All right, great. Good morning, everyone. Thanks for joining us here at the Leerink Partners Global Biopharma Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to stage Disc Medicine, and happy to be joined by CEO John Quisel. John, thanks for joining us.
Yeah, thanks, Tom. Good to be here.
John, why don't you kick us off with a brief overview of Disc for those in the audience who may be a little less familiar with the story?
Yeah, sure. So Disc Medicine, we're a company that went public at the end of 2022, had a very successful year in 2023. We're focused entirely on diseases that affect red blood cells, so hematology, and we have a portfolio of three clinical-stage assets that all affect iron or heme metabolism as ways of controlling red blood cell biology. And the overall vision is that with these three agents, we can address a wide range of disorders that arise in the red blood cell compartment. We've got our first asset called bitopertin in phase II, actually close to a blinded trial readout, that's taking aim at a rare disease called porphyria.
We have a second agent aiming at the heme-onc space, myelofibrosis, as well as a broader anemia of inflammation concept, and a third program that's also aimed at heme-onc and polycythemia vera.
Okay, awesome. Let's start with bitopertin, and maybe you could just give a little bit of background here on the asset, how you came about the asset, the mechanism, and how important glycine transporter 1, the role it plays in the heme biosynthesis pathway.
Yeah, sure. So we in-licensed bitopertin from Roche. Roche was developing. Actually, I'll start with the mechanism. So mechanism, bitopertin blocks the uptake of glycine through a transporter called GlyT1. There was a thesis that this could be helpful to improve cognition or other mental functioning aspects in disorders like schizophrenia or OCD. Roche pursued it in a very vigorous 4,000-patient clinical program for that purpose, ended with a lack of efficacy, but there was a persistent side effect that wrote a new chapter in the story of how heme is synthesized in red blood cells. And that new chapter was, the very beginning of heme biosynthesis actually starts with glycine. That is the first metabolite consumed.
It turns out that in a newly forming red blood cell, there's a tremendous drawdown on glycine in order to make adequate heme, of course, to make hemoglobin, which is what carries oxygen in your blood. What Roche found is that when you block the GlyT1 transporter, this is the very transporter red blood cells turn on as they're requiring glycine to support heme biosynthesis. The effect of blocking it is to actually decrease the flow through the heme biosynthesis pathway in the bone marrow compartment. We were, you know, already hard at work on some of our iron metabolism programs, and hematology had a range of great KOLs, some of whom were also advising Roche on how to manage what to them was a side effect.
And as the program was shutting down, these KOLs told us: "Hey, you know, this, this effect on heme biosynthesis, there's no clinically acceptable way to control heme biosynthesis, and this drug looks pretty safe after 4,000 patients worth of work." So, we went, dug into it, established some IP around the porphyria indication space, which are, we'll get to, I'm sure, disorders of the heme biosynthetic pathway. And we felt that, it would be worth trying the development of the drug in that space, and then the results have been great so far.
Okay, great. And, yeah, I want to talk about porphyria and some of the data you presented at ASH from the open-label BEACON study, really striking improvements in daylight tolerance and, patient-reported outcomes in, EPP patients. I guess, maybe just help us understand, like, what sort of patient population did you enroll in the BEACON? And then obviously, the biomarker that we're looking for here is PPIX levels, reduction in PPIX levels. Maybe just describe sort of the baseline disease severity and kind of like their mean PPIX levels and the kinds of reductions that you saw.
Sure, right. So this disease, erythropoietic protoporphyria, right? It's one part of the complex of porphyria disorders. They're all genetic defects in heme biosynthesis. So here, the last step, a enzyme called ferrochelatase, is deficient due to genetic mutation. It causes a tremendous buildup of a metabolite called protoporphyrin IX, or PPIX, as we call it for short. And that PPIX is toxic. It's not supposed to accumulate in your body. Its toxicity manifests primarily in sunlight. So when these patients expose themselves to sunlight for, on average, about half an hour in a day, that light excites the PPIX molecule in their blood, and it goes and becomes this highly active radical that attacks their tissues, including the nerves, and causes excruciating pain, described as the feeling of like burning oil under the skin.
So an incapacitating disease with relatively modest amounts of sunlight exposure. So we, you know, if you look in the literature, if you can reduce PPIX levels by about 30%, and there have been just a few kind of situations where that happens, these patients experience major clinical improvement. So that was the objective of our program. We saw the bitopertin could reduce the PPIX levels by greater than 30% in cell lines, in mouse models. So we set up two trials to explore this, one, an open-label study called the BEACON trial, being run in Australia, about 20 patients. The other, the AURORA trial, placebo-controlled, 25 per arm, 2 doses, so 75 patients total, reading out in March or April. So across 2023, we present data from the open label study.
