Hi, everyone. Good morning. I'm Tara Bancroft. I'm one of the Senior Biotech Analysts here at Cowen. Thank you for coming to TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a presentation and some Q&A from Disc Medicine. From Disc, we have the CEO, John Quisel. Thank you so much for joining us today. We really look forward to the discussion. Why don't you go ahead with your presentation, and I'll come back for Q&A.
Great. Thank you. Great to be here. Really appreciate the opportunity to speak here. Turns out to be, I think, a valuable moment for some communication. Let's see. I will just note that there's gonna be some forward-looking statements. Those should all be taken into account with the things that we filed with the SEC and on our website. We'll be talking about three different clinical stage programs, none of which are approved in any jurisdiction. You know, briefly, Disc Medicine, we've been public now for a little bit over three years. We've, we're about six years out from our Series A. The company is focused on controlling fundamental building blocks in the red blood cell. Heme and iron, these are essential components of any red blood cell.
Our three clinical agents are all mechanisms for manipulating iron and heme metabolism. By doing that, we hope to affect a whole range of disorders that arise in the red blood cell compartment. What you can see along the bottom of the slide, something I'm actually very proud of, we set out to probe our different programs across a wide range of rare on the left to very common red blood cell disorders. Over the company's, you know, brief history so far, we've already been able to probe a wide range of these, with some pretty amazing results. Tremendous progress across the pipeline. Maybe I'll just pause for a moment and talk about we've been in the news quite a bit recently. We were one of the first programs.
Our lead program called bitopertin for EPP was selected as one of the first Commissioner's National Priority Voucher programs. Prior to that and during that process, it was being reviewed for an accelerated approval based on phase II data. In the end, for a variety of reasons and that were put out, we received a CRL just a few weeks ago. The good news is we have been progressing with our phase III confirmatory trial called APOLLO. That data is really the only thing identified in the CRL as what the FDA wants to see next and will be coming in the fourth quarter this year.
We've been through this kind of regulatory journey over the last year that's created a certain amount of volatility in the stock, but our fundamental business plan is basically intact. This year, we come into the end of the year with a lot of very important catalysts across the pipeline. bitopertin for this rare disease called EPP will have our readout from the APOLLO phase III trial, and that'll be the foundation for coming back, pursuing approval, which we would project to come by the middle of next year. For our second program, DISC-0974, that works by mobilizing iron in the body to treat a wide range of anemias. Our lead indication is the anemia of myelofibrosis.
We've shown a lot of exciting phase II data in process so far. We expect to get through our end-of-phase II meeting, come out with a pivotal trial design by the end of this year. Big progress there to come by end of year on that program. Our third program is coming very fast, DISC-3405. Here, what we're trying to do is actually restrict iron. That's been proven already by others to provide a great therapeutic approach for patients with excess red blood cell production as a consequence of polycythemia vera, which interestingly is actually a HemOnc kind of disorder treated by the same physicians who treat myelofibrosis. There's kind of a portfolio element to that. That PV trial is progressing very rapidly. We've already announced that it enrolled so quickly, we doubled the trial size.
We expect to have a rich data set to present by the end of this year in that indication also with projected progress to, you know, with favorable data to pivotal trial next year as well. Meanwhile, you see on this slide, we're also probing other indications where these iron manipulation mechanisms ought to work. Anemia of inflammatory bowel disease with iron mobilizing agent and sickle cell disease with the iron restriction agent. In all likelihood, we may get some sampling of early data from those trials this year as well. Notwithstanding a bit of regulatory gymnastics to start the year, we are in great shape to deliver on three key catalysts across three programs, plus some additional potential additional indication information.
All of this is being powered by a great balance sheet we have at the end of the year. We have $791 million on the balance sheet that gives us runway into 2029. Again, that doesn't assume, has never assumed any revenue from approval of the, of the lead program. Very conservative runway statement. Let me talk quickly about the lead indication, EPP. Very severe disease, genetically driven by a defect, a deficiency in the last enzyme of heme biosynthesis. Causes the buildup of a toxic metabolite called Protoporphyrin IX or PP9 that does two things, two key things in the body.
One is it leads to excruciating sunlight sensitivity, such that these patients have to live their entire lives basically in darkness, which is by itself quite debilitating and something that people think about every day. How can I meter out the small amount of light exposure I can tolerate? Really severe long-term complication that can result, you see this purple liver, right? This PP9 builds up in the liver, literally turning it purple, and in about 2%-5%. About 30% of these patients will have evidence of ongoing liver damage. 2%-5% will actually go into liver failure, which is a potentially fatal complication and, you know, horrible, horribly, if you replace just the liver, it will again become contaminated with PP9 requiring a subsequent transplant.
