Thanks, everybody, for joining us here at the Piper Sandler Healthcare Conference, day three here. I'm Joe Catanzaro. I'm one of the Piper Biotech analysts. It's my real pleasure to kick off this session here with Disc Medicine. Joining us is their CEO, John Quisel. John, thanks for making the time. Maybe before we jump into Q&A, I could give you a minute or two, you could sort of introduce Disc, what you guys have been up to, what we have to look forward to, and then we could pick through some questions.
Yeah, thanks. It's great to be here. So at Disc Medicine, we just flipped public through a reverse merger at the end of 2022. So this is our first year as a public company. We're focused on developing drugs to treat hematologic disorders, primarily those that arise in red blood cells. We have three different molecules in the clinic across a variety of different indications. Our approach has been to go after what we consider fundamental mechanisms of red blood cell formation, so we're looking at iron metabolism and heme biosynthesis, with a spread of diseases from rare indications up to very common indications. And it's been a great year for us.
I mean, we've really, you know, had good data from our lead program, and we're coming in at the end of the year to the big hematology conference at ASH, and looking forward to some more, you know, interesting data there.
I, of course, want to sort of take each clinical program one by one and talk through those, but maybe first, maybe you could speak to, you know, what makes the hepcidin iron metabolism pathways like a really attractive pathway to therapeutically exploit, which you guys are doing from sort of multiple angles?
Yeah, well, every red blood cell has to assemble hemoglobin. That is the main component, and iron and heme make up key parts of each red blood cell, and these are. So these are huge components in your body. This is like a macroscopic kind of activity going on in the body all the time. And, with respect to iron metabolism and heme metabolism, all of the key players and regulators are very well understood at a genetic level. And in many cases, there's clinical data that tells you how intervening at different points is likely to work. So we've been able to assemble our three molecules with, you know, quite a bit of information at the outset, based either on human genetics or on clinical data, that tell us how these drugs should perform, how the mechanism should play out in humans.
And then we have fantastic biomarkers. You can measure heme, you can measure iron, you can measure the central regulator of iron, hepcidin, all of these readily in the clinic. So we get a lot of insight early on into how our drugs are performing, how they're engaging their targets, and that's allowed us to have a lot of richness in our data, even early in development.
Great. So maybe we could start with bitopertin, and before we sort of jump in some of the really exciting early data that you guys have generated, sort of give a little introduction to bitopertin and sort of the realization that it could have utility in settings where there's sort of dysfunctional heme synthesis.
Yeah, yeah. So bitopertin controls the uptake of glycine, particularly in newly forming red blood cells. It turns out that glycine is the first metabolite consumed in heme biosynthesis. And so if you disrupt the uptake of glycine by a newly forming red cell, you will essentially downregulate heme, the heme biosynthetic pathway. And this set of diseases we're going after first, the porphyrias, they're all genetically defective heme biosynthetic pathways. So these patients have some defect in heme biosynthesis. That pathway spins off a toxic metabolite that leads to a disease state called a porphyria, and our hypothesis is very simple. By slowing down the flux of glycine in at the top of that pathway, we propose to reduce the level of toxic metabolites and hopefully get at the root cause of disease. bitopertin came from Roche.
We in-licensed it from Roche. Roche actually ran 4,000 patients' worth of clinical trials with the drug. They had a hypothesis that it would be helpful in essentially improving cognition or mental functioning in a series of psychiatric disorders, because there's a role of glycine in certain synaptic spaces. That hypothesis failed. There was a lack of efficacy, but throughout the entire program, they observed this effect of bitopertin on the formation of red blood cells and particularly on the heme biosynthetic pathway, and that's when they engaged a set of hematology KOLs to unpack that effect and understand why that was happening.
Those same KOLs were ones that we were working with as we were developing our iron programs, and there was kind of a meeting of the minds there of, "Oh, okay, this hematologic effect of bitopertin would be very interesting to pursue in hematologic indications." And when we looked at this, these porphyrias seemed like a direct hand-in-glove, mechanistic fit.