We showed consistently hitting that 30% reduction in protoporphyrin IX that would suggest we would get major clinical improvement, and in fact, we did see major clinical improvement. I mean, the endpoints performed remarkably well. We had patients who were no longer responsive to sunlight, meaning they went from being able to spend a couple of minutes in light at baseline to spending as much as six hours. It was actually quite astonishing. So if you look at our slides from EHA in June last year and then at ASH in December, you can see we're looking at various different ways of measuring light tolerance to show that improvement.
Have you, I guess, within the context of the 20-patient, 22-patient BEACON study, have you been able to see, I guess, with greater mean reductions in PPIX, greater increases in daylight tolerance?
Yeah, the numbers are too small to do good correlations. So the ASH data set was 14 completers, seven at the low dose of 20 mg, and seven at the high dose of 60 mg. So we do get a range of reductions in protoporphyrin IX, and by and large, people who achieve that 30%, do achieve a major improvement in their light tolerance, whereas those who don't achieve it, of which there were two, still get some benefit, but it's, it's markedly less. So that's as, you know, close to a correlation we can get. There may never be a great correlation 'cause it does appear that there's kind of a threshold. Once you cross that 30%, the improvements are, are, are major, and, and so then you start to lose correlative effect after you get over that threshold.
That makes sense. And I guess, given that a lot of the light sensitivity measures are kind of these patient-reported outcomes, kind of rely on patients' willingness to assess their own, propensity for prodrome. Could you just speak to, I guess, the level of motivation of the patients in the study to go out and actually test this and, and see if they experience prodrome?
Right. Right. By and large, it's a highly motivated patient population, right? I think the thing to remember is that these people are living their disease every single day, right? Every day, they wake up, and they say, "Okay, I know..." 'cause they all know for themselves, you know, I can spend a half an hour of light exposure, and that includes light coming through windows, because it's, it's visible light. So they'll say, "Okay, I get a half an hour today. I'm going to, you know, commute to work, I'm gonna go to the grocery store, I'm gonna pick up my kid at their, you know, after their soccer practice, and those are the three things I can do to expose myself to light. You know, my husband's gonna have to walk the dog," whatever, right?
I mean, they calculate their whole lives around this. So they're highly motivated to get relief from this kind of restriction that they have on their daily lives. And that's what we've seen. You know, one of the things that was really powerful to us in that initial set of data from the open label study was just looking at our diaries, right? Where each patient receives an iPhone with a diary where they're tracking their light, and this is not that different from their mental processes every day with the disease. They're always tracking their light. And we were really gratified to see that we're getting very good, you know, compliance. Patients are actually using the diary. The data we're getting appear to be quite reliable.
And, you know, we see we're measuring light tolerance in several different ways, and all of those point in the same direction, right? So all these tools appear to be working together quite well.
Got it. That makes sense. Can we talk a little bit about the safety in BEACON? I mean, there was really no change on hemoglobin, which I think some investors were a little concerned about.
Sure.
Ahead of the readout, but really looked like low-grade sort of headache, dizziness. Any... I guess anything notable, anything relevant?
Yeah, I'd say everything is tracking to the Roche experience, with 4,000 patients worth of data in our safety database, from the prior Roche work. We do not expect to be surprised on the safety side. And sure enough, the three side effects that are observed in the phase III work from Roche are, you know, call it about a 10% rate of low-grade headaches, dizziness, and somnolence. We didn't actually really see any somnolence. We saw dizziness and headaches, at a higher percentage, probably around, let's just call it ballpark, 20%-30%. But like in the Roche data, they're all transient, meaning they happen early on, like in the first couple of weeks while the patients are on drug, typically for only a fraction of a day.
So really not a major issue for these patients. You know, we saw one discontinuation. That kind of thing just happens sometimes.
Got it. Okay. Let's talk about the placebo-controlled phase II AURORA study, and you mentioned we're on track for data in March or April, so relatively near term here. Can you just talk through a little bit of the design here, how the enrolled patient population compares versus BEACON? Are there any notable differences? Have you talked about baseline characteristics? And then, yeah, let's start there.
