Disc Medicine, Inc. (IRON) September 2026 Conference Transcript

Okay. I think we'll kick it off. I'm Doug South, Senior Analyst at HC Wainwright. We are thrilled to have Disc Medicine with us, represented by the company's Chief Operating Officer, Jonathan Wu. And I think sort of our talk today is a little timely in that you presented initial data for your anti-temporary 6 monoclonal antibody last week at the SOHO conference. This was data in polycythema vera. And I'm just curious, maybe from your perspective, what were you most pleased to see?

Yeah. Thanks for having us here, Doug. Yeah, last week at SoHo, very exciting data for us. And it's a very exciting moment for the company at large. This is the third program now where we've shown POC data in patients. And the thesis with the anti-temporary sex antibody, our drug's called Dix3405, was that by inhibiting this target, you're able to induce the body's own production of a hormone called hepcidin, which is the master regulator of iron. In polycythemia and vera, these patients have systemically low levels of hepcidin, and the disease is characterized by uncontrollable growth of red blood cells, or called erythrocytosis. And the thesis has always been, if you're able to increase hepcidin production and restrict iron that can slow down this uncontrolled growth of red blood cells and what we saw in this initial data data cut is just that the drug is doing exactly what we expected it to do across all the different parameters we're able to see that the drug is able to induce hepcidin production this results in iron restriction that translates into very strong hematocrit control which is very important for these patients because they have a tendency to develop thrombotic events. We reported that patients are feeling better and that also that we were able to reduce phlebotomy burden. And it was exciting to see this just in the first cut of data. We'll have an update at the end of the year, but the profile is looking excellent. I should add that also the safety and tolerability, which we think is going to be something that is going to be important to be able to differentiate in this field, also looks stellar. So we believe we may have a leading profile here.

And Jonathan, maybe, you know, the data that you had presented was with the Q2. Correct. You know, every two weeks dosing. And you expect to present in the next cut data from the Q4 dosing arm. That's right.

And I'm just curious, given the fact that you have familiarity with the drug, you know, is it your expectation that you should see the efficacy seen with the q2 matched that's right yeah so this study studies two different dose regimens one is q2w sub q q2w and the second cohort cohort b is also a single sub q injection q4w and based on one of the things about this drug is and why we like the antibody approach so much is the pk pd relationship is very tight and so what we saw in the phase one study in the healthy volunteers is we're able to see iron restriction that should be relevant for once monthly dosing. I should add that in this study there was a dose escalation portion which started off at Q4W and even at the Q4W dosing it was a lower dose we were already able to see the mechanism engaged. So there's reason to believe certainly believe that Q4W dosing the drug will be active.

And, you know, if we looked at the data, there was, I think it was like a 62 percent, you know, were phobotomy free through the first 26 weeks. But, you know, I think if we looked at, like, weeks 12 through 32, we saw a further increase, I think, up to close to 78 percent. And I know limitations of cross-trial comparisons, right? But, you know, if we think about what we saw with rasveratide, which was recently approved, you know, which is a hepcidomimetic, it did look like there's maybe a slightly faster onset. Do you think that matters in this population? And is there anything that you can reduce it?

I think being able to control hematocrit fairly quickly does matter. I will say that there is a nuance about this data design, the study design that maybe might lead you to believe that there is an onset of action like liability. We don't think that's the case, just because there is a dose escalation portion. So we started off at lower doses because this was the first patient study with the drug. But even at the lower doses, we were able to see the mechanism engaged in the first You see hepcidin increasing in the first week. And in the healthy volunteer study, we were able to see hepsidin increase in iron reduce in the first week. So we don't think there's an onset of action issue here. In fact, even in some of the patients, we already saw a phlebotomy reduction early on. I think just sometimes the numbers get obscured because you're looking at phlebotomy, which is a downstream readout of the drug's activity. But we expect the drug to be acting from the onset.

And maybe I think it would be helpful to just sort of think about the competitive landscape, right? Just because, obviously, we saw resveratide, I guess the brand name is Memorilo, just improved. And, you know, that drug is a weekly, and it does have injection site reactions. And so even the Q2 represents a pretty good improvement for you, and you obviously sound confident on the Q4. We do have the Diverazan, right, which is SRNA, you know, also targeting Tempris-6. and they had data out to Q12, and so I'm just curious, you know, how you're looking at that. I mean, I think I've seen data assessing that, like, patient preference, once you get past monthly, sort of starts to diminish, but just your sort of initial thoughts on that and the relative advantages of just your monoclob. Absolutely.

