Great. good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Thomas Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to introduce our next company to the stage, Disc Medicine, and really happy to be joined by CEO John Quisel and CMO William Savage. Gentlemen, thanks for joi ning us.
Great to be here.
Thank you.
Thanks for having us.
Awesome. John, why don't you kick us off? I think most in the audience are familiar with the Disc story. It's been obviously, like, very eventful last year for you guys, but a ton of data coming in 2026. Potential opportunity for pivotal data for your lead drug, bitopertin and EPP, from the APOLLO study towards the end of the year. Resubmission potential commercial story here in 2027. It's a story. This is one of our top picks for the year, and we very much like it on the basis of data potential setup for 27. Maybe just kinda like level set, like how, you know. Walk us through 2025, what you're most excited about for 26, and then we'll jump into Q&A.
Right. Yeah. Thank you. Yeah, I mean, obviously there's been a tremendous amount of regulatory fireworks around our lead program, bitopertin, which is being developed to treat a kind of porphyria, rare disease marked by really severe sunlight intolerance as well as potential liver failure. 2025, you know, we made progress on that program from a regulatory perspective, bringing it into an NDA filing on the premise of an accelerated approval pathway. You know, on top of that, we were given one of the first nine, Commissioner's National Priority Voucher, which we were honored to receive. We thought the setup was that that would lead to a launch of that rare disease product in the first quarter of 2026.
Behind that, because I don't wanna lose sight of it, we have what I think is a really exciting pipeline that's been building. We've been working our way through a phase II trial of a program we call DISC-0974 to treat anemia in myelofibrosis patients. While there are many drugs to treat myelofibrosis, there are no approved therapies to treat the anemia in these patients. Really first of its kind, first in class, and great, really great data that we presented in phase II, and the goal of this year is that'll transition to at least guidance on what a pivotal trial is gonna look like. Our third program, which now is starting to get some play, also completed its phase I, and we were able to initiate phase II.
Enrollment was, you know, over the moon, actually, enthusiasm for that. We doubled the size of the trial to accommodate the enthusiasm, and that program now will have data as we come into the end of this year. 2025 was a build across all the three key molecules that we have in development in their core indications. You know, lead is a rare disease, porphyria, and the next two are these hemo type indications of myelofibrosis and polycythemia vera. It's set up 2026. We had the big whiplash of getting a, rather than getting bitopertin approved, we got a Complete Response Letter. To your point, and thank you for framing it up that way, in a sense, it puts us back on a more vanill a path.
We are working on our phase III trial. You know, the accelerated approval didn't work out. We're gonna deliver phase III data by Q4. You know, in some situations, a CRL can of course be a death knell for a program, but in our particular situation, it's a looks like a fairly straightforward path to get to data that should then support approval. It has changed our plans for 2026, but nonetheless, the plans are good. We expect to deliver phase III data from that lead program, phase II data from the next two pipeline programs, and start to hammer out what the pivotal trial designs look like for those, so that in 2027, we're actually, you know, hopefully marketing one product and in phase III with two others.
Excellent. Could we just kinda level set and remind folks, the data that we generated in phase II for bitopertin and EPP, and I guess how that informs our level of confidence in APOLLO? I have a lot of questions around APOLLO.
Yeah. Yeah.
Maybe we'll start with sort of the phase II highlights.
The buildup was we in-licensed the product from Roche. They'd had about 3,000-4,000 patients worth of experience in other indications, we had this hypothesis that it would suppress the formation of a chemical called protoporphyrin IX, which is what drives all of the disease sequelae of this porphyria EPP indication. We set up an open label study in Australia and a placebo-controlled trial in the U.S. called Beacon and Aurora respectively. Each probing two different dose levels, a 20-milligram once daily. It's a once daily pill, 20 milligrams or 60 milligrams. The data were remarkable.
I mean, the initial reports out of the open label trial were ones of patients who normally could spend minutes in light, suddenly spending hours and hours, you know, appearing to spend entire days in the sunlight. Newspaper articles from an Australian patient who suddenly could go to the beach for the first time in his life. These remarkable anecdotes coming. We looked at the data themselves, they were pretty good. We were lowering PP IX in a very meaningful way, you know, 40%-50% or so. This is in the whole blood. So really kind of restricting the production of PP IX .
