Okay. Good morning, everybody. I'm Douglas Tsao, senior analyst at H.C. Wainwright. We are thrilled to have with us Disc Medicine up next represented by the company's CEO, John Quisel. It's been a very eventful, you know, two years for you as a public company. You know, now on the cusp of taking your first asset into phase III, but John, maybe just as a starting point, because I think I see some new faces, and just a quick introduction to the company, and then we'll dive into some of the individual programs.
Yeah, sure. That's great. Thank you. It's great to be here. As you say, we've been public for two years. It's been a wild ride. Actually, I joined the company at the Series A preclinical company four and a half years ago. Now here we are, you know, about to, hopefully, if all goes well, start a phase III trial for our lead program, moving into phase II with the next two programs. So a tremendous amount of progress we've made. We went public through a reverse merger at the end of 2022, so now we've been public for two years, focused entirely on hematology. The three assets we have are a mix of small molecules and antibodies, all trying to control... They're all now proven in the clinic to control heme and iron metabolism, and these are the tools by which we control red blood cell biology, and in scope for us is a wide range of indications, running from orphan all the way up to very common diseases that arise in the red blood cell compartment, and we think we can address this wide range of diseases with this set of iron and heme metabolic agents. And so we'll start with, you know bitopertin, because this is the asset that you referenced that's on the cusp of going to phase III. You know I think when you first, you know released clinical data the BEACON data people were really excited. We saw some very compelling data. We did get the, earlier this year, the AURORA dataset, which was a placebo-controlled study that I think, you know, at the time of releasing the data, you sort of characterized it as, as complex. And, you know, I think some of the analyses released earlier, this summer, at EHA sort of unwound some of the complexity.
Maybe just provide people with some perspectives in terms of your evolution of thought, in terms of the AURORA dataset and how that influences your thinking for the phase III study.
Yeah, no, it's a great question, and it has been a journey over these past two years. So the disease we're trying to treat, called erythropoietic protoporphyria, is a genetic disease of heme biosynthesis. It leads to the production of a toxic metabolite called protoporphyrin IX that drives all the symptoms of the disease. So on a day-to-day basis, these patients have excruciating pain attacks when exposed to the sunlight, and then also this compound can build up in the liver and lead to liver failure and even death. So quite a severe disease, all driven by this central toxic metabolite called protoporphyrin IX. And bitopertin is designed to decrease the flow of metabolite through heme biosynthesis, thereby decreasing the level of that toxic metabolite.
Now, when we set out on the program, the literature told us that if we could achieve a 30% or greater decrease in that PPIX metabolite, we should lead to major clinical improvement, even potentially, you know, complete resolution of symptoms. We opened up two trials, one open-label, the BEACON trial you referred to, and one placebo-controlled. So the BEACON trial started providing data first, and that was, you know, kind of the story of twenty twenty-two, was just to-
Twenty twenty-three.
2023. Thank you. Sorry, off by a year. The story of 2023 was the open-label data coming out, showing that we're reducing protoporphyrin IX levels as expected, hitting that target, exceeding that target of 30%-40% reduction. And these patients, using the endpoints that are available, which is a diary of time ina light, an assessment of how long they can be exposed to light before they get a tingling, which is what's called a prodrome. Looking at the rate at which they have phototoxic reactions, these pain attacks, and also looking at their, just their overall quality of life. Across those endpoints, in the open-label study, we saw extraordinary data, I mean, unlike anything that's been seen before, really implying that we are having major symptomatic improvement in these patients.
So that led to tremendous excitement both for us and the public community, patients, doctors, everybody. Then the placebo-controlled trial read out early April this year, and the data were complex, and the complexity came from the placebo group, which performed far beyond expectations. And while we were hitting our reduction of protoporphyrin IX just fine, you know, some of those measures of efficacy lost that sig because the placebo improvement was substantial. But one thing that was there in that initial top-line readout, and continues to be true, and is the reason why we went back to understand the data more thoroughly, is that if you look at the patients at the top dose level, they achieved a remarkable response, right? They spent more time in light by a substantial amount. They were able to be in light more often.
