Morning, everybody. Thanks so much for being at Cantor's Global Healthcare Conference, day one. Very happy to be with Dr. John Quisel, the CEO of Disc Medicine. Thanks so much for being here, John.
It's great to be here. Thank you.
Great. Lots going on at Disc Medicine, but maybe very big picture, do you mind just providing us with a high-level overview of the company?
Oh, sure. Yeah. We've been public for a few years now. As a company, we're focused on controlling red blood cell formation by controlling some of the fundamental building blocks. As you'll hear, our three different clinical candidates all focus on controlling either heme biosynthesis or iron metabolism. By doing that, we try to address a wide range of different disorders that arise in the red blood cell compartment.
Okay. I am going to try to cover a little bit of all of your programs today. Maybe starting with bitopertin, the phase III data are coming next quarter, so maybe we could talk about some of the debates that are still out there on the field. First, when we think about the AURORA study, what did the findings show you as it relates to the average monthly total time in sunlight without pain in the last two months?
Right. Yeah. bitopertin, designed to control heme biosynthesis and thereby control the accumulation of a toxic metabolite in these porphyria patients. To your point, one of the key readouts, the clinically meaningful readout, is looking at how long these patients choose to spend in sunlight. So essentially, a voluntary endpoint. Patients track how much time they go outside and expose themselves to light. They come into the study typically only able to tolerate 30, 40 minutes of sunlight in a day, which completely restricts their lives. In our phase II program, we had a four-month placebo-controlled trial, with about 75 patients at two different dose levels. That was the key data set that we used to design the phase III APOLLO trial. It is reading out shortly.
In that data set, what we saw was all the groups improved their time in light during the first month or two of the study, and then you saw the placebo group trend back toward baseline while the active groups showed continued improvement over time. If you look at the last month of that study, the delta, the effect size, was an additional 14.9 hours of time in light. That kind of averages out to about a half an hour per day, which is about a 50% or more, actually greater than 50% improvement in the time in light. It does not sound dramatic, but the way it translates for patients is not so much that, oh, I get on average an extra half hour per day. It is that actually what they find, what they report, is that they are able to go and do capstone events.
Go out on the boat, go to the beach with their family, go to a wedding, things that they have never been able to do in their lives. That is what really matters to the patients, not so much the numerical average. But nonetheless, for powering the study and designing the statistics in that last month, it was a 14.9 delta. Actually, if you look at the last three months, the average effect size was about 11 hours, and that is the number we used to power the study. In the APOLLO phase III trial, we are looking at the data, time in light in the last month. This time, it is a six-month study, which we think that longer duration will allow a greater separation between placebo and active.
Rather than use the 14.9 that we saw in the last month of the AURORA phase II trial, we chose to give it about a 20%, 30% discount off of that, be more conservative, and use about 11 hours as our presumed effect size for powering the study. That also turns out to be the average effect size you get over the last three months of the four-month AURORA trial. We feel like that's a very conservative and robust estimate of what effect size we can anticipate, and to use that as the basis for powering felt very comfortable to us.
The AURORA study showed a little bit of noise in the first month. Why do you think that's the case? Understanding that this is not going to be part of the primary efficacy analysis, are patients being coached by their physicians, obviously, regardless of what arm they're on, to just be more cautious during that time and time in the sunlight?
Yeah. Patients are counseled about how the drug works, which takes a little bit of time, a couple of weeks, to start reducing the toxic metabolite protoporphyrin IX and really confer what we think are the benefits of the drug. I think it is essentially inevitable and kind of part of our planning now, right, that patients will come into the study with a lot of exuberance about the opportunity to change their lives, and they'll tend to experiment early on, and that's where you see this so-called placebo effect. It's actually every single group. You see everyone spending more time in light at the beginning of the study, at least in our phase II trial.
I think what we did is we said, "Okay, that's a natural behavioral element of coming into a trial, and we're just going to adjust our endpoint now to take that into account." That's why we focused on the last month of the study as our critical endpoint measurement.
Okay. You did disclose the baseline characteristics for the phase III study, which does show a very nice balance between the two arms. One question that we get is around seasonality and the different regions included in the study. How should we be thinking about this?