We expected that that level of decrease, you know, 30%-40%, there's literature suggesting that should lead to, you know, could lead to a complete resolution of symptoms for these patients. It kinda linked up to some of the anecdotal stories. When we looked at the clinical endpoints, you know, several of them were stat sig in a prospective way. There was a key secondary endpoint called total time in light on days without pain that we missed. It was not stat sig. It was numerically superior to placebo, but not statistically significant. When we came out with that unblinding, it was kind of viewed as a mi xed dataset.
We had very clear reduction in the target metabolite protoporphyrin IX, missing on the total time in light, but then hitting on several other very important measurements, like the number of phototoxic reactions these patients had was reduced by 70%, prospectively stat sig. This is 25 patients per arm. We were even stat sig on a measure of just a patient's general impression of change, with most, you know, nearly all patients reporting feeling much better on therapy. It was overall a picture of a high degree of efficacy, and the question was, okay, if the way to kind of convince the regulators about the clinical meaningfulness of the drug is to measure the time that these patients are able to spend in light. Actually, it's really the time they choose to spend in light, right?
Unfortunately, we can't really test how much they're able to spend. It's really just saying measuring how much do you choose to spend. you know, it turned out that that was a heavily placebo-affected endpoint in phase II, and particularly in the, obviously in the blinded study, that all patients on the study essentially showed an increase, a meaningful increase in the time they spent in light at the beginning of the study. Then you saw the placebo patients wane back towards their baseline, while broadly speaking, the treated patients maintained that elevated ability to spend time in light. It wasn't super sophisticated to figure out how to optimize that endpoint. We could see, okay, the learning was, oh, there is a placebo effect, and we need to manage that.
It's a placebo effect like many that wanes over the course of the study. In the planning for a 6-month phase III study, we designed that final you know, the endpoint to just look at the final month of time in light, rather than looking at the whole period where you capture that placebo effect.
Yeah, I guess playing this forward to the changes that we've made in Apollo, initially designed as a confirmatory study. Now, I guess approaching it as kind of a pivotal study. You're gonna have a Type A meeting to, I guess, confirm alignment right around the design. Maybe just, yeah, remind us, like the change in timing that we're looking at, this time in daylight endpoint is one important change. Are there other important changes we should be considering? What are the expectations for this Type A interaction?
Right. I'll walk through the regulatory steps, actually, and then Will can comment on the endpoint changes. From a regulatory-- it's good to remember we came out of that phase II program where we approached the FDA for an End-of-Phase II meeting. In that meeting, our primary objective was just to get a nice phase III design. We threw out the idea, "Hey, maybe this could support accelerated approval. We have a great biomarker." It's not just a biomarker. PPIX is literally the cause of the disease. We felt that that had some traction and it did have traction.
They said, "Well, why don't you show us the design to your confirmatory trial, and let's come back and have a Type C meeting just on that topic." That meeting happened in December of 2024, reached complete alignment. There were some adjustments. The FDA wanted to promote PPIX in as a co-primary endpoint with the time in light endpoint. That was aligned back as of December 2024, we went on to have a series of other meetings culminating in the pre-NDA meeting last summer, where it was agreed that we would submit our NDA on this accelerated path, everything else went from there. We eventually got the CRL. The ne xt step is a Type A meeting.
There's been, you know, plenty of opportunity for there to be debate about what this phase, you know, now phase III APOLLO trial looks like. There hasn't been any real daylight. You know, there's no, there's no sense that there's any different view on this. In fact, even in the CRL, and I'm grateful for this, that, you know, the way the FDA wrote it, they basically said, "Hey, we're not convinced you've shown us the clinical benefit. We, we agree you've decreased your biomarker. We're not sure that that reasonably predicts clinical benefit." We obviously disagree with that, but okay, it's an area of very wide discretion, and they're taking a different view. "Come back and show us your APOLLO phase III data," was essentially what's written.
It feels to us like the Type A meeting is more or less saying, "Well, you know, are we reading this correctly? Are you looking for our phase III data to kind of rectify the deficiency?" It seemed to be a sole deficiency with the package. Which is, you know. Because there's been tremendous interest from patients, we're very thankful for that. It's moved very rapidly, and we're gonna be able to deliver that data by the, by the fourth quarter and probably respond to that CRL by the end of the year. Do you want me to get into the, or Will to ta lk about the trial design? Do you have?
I guess two points. The FDA, I guess, with the Scenesse review, which is the only approved therapeutic for these patients, they did explicitly acknowledge that PPIX is the driver of disease as part of that review. I guess one question around, you know, the elevation of PPIX as the co-primary, like, I guess, is there, perhaps some risk or some chance that you go into this meeting and based on their review of your clinical data, they suggest some other changes to endpoint definition? I'm just trying to think through how that may or may not impact powering or other assumptions around, like, how you've designed and executed Apollo.