I mean, this was very much on our mind when we entered this field, and one of the reasons why we went after an antibody modality because exactly to your point we think there's a sweet spot here you know q12w i mean i can see why nucleic acids are being pursued for this target because hepcidin is produced in the liver and you know these nucleic acids they have a tendency to uh they're very good accumulating in the liver but i'm not entirely convinced that a q12w it's less frequent but i'm not sure it's that much more convenient You know, I don't really know people who do things on a quarterly basis other than you and public companies and who report on a quarterly basis, and it may be difficult to just to remember when to dose things. So we definitely think that there is a sweet spot for dosing interval. And I think the other reason why we chose an antibody modality and why we think having that sort of the goldilocks you know q2 wq4w frequency is because we believe that control is going to be very important to these patients you know iron restriction it's a homeostatic process so that you're going to want to make sure you have you're able to strike the right balance between you know iron restriction not too much not too little and to be able to manage things like you know, anemia in injecting site reactions. We're seeing that, so this is why we believe that being able to have some level of titratability to customize the level of iron restriction you need is going to be important, and the antibody is the right modality for that. I think, you know, Memorilo, you know, it's a peptide. It has limited PK. That's probably why they require that such frequent dosing, but, and of course, they're associated with very high injecting site reactions.

And I'm curious just based on something that you said, you know, because I think over the years I've sort of thought that your target was the monthly, but do you anticipate sort of only developing the monthly or do you think that sort of there is value in dosing flexibility and perhaps you would want to have the Q2 and the Q4? I mean, our base assumption is that it will still be Q4W, but I think having the flexibility if needed to be able to go to Q2W, I think is something that will be important for these And, you know, with 3405, it's sort of an important year for you because we should also get data from sickle cell by year end, and it's sort of interesting to me because sickle cell is an indication, right, the protagonist passed on, right, you know, did not do, you know, advance with resveratide. And, you know, maybe help us understand your thesis in that indication, which has obviously been a challenging indication for a lot of different mechanisms over the years and sort of what you're looking to get in terms of a go-no-go decision. Yeah.

I mean, it's a very fascinating thesis for sickle cell. I mean, the premise of it is that the tendency for cells to sickle and to hemolyze and to develop all the downstream complications is a result of the aggregation of hemoglobin S, this mutated hemoglobin, and its propensity to aggregate. And there is very good literature that says, that indicates that that tendency C to aggregate and sickle is driven by the concentration of hemoglobin S. So the theory here is if we can restrict iron, that is able to, that will be able to reduce the amount of the concentration of hemoglobin S within the red blood cell and therefore reduces propensity to sickle. And from there, the downstream complications and issues associated with sickle cell disease. And there's very good human clinical evidence, practice evidence that this is this this works case study but in Europe for instance patients are phlebotomized to be able to drive them into iron deficient state to reduce their hemoglobin concentrated hemoglobin s and that results in patients feeling better and reduction in VOC and hemolytic events and so that's the that's the hypothesis we're trying to prove out with this first study now you know this this first study is a safety study and and and at the end of the year we anticipate will be like single number of patients kind of data. But because this is hematology, we should be able to get a sense of whether or not the mechanism is being engaged. We'll understand safety, we'll understand PK, but we'll get a read on iron. We'll be able to understand how much hemoglobin is within each red blood cell and hope to have some read on hemolytic biomarkers as well.

And I think you've talked a little bit, although you prioritize sickle cell, right, but also doing beta thalassemia. And I'm just curious, because that was an indication that we saw protagonists initially target with resveratide, and they had what I would call sort of mixed data. And so what makes you think your asset will sort of be successful, or are you going to look at it in a different way than they did?

Yeah, yeah. I think, you know, just to be clear about where we think about indication and development strategy, I agree with you. I mean, the beta-thal, there was a thesis long ago and very strong preclinical data that, you know, the drug might work and where this approach might work, but the data just has not translated. I don't know if it's because folks are choosing the wrong endpoint or because it's a complicated patient population. So I think for us, beta-thal probably is not a priority for us to go after. Polycythemia, Vera, especially after this data readout, certainly is, and given the profile that we're sort of seeing. and it is a very significant opportunity. We estimate there's about 150,000 patients in the US and you can sort of, so that opportunity is quite significant. And then you also have sickle, early days still, but if we start seeing traction there, that will be our next, that's the next indication for us to go after. And in both cases, there is, those are very sizable patient populations where we think iron restriction will have a very important role.

