Hi, good morning, everybody. Welcome to day three of the Cantor Global Healthcare Conference. I'm Kristen Kluska, one of the biotech analysts here. Very happy to be hosting a company that I cover, DISC Medicine. We have Dr. John Quisel, the CEO, joining us on stage. Thank you so much for being here.
Oh, yeah, it's great to be here, Kristen. Thank you.
Appreciate the support. So maybe to start, can you just give a general overview of DISC and what you're most excited for these days before we jump into some of these programs in more detail?
Sure. So for those of you who don't know us, DISC Medicine is a hematology-focused company. We have three assets in the clinic, all designed to control red cell biology and address diseases that arise in the red blood cell compartment by controlling the metabolism of iron and heme, which of course, are the key building blocks of red blood cells. So right now, our lead asset, called Bitapertin, which we in-licensed from Roche, has completed its phase II program, and we're headed into end-of-phase II interactions with the FDA, with an objective of starting up a pivotal trial next year. That's the lead program, and then meanwhile, a lot of data coming out of our second program called DISC-0974, an antibody designed broadly to treat anemias of inflammation.
and we're very excited about the building phase Ib, phase II transition of that program.
Okay, thanks. So I'm actually gonna do something a little bit different here. Let's start in reverse from your earliest stage pipeline assets up, first with the anti-TMPRSS6 program with DISC-3405. Can we start by talking about the unmet need that exists in the polycythemia vera space? Why is this target strategy the right way to go versus focusing on hepcidin mimetic, for example?
Yeah. So happy to start with our newest into the clinic asset, an antibody against a target called TMPRSS6, and we call this program DISC-3405. So what this antibody does is elevate the central regulator of iron, called hepcidin, thereby restricting the availability of iron for red blood cell formation. Now, polycythemia vera, like you mentioned, it's essentially a pre-cancerous state, where the bone marrow is producing excess red blood cells, and that leads to a thromboembolic risk. So certain, significant number of these patients, and I think they're estimated at about 150,000 PV patients in the U.S. alone, about half of which are rated as severe or serious at risk for these thromboembolic events, which can be quite damaging, stroke, etc.
The objective for these patients is to reduce their hematocrit, right? A measure of red blood cell volume. If their hematocrit can be held at 45% or below, studies show that greatly reduces the risk of these thromboembolic events. The only tool really for achieving that right now, short of very serious cytoreductive agents, is primarily phlebotomy, just drawing blood out, and the goal of that therapy is to draw blood out until the patients become iron deficient, right? 'Cause every time you take blood out of the body, you're actually taking iron out of the body. Eventually, these patients become so iron deficient that they're no longer able to reproduce that excess amount of red blood cell, and their hematocrit theoretically comes under control.
The problem with this approach is that it's not comfortable to be iron deficient, right? This leads to a wide range of symptoms, including notably a lot of mental issues, brain fog, et cetera, and moreover, it's difficult to stay on a regimen that really keeps the regular phlebotomy to keep the whole thing under control adequately, so there's been a push to create medicines that can replace that phlebotomy, keep the hematocrit below 45%, eliminate the need for phlebotomy, and this has been proven out by a program at Protagonist-
Mm-hmm.
Called Rusfertide looked very good in phase II. They've moved into phase III. It's actually a hepcidin mimetic, requires administration every week or so. So we're looking to create a profile that may be easier for patients to take, a monoclonal antibody that can be delivered , looks like based on our phase I healthy volunteer data, could be delivered on a once monthly type basis.
Okay, great. Thanks. And, and as I like to say, the company went three for three at EHA this year, and this program was part of that. And wanted to just kind of first recap some of the data we saw, and then looking ahead to the multiple ascending dose data, how does the bar change for what you would view as a success here? You previously hit 50% plus iron suppression, so how should we be thinking about expectations?
Yeah, as you say, EHA, the data looked great for this program, as well as the whole portfolio.
Yeah.