They were post-hoc. I mean, sorry, pre-specified stat sig, 75% reduction in the phototoxic reactions. So the amount of pain attacks went down dramatically in these patients, and actually, almost 90% of them felt much better on these PRO endpoints. So the actual profile, if you look at a patient and say, "Hey, if you take this drug at a 60 milligram dose," that data would tell you, you'd spend more time in light, you'd vastly reduce your phototoxic reactions, and you'd feel much better, which is a great profile and the only place the placebo was really, you know, destroying the statistical readout was on that time in light endpoint, which is an important endpoint because it's the endpoint the FDA has approved the one drug in the space on. The path was gonna be very easy and straightforward.
If we hit that stat sig, we'd run a phase 3 study very clean, but what we've shown now is that, you know, there are ways of looking at that data with bringing in a time factor that would have been stat sig, and we analyzed it that way, so post-hoc looks very good as an endpoint we could use in phase 3 and those phototoxic reactions, that reduction in rate, that's been stat sig across every trial we've run, so that could also be a very good basis for a phase 3 study, so I think, you know, the initial top-line readout was complex 'cause we weren't stat sig on everything. We were on some things.
Yeah.
We needed to figure out, okay, what's telling us the truth here? And now I think we understand what the truth is. It looks, you know, we're very excited. The drug seems to be working.
I think it's worth noting, you know, 'cause you referenced the sort of FDA's approved one product, you know, in the past, and I think it's important to note sort of the blinding element that may or may not have occurred with that study.
Right
... and also just sort of the regulatory background, right? And how that product ultimately ended up with sunlight exposure as a primary endpoint was not necessarily perfectly straightforward. And how does that influence your thinking about regulatory flexibility you might have?
Yeah, right. To talk about Scenesse for a minute, this is the one approved drug. It's surgically implanted, meaning patients have to go for an in-office visit, receive anesthesia, and a surgical implantation of a drug-eluting pellet that then provides drug for two months. It leads to tanning, which provides a barrier against sunlight for these patients. Presumably, it doesn't address the underlying liver disease or reduced protoporphyrin IX. This drug was, you know, in phase 2. The endpoint was looking at reduction of phototoxic reactions, actually missed on that endpoint, but apparently the FDA is interested in that endpoint. It appreciates the clinical meaningfulness of it.
Then they went into two phase 3 trials, and in one of those in the U.S., they also missed on the phototoxic reactions, but they had pivoted at that point to time in light as the primary endpoint, and ultimately they were able to kind of finesse that as the basis of approval. So we see in that record. Well, and you actually mentioned the blinding thing, right? So the tanning mechanism does lead to unblinding, and I think this was a feature that we, you know, probably should have paid more attention to, right? It's in the regulatory documents, an acknowledgment that patients on that study were unblinded, were aware of-
Yeah
... whether they were on drug or not, and so there was no real placebo effect observed in that trial. We and the KOLs, thinking about our drug, essentially felt that, you know, the placebo effect would be quite mild based on that data, but we appreciate now that our drug is truly blinded. Patients aren't able to tell if they're on it or not, whereas, you know, the precedents we were looking at have this tanning feature where patients know how they're allocated, and so that led us to probably not armor up against a placebo effect as much as we could have, and now we understand that.
Yeah.
That's the nature of drug development and what phase 2 is for.
I think it's important to note, when you say they were unblinded, they were functionally unblinded, right? Like, meaning-
Yeah. Correct. Correct.
They were not aware that they were on Scenesse in the trials, but simply-
They could tell if they were tanning.
... they could tell if they were getting tanned or not.
Right. Correct.
And we've spoken to investigators who have told us that,
Exactly
... it's very apparent, right?
Exactly.
There's no mystery involved here.
Correct.
And so maybe just from a timeline standpoint, the next steps with bitopertin, and what we should be looking for.
Right. So, we have now two endpoints we think would form a great basis for a phase 3 trial. So and we, we think the safety looks good, and we understand the doses. So next step is to have an end-of-phase 2 meeting with the FDA, and what we're guiding now is that we'll, you know, we'll have that meeting, we'll get through the thirty days to get to the minutes, and then after that, we'll come out with our guidance to the public about how that trial is shaping up. And we're projecting to provide that guidance in the fourth quarter.
And I did wanna touch on another indication for Bitopertin, which is Diamond-Blackfan anemia.
Yeah.
