Okay. I'm Doug Tsao, Senior Analyst at H[inaudible]. Disc Medicine is with us, represented by the company's Chief Operating Officer, Jonathan Yu. I think our talk today is a little timely, in that you presented initial data for your anti-TMPRSS6 monoclonal antibody last week at the SOHO conference. This was data in polycythemia vera. I'm just curious, maybe from your perspective, what were you most pleased to see? Yeah. Thanks for having us here, Doug. Last week at SOHO, very exciting data for us. It's a very exciting moment for the company at large. This is the third program now where we've shown POC data with the anti-TMPRSS6 antibody, our drug's called DISC-3405, 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 vera, these patients have systemically low levels of hepcidin, and the disease is characterized by uncontrollable growth of red blood cells, or called erythrocytosis. 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. What we saw in this initial 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 thrombotic events. We reported that patients are feeling better, and that also that we're able to reduce phlebotomy burden. It was exciting to see this just in the first cut of data. We'll have an update at the end of the year. 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. We believe we may have a leading profile here. Jonathan, the data that you had presented was with the Q2— Correct —every two weeks dosing. You expect to present, in the next cut, data from the Q4 dosing arm. That's right. I am just curious, given the fact that you have familiarity with the drug, is it your expectation that you should see the efficacy seen with the Q2 matched? That's right. So this study studies two different dose regimens. One is Q2W, subQ Q2W, and the second cohort B, is also a single subQ injection, Q4W. Why we like the antibody approach so much is the PK/PD relationship is very tight. What we saw in the phase I study, in the healthy volunteers, is we're able to see iron restriction that should be relevant for a once monthly dosing. I should add that, in this study, there was a dose escalation portion, which started off at Q4W. Even at a Q4W dosing, it was a lower dosage, we were already able to see the mechanism engage. So there's reason to certainly believe that Q4W dosing, the drug will be active. If we looked at the data, there was, I think it was like 62% were phlebotomy free through the first 26 weeks. I think if we looked at like weeks 12 through 32, we saw a further increase, I think up to close to 78%. Exactly. I know, limitations of cross trial comparisons. Right. Right. If we think about what we saw with rusfertide, which was recently approved, which is a hepcidin mimetic, 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? Sure. I think being able to control hematocrit fairly quickly does matter. I will say that there is a nuance about this study design that maybe might lead you to believe that there is an onset of action liability. We don't think that's the case. Just because there is a dose escalation portion, we started off at lower doses because this was the first patient study with the drug. Even at the lower doses, we were able to see the mechanism engaged in the first week. We see hepcidin increasing in the first week. In the healthy volunteer study, we were able to see hepcidin increase and iron reduce in the first week. We don't, in fact, even in some of the patients, we already saw 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. We expect the drug to be acting from the onset. Maybe, I think it'd be helpful to just sort of think about the competitive landscape, right? Just because obviously we saw rusfertide, I guess the brand name is MIMRYLO— MIMRYLO, yeah. —just approved. That drug is a weekly, and it does have injection site reaction. Q2 represents a pretty good improvement for you, and you obviously sound confident on the Q4. We do have the divesiran, which is an siRNA— Right —also targeting TMPRSS6. They had data out to Q12. How you're looking at that, I think I've seen data suggesting that patient preference, once you get past monthly, sort of starts to diminish. Exactly. Just your sort of initial thoughts on that and the relative advantages of just your mod hold. Absolutely. 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 is a sweet spot here. Q12W, I can see why nucleic acids are being pursued for this target because hepcidin is produced in the liver and these nucleic acids, they are very good at accumulating in the liver. But I am not entirely convinced that a Q12W is less frequent, but I am not sure it is that much more convenient. I do not 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 just to remember when to dose things. We definitely think that there is a sweet spot for dosing interval. I think the other reason why we chose an antibody modality and why we think having that sort of the Goldilocks Q2W, Q4W frequency is because we have supported these patients. Iron restriction, it is a homeostatic process, so that you are going to want to make sure you are able to strike the right balance between iron restriction, not too much, not too little, and to be able to manage things like anemia, injection site reactions. 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 MIMRYLO, it is a peptide, it has limited PK. That is probably why they require such frequent dosing. Of course, they are associated with very high injection site reactions. I am curious, just based on something that you said, because I think over the years, I have sort of thought that your target was the monthly. Do you anticipate sort of only developing the monthly, or do you think that there is value in dosing flexibility, and perhaps you would want to have the Q2 and the Q4? Our base assumption is that it will still be Q4W, but I think having the flexibility to go to Q2W, I think is something. Okay. With DISC-3405, it is an important year for you because we should also get data from sickle cell by year-end. It is interesting to me because sickle cell is an indication that Protagonist passed on, did not advance with rusfertide. Maybe help us understand your thesis in that indication, which has obviously been a challenging indication for a lot of different mechanisms. Yeah Over the years in a go, no-go decision. Yeah. It is a very fascinating thesis for sickle cell. 