA. And so to run those large studies, I mean, you know, we'll see where we are as a company at that point.
Right.
If we had to do it today, we wouldn't be able to do it ourselves. But where we are in the future, maybe that is something we can approach on our own. We'll see. We're, you know, open to partnerships as well.
Got it. Maybe the last couple of minutes, maybe, you know, just talk about the last program, MWTX-003.
Yeah.
So, you know, interesting mechanism of action. Maybe just give us some background on that and kind of timing of, you know, some updates that we'll get from that program.
Right. So this is essentially going, this is the off switch to the on switch, right?
Sure.
DISC-0974 is releasing iron by suppressing hepcidin. This MWTX-003 antibody basically restricts iron, you know, by elevating hepcidin. So it's decreasing iron availability in the body, and that is useful in settings where there's too much red blood cell production. So polycythemia vera, a pretty common, well, you know, it's an orphan disease, but, you know, 100,000+ patients in the U.S. with this problem of excess red blood cell production. And it's, you know, been genetically demonstrated now that actually iron availability and genotypes related to iron management and hepcidin are associated with this excess red cell production. And a company called Protagonist has, you know, kudos to them.
They've developed a hepcidin mimetic that they've shown in clinical trials can restrict iron and actually reduce that excess red cell production in these patients, and has the benefit of making these patients feel better, which is pretty interesting. So you're both reducing the risk of clotting and stroke, and you know, these are the kind of morbidities you worry about, as well as just generally making the patients feel better. That drug has to be administered, you know, once, twice a week by injection. So our goal with this anti-TMPRSS6 antibody would be to provide a presentation, which is more like a, call it, once-monthly subq way of managing it.
Got it. And when do you expect to get that into the clinic?
Yeah. Guidance is second half of this year.
Okay.
The IND was already filed and cleared.
Okay.
We'll start with healthy volunteers, SAD/ MAD study. Expect to show elevations in hepcidin, restrictions in iron in the healthy volunteer setting. That'll be very. Essentially allow us to predict the entire kind of development program in polycythemia vera.
Got it. Maybe last question, just on kind of, your cash runway and in terms of, you know, I think you just said, you know, earlier comments that you did a deal and you raised money. Like, what's that get you to in terms of, you know, clinical milestones for, you know, the numerous programs we talked about today?
Yeah. So at the end of the second quarter, we had over $370 million in cash available. That's partly because we were able to raise money and do an offering at on the heels of the successful BEACON trial data with bitopertin.
Yeah.
So that funds us for, well into 2026 is our guidance at this point. So, you know, ballpark-ish, three years of cash.
So flipping the cards over on a couple, you know, multiple datasets.
Oh, yeah, we'll get to see, you know, the randomized placebo-controlled data in the bitopertin program in EPP. We'll get to look at the Diamond-Blackfan data. We'll get to see true phase 2 proof of concept on myelofibrosis and chronic kidney disease, and we'll even get a pretty decent early look at the polycythemia vera study as well.
Yeah.
So a lot of data we can get with the financing we have in hand.
Well, that's great. Well, John, thanks so much for joining us.
Yeah.
We'll leave it there.
Thanks so much.
Perfect. All right.
Great. Appreciate it.
Yeah, of course.