Well, protoporphyrin IX is we've clearly demonstrated that bitopertin reduces in a highly statistically significant way. The, you know, we have high confidence that that's gonna be reproduced in an even larger dataset. Whether it's a co-primary or not, I think we're gonna win on that. You know, as a co-primary, we are not increasing the alpha spending by analyzing it, so we have to hit P equals 0.05 on both the PPIX reduction and the time in light. You know, in a sense, PPIX, whether it's as a co-primary, which FDA proposed and we aligned on, you know, it, I think it's gonna read out wherever it is in the hierarchy.
There's, you know, I don't think any indicator, as John said, that there's, you know, the study's gonna need to change in any way.
Right. Okay. You've APOLLO is enrolled rapidly, like well ahead of pace. You've got it to enrollment completion here in March versus, I think before you were saying kind of summer of 2026. You've also said two-thirds of the patients coming from the U.S. maybe just, yeah, describe, I guess, the level of demand to get into the study, and then I would love to hear, I guess, what you're hearing from study sites, KOLs, clinicians, and patients after this CRL announcement?
Sure. As far as study enrollment, I mean, we, there was a lot of demand both in the U.S. and abroad. The study's open in Australia, U.S., U.K., EU, and, you know, good for enrollment that we have a number of patients waiting to get in. We've had, you know, a large excess of patients actually, who've wanted to get in and couldn't, because we wanna stick to our timelines and get, you know, get the study done as soon as possible. I think one of the things about enrollment is that, you know, as we've rolled out in Europe and spread out to a number of sites, we want to ensure that there is representation of the people we've partnered with, and we wanna maintain those relationships.
You know, we have, even though we've, we're cutting off enrollment, this month, we are allowing some extra patients into the study to make sure we honor commitments that we've made to some of those sites in Europe.
Great. I think you've talked about the study being 80%, roughly 80% powered to show benefit across. Is it the time and daylight endpoint? Just what can you tell us? Can you give us any more details around sort of the powering what you've assumed for this time and daylight endpoint?
Sure. We looked, of course, at our AURORA data, both for the variability on the endpoint and the treatment effect. We took a conservative look at that, and used that as our powering assumption for APOLLO. Even with a more conservative outcome than what we saw in AURORA, we're still well over 80% powered. You know, we did do a blinded sample size recalculation after the first 50 patients exited the APOLLO study, and that was looking in a blinded way at the daily diary variability. That variability lined up exactly where we saw the AURORA data showing in the last month of the study. There was no statistical reason to increase the size of the study.
What it also did is it validated our assumption on diary variability. You know, we predicted it would be that, and we saw that in a, you know, even in a smaller data set of N of 50, that we're on track for that.
Yep. Got it. You had accelerated a lot of activities in anticipation of a potential earlier approval. A lot of those, some on the manufacturing side, some on the sort of commercial readiness side. Maybe just talk a little bit about now what that, this extra time maybe gives you in terms of continuing to work through some of the pre-commercial plans. Are there any other kind of like outstanding or gating factors we should think about with respect to resubmission, which I think you've kind of outlined could happen by the end of the year?
Right. Right. Yeah. An unfortunate part of this, you know, whiplash, is that we hired a launch team, and we were rushing, you know, tremendously to get ready for a first quarter launch. Now, of course, we're no longer doing that, and we're, you know, the regular wait timeline here would be get our response to the CRL filed by the end of the year. That would then set up about a six-month review period to get to the next approval point, so middle of next year. We looked at that kind of gap now and said, "Okay, we really, you know, we can't justify, you know, meaningful jobs for a good part of that launch team." We did have to do a layoff for that.
We retained about a third of the team, and the reason we did that is one of the activities that we felt that was absolutely critical in building this market and preparing for a launch here, is to actually figure out what doctors are treating these patients for real. We have access to claims data. There's an ICD-10 code for EPP, so that gives us a list of doctors who've treated patients and, the patient's, you know, obviously, the patient's identity are protected, but the doctors are identified.
We were in a process with our MSL and then starting with our sales force as well, to call on physicians and, you know, kind of assess whether they were in fact treating patients, and kind of, you know, building out that number, validating the claims data. Now we've retained about a third of that team to continue that activity with the goal that eventually when we launch
Hopefully we understand where all these patients are retreating, how to then call and contact those physicians once there's an actual available therapy.