Yeah, no, it's a good question, and a popular question is, you know, if BEACON looks good, is there anything as we transition that to this placebo-controlled trial, AURORA, that may cause variability or may cause those effects that we saw in BEACON to not really predict the outcome in the randomized setting? As best we can tell, there's no, there's no major differences. It was gratifying to see, in Australia, we captured a very wide range of baseline patients, you know, running from very severe patients with exceptionally high protoporphyrin IX levels, and very, very short amounts of daylight tolerance, to patients who are at the relatively mild end, which, you know, gets up to about two hours of daylight tolerance.
So we saw all that range in the BEACON patients, and we haven't disclosed baseline characteristics for the AURORA trial, but safe to say it's in the same range.
Okay, and how are you accounting for some of the regional differences here? I guess one of the questions we get most frequently is, you have these trial sites pretty much across the U.S., and you're thinking about potential daylight exposure in places like Miami versus places like Seattle. Like, how are you controlling for some of those regional differences?
Yeah, so we did extensive KOL and patient, you know, advice-seeking panels to try to design this trial well. And in the end, the advice actually all boiled down to stratifying by light tolerance. And I think the point to that is that your light tolerance is dictated by where you live, to some degree, right? And so, as long as you're stratifying, basically, we did it above and below the 30-minute light tolerance line, so cutting it right at the median level for these patients. You know, if someone has a 15-minute tolerance in Seattle, they come into the study as a 15-minute tolerance person. If they have a half an hour tolerance in Miami, they come in with a half an hour tolerance in Miami. But as you...
It already builds in their experience of their local geography. So we thought that was actually pretty smart advice and allows us to be pretty efficient about the trial. You know, with 25 patients per arm, we don't want to do too much, you know, subgroup analyses anyway. So that is the way, the fundamental way that we've been controlling for this.
Got it. That makes sense. John, maybe you could just help sort of set expectations for the AURORA readout. Like, what would you guys consider a good data set in AURORA?
Yeah, yeah. So there's probably a wide difference between what is good and what we would expect. So I think, you know, our best prediction is really the BEACON data that we shared. I think everybody assumes, and I think we do, too, that the protoporphyrin IX reduction, which is the primary endpoint for both studies, should carry very well from BEACON over to AURORA. There should be no difference, open label, placebo-controlled, to that objective metabolic endpoint. I think the focus really turns to the, what we call the key secondary endpoint, which is measuring the total time these patients spend in light across, the study.
There in the BEACON trial, what we shared at ASH in December was, on treatment about over 200 hours of total time and light that our patients were able to spend across that study in a six-month study. If you compare that to the one meaningful historical control we have to look at, that metric was about 60 hours on average there. So, you know, threefold, vastly improving over placebo. That's probably the prediction, right? That's as good as we have. In terms of what we need to do to have a good profile, the one approved agent out there called Scenesse is a surgically implanted pellet that patients receive every two months at a dermatological surgical center.
That, using the same endpoints, you know, where the placebo group was around 60, showed around 100 or 110. So, you know, 50%-60% over improvement over the placebo group. So that's probably what we would say. We want to achieve that or see that in our data to feel like we have a profile that's gonna be substantially better for our patients. And I will mention that bitopertin is a very convenient pill. Patients just are taking a pill once a day. So very straightforward modality that gives, I think, an inherent advantage to our profile.
Okay, that's helpful. And just, I guess, help us think about expectations for the placebo group relative to the Scenesse study. Like, are there any notable differences there? And maybe just help us sort of understand some of the variability and some of the things you're looking at. So PPIX levels-
Right.
I think of as being obviously, like, very objective biomarker, but how much variability is there in the measurement of that, and then how much variability should we expect on things like daylight tolerance, time to prodrome?
Right, right. Yeah, so we've powered the study to see a 30% difference between the placebo group and either of the dose groups on protoporphyrin IX. There really should be no, no reason why that would differ between BEACON and AURORA. We're using, in fact, the same central lab to do those measurements. You know, in the control studies that have been run, where people have measured protoporphyrin IX levels, it's been remarkably stable. So we don't expect to see a lot of change or, or sort of inherent variability in the patients. Changes should be driven by drug effect. So that endpoint feels quite predictive from BEACON to AURORA. I think there was another part to your question.
Yeah, and then I guess, similar sort of how much variability do you expect on sort of the patient-reported outcomes?
Yeah, yeah. I mean, no doubt there's more variability there. And I think that you can see that in the data we presented at ASH, where you see, you know, pretty good range around those total hours of time in light. But nonetheless, we feel like what we're seeing is these patients are using their diaries. We are collecting many, many, you know, entries per patient, I mean, literally hundreds, you know, across the course of a study. So we feel good about... And the, you know, these endpoints are really aggregating all the hours across the trial. So there's a lot of richness to the data that we're collecting, that it gives us some confidence.