Yeah, that, that, that's perfect. And, maybe before, again, we dive into the data, you could sort of talk about EPP and porphyrias. You know, we just talked about dysfunctional heme synthesis, but the disease kind of manifests with maybe symptoms that you perhaps wouldn't expect from something like that.
You wouldn't expect. Yeah, the porphyrias are, you know, typically a dusty paragraph in a medical textbook, right? They're pretty rare diseases. A lot of people don't pay much attention to them, but it's a real burden of disease for the patients. And so what's happening mechanistically is you have this, a genetic defect in heme biosynthesis that leads to a toxin being produced. In EPP, which is erythropoietic protoporphyria, here, the toxin is produced by newly forming red blood cells.... when it goes through the skin and the skin is exposed to light, the toxic metabolite, which is called Protoporphyrin IX or PPIX, absorbs that light energy and re-emits it, causing tremendous pain under the skin in these patients. So it's described as a feeling of burning from the inside.
So this particular form of porphyria, the main clinical manifestation for these patients is when they go outside for a median of about 30 minutes over a day, you will experience an extreme pain attack that can last for days on end, completely incapacitating. And then patients adapt their entire lives to avoid, to absolutely minimize any exposure to sunlight, which creates real limitations on the way they interact with the world. And then there's also an effect that this Protoporphyrin IX builds up in the hepatobiliary system, can lead to needing for need for gallbladder removal, and can also lead to liver failure, which can be fatal from, you know, in certain cases.
So quite a severe disease, quite an unusual linkage between something going on in the bone marrow, where red cells are forming, to this, skin pain manifestation and then the liver toxicity that comes with that.
So you guys generated and reported sort of the first initial data for bitopertin and EPP back in June at EHA. I guess when you look back on that data set, sort of what definitive questions around bitopertin in this setting do you think were definitively answered?
Yeah, that's great. You know, we-- the first thing we wanted to see with the drug is, can it reduce the toxic metabolite, right? That's the first mechanistic step. Again, the beauty of this field is you can measure these things readily in the bloodstream. So our primary endpoint for our open-label BEACON trial and for our placebo-controlled trial is to look at the reduction of the Protoporphyrin IX metabolite. And the literature suggested that if you could get a greater than 30% reduction, that would lead to a major clinical improvement in these patients. And that's what we saw. So the first piece of data... So this was a data cut of about 15 patients enrolled in the study, snapshot in time. Many of them had only been on drug for a few months.
A couple of them had made it out to about 6 months, which is the duration of the study. We saw a really great reduction in Protoporphyrin IX. We had two dose levels, a 20 mg dose and a 60 mg dose. We view that as a mid and high dose. We saw about, you know, 30%-40% reduction at the 20 mg dose, and about 50%-60% reduction at the 60 mg dose. So it told us we were hitting that target beautifully. So question number one: Does the drug reduce the level of toxic metabolite to the range that we want it to? And the answer to that was yes, pretty definitively, because this is an objective endpoint, really can't be biased. Like, you don't really need a placebo group to feel good about that data.
And then the second question was that question of, well, is it true that if you reduce Protoporphyrin IX by more than 30%, the clinical response will be meaningful? And when we did looked at a variety of different metrics of sunlight tolerance in these patients, the results were profound. I mean, you had patients coming in, the first two who completed the 6 months of study, they each came in being able to tolerate only about 1-4 minutes of sunlight. And in the course of the study, they basically be became able to tolerate as much sunlight as they wanted. And the way we measure that, we tell them, "Go out and stand in the sun until you get a sign that you're going to have a pain attack." It's called a prodrome. At baseline, everybody has a prodrome.
Every single test, you go out in the sunlight, you get that tingling response. On drug, by the end of the six months, the patients were no longer eliciting prodromes, and some of them had tested that themselves out to, like, four to six hours of time and were simply unable to elicit a prodrome anymore, which, you know, at that point, the major clinical manifestation of the disease appeared to be resolved for these, these two particular patients.
So one thing you didn't mention there was sort of the safety of the drug that you guys have observed and sort of the tolerability at the 20 and 60 mg dose and what it said about... I know there were some questions maybe going in around whether you would sort of induce anemia and things like that. What do you think we know is sort of those questions definitively answered? And maybe sort of looking through to ASH, so what have we learned new about bitopertin within EPP there, and maybe sort of frame up that data set?
