Everyone, this is Eun Yang, a biotech analyst at Jefferies. It is my pleasure to host a fireside chat with Jasbir Seehra, Chief Executive Officer with Keros, at the Jefferies Virtual Healthcare Conference. As a reminder, Jas will be taking questions from the audience later, so feel free to type any question you might have in the box under the video. Before we go into Q&A, Jas is going to give a short overview, and then we'll do Q&A. Jas? Sure. Thank you, Eun. Thanks for this opportunity to have this discussion. As you know, Keros is a developing therapeutics that target the TGF-beta pathway, and we've shared three product candidates, KER-050 in MDS and myelofibrosis, 047 in diseases where iron imbalance leads to failure to incorporate iron into hemoglobin and results in anemia, and then 012 for treatment of bone disorders and PAH. All three programs are on schedule as we've highlighted before in our filings and have shared with investors. I think when I look at the preceding five months of 2021, I think the highlights of the year so far have been, we've had multiple presentations at multiple meetings, starting with the European School of Haematology. We'll have some presentations at EHA. We also had the presentation at the American Thoracic Society. Importantly for us, our foundational patent on the activin receptors was issued, so it really provide us with a very strong scientific and operational stance going into the remainder of the year. With that, I'll hand it back to you. Great. Thank you. Let us start with a big picture question on the TGF-beta pathway. You are developing potentially a differentiated product compared to Acceleron, but targeting the same biological pathway. Aside from the different ligand binding properties, can you talk about how Keros' approach in Milta will be differentiated from Acceleron's approach? Yeah. Look, I think Acceleron's approach has really highlighted the translation of biology from lower species to higher species. They've got approved product, REBLOZYL, which is approved for treatment of anemia in MDS patients that are ring sideroblasts positive. I think the early biology with 050 shows that it not only has the impact on red blood cell production, but it is a drug that targets multiple lineages, including platelets. It is having an effect on the myeloid lineages. For us, okay, that's very exciting. Furthermore, when we look at just the erythropoiesis, REBLOZYL, which has been shown to have the effect on the terminal stages of differentiation, whereas 050 will now continue to provide additional data in 2020 and what is in 2021, that it actually impacts all stages of erythropoiesis. That, I think, gives us reason to believe that it could work in correcting anemia in patients that are ring sideroblasts as well as those that are non-ring sideroblasts. I think that's where the differentiation can come. It can come, okay, at a number of different levels. First of all, we're going to be treating the patients on a monthly basis. It's our decision to treat on a monthly basis panned out by the data. It is supported by the data because that's the first level of differentiation. Of course, it's ring sideroblasts versus non-ring sideroblasts. Do we have activity in both sets of patients? That's the next level of differentiation. Then on the platelets, that's the third level of differentiation. We've got multiple opportunities to differentiate 050 from the approved REBLOZYL. Okay. Obviously, the focus is on the phase II data, initial data for 050 expected by the end of June. As you pointed out, there are multiple levels of differentiation that you can potentially show. This is one of the two low-dose endpoints data, 0.75 mg/k and then 1.5. Maybe, Jas, you can talk about the monthly, bi-monthly dosing, but at the same time, in current phase II, you have three additional months of follow-up after the last of the dose to see if you can potentially dose even less frequently than monthly. Can you talk about, although you may not be able to talk about much on what we should expect, from those three key differentiating points, can you give us the kind of data that you had in healthy volunteers as a preclinical data to support your confidence in. Now, points of bullet to differentiate from REBLOZYL? Yeah. You're absolutely right. Okay. We're going to be sharing data from the first two cohorts, the 0.7 and the 1.5 mg per kg dose. We're currently in the 1.5 mg per kg dose. I think the first thing is that the 0.7 mg per dose was deemed to be safe by the SRC, allowed us to dose escalate. When we go back and look at the healthy volunteer data, what did we see? We saw that in the healthy volunteer study, that the 0.75 mg, which was this single dose that we tested in the multiple ascending dose, we saw signals of changes in hematologic parameters, red blood cells as well as in platelets. Are we seeing those changes? Because I think that's the first thing. Do we have the biology that we saw in the healthy volunteers now translating to patients? That tells us where we have a drug that's working. It's all about finding the right dose level at that point. I think the first thing, okay, is are we seeing changes of hematologic parameters in patients at the 0.75 and at the 1.5? How does that relate, okay, to what we saw in the healthy volunteer study? Remember, okay, that in the healthy volunteer study, those are individuals that are relatively normal individuals, okay? Where they don't have any significant disease or inflammation. Whereas here, these patients are very heterogeneous. There's going to be patients that are ring sideroblasts, those that don't have ring sideroblasts. Within