Yeah. What we saw, the AURORA phase II trial was U.S.-based. That means you've got sites from Seattle to Boston, Texas to Miami. So a broad range of seasonal effects, right? You, in fact, might. I guess, behind all this, there's an assumption, which is that the best time to detect a drug benefit is when the weather outside is such that a person would like to go outside, would choose to spend time outside, but is perhaps prohibited by sunlight exposure. That would typically be summer in the northern latitudes, might actually be winter or spring in the southern latitudes. That's what we saw in the phase II, is that there's some effect of seasonality, but it wasn't dramatic. You see roughly the same drug effect regardless of season at different sites across the U.S.
Europe is the new part of the phase III APOLLO trial. We are getting about half the patients from the U.S. and about half the patients from Europe, a smattering from Canada and Australia. I guess one of the questions was, well, in Europe, will there be a different seasonal impact on these endpoints? We had heard anecdotally that it, in fact, in northern European sites, London, Norway, perhaps Amsterdam, that in the winter you might have trouble detecting a drug effect. I think that was one of the concerns. As designed, we just built the study robustly enough to kind of tolerate that. Just accept that you might get some patients reading out in midwinter in Amsterdam, and you may not have a great drug effect at that point, and that's okay.
The way it worked out operationally, interestingly, is we were only able to open the European sites in November of last year, and then the demand for the study was so high that we had to cut off enrollment in March. Even so, ended up enrolling more patients than we designed for the study. Now we got up to about 183, which is great, and it gave a lot more patients in Europe access to the trial, which is something we're pleased about. But the other effect of that is actually that all of those European patients enrolled between November and March, and so they will all read out between May and September, which we believe to be the best months for detecting a drug effect in these patients. So we think these questions about seasonality got managed through the enrollment dynamics.
That's very helpful color.
Yes.
Thank you for sharing that.
We're very excited about that.
Yeah. Given that you saw reduced ALT in the HELIOS study, are liver assessments being collected in APOLLO, and could supported findings potentially contribute to the label at all?
We are tracking liver enzymes. We do expect, based on both the mechanism of reducing protoporphyrin IX, which is of course what causes the liver damage. We have also seen and published in mouse models really nice liver-protective effects. Showing that translating to the clinic is tough. We are only allowing patients into the study who have no greater than 3x upper limit of normal on their liver enzymes. The trial is not designed to detect a benefit in people who are carrying meaningful liver damage. Nonetheless, we may see a reduction in liver enzymes. It would be great to see that. I would not anticipate that we will get that into the label, at least at the outset. It may require some follow-on study to do that.
Okay. How is the expanded access program going? If you do ultimately receive an approval next year, how should we be thinking about these patients in particular, and perhaps a more rapid conversion to the commercial drug?
Yeah. We are really excited that the FDA opened a pathway to allow us to provide compassionate use and access through the EAP to these patients. I think everyone has seen the anecdotes, the degree of engagement, and the experiences that some of the patients are reporting. We really felt it was important to make the drug available as much as possible. The EAP, we have had extremely, as you would expect then based on that, very high demand. We did have to cut off enrollment in the U.S. and in Europe. There was a lot of leftover demand in the patient population, and no surprise, they are turning up for the EAP study. We have not yet disclosed how many we are enrolling.
I would say, to manage the expectations, while demand is very high, we are also, because we are still in a regulatory process, we are not able to just use it as a way of giving drug to anyone who wants it.
Okay.
We are absolutely qualifying the different sites, ensuring that the physicians are people that are going to provide reliable data and manage the drug well for these patients. We are also screening patients more or less with the same criteria that we are using in the clinical trial. The enrollment into the EAP is running at a pace that is kind of similar to what you would see in a clinical trial setting. It is not just you blow it out and suddenly everybody has access to it. But we are doing our best. Demand is very high, and of course, when we come to launch, we will wind down our long-term extension study and the EAP transition patients onto commercial drug supply.
If you want to think about a reservoir of patients who are ready to be transitioned, it will be the sum of people in the U.S. who are on the HELIOS long-term extension study, which is going to be somewhere between 100, 150 patients, I think, all in the U.S. Then you can add on to that whatever patients are in the EAP as well.
Okay. Last bit of pertinent question is just how many patients you expect could be identified by the time of a launch in the U.S., and if you are approved and you are introducing a very efficacious product to the market, how might that change that pattern as awareness grows?