Yeah, no, it's a good point. So safety was another important question we wanted to answer early on. bitopertin has a safety database from Roche of over 4,000 patients, so pretty well understood what it would do. I'd say the only real controversy that we wanted to address was this question of: Would the drug induce anemia in these patients? Because if you think about it, when you reduce heme biosynthesis in a normal person, that will result in a reduced hemoglobin production. And that is, in fact, what Roche saw very consistently in their 4,000 patients. You'd get a dose-dependent reduction in hemoglobin. Not huge, so at the top dose, it would be about 2 grams per deciliter, at the mid dose, about 1 gram per deciliter.
In the setting of an EPP patient, these—if you think about it, these patients have a defect in heme biosynthesis, and they're building up this huge reservoir of one of the intermediate metabolites, Protoporphyrin IX. Our thesis was that in those patients, what we'd see is a reduction in PP IX, but it would not translate into a reduction in hemoglobin in the end, and that was borne out. So we did some in silico work at the beginning of the program, suggested that would be true. We did cell-based models, we did two mouse models. All of those showed no meaningful effect on hemoglobin.... but it was very important to, to see whether that would bear out in patients. In fact, it did.
We showed, you know, a very stable hemoglobin level across all the dose patients at that, at the data cut at EHA in 15 patients. And so to us, we feel like that's a settled question now. But we will certainly continue to present that data, you know, at ASH in future presentations as well.
Yeah, so then maybe jumping to ASH, I guess, expectations there. I think you guys have said that sort of all the patients will have six months of follow-up. What will that tell us about sort of, sort of durability and ability to keep PPIX levels suppressed? I know there's some endpoints around time and sunlight at six months, so maybe you could just speak to that and, you know, what we should consider a good outcome in terms of the time and sunlight endpoints.
Yeah. So the trial, we fully enrolled the 22 patients. Roughly 15 of them will be completers for the ASH analyses. So some of our analyses will include the, you know, the roughly 15 completers. Some of the analyses will have aggregate all 22 patients. We'll be able to march through all the same kinds of data that we presented at the EHA event. That'll allow people to see how this data evolves as you go from the 15 patients distributed at various points in time to a more full data set. So we'll look at safety, hemoglobin, we'll cover that. We'll look at the Protoporphyrin IX reduction, where again, the goal is to be showing 30% or more reduction. And then we'll look at all the different metrics of sunlight tolerance that we used.
And now we'll be able to add one more very important data point, which is, there's a precedented regulatory endpoint, which was used for the approval of the only drug that's approved for these patients. This is an aggregate of all the time the patients spend in light over a six-month period of time on days without pain. So because we have 15 completers now, we'll be able to run that analysis on those 15 patients and present that at ASH. And I think that will give people a good feel for how the treatment arms of our placebo-controlled trial are likely to read out.
What's the sort of reference point for what a sort of baseline assumption is for an EPP patient on nothing? Or how much time in sunlight could they spend over six months as we think about what, what bitopertin might show?
Yeah. So the one approved drug, Scenesse, which is causes tanning, it's a surgically implanted drug. In their placebo-controlled trial, the placebo group achieved about 40 hours of light time in light over 6 months. So that would be, you know, the comparator, and then on the treatment arm, they showed roughly a 50% improvement to that, so something around like 65 hours or so over the 6 months on treatment.
Great. So we've spoken a lot about, about BEACON, but you guys also have the AURORA study, ongoing. Maybe you could speak to sort of its design and some of the questions, it will address that maybe BEACON cannot.
Yeah. So AURORA is a much larger placebo-controlled trial. So 3 arms, placebo group, two dose groups, the same 20 and 60 mg doses, 25 per arm, so a total of 75 patients fully enrolled. We announced that in early November. We're saying we'll have the top-line data early next year. It's a 4-month duration of therapy, and so it'll provide a bigger N than we get in the open label study. And then importantly, it provides a placebo control, right? Because this sunlight tolerance is somewhat subjective as an endpoint, having that placebo reference point is important for making final conclusions about how well the drug is working. So I think that's the important piece that's gonna be... That we just simply can't address through the open label study.