each category, you're going to have patients that have not had a transfusion, so no transfusion, to those that have had transfusions. Therefore, you're going to be looking for signals of activity. I think the way I tend to think about it is on an individual patient basis, did you see any changes in hematologic parameters? Okay. The first one of those is indeed reticulocytes. Can you see changes in reticulocytes? If you are, that's saying that the drug is trying to do something in those patients. The next question, okay, I think, is in patients that never saw a transfusion, where their bone marrow, while it's progressively declining in function, is still functioning enough that they're making red blood cells. Do you see an increase in reticulocytes that leads to an increase in hemoglobin? What is the magnitude of that change? That's one level. In patients that have had a transfusion, they're further along in their journey in terms of progression of the disease. Those patients' bone marrow is further advanced, okay, where it's not producing enough red blood cells that they're needing transfusion. Now do you see a change in reticulocytes? Does that reticulocyte increase then lead to either an increase in hemoglobin or maintenance of hemoglobin? That would be a measure of early indicator of transfusion reduction or transfusion independence. You want to see that in both RS patients as well as in non-RS patients, because then that gives you confidence that you can see that in both patient populations. Now it's a matter of what's the dose, okay, that's optimal for each patient population. It could well be that the dose that's optimal for RS and the dose that's optimal for non-RS is different, okay? Remember, okay, that this is a phase II dose escalation study with the primary endpoint of safety. Because you can see changes in red blood cell and platelets rapidly, you're actually getting data about your response in these patients. Do you expect to see RS and non-RS patients, you want to see the hematologic changes, but at the same time, necessary to determining what the optimal dose would be? For patients on transfusion versus non-transfusion patients, do you expect to see differences there as well in terms of potential dosing requirements? I don't know. Okay. I think, okay, right, that one of the things, okay, that you can see from the data that was there with sotatercept and with the sotatercept, there were patients that did not have any transfusions that were pretty strong responders, okay? Because it depends on where you are on the journey, right? When we talk about transfusion-independent patients, those that haven't had any transfusion, they're still heterogeneous, okay? There's those that you catch early on in the disease, those that you catch a little bit further along. What is the response? Don't know, okay, right, how to characterize that. We have to see that, okay. It may well be that some patients are responding at a lower dose, and others require a higher dose. That could be both for RS and non-RS. When you look at, okay, how REBLOZYL is being treated, they start at a lower dose with a dose escalation, okay, right? Even in the RS patients. You don't have to dose at the higher dose if the patient is responding. I would suspect that as the patient progresses in their disease, you're going to have to modify that dose. Earlier, Jas, you mentioned that currently you are at 1.5 mg dose, second cohort in the trial. I don't know if you have disclosed, when are you moving to the third dosing cohort, which is the 0.5 mg? Yeah. The next dose will be determined by the SRC, and it is following the Fibonacci rules, whereby the first dose escalation is two times the first dose, and then it's three times that for the next. It should be 2.25, subject to the SRC modifying it. They always have the ability to modify it, and that depends upon whether they're considered to be safe, if they're seeing a response or not. There's always that modification. 2.25 was what was planned as the next dose level, subject to modification by an SRC. When are you moving to that dose in cohort, third of dosing cohort? We have not shared that. Look, the study's ongoing. We'll progress up to that dose level, and when it's considered to be safe, we'll move to that. If that's safe, we'll go from there to the next dose level. I can't tell you that because I don't have that full information, and we haven't speculated or shared that as yet. Okay. The question is that you said depends, initially you said certain doses, but it depends on the safety profile before you move into the next dose. Let's say 1.5 is safe and it's efficacious, so you want to move on to the next dose. Can you go above 2.25 a milligram at the third dosing? Yeah, we could. You could? Yeah, we could. Yeah. Look, this is a safety study, first and foremost. This is our opportunity to look at what is the maximum dose that we can go to where we see an effect. It could well be that you see a response at different dose levels in different patients, and therefore, you want to know what is the dose that you can go to if you need in order to treat a patient. This is our opportunity to do that, and if there's no dose-limiting toxicity, then you want to do that, and go up as high as you can, as long as it's safe, and you're not putting patients at risk. This is your opportunity to test that. I see. Let's say hypothetically, you choose a third dosing cohort at 2.25 a milligram. The next cohort is, I think, at 3.75 mg. If you see really good efficacy at 2.25 mg, then do you feel that you need to go to the 1st dosing cohort, or we can potentially stop before that? Yeah. You're