So what we were looking for with a single dose was to show greater than 50% restriction in iron in the blood. That, per our models, would suggest it should translate to a therapeutic benefit, hematocrit control, eliminate phlebotomies in these patients. And we wanted to see that effect in a way that was durable enough to be consistent with once-monthly dosing. And we hit those objectives with just one dose at dose levels that are also consistent with a sub-Q formulation. We believe having that presentation is important for these patients. IV probably wouldn't be convenient enough for them. So we saw all that in our single ascending dose work at EHA. We project to be sharing multiple ascending dose data by the end of the year.
Most likely ASH is the typical place where we present EHA, ASH, the two big hematology conferences, and I think the expectations are actually quite similar. Really just looking for, iron restriction, keeping it below 50% as you dose, dose over multiple doses.
Anything on hemoglobin?
Well, we already saw hemoglobin coming down about 10% in the healthy volunteers. It's possible with multiple dosing, it will continue to go down. It's not really an objective in healthy volunteers. I think-
Sure.
We're happy if it stays kind of at that 10% level.
I think something unique with DISC Medicine is, for a lot of these indications you're reading out data, we all recognize that the mechanism could be applicable in other disorders as well, many of which you've listed as potential ones, and beyond this, the list goes on. So these parameters that you're describing, are they really a good benchmark, thinking holistically about the drug's potential? Or is it really going to differ in terms of the different indications down the line, potentially?
It's a pretty good benchmark.
Okay.
It really shows you how this is controlling iron in the body, and that's gonna read through from polycythemia vera, the lead indication. There are disorders of iron overload, like patients with beta thalassemia or hereditary hemochromatosis. And then, actually, there's a growing story of the potential utility for iron restriction in patients with sickle cell disease, where you can actually, by restricting the formation of hemoglobin, limit the sickling that may happen. And there's been some readouts from preclinical models that suggest potential there. But all those fundamentally driven by this central control of iron in the bloodstream, and that we're able to read out in a healthy volunteer study very easily.
Okay, thank you very much for that, and moving on to DISC-0974, this is another pipeline and a product potential, but first starting with MF anemia. So you had a durable hemoglobin response, again, in your recent EHA update. So can we talk about how this removes some of the risk around the target and shows how the mechanism is truly working to raise these levels?
Yeah, I mean, I think these data are fairly remarkable. Myelofibrosis is a very severe, again, near cancer-type disease, where there's fibrotic scarring in the bone marrow, a highly inflamed state, and that combination, plus an enlarged spleen, leads to really severe anemia in these patients that often pushes about half that patient population into transfusions, about two-thirds into very serious anemia, needing therapy. And it was an emerging theory. I'll give a lot of credit to the Mayo Clinic building the story around the elevation, the observation that hepcidin is elevated in these patients, leading to iron restriction and contributing to this really deep anemia.
So we went into, we've been doing what we call a phase 1b dose-escalating study, six months of dosing, at a series of different dose levels, and we saw response rates at 60%. And as you noted, at EHA, the big change was we were showing not just increased hemoglobin by 1.5 grams per deciliter, which is the accepted standard for an anemia therapy, but actually showing durability for 12 weeks and more. And seeing that at a level of around 60% is remarkable. Most other drugs that have been tested, show a response rate in the range of 20%-40%.
Okay, thanks. And I think when people look at this data, they certainly see the potential in MF anemia, but one of the top questions we get is: What is the translatability for this data for CKD anemia? So maybe just before we talk about that program on a surface level, again, similar question, is this something that there could be a lot of read-through? What are the key differences in a different patient population you would focus on?
Yeah, it's a great question. You know, the vision here is a broad anemia therapy, right? There are a lot of patients with inflammatory and chronic diseases that lead to elevated hepcidin, and that leads to iron restriction and anemia. So it runs the gamut from where we started in myelofibrosis, severe hemolytic disease, chronic kidney disease is well-recognized as a disease of elevated hepcidin, and anemia due to iron complications. And then a range of autoinflammatory diseases, anemias associated with cancers. The list really does go on, and in many ways is occupying a space where the ESA class of agents, EPO, used to be used and then retreated once it was observed that high doses of EPO could lead to some dangerous side effects.