Sure. There is no doubt that disease awareness is a huge factor here. We have seen in the claims data there is about 14,000 patients, but more than half of those have only really been treated, according to the claims, once in the last seven or eight years for their disease. That implies that there is half this patient population out there really not being managed by a physician. Which is no surprise. There are no great options for patients.
Right.
You see them just self-manage, meaning they just design their entire lives around living in the dark. Making those folks aware if there is a new therapy available, that is going to be a huge part of the effort to bring a new drug to market here. Behind that, we have about 6,000 patients who do show some level of engagement in their healthcare, and our expectation is that that will be the population we are launching into. It comes in several different concentric rings. You have the easiest patients to make aware of the drug are those who are already on it. To the point about the HELIOS long-term extension plus the EAP. That is the first kind of wave of launch. Then we will have the key centers of excellence, which probably account for, I do not know, 1,000-plus patients who will be there.
Essentially our clinical trial sites, those should be very straightforward to access. Then you have the 3,000- 6,000 of the so-called engaged patients who are clearly seeking care on a regular basis for their disease. Then the much more challenging long-term is kind of getting out to that full 14,000 that we see in the claims databases.
Okay. We are rooting for you for these upcoming data next quarter.
Yeah. Thank you. Thank you.
Maybe to switch gears to selcodebart. People may also know this as DISC-0974. It feels like people have been very supportive of all the great data you've shared, but there's still a lack of appreciation around the seriousness that comes with anemia and myelofibrosis. We also wanted to learn more about this and published a survey last week that showed 80% rated the anemia as either highly or extremely concerning. Maybe to start, do you mind just walking us through why anemia is such a central issue in myelofibrosis, including the multifactorial cascade that's a part of that?
Sure, yeah. Well, myelofibrosis is typically or often diagnosed first as a cryptic anemia. It is a disease that arises in the bone marrow compartment, an inflammatory process sets in, fibrotic damage sets in, splenic enlargement sets in. All of these things are driving anemia in these patients, and that anemia leads to fatigue as well as a variety of other just feelings of malaise in these patients. One of the first things physicians want to do is manage the anemia. At present, there's no approved tool to do that with. People have probed the use of ESAs, those are generally not effective. Luspatercept has been studied, missed their primary endpoint, but nonetheless have submitted a supplemental BLA. There's really no great and highly efficacious option for these patients. The anemia leads to fatigue. It's also associated with mortality, as is high hepcidin.
A lot of reasons why doctors would like to manage it. The other issue is that the mainstay therapy for these patients to manage their spleen size and other symptoms are these JAK inhibitors. JAK inhibitors are inhibiting, specifically JAK2, as well as some of the other JAKs. JAK2 is the downstream effector of the EPO receptor. You can't make red blood cells without signaling through JAK2. As soon as you start inhibiting that to try to manage other aspects of the disease, you get an anemic side effect. That's the other issue physicians are facing is, well, when I want to treat my patient with a JAK inhibitor, if they're anemic, I have to make a trade-off here. Do I truly go in heavy with JAK inhibition? If so, I'm going to exacerbate the anemia.
That's why it's been so important in our data to show that not only does our drug show a clinical benefit in patients who are not on a JAK inhibitor, but patients who are on a JAK inhibitor show quite a meaningful increase in their hemoglobin. It suggests that selcodebart could now be a tool for physicians to manage anemia in their patients while they're trying to put in the JAK inhibitor and allow them to kind of be more aggressive about managing the disease.
Okay. It feels like no two patients are alike in terms of their myelofibrosis cascade. Some of them are earlier in development, some are later, and then of course, whatever treatments they are getting are all different. So again, no two patients look the same. You fortunately studied a very broad range of patients with this disorder. I am curious when you believe the optimal time could be to intervene with selcodebart.
Oh, yeah. I mean, the vision would be that people would be able to manage anemia right out of the gate in these patients. We have had some of our best responders are frontline patients who have not been treated with any other therapy for myelofibrosis. I think if you can get anemia under control immediately and early in the disease, then that sets up a situation where when the disease gets more serious, more severe, physicians want to bring a JAK inhibitor or some other therapy into play, they do not have to worry about anemia as a side effect. That will be managed, and I think our data so far shows it helps patients feel better as well, less fatigue, et cetera. So that is, I think, the goal.
The way we are going to design our phase III program is really to treat all patients who are anemic with this disease. Hopefully we are able to replicate the phase II data, which shows a benefit across the broad spectrum of patients, and then physicians can choose to bring in the therapy whenever they want to.