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. There is very good literature that indicates that tendency to aggregate and sickle is driven by the concentration of hemoglobin S. So the theory here is if we can restrict iron, that will be able to reduce the amount and the concentration of hemoglobin S within the red blood cell, and therefore reduce its propensity to sickle, and from there, the downstream complications and issues associated with sickle cell disease. Clinical evidence, practice evidence that 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 concentration of hemoglobin S, and that results in patients feeling better and reduction in VOC and hemolytic events. So that is the hypothesis we are trying to prove out with this first study. Now, this first study is a safety study, and at the end of the year, we anticipate it 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 able to understand PK, but we will get a read on iron. We will be able to understand how much hemoglobin is within each red blood cell and hope to have some read on hemolytic biomarkers as well. I think you have talked a little bit, although you prioritize sickle cell, but also doing beta thalassemia. I am just curious because that was an indication that we saw Protagonist initially target with rusfertide. What makes you think your asset will be successful, or you are going to look at it in a different way than they did? Yeah. I think, just to be clear about where we think about indication and development strategy, I agree with you. The beta- thal, there was a thesis long ago, and very strong preclinical data that the drug might work or this approach might work, but the data just has not translated. I do not know if it is because filtered patient population. I think thalassemia, especially after this data readout, certainly is, given the profile that we are seeing, it is a very significant opportunity. We estimate there is about 150,000 patients in the U.S. You can. That opportunity is quite significant. You also have sickle, early days still, but if we start seeing traction there, that is the next indication for us to go after. In both cases, those are very sizable patient populations where we think iron restriction will have a very important role. Okay. I do want to spend a little time on bitopertin and DISC-0974. Just because I think people would think I was not doing my job if I ignored them. You have done some changes in APOLLO versus AURORA, right? In particular, focusing on the last month of the six-month study for the co-primary endpoint to wash out the placebo effects. Exactly. And one of the dynamics that I think sort of probably surprised you or caught you off guard in AURORA was the fact that you basically had the first blinded study, versus other EPP studies which sort of ultimately had sort of functional unblinding. I am just sort of curious, were there other operational changes versus AURORA to sort of really keep the study— Yeah —maintain the sort of integrity, versus what had occurred previously? Exactly. It was a truly blinded study. When you look at an endpoint on an aggregate basis, you are not able to see as much of an effect size because early on, if everybody, whether you are on active or placebo or going out, trying to put up time in light, it is going to obscure the signal. What we did was we did the post hoc 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, double-blind study. We actually learned from AURORA into APOLLO. APOLLO looked as much as we could like AURORA. Yes, we are looking at the last month of the treatment period now, much as we did on the It is now a six-month study. That should be able to give you that much more of a washout of a placebo effect and see greater separation. We are also powering up the study. Originally, it was a 25 patient per arm study in AURORA. That is 25, if you are just looking at a 60 mg dose level, it is 25 patients in 60 milligrams, 25 patients in placebo. Post hoc analysis, we were able to show statistic difference on that endpoint, and now it is 75 patients per arm, 16 mg. I guess the only other nuance, I guess what I would add that the difference between APOLLO and AURORA is that we are now introducing European sites. The only, I guess, change we have made in terms of the study design is now we are stratifying by geography. It is just because we do not have experience with European sites from AURORA. It is just kind of a safeguard. Otherwise, the study is designed to be as similar to AURORA as possible. I guess I am just curious, how do you handle dropouts? 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 phototoxicity. Because we sort of think about the fact that you are truly blinded. You do have some patients who have phototoxic reactions in the early going. They might drop out. Right. Then you sort of end up with, in your placebo arm, patients who just have naturally more sunlight tolerance. Yeah. No, it is a very good theoretical question. I think that the reality is that we have had very, very little dropout. The study, we originally intended for the 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. Of those 183 patients, only two dropped out. Not for safety reasons, just vagaries of clinical operations. Of the remaining 181 patients who completed the study, 100, the open-label extension or the EAP. 