So these patients are largely this broad range of patients are largely untreated for their anemia right now. There's no great therapy. So your point is, myelofibrosis is actually one of the more complex and severe versions of anemia, so we're delighted to see the effect of the drug in these patients. What we're addressing there is primarily a highly inflamed kind of anemia. That probably does point in the direction of some of the autoimmune diseases, where that inflammatory state can also drive anemia. That might make sense as a, as an area to progress to in development of this product and this franchise. Chronic kidney disease does have an inflammatory component, which has some linkage to myelofibrosis. It does have a unique component, which is that hepcidin is normally filtered out through the kidneys.
So as kidney filtration rates decline in these patients, you get a natural accumulation of hepcidin, which drives some of this, iron difficulty in these patients. So that's, a different aspect, right? Our drug is designed to stop the production of hepcidin, and you can imagine that if filtration rates are lower, that mechanism may take a little bit longer to work. And we saw some signs of that actually at data we shared at ASH in December. We could compare, just the first lowest dose in CKD patients with some of the low-dose work we've done in healthy volunteers and also in myelofibrosis patients. And it was apparent just on that one first dose that, these CKD patients are gonna take a higher dose to get to, an effective level.
But we're running a single ascending dose study now. We're confident as we get to higher and higher doses, we'll start to see real control of hepcidin, real mobilization of iron, which is, of course, the objective of this drug.
Okay, and similar question. I think this is one of your next clinical data readouts, potentially Kidney Week, but you've guided the second half of the year. Give us a sense first of what level of data we're going to see. Have you guided patient numbers, doses? What can we expect just on the surface before we get into expectations?
Right. So it's a single ascending dose study-
Mm-hmm.
As was our healthy volunteer study. So, similar kind of data set that we can look at. You give a dose of the drug, watch for first hepcidin to come down, then see iron get mobilized. In our experience, what you wanna see is iron mobilized for about two to three weeks. That tends to translate then into the production of hemoglobin.
Mm-hmm.
That comes in a wave. First, you see increased reticulocytes, which are the red blood cell precursors.
Right.
And then that's followed by an increase in overall whole body hemoglobin levels. So what's an interesting question with a single-dose study is, how quickly can you get that hemoglobin effect, right? In healthy volunteers, it took about three weeks for hemoglobin to start to separate from-
Mm.
Between the treated and placebo groups. In myelofibrosis, it takes about six weeks, right? So here with single-dose chronic kidney disease, certainly an objective would be to show good reduction in hepcidin, good mobilization of iron, and then some sign of, i f we're able to hit that target of, of, iron elevation for, two to three weeks, then you would expect to start to see some improvement in, in erythropoiesis. It may manifest first as some increase in reticulocytes. Whether we're able to get to a meaningful hemoglobin response in the space of one dose or whether that will come with multiple dose work that remains to be seen.
But I think a successful single ascending dose study in these patients shows that there's a trend, that the drug is working, and that we can reveal the full benefit of the drug with multiple dosing.
Okay. Is there a specific bar that you're trying to see in terms of that, the single ascending dose study before essentially giving you that confidence to move into the MAD portion or-
Oh, yeah.
Any specific bogey or bar that people should be considering?
Right. Right. Well, I think just seeing the elevation of serum iron levels, cresting outside the upper limit of normal, which is around a 50% TSAT, seeing that sustained for over a week, that would tell us we're on the right path. Seeing that convert into some improvement in erythropoiesis, whether reticulocytes or hemoglobin, that would certainly also tell us that this is pointing in the right direction. And I think, a bad result would be showing that we're not able to really control hepcidin in these patients, or that we are, and it's just not converting to any improvement in erythropoiesis. That would give us pause before we progress the drug.
Okay. I think of your current in-the-clinic pipeline assets, this is by far the largest market opportunity, can frankly be the biggest driver in terms of all the ways myself and my peers are valuing the company. So can we, can we walk through what that opportunity can look like? Why is it that standard of care... I know you talked about some, some serious side effects there, but beyond that, why, why is this such an open field that somebody like you can take?
Yeah, I mean, the CKD anemia space is a very open field.
Yeah.
It is remarkable, and I think it's because what I mentioned, the ESA use has become much more restricted. IV iron is used, but it's really only appropriate for patients who have full-on nutritional iron deficiency, which is a relatively small part of these patients, and then there was a huge campaign, many of you may remember, the HIF-PHI class of drugs. There were three of them developed in this space, and large, large phase III trials. The premise was that there would be an improvement in safety relative to the ESA class of drugs, and it didn't prove out that way.