The treatment of choice now for these types of patients is actually a joint bone marrow liver transplant, which is an extremely dangerous procedure. Very serious disease impairing people's lives on a daily basis, as well as threatening, you know, overall lifespan through the liver damage. There's only one approved therapy called Scenesse. It works through a tanning mechanism and requires a surgical implant, so it's not widely used in the patient population. We estimate that there's 20,000 patients genetically, or that's actually an MGH estimate. We looked in the claims data, we see 14,000 diagnosed patients, and we see about 6,000 that we consider engaged, meaning they've sought treatment multiple times.
That was our kind of our launch population, and we've been doing a lot of work with our field teams, both medical and sales teams, to validate those numbers. By and large, actually, they appear to be checking out as we progress through that. I will note, you know, because of the adverse regulatory outcome, you know, we're now waiting about 16 months before we anticipate our next opportunity to launch the drug. We have reduced the force in the company, primarily in the commercial team.
We did retain a core team whose mission is to continue validating these accounts, confirming where the patients are getting treatment. When we do come to our next launch moment, we'll do so with a wealth of information about where these patients are seeking their care. Just a reminder of our phase II data was very exciting, profound reductions in this toxic metabolite Protoporphyrin IX and a host of very important improvements on clinically meaningful endpoints. We've designed a clinical program that includes our, you know, our two phase II trials that are done, BEACON and AURORA, and then our phase III trial, APOLLO. Patients on all three trials have the opportunity to roll into a long-term extension called the HELIOS trial.
APOLLO is about 150 patients. We really have optimized those endpoints, to, based on all the learnings we had from the phase II program. Very highly powered trial. We recently announced that it has enrolled, you know, much faster than expected. We project complete enrollment by the end of March. In fact, we'll just have to cut off enrollment at that point. We've been able to look at our powering assumptions in the first 50 completers to confirm in a blinded manner that the variability is tracking exactly the assumptions we learned in phase II. A lot of reasons to believe that this now critical phase III trial is gonna give us good data as we come into Q4 this year. In terms of where do we go now, we have our CRL.
If you read it's publicly available, made public by both us and the FDA the same day, literally within hours. Remarkable transparency, which we support. You know, so we'll have a Type A meeting, presumably in Q2, to just confirm what that CRL says, which is basically, we would like to see your APOLLO trial data. Presumably, that's the main thing we have to do. We'll complete our enrollment in March, several months ahead of guidance, get to the top-line data in Q4. We'll file our response to the CRL. We intend to do that before the end of the year. Typically, that would take a six month review period, implying that we get to a PDUFA date at the middle of 2027.
Meanwhile, as I mentioned, we'll be focused on validating the accounts for the developing the market and finding avenues by which to provide access to patients because I think one of the most remarkable things about this program to me is, and it's very gratifying, is just how excited the patient community is about this. I mean, if you Google the drug name, you'll see articles of just people all in, you know, across the country saying how this drug and their access to it has changed their lives and enabled them to do things they've never done before. That's what gives us faith that this is worth doing and pushing ahead. That's the lead program, bitopertin, what we think is a very substantial rare disease market, projected launch middle of next year.
The rest of our pipeline focuses on controlling iron metabolism, as I mentioned. The central regulator of iron in your body is called hepcidin. When hepcidin becomes high, iron becomes trapped. That leads to an anemia called anemia of inflammation. That's because inflammation often drives high hepcidin, traps the iron, leads to reduced red blood cell production. Our drug is designed to release that. That's DISC-0974, we've chosen myelofibrosis as our lead indication. You know, that's based in part on the success we've seen. I mean, the data have genuinely been remarkable in that field, I'll touch on it briefly. Our third program is actually designed to treat diseases where hepcidin is too low, this has been, you know, validated most recently in polycythemia vera, a disease of excess red blood cell production.
No surprise, if you restrict iron availability, you will restrict red blood cell production, allow patients to achieve their target hematocrit, avoid cardiovascular complications that come from that. We're developing this monoclonal antibody designed to have a convenient, you know, once-monthly, SubQ administration profile. We're also probing additional inflammatory diseases like IBD anemia with this program and probing sickle cell disease with the iron restriction program. DISC-0974, a monoclonal antibody targeted to a genetically validated target called HJV or hemojuvelin. We have already shown now preclinically and clinically what the genetics told us at the outset, which is if you inhibit this target, you will profoundly reduce hepcidin, you will profoundly mobilize iron even in the face of severe inflammatory disease, and this will enable red blood cell production.