We talk a lot about the anemia cascade, the importance of addressing anemia. Thinking about treating the myelofibrosis as itself, it feels like talking to these doctors, it is a little bit of a seesaw effect where you need to control the anemia in order to properly treat with these JAK inhibitors at a certain dose, amount, regimen, et cetera, to make the myelofibrosis under control. Mechanistically, why are these JAK inhibitors worsening the anemia? Does this effect differ if we think about different therapies?
Right. Yeah. What we see in this disease is excess JAK signaling, particularly through JAK2, driving derangement in the platelet compartment, derangement in the red blood cell compartment. The JAK inhibitors are intended to hit that. But as I mentioned, JAK2 is directly responsible for channeling the EPO signal. Your body, when it is trying to make red blood cells, needs to trigger EPO. You see these patients have very high EPO levels, so they are trying to drive more red blood cell production. But when you have a JAK inhibitor on board, you are basically shutting off that signal. So then the red blood cells do not signal, and fail to produce. So you get a deepening of anemia with JAK inhibitor therapy.
It has been well understood at the molecular level that actually iron, which is what our drug does, is mobilize iron, make it available to red cells. Iron will actually improve the sensitivity to EPO and improve signaling in the red blood cell compartment. So it essentially allows a physician to use a JAK inhibitor while opening up a door for red blood cell production to happen under that regime. So that is the therapeutic intent with anemia management with selcodebart is to just allow anemia management in the face of JAK inhibitor therapy, but then also allow frontline anemia therapy.
Okay. Momelotinib has been developed in part to help address the anemia, yet many patients remain anemic, and sometimes it limits the ability for the JAK inhibitor to do its job and actually treat the myelofibrosis. So it feels like physicians are kind of facing a trade-off in a way. So what does the RALLY-MF experience suggest about the residual unmet need for this population in particular, and why do you believe you could provide incremental benefit beyond momelotinib alone?
Yeah, momelotinib, its development is fascinating, really shows the need for a selective anemia therapy. Because what you see is head-to-head momelotinib and ruxolitinib, Jakafi. That study has been run. Ruxolitinib was the better JAK inhibitor for managing spleen size and symptoms. But ruxolitinib by being perhaps a milder JAK inhibitor, is more protective of the anemia side effects. So today, a physician has to make a choice. Am I going to take my patient and drive them deeper into anemia, but give them the best JAK inhibitor, ruxolitinib, or am I going to choose perhaps a less effective JAK inhibitor to try to manage the anemia side effects? Which is just not a great choice to be making. Our goal is, hey, let us give you a real anemia therapy, selcodebart, then you can pick the best JAK inhibitor and do what you want to do to manage that.
That is our goal. What was fascinating in our phase II RALLY-MF study, we opened a cohort designed for momelotinib and pacritinib patients to come into. We enrolled about 10 of those patients, and what we saw was a lot of momelotinib patients coming into the study where their anemia was not fully managed on that drug. They responded very well to selcodebart therapy. What it tells us is, there is still a need for a way to manage anemia in the setting of JAK inhibitor therapy, and that frankly, regardless of which JAK inhibitor a physician chooses to use, you can layer selcodebart on top and presumably benefit the anemia side of the patient experience.
Okay. Something that has been a little bit mind-boggling to me is I have seen investors focus on different MF readouts that address just a certain patient population, yet the anemia and MF affects essentially all patients at some point. The TAM is humongous here. What are some of the ways that you think investors really should be focusing on the TAM, the market size, and also penetration potential if you are successful?
Right. I think a lot of complexities to how a physician chooses to manage any one patient. But the background fact is that probably 80% or so of these patients are anemic. You are talking about 22,000 or so anemic MF patients in the U.S., all of whom would benefit from anemia therapy. We show in our clinical data broad efficacy or obviously we have not proven it in a placebo-controlled setting, but broad improvements in hemoglobin and transfusion dependence. This drug ought to be broadly applicable. While JAK inhibitors and other therapies for MF patients may be tailored and narrowly slotted to different kinds of patients, we think there is probably about 22,000 of these patients in the U.S. who really ought to be managed on their anemia and would therefore be candidates for selcodebart.