I think you guys have said post-BEACON, post-AURORA, then a discussion with the FDA.
Correct
... will be had on sort of next steps. What are some key questions that you think are gonna be asked and be answered, hopefully, in that discussion with the FDA?
Yeah. So, I think we pretty well know that the six months of time and light is the precedented endpoint. What we'll have to learn is, you know, whether the aggregate of data we have in terms of a 4-month placebo-controlled trial, a 6-month open-label trial, and then 4,000 patients worth of safety database, you know, how that quantum of data is viewed by the regulators. Our base assumption is that there will be an additional trial yet required, although we think the precedented trials are typically of a similar size to what we're doing with AURORA. So, should be highly de-risked at that point.
Maybe, last question on, on bitopertin, because I do want to cover, the Anti-hemojuvelin. Just maybe how we should think about the commercial opportunity. What do we know about the size of the EPP population, and how you guys think about that?
Yeah, so there's a lot of literature about the prevalence of these patients. It tends to guide towards about, you know, 7,000-8,000 patients between the U.S. and Europe, so call it 3,500 U.S., 4,500 Europe. Those are viewed as prevalent, symptomatic patients who are engaged with the healthcare system. The genetics suggest that there's 20,000 people in the U.S. with the genotype for EPP, but some number of those are probably, you know, asymptomatic or mild in nature. So the question, I think, really is: there's probably 3,500 engaged patients in the U.S. that can be approached early on, and then there's a question mark about how many additional patients you know, can also be served with the drug.
So, maybe shifting gears to the Anti-hemojuvelin, I know again, we'll get some data at ASH, but we've seen healthy volunteer data that you guys have generated with the asset. Maybe another benefit of targeting hepcidin and iron biology is healthy volunteers tell you a lot.
Yeah.
What did that healthy volunteer experience tell you about DISC-0974's profile?
The profile looked great in the healthy volunteers. Genetically, the target Hemojuvelin is, should be very powerful and very safe. So there are human knockouts or human loss of function of this target. The result of that is near zero hepcidin production, so profound loss of hepcidin, which is a central regulator of iron, and then you get this very high level of iron available in the bloodstream. So we went into the healthy volunteers assuming that we'd be able to achieve a very profound effect. And in fact, we did. We saw we got to a dose level of a 56 milligram fixed dose. We saw 75% reduction in hepcidin and, you know, 2-3x release of iron into the bloodstream.
That all by itself was a remarkable level of impact, and it translated into about a gram per deciliter increase in hemoglobin in the treated patients versus placebo. That result was unprecedented for this kind of drug. No one else has shown that with a hepcidin-reducing agent. And to us, that validated our thesis, which was that this target was a very powerful target, and with an antibody, we were able to create very sustained control of iron, and that would result in a meaningful change in erythropoiesis. And to see it in the healthy volunteers, where there's not even a problem with hepcidin or iron, that was very encouraging as we then transitioned into these studies in patients who are known to have very elevated hepcidin, and therefore, you know, iron-restricted erythropoiesis.
Maybe a naive question. So you've mentioned in EPP and bitopertin that, like, you know, this precedent, 30% reduction in PPIX translates to some symptomatic benefits. Is there a similar number in with regards to hepcidin and sort of like % reduction translates to X amount of hemoglobin?
Not so clearly. You know, there aren't a lot of hepcidin-reducing drugs that have been able to translate into a hemoglobin benefit. But, I guess in myelofibrosis, the first indication we're going into, there is a precedent for a drug that was able to reduce hepcidin by, you know, call it 50%-60%, mobilize iron by about 50%, and that achieved a pretty meaningful hemoglobin effect.
So maybe looking towards that, you mentioned myelofibrosis is the lead indication that you guys are choosing. Maybe just help frame up the type of data set we could see there, the dose levels that you're looking at within the early stages of the trial, and maybe how they compare to what you looked at in healthy volunteers that saw that profound effect on hepcidin.