What we've seen is just exceptional responsiveness in the myelofibrosis population. The anemia of myelofibrosis is a grinding chronic anemia, typically present at diagnosis. About 87% of these myelofibrosis patients are anemic. There is no approved therapy for this. People have been hunting for a way to treat anemia in these patients for several decades. It is a fundamental feature of the disease caused by bone marrow damage, progressive bone marrow damage. It is also exacerbated by the backbone therapy called Jakafi or ruxolitinib, which while providing great benefits in many ways for these patients, actually makes their anemia worse. The attractiveness of managing anemia is to manage one of the major morbidities of the disease, but also allow physicians to achieve optimal doses with one of the key therapies for these patients also.
When we look at this, it's a well-established market. We see 22,000 addressable patients in the U.S. only. Assuming oncology-type pricing, it implies a $4 billion or greater total addressable opportunity here. Very important medical and commercial potential to this program. To quickly touch on the data, you know, we've done this now across phase I. We looked in chronic kidney disease patients and in myelofibrosis patients. There's really no surprise now about what the drug does. If you look at baseline hepcidin in these MF patients, normally you'd be at about 10 to 15. We're seeing, you know, 50-125, we profoundly reduce that. There's just no doubt about it. The drug works in that regard. When you lower hepcidin, you get this mobilization of iron.
If you look at hematologic response, if you look for a major response, which is, you know, sort of the KOL academic community stringent requirement, we're getting about a 50% major response. That is essentially unprecedented in the myelofibrosis population. It really looks to be one of the best or the best mechanism for treating anemia in these patients that's been probed clinically yet. To break that down even further, you can see the hemoglobin benefit, 1.5 grams per deciliter is a typical target for the NTD population. The responding group is well above that. If you look at fatigue, which is one of the common clinically relevant consequences of anemia, we see a great increase, three points on the scale being clinically precedent, clinical meaningful target.
Again, you see that improvement going along with the hemoglobin benefit. We broke patients into those who are not transfused, those who are lightly transfused or TD low, and we saw even more profound increases in hemoglobin in the low transfused population, probably because their baseline hemoglobin is lower, so there's a wider window in which to show the improvement. One of the important questions when you're looking to treat anemia in this MF population is can this therapy be combined with the JAK inhibitors, which are the backbone therapy? We wanted to probe that, and the answer is yes. Again, we lower hepcidin regardless of what JAK inhibitor you're on.
Kind of intriguing, one of the groups here, the blue triangles, is patients who came into the study on momelotinib, which is a newly approved JAK inhibitor, which is supposed to have a hepcidin-lowering activity. We see these patients sitting at around 100, so still high, very high hepcidin. We, with our drug, do decrease that, we do mobilize iron, the response rate is essentially identical regardless of whether you're not on any JAK inhibitor, that's the 50%, on any JAK inhibitor, 50%, on ruxolitinib, 63%, momelotinib, 40% major response rate. All in the same basic, call it 50% general, neighborhood for response rates, which is fantastic, right? 'Cause it lets us set up then a plan for a pivotal program that's just designed to be very simple.
If you are anemic with myelofibrosis, whether you're not transfused, lightly transfused, heavily transfused, it appears that this drug has the potential to work, and regardless of what backbone therapy you might be on, ruxolitinib, pacritinib, momelotinib, If you are anemic, this drug will still, on those co-therapies, address the anemia. We see ourselves taking aim at the entire anemia of MF space, which again is about 22,000 U.S. patients. As we come into the end of the year, we expect to get the final or the top line kind of RALLY-MF phase II data. We typically aim at ASH as the main conference that we look at. Of course, we don't know yet whether we'll present there.
We expect to also have an end-of-phase II meeting and be able to provide guidance about what our pivotal trial is gonna look like as we come into the end of the year. That would set up starting a pivotal trial in the first half of 2027. Anemia of inflammation is actually a very broad problem. Millions of patients fall into that category. We believe this mechanism will be effective, particularly for those who have elevated EPO at baseline, endogenous EPO levels at baseline. Right now we're probing the anemia that goes along with inflammatory bowel disease as a place to check that hypothesis. We should have some data on that.