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 probably do not need to worry too much about it. As a technical matter, I think that data would be imputed, but we are really excited to see this kind of, I think it is kind of unheard of to see this level of retention. We had one big versus sort of the tanning agents, is the fact that it should, because the mechanism have a liver protective effect. Yeah. Suggesting improvements in liver enzymes. I think John has been clear that you do not have an expectation that that would be to get you a labeled claim. Correct. I am just curious, when you talk to clinicians, do they, for the most part, sort of just get it? Sort of understand, like, we lower PPIX, so yes, this should be protective. Yeah of patients' livers. Is there anything or any clinical work that you could do to characterize it? Or just given the sort of timescale and the frequency, just too hard, too expensive, and probably just not worth it. Yeah. So exactly. APOLLO was not designed to be able to probe this question. We have included measures of liver enzymes and things like that as an exploratory measure, but it's primarily designed to get us to approval. It's very clearly understood, particularly among the treater community and amongst KOLs, that PPIX is a driver of hepatobiliary complications. The physiology of that is very clear, and there's data showing that if you have lower PPIX levels, you have a lower propensity to develop these complications. We firmly believe that if you have lower PPIX levels, that should probably be better for your liver health. It'll probably be a part of our long-term life cycle management, but I think it will be implicit in our mechanism of action. 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 a disease that has a significant. I think you have had data, and I think you're sort of 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. Yeah. I am just curious how you are thinking about eventually getting to those patients as well. 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, that is very important in your formative years. We do have 32, I believe, adolescents in the APOLLO trial. That should be able to, in the 12 and above patient population, that would be the first entry into the younger patients. Then we are thinking about long-term, what the life cycle approach is to be able to access even younger patients. But, for the majority of these patients, they do not get diagnosed until they are in their teens anyway. We hope that being able to study adolescents already in APOLLO, we will be able to enable access into this segment early on. I did want to turn and spend a couple of minutes. I think technically we are out of time, but maybe we will go into stoppage time. European football rules. Okay. In 0974— Yes —The data from RALLY-MF so far has been really strong, right? Yes. It's been strong across all the different patient groups, right? Regardless of what JAK inhibitor they're using, right? Exactly. I guess, but stepping back, right, I don't think the data was as strong, but BMS had luspatercept, and it had good data, and they went into phase III, and then they narrowly missed. I guess I'm just curious, when you think about designing your phase III study, what was the takeaway that they had or any learnings that you had to keep yourself grounded in trying to maximize success? Yeah. I think effect size is going to matter. When we looked at their data, it's active, but the response rates were only in what they studied in their phase III trial, was only in the segment of patients where they performed the best. Even their phase II trial was in the 28% kind of range. That's kind of what they put up in phase III as well. They missed on stat sig because of the 20% range. Right. It makes us feel more comfortable given that we're starting to see response rates, major response rates in 70%-80%. That gives us great comfort. I think the main learning from the REBLOZYL example is that there's probably some noise in these patients. There's heterogeneity to account for, so making sure you have sufficient powering, that's very much on our mind as we move forward. The one other question, because you did start a study, in DISC-0974, in anemia associated with IBD. Yeah. It was sort of interesting that you have also characterized DISC-0998, sort of your longer-acting anti-HJV mAb, as targeting sort of anemia associated with inflammatory disease. Yeah. I'm just curious, 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 DISC-0974 data, and if it reads out favorably in IBD, that DISC-0998 would sort of become the molecule? That's kind of how we're thinking about it. We are the pioneers of lowering hepcidin and increasing iron, and the opportunity here could be very vast if you go into anemia for chronic disease, because inflammation drives high hepcidin and locks up your iron. DISC-0974 is very much looking like an excellent agent for MF. I think there's still a lot we can learn about some of these other indications using DISC-0974. So that's how we're thinking about. Anemia is very pervasive in IBD. Yeah. It's a serious issue, and if we're able to see a signal, 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 other anemias and inflammatory disease. I guess the final question, when you think about sort of inflammatory diseases, presumably you're going to have to go after each individual one, or do you think there's the possibility for doing a basket study? It's possible, yeah. IBD, there's precedents where it's IBD low irons, where you do a basket study, one with, typically it's been CKD and then a basket of other anemias of, iron deficiency in their case. Those are the sort of thing. I think the first priority is to understand if we see POC in IBD, then we'll start thinking about should we explore in some other indications if they're sufficiently similar, then you create a basket study kind of a situation. Well, I think we do have to probably wrap it there, unfortunately. Great. Thank you very much, Doug.