Yeah. So we're in dose escalation. At ASH, we'll be presenting a slice of that data from 10-20 patients. We started at a 14 mg dose, which was essentially the lowest active dose in the healthy volunteer study, and we're able to double that seven times. And it's designed to be a very lean escalation. We can escalate single patient at a time until we see meaningful iron mobilization, and then we start to expand at each dose cohort. So we haven't disclosed precisely which cohorts we'll be sharing at ASH, but, you know, suffice to say, we'll have moved through several different doses, and we'll be showing the effect on hepcidin, where I think, you know, to be kind of best in class, you'd want to see more than a 50% reduction.
We'd want to see that translating into meaningful iron mobilization. Then we'd want to, you know, I think a good result would be we're able to show that that's translating into a hemoglobin benefit.
Are you? So I know you guys have sort of positioned DISC-0974 as an opportunity in settings of anemia related to high hepcidin. Are you doing anything within the context of myelofibrosis to sort of screen to ensure that these patients are anemic because they have baseline levels of hepcidin that are relatively high?
Our primary enrollment criteria is simply that you're anemic and have myelofibrosis. It's a very much an all-comers kind of study. Essentially, everyone is likely to have an elevated hepcidin. That's pretty much universal in the disease. I think they all have a target that the drug can meaningfully engage with.
And then maybe last question in terms of the sort of the mix of the population within this early look, you know, the split between sort of transfusion-dependent, independent. I guess, does that ultimately matter? I guess we're just, you know, at this early look, looking at, you know, decreases in hepcidin, increases in hemoglobin, and whether these patients will be on any background therapy.
Right. Yeah, so you know, I mean, the precedent, there's no drug approved to treat anemia in myelofibrosis. The most advanced program is luspatercept-aamt from my old company, Acceleron, now being operated by BMS through their Celgene acquisition. They, in their anemia study, in phase II, divided these patients into four quadrants: transfusion-dependent, non-transfusion dependent, on Jakafi, not on Jakafi. And they showed about a 30% response rate in one of those quadrants and took that forward into phase III. So for us, you know, at this point, we think our mechanism should be generalizable, where I think we'd be excited, most excited if we see you know, efficacy across essentially all of those four categories. We'd frankly rather not divide the world into those quadrants.
We'd love to design, you know, the next stage of the program to be broad-based, preferably early in the disease, because we think our drug should be, you know, should have a good safety profile in the end.
Last question, I think you guys are also expected to provide some early insights around 0974 within the context of CKD.
Yeah.
Around ASH, maybe just what informative data points should we expect to see the outside of just simply a different indication?
Right. Right. So anemia CKD is, I think, it's a huge indication, a huge unmet need, particularly in the non-dialysis patients. We're talking millions of patients. Hepcidin, we know, is elevating these patients. Iron-restricted erythropoiesis is a common problem. The efficacy bar appears to be about a gram per deciliter increase, which, as we already mentioned, you know, we saw that in healthy volunteers. Gives us a good feeling that this indication is approachable for us. So we're doing a single ascending dose trial starting at a 28-milligram dose, which is highly active, although not in the healthy volunteer setting, that was not active enough to drive a hemoglobin change. And so we've been very clear that at ASH, what we're going to present is simply that 28-milligram cohort from the CKD patients.
We do not expect to show a hemoglobin change there because we didn't even show it in healthy volunteers. Really, the only purpose for sharing the data is to answer the one, kind of the first preliminary question when we're headed from healthy volunteers into disease, which is when you go into a patient who has an elevated disease-driven hepcidin level, can you control that with the drug? And if you can, is it at a similar dose to what was needed in healthy volunteers, or should we expect that we need to go to really high doses to get that under control? And I think by comparing the 28-milligram cohort from healthy volunteers in CKD, looking at hepcidin and iron, it'll give a very clear picture and answer that first preliminary question.
But we don't think it's really profound from a de-risking point of view for the program.
Perfect. Great. Well, looking forward to a number of updates over the next couple of weeks from you guys. With that, we're out of time. Wanna thank John for his time and thoughts. Thank everybody for joining us. Take care and enjoy the rest of your day. Thanks.
Thanks so much.