So in the U.S., at least, for this group of non-dialysis dependent CKD patients who are anemic, which we estimate to be about six million people in the U.S., there's actually no new therapy right now and nothing really in the pipeline other than this approach of controlling hepcidin.
Mm-hmm.
Which I will note, CKD is where hepcidin was discovered, and it has been a target of interest for well over a decade, and we're delighted to have what appears to be the best-in-class tool for approaching these patients.
Okay, thank you for that. So let's, let's switch gears now for Bitapertin in EPP. Thinking about it, you've had two wildly successful trials. I will use that word-
Thank you. Thank you.
Because I cover the company. I mean, it's very clear this is a great example that you have a very clear biomarker that literally correlates almost nearly perfectly to some of these clinical outcome measures. I think in the recent trial you shared back in April, there was an unexpected placebo response in a key secondary outcome, so there was a negative reaction from the market. But again, I think truly at EHA, you came out with a powerful message that, one, you have a really better sense now of understanding why that may have happened. Two, you reiterated through all of these endpoints that the drug still works extremely well. And three, there are ways to consider the path forward here, and that there really isn't any clear FDA guidelines for this indication. You can go into those conversations with your own data.
So beyond everything I just said there, why do you think you're not fully getting credit for this yet?
Good question. I think the drug is working very well, actually. The profile you see-
Yeah
... particularly at the top dose, the 60 milligram dose, is a remarkable profile. We have greater than 40% reduction of protoporphyrin IX, which, as you mentioned, this is both a biomarker, and it is literally the toxic metabolite-
Yes
-that drives the disease. So seeing that reduction greater than 40%, that should translate into major clinical improvement for these patients. And what we saw at that 60 milligram dose was actually patients spending much more time in light, in their life. We saw after two months, no patient out of 25 experiencing phototoxic reactions, which is the main symptom of the disease, this intense pain attack that comes with exposure to sunlight. And, about 90% of the patients are saying they feel much better. So eliminating the pain attack, allowing patients to spend time in sunlight, having them feel much better, that's a remarkable profile. And as you noted, the one kind of cloud on that parade was that in some of those endpoints, there was a meaningful improvement in the placebo group as well.
So that time in light endpoint, which was the basis for approval for the one approved drug, Scenesse, which requires surgical implant and therefore hasn't been broadly used, that was a time in light endpoint. So, the FDA had pointed us towards that as, "Hey, that's precedented. If you can hit on that, we know that's clinically meaningful." And so having the placebo effect destroy stat sig on that endpoint-
Sure
Did cause some dislocation in the stock price and investor reaction. And I think, it just takes time to prove it out, but I think there's some perception of risk around our end of phase II meeting with the FDA. The question is: Will we need to use the precedented endpoint, which would require a somewhat larger trial to. We can power that trial. We can run that trial, but it would require more patients to do it, to turn that numerical benefit that we saw into a stat sig signal, versus some of the other endpoints where we were hitting right out of the gate, pre-specified in the AURORA study, like the rate of phototoxic reactions, where we saw stat sig 75% reduction at the top dose group, pre-specified.
You know, that endpoint we could power with a much smaller number of patients, and then the other endpoint that looks really promising for us is what we learned is there's this wave of placebo effect at the beginning of the study, which is characteristic, right? This is what happens. Our endpoint is a subjective endpoint, where patients are reporting on the time they spend in light. You see all the groups performing very well during the first month, and then the placebo group fades back to baseline, where the treatment groups stay elevated, and that separation then is quite stable after about month two. Now, AURORA was only a four-month study, so we only got two months of stable separation between the groups.
Right.
If we can run that study for six months, that will help a lot, and if we're able to analyze that endpoint beyond that period of placebo effect, call it from months two to six or just month six, whatever, that helps a lot. That allows us to power the study with a relatively small number of patients. So I think that's. You know, people are, I think, watching carefully to understand what, what comes out of our FDA interaction around endpoint selection. Dose is also an open question. The safety profile looked good to us. There's really no major side effects. But nonetheless, you always have to wonder: Are we gonna be able to go with just the high dose at 60? Will we want to include 20s and 60s?