Got it. That makes sense. And, I guess just help us think through next steps from here, assuming positive AURORA data. I think you've been pretty consistent from the beginning that you think you would probably need a phase III study.
Right, right.
Right. But is there, I guess, is there a scenario where there could be a more expedited path?
... Well, yes. I mean, it's a rare disease. We do have a very large safety database, and you know, our expectation is we'll get some kind of readout from this placebo-controlled trial. We'll take that 75-patient study plus our 20-patient open-label study and bring that all to the FDA as well as the EMA for end of phase II discussions. And you know, our base expectation is that we will run a phase III trial. We'll use the data to help us power the light endpoint, the total time and light as the primary endpoint for a pivotal study. Those studies historically tend to be about 80-100 patients. They tend to enroll in about a year. It should be highly de-risked by AURORA.
It would be a very similar study design. That's the base expectation. You know, if the data are great and everything looks aligned, of course, we'll ask about an expedited path, but we're really not trying to guide people to that.
Got it. That makes sense. Let's just briefly talk about sort of the competitive landscape here. You mentioned Scenesse. There's another oral drug with a similar mechanism, dersimelagon. Very different mechanisms, though, not really altering the underlying disease pathogenesis. Could you just kinda talk through, I guess, how you see bitopertin fitting in amongst the competitive landscape?
Yeah, sure. Right. So our core mechanism is that we can reduce the level of protoporphyrin IX, a toxic metabolite, that has a direct effect on sunlight tolerance. It also affects something we haven't talked about yet today, which is liver health. These patients have about a third of them will have evidence of liver damage. They can end up with gallbladder surgery, and then, a few percent of these patients will actually go on to complete liver failure, which is a very severe, obviously, outcome of this disease. Liver damage is caused directly by protoporphyrin IX precipitating in the liver or in the bile duct. And so it should be that by reducing protoporphyrin IX, we're able to improve liver health. We're not directly studying that in these current trials.
We'll be, you know, looking at that over time, but that is one of the potential benefits of our drug relative to these other two approaches that are in one case, approved, the other case in development. So the two agents you mentioned, the one approved agent, Scenesse, works by stimulating the melanocortin-1 receptor to cause tanning, and as I mentioned, that causes about a 60% improvement in time and light by improving, you know, basically creating pigmentation of the skin and a barrier to light penetration. And that drug has a presentation where patients have to travel to one of a handful of dermatologic surgery centers to get a pellet implanted every two months.
So it hasn't seen, you know, really wide use in the, in the patient population, despite, I think, a very strong desire for therapy amongst these patients. The other program you mentioned is called dersimelagon. This is an oral melanocortin agonist, so improving on the modality, but the mechanism is about the same. They had a successful phase II trial showing about a doubling in light tolerance, and then they went on to a phase III trial, results of which were published at one small porphyria conference. It hasn't really been disseminated publicly, but that trial failed for lack of efficacy, and showed more like about a 50% improvement in light tolerance, without reaching stat sig.
So Mitsubishi Tanabe, the sponsor of that program, has gone back to run a subsequent phase III trial and try again.
Okay. Let's shift gears and talk about your anti-hemojuvelin program, and this is DISC-0974. You have a study in myelofibrosis and a study in non-dialysis dependent CKD. Maybe if you could just give a little background on why those two indications first, and some of the differences, I guess, in trial design between the two, 'cause you're looking at two obviously very different disease states.
Right. Right. So the core of what we're doing is trying to mobilize iron in patients who have inflammatory disease. So what happens in inflammation is a key regulator called hepcidin becomes quite elevated, you know, often tenfold elevated over the normal level of this regulator, and that restricts iron, meaning iron is in your body, but it's not being accessed to support red blood cell formation. And what is astonishing about this biology is that it's literally milligrams of iron per day cycling through your body to support red blood cell formation. So when that iron becomes trapped away, very quickly, patients become anemic.
And so it's a broad syndrome called anemia of inflammation or the anemia of chronic disease, marked by high levels of this regulator, hepcidin, and low levels of iron in the blood, which is often measured as something called transferrin saturation. So the goal of our drug is, you know, it is basically to reduce the level of hepcidin. We're attacking it at a key regulatory point as defined by human genetics. Our target, hemojuvelin, is actually there are loss-of-function mutations known in humans. The sole effect of those mutations is to lower hepcidin, right, which is the therapeutic objective. So we feel very good about both the power and the expected safety of our target, given that it's defined by knockout mutations in humans.