We're working on bringing forward a extended half-life version of this antibody probably to address those broader anemia of inflammation type patients in the end. Finally, the third program, DISC-3405. This is an antibody designed to do the opposite. Here we're trying to increase hepcidin, restricting iron availability, thereby restricting red blood cell production, which we know has been useful for controlling Hematocrit in polycythemia vera patients. Here, I won't go through the details on this slide, but, you know, PV, very significant rare disease, 150,000 U.S. patients, most of them receiving phlebotomy as a standard of care way of controlling Hematocrit. What we know now is that iron restriction is just a better way of achieving that. It makes patients feel better while getting to the same Hematocrit targets.
That's the domain that this kind of drug should fill, that, you know, a huge amount of these patients are receiving phlebotomy. I think all of us in the iron restriction field hope to show that that's medieval and should be out, you know, phased out and replaced with a good drug therapy. Our phase I data suggests that this mechanism is working fine. PK, typical monoclonal antibody. We expect a dose Q2 weeks, Q4 weeks, something like that. SubQ, very convenient. We show a restriction of hemoglobin, restriction of hematocrit, both this is in healthy volunteers, but these levels of downward pressure on red blood cell production should lead to success in the PV indication. Again, we'll have data on that later this year. This is the catalyst for the year.
Well, you know, typically at the European Hematology meeting in June, we present some data. We'll likely do long-term extension data from the HELIOS trial in EPP, some type of interim update on the RALLY-MF trial. We have initiated the IBD trial. As we come into the second half of the year, that's where we'll have our critical phase III APOLLO top-line data, respond to the CRL, get our key RALLY-MF phase II data, complete our end-of-phase II meeting, then get our initial proof of concept data in the phase II PV trial, which we call RESTORE-PV.
Again, all of this powered by a great balance sheet, $791 million, which provides us runway into 2029. That's the overall, and we think these are all three really taking aim at important markets. You know, if you look at the TAM, $2 billion-plus for EPP, $4 billion-plus for MF, $7 billion-plus for PV. That is the presentation. Tara, Q&A.
Okay. All right. Mic is working. We can come sit over here.
All right.
Yeah. I feel like this is cozier. All right. Don't have a whole lot of time yet, so I think I'll ask an overarching question on bitopertin and the CRL situation. Can you play out for us a little bit more on the timing of, you know, how long does it take to request a Type A meeting? How long does it take to get minutes to understand when the soonest time that we could possibly hear an update from that and your thinking on a few possible scenarios that could come out of that?
Right. Yeah. No, great question. When you get a CRL, there's a matter of right to have a follow-up meeting with the FDA. It's a 30-day request period, so you request the meeting, you get it 30 days later. You have to have a briefing book when you submit that request, which is somewhat unusual amongst FDA meetings. There's some onus on us to kind of get all of our ducks in a row and be fully prepared before we request that meeting. At this point, we have not yet requested that meeting. It will happen soon. The meeting will come 30 days later, and then we'll get the minutes from the meeting 30 days after that.
That's the point at which we typically are able to educate the public about what went on at that meeting. Our guidance is to expect that update sometime in Q2 of this year. In terms of what we're likely to address in that meeting, I think the primary question is to simply confirm what the CRL appeared to say, which is, you know, they looked at this through the lens of an accelerated approval. They agreed that we reduced Protoporphyrin IX, the critical toxic metabolite, very clearly, but they did not agree that that was reasonably likely to predict clinical benefit and asked us to prove out the clinical benefit in the phase III trial.
This is exactly what the APOLLO trial is designed to do, and the CRL actually made reference to that trial, so it appears that the door is open to come back and respond to that CRL once we have the APOLLO data in hand demonstrating an improvement in clinical benefit. We expect to get that data in Q4, turn that around into a response to the CRL by the end of the year, and that then sets up a six month target review period that would end then in the middle of next year.
Okay. Do you think that there's any potential risk to the design of APOLLO? I know that it was designed in complete alignment.
Yes.
several times over.
That's right.
You know, just maybe your confidence in that remaining as it is, you know, and how that plays in with some of the language in the CRL, like, if they're still open to, you know, biomarkers like PP9 expression and if they'll ask you for statistical correlation, things like that?
Right. Well, now it'll be a full approval concept-.
Mm-hmm
W hich no longer, you know, requires some kind of correlation between the biomarker and.