Okay, so I do want to spend a little time on Bitterpertin and 974, just because I think people would think I was sort of not doing my job if I ignored them. You know, I think, you know, you have done some changes in Apollo versus Aurora, right, in particular, sort of focusing on the last month of the six-month study for the co-primary endpoint to sort of wash out the placebo effects. Exactly. And, you know, one of the dynamics that I think sort of probably surprised you or caught you off guard in a war was the fact that you basically had, you know, sort of the first blinded study versus other EPP studies, which sort of ultimately had sort of functional unblinding. And I'm just sort of curious with the other operational changes versus Aurora to sort of really keep the study sort of maintain the sort of integrity, you know, versus what had occurred.

Exactly. I mean, that was an important learning for us, because, as you say, it was a truly blinded study. And when you look at an endpoint on an aggregate basis, you're not able to see as much of an effect size, because early on if everybody whether you're on active or placebo or going out you know trying to put up time time in light it's going to obscure the signal so what we did was we did the analysis the postdoc analysis in aurora and looked at the last month where the placebo effect would have washed out and we were able to see a very clear separation between active and placebo the rest of the study was run extremely well it was a very robust study you know double blind study and so So actually, when we were translating what we learned from Aurora into Apollo, we tried to make Apollo look as much as we could like Aurora. So, yes, we are looking at the last month of the treatment period now, much as we did in the post-doc analysis for Aurora. It's now a six-month study. So that should be able to give you that much more of a washout of a placebo effect and see greater separation. And we're also powering up the study. So originally, it was a 25-patient-per-arm study in Aurora. So that's 25. If you're just looking at a 60-milligram dose level, it's 25 patients and 60 milligrams, 25 patients in placebo. Post-doc analysis, we were able to show stat-sig difference on that endpoint. And now it's 75 patients per arm, 60 milligrams of placebo. vote. And I guess the one last, the only other nuance, I guess what I would add that, you know, the difference between Apollo and Aurora is that we're now introducing European sites. And I think the only, the only, the only, I guess, change we've made in terms of the study design is now we're stratifying by, by geography, just, it's just because we don't have any experience with European sites from Aurora. That's just kind of a safeguard.

Otherwise, the study is designed to be to be as similar to aurora as possible and i guess i'm just curious how do you handle dropouts right just because in the study just given the fact you sort of have a longer period when i think about it you might have patients who do have photo right because you know we sort of think about the fact that you are truly blinded right and you do have some patients who um have phototoxic reactions in the early going, they might drop out and then you sort of end up within your placebo arm patients who just have naturally more sunlight tolerance. Yeah.

No, it's a very good theoretical question. I think that the reality is that we've had very, very little dropout. So, you know, the study, we originally intended for the study to be a study size of 150, as I said before 75 and 75 but there was a lot of exuberance in the enrollment and we ended up with 183 patients instead of 150 and of those 183 patients only two dropped out not for safety reasons just vagaries of you know clinical operations and so that means and of those of the remaining 181 patients who completed the study 179 have moved on to either the open label extension or the eap so um so to answer your question, the dropout issue, we had budgeted, I think, at 8% in our statistical analysis, an 8% dropout rate, but the reality is we don't probably don't need to worry too much about it. As a technical matter, I think that data would be imputed, but I mean, we're really excited to see this kind of, I think it's kind of unheard of to see this level of retention.

And, you know, we have one big clinical advantage of the bid department, right, versus sort of the tanning agents is the fact that it should, because the mechanism have a liver protective effect. You know, we saw some data suggesting, you know, improvement in liver enzymes. Probably, I think John has been clear that you don't have an expectation that that would be, you know, to get you a labeled claim. And I'm just curious, when you talk to clinicians, do they, for the most part, sort of just get it, We sort of understand, like, we lower PP9, so yes, this should be protective of a patient's livers. And is there anything or any clinical work that you might, could do to characterize it, or just given the sort of time scale and the frequency, just too hard, too expensive, and probably just not worth it?