Got it. I also wanted to ask, just competitive landscape-wise, one approved therapy today, Scenesse. There's another oral called dersimelagon, I think has a late breaker for their phase III, their third phase III study, at AAD the end of the month. There are a couple other therapies that are earlier in development. Maybe just talk about how you, like, view the competitive landscape. I guess the one we get the most, investor inbounds on recently has been around dersimelagon. I guess if you could comment on kind of the competitive profile there and how bitopertin fits in versus that agent.
Right. Right. Well, the one approved product, Scenesse, is surgically implanted every two months. It works by affecting the melanocortin pathway and triggers tanning, and this provides some, you know, some measurable benefit for these patients to spend more time in sunlight. It hasn't been widely adopted, probably because that surgical implant on an every two-month basis is a bit much. Dersimelagon is an effort to recapitulate that tanning effect but with an oral presentation. They failed their first phase III trial, went back and tried again, and at least from a press release, we understand they hit their primary endpoint. That will presumably be making its way through a regulatory process.
I suspect, you know, teeing up for, I would imagine a launch sometime next year as well, although of course, we don't have direct insight into that timeline. I think you know, what's different about bitopertin is that we're actually targeting the root cause of the disease, which is this buildup of this toxic protoporphyrin IX. Our drug works by shutting off the production or reducing the production of protoporphyrin IX. You see this decrease in the whole blood and frankly in, you know, in the whole body of this toxic compound at levels that we think will, you know, translate to meaningful clinical differences. That feature is very attractive, right?
Although light sensitivity is what patients live with on a daily basis, the buildup of PP IX in the body can have other problems, including liver damage. These tanning mechanisms, you know, generally are not shown to actually impact the level of protoporphyrin IX in the body.
Yep. That makes sense. I wanna switch gears and talk about DISC-0974.
Great.
You presented some really interesting initial phase II data in myelofibrosis at ASH last year. We're gonna get sort of the full RALLY-MF readout later this year. Maybe just kinda like level set us on mechanism and what the opportunity is in myelofibrosis, and then we'll talk about sort of expectations for that full data set later this year.
It's a very exciting opportunity. myelofibrosis is a severe progressive, kind of almost oncology-type indication where you have this progressive scarring in the bone marrow, highly inflamed bone marrow. usually, the diagnostic or initial problems patients have is anemia, right? It can progress from there. You get an enlarged spleen, a great deal of discomfort from the high degree of inflammation. The anemia is multifactorial, but one of the more recent hypotheses is that there's an iron problem, right? Iron being a fundamental building block for red blood cells. If your bone marrow doesn't have access to enough iron, you cannot make enough red blood cells, and you will get anemic. There's a central regulator called hepcidin. When hepcidin is high, your body's iron supplies are locked away, primarily in the macrophages.
Then when hepcidin becomes low, that iron is released. Inflammation drives hepcidin up, restricts the iron away from the bone marrow, and leads to a kind of anemia called anemia of inflammation or chronic disease. Myelofibrosis, you know, at the Mayo Clinic, they measured hepcidin levels in these patients and found out they were sky-high. This was not necessarily expected, but, although it is a highly inflamed disease. That led to the hypothesis that, well, if you could lower those hepcidin levels, you might be able to restore the iron supply to the bone marrow and drive red blood cell production in what otherwise has been an untreatable anemia, right? EPO can be used a little bit. There's a drug called Danazol. It's an androgen that's used a little bit. Neither of which are, you know, viewed as... They're not on label.
They're not highly effective. Luspatercept was recently tried, but missed its phase III trial. At this point, there's no drug approved to treat this anemia. We went in, tested our mechanism, DISC-0974, an antibody that hits a genetically validated target that controls hepcidin in the body, mobilizes iron very clearly, very profoundly, and those results were fantastic. They were just, you know, kind of levels of hemoglobin improvement that have not been seen with other therapies in these initial phase 1-B data. At ASH last year, we had almost 50 patients of phase II data. Really exciting, profound effects for an anemia that heretofore has no label treatment. Importantly, these patients get a lot of different co-therapies.
Many of them are on different kinds of JAK inhibitors, ruxolitinib, momelotinib, pacritinib, fedratinib. We had experience with all of these JAK inhibitors and our anemia therapy works on top of all of them. It just seems to be a broadly applicable, so far appears to be safe, you know, well-tolerated approach once a month, the antibody, you know, subQ injection. Just a patient-friendly kind of treatment that appears to have good effect on anemia. It's really exciting. There's probably 22,000 anemic patients with myelofibrosis in the U.S., that's the target population. We think all of them are addressable with our mechanism.