Mm-hmm
C linical endpoint, the time in light endpoint. Nonetheless, the trial's designed to deliver all of this data, right? The co-primary endpoints are a reduction in P P9 and improvement in the time these patients spend in light in month six of the study. We have to hit those co-primary endpoints independently, each p-value 0.05. As you said, that design has been on the table and open for discussion for well over a year, and there's been no effort to revise that trial design. I don't anticipate any issues, and I think the CRL actually pretty much confirms that, but that's what we'll, you know, wanna just touch on and make sure we're not missing anything in that Type A meeting.
Okay, great. I know you have several other data sets this year, PV, SCD, you're starting IBD anemia, all of those are super interesting. But in the remaining time I'd like to maybe focus on myelofibrosis. We had a really interesting panel this morning with a couple of physicians, and we were talking about expectations for that data. Of course, you know, you guys have communicated this and it's pretty clear from the interim data that, you know, consistency with the phase I data is probably, you know, it's the expectation.
As we think ahead to a phase III, one of the interesting things that the physicians brought up this morning was that, you know, transfusion independence, very simple, easy concept in the TD-high and TD-low patients, even though we know those are, you know, especially the TD-low are kind of less well characterized. In the NTD patients, the regulatory endpoints are a little less clear because transfusion and dependence is-.
Right
is not. Obviously it doesn't make sense. What would you be thinking for a regulatory endpoint in NTD patients?
Yeah, it's a great question, and that is what we're gonna try to sort out in the end-of-phase II meeting, as we come into the end of the year. To your point, hemoglobin, the FDA has been very consistent, is not a clinically meaningful endpoint. It's obviously a marker that the physicians care tremendously about.
Mm-hmm.
When you're talking about a patient who's not being transfused, simply showing you've improved hemoglobin in those patients is not sufficient as an endpoint for approval. You have to add something else to that. I think our end of phase I meeting suggested the FDA is pretty much open to suggestions.
Mm-hmm
A bout what might be clinically meaningful. If you look at other NTD, anemia type studies, people commonly look at things like fatigue, right? It's a well-documented consequence and clinically meaningful consequence of anemia, so fatigue might be one thing you'd address. As I showed when I was going, spinning quickly through the data, we do see very nice improvements in fatigue score, and it does appear to be associated with improvements in hemoglobin. Not that it necessarily has to be, but it's kind of nice to see the mechanistic connection there. Also you can look at things like exercise tolerance, durability of exercise, all those things.
You know, we're gathering all that data in our phase II trial, and we're gonna kinda form that into a strategy, propose some type of pivotal trial design to the FDA. Absolutely our goal is to encompass the full range of patients here. Whether we can do it all in one study, whether there could be multiple studies, you know, or, you know, I'd say no more than two, is still to be determined.
Mm-hmm.
That's the thing that we'll get clarity on in the end-of-phase II meeting.
Okay. Yeah. Great. like you said, they did really like hemoglobin. They personally found it.
Yeah, it's one of those situations.
M eaningful. They suggested fatigue and prevention of transfusion dependence. So.
Yes. That's one we're looking at as well.
Yeah. Nice.
Yes.
Okay. I know we don't have a whole lot of time left, so I guess, let's see, you have the PV update, the SCD update, which one do you wanna talk about in the remaining minute, and maybe tell us why you're excited about that?
Oh, well, the PV update is very exciting.
Yeah
B ecause it's going very fast. You know, we know through the good work at Protagonist, Rusfertide proved out that iron restriction is beneficial for PV patients. I think there are things about the TMPRSS6 antibody that may improve upon that for, you know, improve upon the patient experience, but we're going into a place where we have a lot of scientific validation, and it's kind of nice not to actually be the pure pioneer in this space. We understand what the clinical trial designs are gonna look like, and we're able to execute in our phase II. I think when we show that data, the path forward will be very clear very quickly, right? I think that data that as we come into the end of the year will be very impactful and should allow us to move very quickly into a pivotal trial next year.
Okay. Great. In the remaining five seconds, what do you think is the most underappreciated aspect of Disc?
Oh, interesting. You know, I think it's our commitment to capital efficiency, actually.
Hmm. Mm-hmm.
I think we've always. We've done what we've done. We have more money in the bank than we've ever spent as a company. We intend to maintain that commitment. We've been able to, I think, approach approval very rapidly with a very lean, efficient team. Our goal is to continue to try to deliver on important drugs in a way that's capital efficient.
Okay. Great. Thank you, John. Thank you Disc team for being here and everyone here for listening.
Thank you. Appreciate it.