So these diseases, we're starting with myelofibrosis, a very severe heme- onc kind of indication, where nearly everybody ends up with, you know, regular transfusions in order to support the red blood cell production. That is a highly inflammatory disease, and it became apparent relatively recent from work at the Mayo Clinic that, hepcidin levels were quite elevated in these patients, and that iron restriction may be a major contributor to anemia in these patients. So that's where we're going first with the program. And then, chronic kidney disease, is also a disease. You know, there's obviously a lot of knowledge in our field about EPO and the role of EPO, the loss of EPO production as a major driver of anemia in chronic kidney disease patients.
What gets less attention is the fact that iron is the other major driver of anemia in these patients, and in fact, in patients who are in the earlier stages of disease, often their EPO level is fine, but their hepcidin levels will be very highly increased, and iron restriction has set in and is actually the main driver of anemia. It's actually chronic kidney disease patients where hepcidin was discovered as this key iron regulator. So that represents an enormous market opportunity. There's, you know, estimated about 6 million patients with non-dialysis kidney disease who are anemic and in need of therapy. The available options are not widely utilized for a variety of reasons. So by and large, when people look at, you know, how many patients are anemic and not receiving therapy as they head towards dialysis, it's remarkably high.
So this represents a very high unmet need population, and the mechanism makes perfect sense. You know, we saw the HIF-PHI class of drugs that were being developed in this space in the U.S. for the non-dialysis patients, all of them were declined by the FDA. Safety was no better than EPO, which has a black box warning around cardiovascular effects. So these patients now have no real therapeutic option for them.
Yeah. Okay. You presented some initial data across both indications at ASH, but I guess drilling down into the myelofibrosis data set showed really nice reductions in hepcidin and translated to hemoglobin increases in patients, which is obviously, you know, clinically, clinically relevant hemoglobin increases. I guess just help us sort of think through your next steps with this program. Like, we're looking for data updates later this year. How many additional patients? We're still in dose escalation with this-
Right.
data set, right? So just help us sort of think through expectations for subsequent update.
Right. So the ASH data set was our 11 initial patients, mostly at what we consider to be a very early dose, a low dose of 28 mg. We saw over half the patients with very meaningful hemoglobin responses. Admittedly, we need to track that further out in time to really prove that out. And so we've guided, you know, but, but we're very excited. We've guided this year, we'll have data at both the first half and the second half. At this point in the first half, our expectation is that we'll present at EHA. Those of you who know the process there, you submit an abstract, eventually, you get a conference speaking slot or poster slot. We haven't announced that yet. Those aren't known yet, but that's our expectation.
In terms of what that data looks like, you know, we presented 11 patients worth of data at ASH. It was exciting data. We've seen that translate into enthusiasm, momentum, and engagement at the sites. So enrollment's been going very well, and I think we'll have probably double that number of patients to present as we come to EHA. And, you know, the typical endpoints in terms of looking at, you know, hopefully to see hepcidin going down, to see iron levels going up, and to see that translate into either hemoglobin increases in those patients who are not regularly transfused or reduction in transfusions, transfusion burden in patients who are highly transfused.
Got it. That makes sense. And, just on the CKD study, patient population, next update—I mean, similar question, right? Like, how should we expect this data set to evolve? It's a placebo-controlled study, right? So...
Yeah. So, right. So myelofibrosis, I should say, is open label. We're able to give six doses over six months, taking advantage of some regulatory doorways that were open at the time we started. We didn't have chronic tox. At this point, we do, and it's all clean. But for CKD, we started with single ascending dose, where we do six patients on drug, two on placebo, and then move up to the next dose. We presented the 28 mg dose cohort, again, the low dose, which was highly active in myelofibrosis patients, not that active in healthy volunteers, and similarly, kinda similar activity in the CKD patients. So just starting to see the iron mobilization. So the goal here as we go across the year is to keep escalating through different dose groups.
In the healthy volunteers, it was a 56 mg dose that translated to a hemoglobin benefit, which, by the way, was the first hepcidin inhibitor ever to show hemoglobin benefit in healthy volunteers. And so we'd expect when we dose escalate into that zone, call it the 60 mg dose, which I think is our third cohort, we might expect to see that translate into a hemoglobin benefit. In terms of timing, we've guided to having that data in the second half of the year, and our focus would probably be one of the large kidney disease conferences.
Got it. That makes sense. All right, John. Well, unfortunately, we're up against time, but, appreciate you joining-