Yeah, yeah. So, exactly. I mean, Apollo is not designed to be able to probe this question. We have included measures, hepatobiliary measures of like liver enzymes and things like that as an exploratory measure, but it's primarily designed to get us to approval or designed to get us to regulatory approval. I think that it's very clearly understood, particularly among the treater community and among these KOLs, that PP9 is a driver of hepatobiliary complications. The physiology of that is very clear, and there's data showing that if you have lower PP9 levels, you have a lower propensity to develop these complications. We firmly believe that if you have lower PP9 levels, that should probably be better for your liver health. It'll probably be a part of our long-term lifecycle management, but I think it's already, I think it will be implicit in our mechanism of action. and I think the experience that patients have on the drug itself will be sufficient. If you're thinking just about photosensitivity, we believe that the activity will be such that that by itself would be compelling.

This is an indication or disease that has a significant impact on kids. I think you have had data, and I think you're hopeful that you'll be able to get adolescent labeling, But obviously, this is a disease, right, for kids even younger, can be even more impactful on them. And so I'm just curious how you're thinking about eventually getting to those patients as well.

Yeah, I mean, from a prevalence perspective, the vast majority of the commercial opportunity is adults. But as you can imagine, being able to go out in the sunlight, I mean, that's very important in your formative years. We do have 32, I believe, adolescents in the Apollo trial. And so that should be able to, you know, in the 12 and above patient population, I mean, that would be the first entry into sort of the younger patients. And we're thinking about long-term or the life cycle approaches to be able to access even younger patients. But, you know, for the majority of these patients, they don't get diagnosed until they're in their teens anyway. And so we hope that, you know, being able to study adolescence already in Apollo, we'll be able to enable access into the segment early on.

And I did want to turn and spend a couple of minutes. I think we're all, technically we're out of time, but maybe we'll go into stop. European football rules. You know, in 974... you know the data from rally mf so far has been really strong right and it's been strong across all the different patient groups right regardless of what jack inhibitor they're using right exactly um i guess but stepping back right you know and i don't think the data was as strong but bms had lucifercept and it had good data and they went into phase three and then they narrowly missed And so I guess I'm just curious when you think about designing your phase three study, sort of what was the takeaway that they had or sort of any learnings that you had to sort of keep yourself grounded in trying to maximize success?

I mean, I think effect size is going to matter. You know, when we looked at their data, I mean, it's active, but, you know, the response rates were only, and what they studied in their phase three trial, was only in the segment of patients where they performed the best. And that was, you know, even their phase two trial was in like the 28% kind of range. That's kind of what they put up in phase three as well. and they missed on stat sig because the comparator arm was in the 20 percent range you know and so it makes us feel more comfortable given that we're starting to see response rates you know major response rates in 50 to 60 percent overall response rates in 70 to 80 percent so that gives us great comfort I think you know it the learning main learning from the rubazil example is that there's probably some noise in these patients there's heterogeneity to account for and so making sure you have sufficient powering i mean that's very much on our mind as we as we move forward and then the one other question because you did start a study um in 974 in anemia associated

with uh ibd um and it was sort of interesting that you have also characterized 998 sort of your longer acting um anti-hdvmab as targeting um sort of anemia associated with inflammatory disease And so I'm just curious, you know, are you looking at those, is there sort of a separate bucket of inflammatory diseases you're looking at, or is it sort of like, look, you're going to take the 974 data, and if it reads out favorably in IBD, that 998 would sort of transition, become the molecule. That's kind of how we're thinking about it.

I mean, we are the pioneers of lowering hepcidin and increasing iron, and the opportunity here could be very vast if you go into anemia of a chronic disease because inflammation drives high hepcidin and locks up your iron. 974 is very much looking like an excellent agent for MF, and so I think there's still a lot we can learn about some of these other indications using 974, so that's kind of how we're thinking about this IBD study that, you know, anemia is very pervasive in IBD. It's a serious issue. And if we're able to see a signal, you know, we're moving as fast as we can on the long-acting version, that may be a very appropriate agent for IBD and some of these others, anemia is an inflammatory disease.

And I guess the final question, when you think about sort of inflammatory diseases, I mean, presumably you're going to have to go after each individual one, or do you think there's the possibility for doing like a basket study?

It's possible yeah IBD there's there's precedence where it's IBD alone there's precedence with the IV irons where you do a basket study you know one with typically it's been CKD and then a basket of other of other anemias of well iron deficiency in their case. So those are sort of things that we're kind of exploring right now. I think the first priorities to understand you know if we see POC in IBD then then we'll start thinking about should we explore and some other indications that they're sufficiently similar then you're able to you know then you could feasibly create a basket study kind of thing.

Okay well I think I think we do have to to probably wrap it there, unfortunately.

Great, thank you very much, Doug.