That's a study that you have ongoing in conjunction with NIH, and just broadly, how is that opportunity, you know, sort of compare to the one in EPP, and what's the timeline or pathway for development there?
Right. Yeah, so Diamond-Blackfan anemia, this is an interesting story that's really been drawn out of us by the KOL community. It's a very severe rare anemia. No, no therapy really. Patients initially get corticosteroids. There's some response. Then after that, it's really all about transfusion and iron chelation to try not to die of iron overload, and so desperate need for therapy. Many KOLs have a theory that that anemia is driven by heme toxicity, a toxic build-up of heme inside the newly forming red blood cells. Obviously, bitopertin would control that by mechanism. They came to us to do some cellular and animal models. Those checked out well. There's a group at the NIH that has one of the world-leading trial centers for DBA patients.
They have a prevalent pool of patients who have, you know, been willing to move from study to study. And, you know, frankly, nothing works in this disease. It's a very difficult anemia to treat. But, you know, if we're able to get any signs of activity from the heme restriction approach, it would lead, I think, to a pretty efficient sponsored, you know, pivotal program. So the NIH is running this. We don't have direct control over how they do it. We don't have direct control over when the data gets pulled together. So we've projected that we should get some data by the year-end, but that's just a rough estimate. We know they're doing a great job, but we don't really control when we'll get a data delivery.
If that data does check out, how quickly would you be thinking about sort of transitioning to that sort of company-sponsored registrational study?
Oh, I think we would move with efficiency on that. I think we'd find, because of the just very high level of unmet need, I think, regulators would be open to a pretty swift program.
Okay, and would that be something you'd be thinking about initiating next year then?
Yeah, that would be in scope, again, if we were able-
Yeah
... to get data by the end of this year, and if it looked good and all, all those conditions, but yeah.
Okay, and I did want to talk about 974 right?
Yeah.
Which is your mAb that reduces hepcidin, and you have had a couple cuts of data in the course of the year, especially in myelofibrosis. I'm just curious, you know, your initial takeaways there, and I know your perspectives because I think, you know, investors have generally broadly been very impressed by the data. You know, the dose response sort of data's a little noisy, and I know some of that's a function of the number of patients in the study. And so how do you think about sort of the next steps with that program?
Yeah. So we've done dose escalation from 14 milligram once a month fixed dose, all the way up to 100 milligram once a month fixed dose, and the 14 milligram was not efficacious. The 28 milligram was. Everything from 28 on up, you know, roughly speaking, we hit around a 60% response rate, which is a remarkably high response rate for this patient population. And here, what we're doing is trying to treat the severe anemia.
Yeah
... in these myelofibrosis patients. The 100, I think what you're alluding to, the 100 milligram dose actually, at least in the early data points, seemed to underperform.
Mm-hmm.
We'll see when we have the more complete data, whether that continues to be true. But the fact is, once we get to seventy-five, we're kind of hitting maximum iron mobilization anyway.
Yeah.
So I think, you know, where we are in the program now, we've completed the dose escalation exploration, right? The six-month multiple ascending dose part of the trial is done. We've paused enrollment now while we, you know, design the phase II program, get that vetted by the FDA. Our guidance is that we'll start that phase II program before the end of the year. And then I think, you know, we'll expect to have a data cut, as we typically do, at ASH. And that data cut will really be just a, you know, kind of the complete follow-up from that multiple ascending dose, not the n won't increase, it's just that all the patients will have concluded the study, so about 35 patients.
Okay. And all those patients at the ASH data cut will have completed the-
That should be true.
Okay.
Yeah.
And you know, one of the other indications that you're pursuing about is chronic kidney disease. You know, how do you look at that opportunity? You know, obviously, anemia is a challenge for those patients. There are treatments available with significant limitations.
Mm-hmm.
So what's the sort of niche that you look... Maybe niche isn't the right word, but you know.
Yeah
... the unmet need that you're looking to fill?