We have seen how, I think an analogy is luspatercept in myelodysplastic syndrome has been broadly adopted. There is just generally a strong desire to manage anemia in these kind of pre-malignant hematologic conditions like MDS and MF. I think you can expect to see broad usage of selcodebart once we are able to prove that out in a phase III trial.
Okay. Last question for this program is just expectations around year-end. I believe you are going to have some updated data, and then you are going to have an end of phase II meeting, which will be important to understand next steps. What is the latest you could share with us on that?
I am sorry. Just repeat that again quickly.
Yeah, just the upcoming catalyst around.
Right.
Upcoming data, regulatory interactions.
Right, exactly. Yeah, thanks. We've presented now most of the data from the RALLY-MF phase II trial at EHA in the summer. As we come into the end of the year, we'll have another data cut, and the purpose of that data cut is actually to bring it to the FDA for an end of phase II meeting to discuss the phase III trial design. The way we're setting up our plan is as we come into the end of the year, we should be able to present that data cut at a scientific conference, and then also around the same time come out with the results of that end of phase II meeting. I think that's been one of the last questions.
I think everybody looks at our data and says, "Yeah, this appears to be working across a broad range of patients, but what is the phase III trial design? Are you going to be able to design a trial that will give you a broad label that covers this full market opportunity?" That will be the clarity that we can deliver from that end of phase II meeting.
Okay, thanks. Speaking of upcoming catalysts, you have one quite literally in a few hours.
Yes.
With the DISC-3405 data for polycythemia vera that are going to be presented at the SOHO conference. Maybe just can you help us set expectations for what we could expect? Because as you know, investors, they don't have the patience to just wait a few hours.
Right. Exactly. Yeah. The poster session at SOHO is, as you say, this evening. You can expect our data will become publicly available by then, and there is an oral presentation tomorrow. This is super exciting, the first patient data from our anti-TMPRSS6 antibody. This is iron restriction to manage excess red blood cell production in patients with polycythemia vera. I think this is a sector that has really caught fire recently.
Yeah.
Protagonist, in collaboration with Takeda, had just recently got approval for rusfertide, which is a way of restricting iron in these patients, and they proved out. I think as pioneers in this space, kudos to that group, that iron restriction not only helps patients achieve better hematocrit control. The goal here is to keep patients at 45% or lower to avoid thromboembolic events. It also, in doing that, made patients feel much better. The current regime is phlebotomy, which is cheap and reliable and safe. Patients end up feeling miserable because you are basically inducing a whole body iron deprivation that sets in, and that does not feel good. What is exciting about this category of drugs, we have rusfertide as a lead. There is us in TMPRSS6, there are two other nucleic acids targeting TMPRSS6.
The goal here is to help patients achieve an iron-restricted status, but we are not actually removing iron from the body. You are basically just walling it off from the red blood cell compartment. You get reduced red blood cell production, you can control their hematocrit, presumably avoid thromboembolic events. In doing so, you are no longer depriving the body of iron, and the result, as we have seen so far, is that patients feel better on these kinds of drugs. I think it is super exciting. There are 150,000 estimated polycythemia vera patients in the U.S. It is quite a large, rare disease setting, probably 50,000- 100,000 of them being managed by phlebotomy, and we are hoping that all this data shows that all of those patients really ought to transition off phlebotomy onto an iron restriction therapy. Rusfertide is a choice they have today, which is great.
We are hoping to bring what may be a more tolerable, more patient-friendly kind of presentation in a simple antibody approach. The data we have shown in healthy volunteers, the drug clearly restricts iron, reduces hematocrit. There has been very little in the area of side effects with the therapy. The goal with this data would be to show cohort A, which is the first cohort. It is the highest dose we are chasing Q2 weeks, but it gets there through a bit of a dose adjustment, dose escalation period. You will see what I would call the crude first cut across multiple different doses. As we come into the end of the year, we will have a more fulsome where we can have cohort B, where it is a simple once-monthly dosing. Are these healthy people? They are the volunteers. No, these are polycythemia vera patients. Yeah.
This will be our first patient data, and the goal is to show a profile that in efficacy is similar to what we have seen from the other TMPRSS6 agents, as well as rusfertide, and hopefully show signs of a more convenient and better tolerated profile for patients.
Okay. Great. Well, thank you so much, John. There is a lot of great exciting things coming up, and we are wishing you all the best through these catalysts.
Yeah. Thanks so much. Appreciate your time.
Thank you.