You know, in terms of how you think about pricing in this indication, it's probably useful to look at myelodysplastic syndrome, another hem-onc type disorder where anemia has been difficult to treat. Luspatercept was approved in that indication and prices somewhere in the $200,000-$300,000 range. Of course, we won't, you know, we don't know what our price will be until we get our final package, but that's an interesting comparator where you're managing anemia in a hem-onc setting.
That's great. One of the nice things about the data you've generated to date, it looks you mentioned equal effect JAK or no JAK, also across transfusion dependence status. Yeah, maybe just help frame expectations for sort of the full phase II data set and then what you're looking for out of a phase III regulatory engagement later this year.
Sure, sure. We typically present data from MF at two different conferences, the European Hematology Association and ASH, the American equivalent. EHA and ASH, EHA in June, ASH in December. Of course, there's a whole conference submission and acceptance process, so I can't confirm that that's where we'll present, but that's the typical cadence. We will guide to some data in the first half of the year, likely at EHA, data then in the second half of the year, likely at ASH. You know, by the time we get to the end of the year, it should be essentially the full phase II data set. I think, by and large, you know, there's three different populations. There's the non-transfused, which probably represent ballpark 60% of the patients.
There we have a wealth of data, right? They've enrolled very quickly into the study and the drug seems to show a very nice hemoglobin benefit there. I would say it's unlikely that as we add more data to that, it's really gonna change that signal. There's a low transfusion burden group. This is a group that's getting 1- 2 transfusions in a 12-week period. There the efficacy, again, the hemoglobin benefit looks great, you know, more data will be helpful to build that out. We have the highest transfusion burden. They represent only 15% of the population, roughly. They're a little bit harder to enroll, and we've seen, you know, as of ASH last year, we had three patients with zero responders.
If you look at the next three, they look to all be responders. The response rate is flopping somewhere between 0% and 50%. 0% being, of course, you wouldn't bother to treat this anymore, 50% being, you know, essentially best ever kind of data. We'll get more data and kind of stabilize that signal as we come into the end of the year. All of that will get packaged up and our plan is to have an End-of-Phase II meeting with the FDA to discuss what kind of pivotal trial we might run, where we hope to encapsulate into, you know, one or two trials, all of these different anemia categories, at least all the ones where we see clear evidence that the drug show, you know, appears to work.
Yeah. Got it. You've also kicked off a phase II program in IBD anemia?
We did, yeah. This mechanism, anemia of inflammation, is a wide-ranging problem, potentially millions of patients. Inflammatory bowel disease is one of those possible indications where we saw really nice mouse data, intriguingly. We also learned, you know, we were studying in chronic kidney disease patients who have a range of different EPO levels. We learned that baseline EPO matters a lot. IBD is a high EPO condition, so we have a lot of reason to think that there may be a nice signal there.
What are we looking for? You've got it to initial data later this year. Like, what are we looking for as like a confirmatory signal in that?
Yeah. Why don't you speak to the likely data timing and.
Sure. For IBD, we're looking at data next year. I think we're gonna be looking at all the same PD and efficacy markers that we do in all of our studies, so hepcidin, iron, hemoglobin, in particular. The IBD study is a double-blind study, so we'll also have PRO data and we're even doing endoscopies to look at disease status.
Interesting. Okay. Wealth of data from IBD. We have about a minute left. I wanna talk about DISC-3405 'cause as you said it has been getting more air time. We're gonna see initial data in polycythemia vera later this year. Validated target, TMPRSS6. We've seen data from other TMPRSS, like clearly effective. Maybe help frame expectations for that readout in PV, John.
We came into the end of 25 and started this study up. We designed it to a cohort of 20 people where we would go through a lot of different doses, try to be very patient sparing 'cause enrollment has been a challenge in other studies. What we found was enormous enthusiasm, and I think, you know, credit, I think the next company presenting is the one that broke this open with Rusfertide. Now we know that iron restriction works in PV patients and makes them feel better. We saw enormous enthusiasm. We doubled the size of our study, and we should have essentially full data from the 1st cohort of patients, and we'll probably have a good solid look at even the 2nd cohort.
That package of information can probably form the foundation of an End-of-Phase II meeting perhaps in 2027 to drive, hopefully, a pivotal trial start, you know, next year.
Awesome. All right. Well, data coming across the entire heme portfolio, multiple indications. I'm looking forward to the updates later this year. Thank you Disc team for joining us and sharing the insights.
Great. Thank you.
Thank you.