Yeah, so this is a huge indication. There's probably six million patients in the U.S., who have chronic kidney disease, who have not yet reached dialysis and are anemic, and therefore in need of treatment to improve their quality of life. And so, the two therapies that are available are EPO, ESAs, and IV iron. EPO comes with, you know, well-established cardiovascular side effects, requires a lot of monitoring, and doesn't get broad usage. Also, it's worth noting that these early-stage CKD patients, their EPO, endogenous EPO production has not crashed yet. They tend to have roughly normal levels of EPO-
Yeah
... in production, so it doesn't even look like the optimal therapy for those patients. IV iron is the other treatment, and there are some of these patients who become frankly iron deficient and who should receive IV iron, and by and large, they do, but there's a lot of these patients who are anemic, who have plenty of iron on board, as measured by their ferritin levels. You know, they're 50 or above. It would tell you, you know, the IV iron might work, but it doesn't seem to be really getting at the problem. There's something else, and it's, I think, well established at this point that the something else is hepcidin.
Yeah.
It gets quite elevated in these patients. It traps their internal iron stores away, so the red blood cell compartment can't use them. So the concept here is, you know, give our drug, reduce hepcidin, mobilize that iron, allow the red blood cells to form. Pretty simple approach, and I think one that would be broadly used, especially with our presentation we think is quite convenient. SubQ, once monthly, as it's framed right now. It may even be less when we, you know, get into this more. So we're quite excited about, you know, this program. We think it's a huge opportunity.
It will take some long, big trials in the end, but to prove out the efficacy goal, which is, you know, roughly a gram per deciliter increase, we think we can do that with a fairly efficient program of, you know, call it 100, 150 patients across phase Ib and phase II, to get to that efficacy POC and then run the large trial to really prove out the safety. So our guidance is the data will come in the second half of the year. We are telling people our expectation is, or our goal is to present it at ASN, American Society of Nephrology Kidney Week conference, which is at the end of October. Those abstracts publish on October eleventh, so that's when it'll become apparent whether we're presenting the data there or in some other forum.
Okay. And how many patients will be in that initial data cut that you've released?
Yeah, so the way the trial is designed, it's six on drug, two placebo at each dose level. We presented the first dose level, 28 mg, at ASH last year. We progressed from there to 40, 60, and 90. So we'll have some additional dose cohorts in that six and two ratio at the next disclosure.
Okay. And you know, I did want to also touch on, and we're running out of time, your last asset, which is being developed for polycythemia vera, which targets the TMPRSS6 mechanism-
Right. Right.
For patients who arguably have sort of too low hepcidin. Maybe just walk through that opportunity. You know, that's an, you know, an area that has seen a lot of interest, obviously. You know, in PV, we have Protagonist developing, rusfertide, but there are others who are taking alternative approaches, right, targeting TMPRSS6.
Right.
And so what do you think are your advantages in that space, and how are you looking to sort of move ahead?
Yeah. So the goal of this whole category of drugs is to achieve iron restriction, so basically shut down red blood cell production by restricting iron. And there's actually a broad set of diseases where this may be helpful. Polycythemia vera, I think, is one of the best proved out because of the Protagonist program. There, the profile of the drug is a once-weekly injection. There is, you know, an 80% plus injection site reaction, as presented in their recent publication. But a, you know, phenomenal pioneering effort to demonstrate that this mechanism does a really nice job of controlling phlebotomy and hematocrit in these polycythemia vera patients. So we're chasing that with a presentation using a monoclonal antibody against TMPRSS6.
We think what we'll be able to achieve, based on what we've seen already in our healthy volunteer study, is a level of iron restriction that should translate therapeutically in PV patients, achieved with a once-monthly dose and no. You know, at this point, we're seeing no signs of safety, of side effects whatsoever, certainly no injection site reactions. So we think that profile will be very attractive to these patients and will provide a more convenient, a kind of second-generation alternative to the Protagonist program. And we're not alone, as you mentioned, there are several other companies developing agents targeting TMPRSS6, some going after PV, like us. Others, you know, spread across other indications, like, Regeneron's going after iron overload in beta thalassemia patients. Folks have put together data packages in animal models of sickle cell disease.
Yeah.
It's an interesting space. Hereditary hemochromatosis is another iron overload disorder that's in scope and quite large, actually. So I think this is becoming a fairly hot area for drug development, with a broad set of possible markets.
Okay, well, I think that's a conversation that I'd like to follow up, but the clock is showing that we're out of time.
All right.
So let's wrap it there. So thank you so much.
Great. Thank you.