Depends to some degree on how the FDA is viewing this program.
The sense I'm hearing from you, though, is no matter which way you go, you think that there's a path that you can reach stat sig. It's just a question of, is there gonna be a trial that maybe requires a little bit more patient enrollment if you use one endpoint versus the other, and maybe it's a little bit longer. But regardless of which way you choose, I think the bigger variable here is, is time and not so much level of confidence or questionability about whether or not you can be successful. Is that kind of where we're at with that?
I agree with that. Yeah, that is our basic-
Yeah
Point of view. I've learned to always be cautious approaching regulatory interactions.
Of course.
You never quite know what's going to happen, but our assessment and speaking with our advisors is that the program looks safe. It looks to be providing substantial benefit to patients in this phase II program, and the likelihood that we'll be able to design a successful phase III program is quite high.
You've said that this meeting with the FDA will take place in the second half of the year. The next time you give an update to the street, once that takes place, what should that announcement look like? Is it gonna be telling people the endpoint that you want to bring forward at that time? Will you have a sense about what the trial design might look like? What can we really expect?
I think that's about right. [crosstalk] We plan to come out with some information about how are we designing our pivotal program? And I think embedded in that, of course, will be the feedback that we've received from the FDA in terms of how to design that study.
Okay, and then you'll, whatever endpoint it is, you'll essentially remind us about your assumptions and why that you're confident with that agreement in place?
That's right, exactly. You know, and to the extent we haven't shared it already presumably we'll do some effort to show how that endpoint would perform post hoc in our datasets that we have today.
And then at EHA, you had a lot of really in-depth analyses that you shared, which kind of brought you to this point of, right, there are a couple endpoints that maybe we could consider. But beyond this, is there anything else or any other collections that you're presenting to the FDA during this second half of the year meeting or you're also kind of walking them through why these endpoints are critical in this disease to consider and why these benefits can strongly suggest an improvement to life?
Yeah, I mean, an important part of the interaction that we're gonna have, and frankly, an important part of our story around the program, is just recognizing the centrality of protoporphyrin IX, right? Which the KOL community obviously understands it. They're the ones who discovered that the genetic root of the disease, and therefore, the metabolic toxin that's produced, protoporphyrin IX, that drives the whole thin really helping all the stakeholders, including the regulators, understand that the goal for these patients is to get the protoporphyrin IX down because that will both help resolve the sunlight sensitivity. But in the long run, at least based on the mouse data, and certainly based on intuition, that should improve liver health as well.
And these patients do, about a third of them have signs of ongoing liver damage, gallbladder damage, and, as we've talked about before, a few 2%-5% will go into complete liver failure, which can be a fatal complication of the disease. So I think, we really want the KOLs have told us, "Hey, Protoporphyrin IX is critical." And I think an important part of our story is helping all stakeholders understand that our drug, by reducing that central driver of the disease, is likely to achieve a lot of great benefits for these patients.
Okay. Maybe I can just close by asking why this is an optimal time. I always joke with you that you keep me on my feet because all of your catalysts are staggered so nicely, that the programs are in such a way that there's always something going on-
There's always something.
to pay attention to, right? So why is now an optimal time, again, ahead of these really big catalysts in the second half?
Yeah, it is a busy moment for us, but like you said, every moment is busy. We got three programs going. We have these wonderful biomarkers, right? I think that's one of the strengths of our programs. You can always see pretty early in patients what's going on. So what's important here is we're about to transition to phase III. People will get a feel for how bitapertin is progressing. And the other two programs are about to transition to phase II, and in myelofibrosis and polycythemia vera, and then we're gonna get the first real look at chronic kidney disease data.
A lot, a lot of data coming with the asterisk, I think on CKD, that is single ascending dose, so we're not gonna see, I think, the optimal effects of the drug. But getting some sign of whether or not that drug is working in those patients, it's a huge opportunity and I think has the potential to be pretty interesting.
Okay, great. Well, thanks so much for your time, as always, John. Appreciate it.
Yeah, appreciate it, Kristen. Thanks so much.