really talking about starting part two. Okay, right. I think that's what you're asking. Yes. The answer to that is, we have not shared that publicly. I think this is where it's really important to ensure that you don't shortchange yourself in terms of understanding the drug at this point in time. It doesn't mean that you have to wait for the entire dataset from the highest dose in order to start part two. You should really try and find out the maximum information that you can get. It is highly likely that even in part two, you're not going to start everybody at the highest dose. There's going to be some dose titration. Okay. Let's just say you found the phase III dose. When you start the phase III, obviously it's going to be sometime next year. Do you think that you would immediately compare KER-050, or do you think we can compare with placebo in phase III? Yeah, I think in the U.S., it is likely that it will be a placebo-controlled study. I think if we're only working in RS patients and we're not providing benefit in other ways, I think certainly in Europe, it is going to have to be a comparator arm there. I think in the U.S., it's not necessary. The FDA doesn't require it. Payers may want that. We have to look at that. I think this is why our phase II study is designed to really understand the drug, therefore, our hope and desire is to go right from the beginning as a frontline therapy, as opposed to having to do a comparator. We're seeing activity in RS and non-RS. We're seeing changes in platelets as well. We've designed a phase III study that is basically a frontline therapy. As you know, in the U.S., that is still erythropoietin. MDS patients get treated with an agent with erythropoietin. It would be a placebo-controlled study under those circumstances, but it might be also one where you do in comparison to the support. Early days. I think we need to see the data. Okay. Let's just say you have shown efficacy in RS patients as well as non-RS patients. Would you actually run two different registrational trials of RS and non-RS patients, or it's going to be a combined one trial? I think we have not made a decision on that as yet. It behooves us to really look at a study that includes both groups so that you minimize the size of the study. If you go back and you look at the REBLOZYL study, right? It basically had, roughly speaking, 300 patients in it. If you did a placebo-controlled study in RS and non-RS as separate studies, then potentially that could be twice that size. On the other hand, if it's the same placebo group, the study will be smaller than twice that size. I see. Okay. This initial phase II data coming out at JPM later this month. We sounds like based on healthy volunteer data as well as the preclinical data, you seem quite confident that you will show changes in hematologic parameters. In terms of the dosing, it's ordered as a monthly. As I mentioned, you have additional three months of follow-up after the last dose. Would we be able to see your ability to dose it less frequently than once a monthly in the initial data? Well, I think the first thing is the data supportive of our decision to go on a monthly basis? That's the first thing. The second thing indeed is, as we continue to do, understand the drug in that follow-up period, are you able to dose less frequently than a monthly, every six weeks or every eight weeks? You want to do it on that two-week cycle, where patients are actually used to having two visits, every two weeks. We'll have to see what the data shows. It may well be that you will only get that at a higher dose. You may not see it at the lowest dosage, and you may have to go to the higher dosage to see that less frequency. I see. Okay. Another activin receptor 012 in PAH, you have this additional preclinical data, ATS, and then you are moving into phase I in second half of this year. The phase I initiation, is it going to be a healthy volunteers? It will be a healthy volunteer study. Yes. Okay. There we are looking for whether you have increases in hemoglobin levels and red blood cells in terms of safety. Yeah, so- What should we look for in that phase I study data? Yeah. Look, I think we showed with the KER-050, beyond the hematologic changes in FSH and bone biomarkers. Remember, this is a drug that is going to target the same biology as sotatercept but lacks the red blood cell effect. We can go into healthy volunteer studies, postmenopausal women. We can look at changes in FSH. Those changes in FSH will tell us how much target engagement we get. When you get a 50% reduction in FSH in postmenopausal women, that is equivalent to 100% target engagement in terms of activin in the pituitary. That will really provide us with where we are in terms of target engagement as we dose escalate. Furthermore, looking at bone biomarkers, which is a slower change. That's a change that's as a result of kicking off the biology. Therefore, you'll see that over a period of time. The bone biomarkers also tell you what the consequence of that target engagement are. We have shared that we'll start the study in the second half of 2021, and we'll share data from part 1 of that study in the first half of 2022. What is first in part 1? Part 1 is a single ascending dose, okay, right, component of that. We believe, okay, right, from that information, we'll get an idea of where we are in terms of target engagement. We'll also be able to confirm that what we saw pre-clinically in terms of red blood cells, where we didn't see it in rodents, we don't see it in monkeys, translates, okay, right, to humans. Based upon all of the experience with multiple activin receptor ligand traps, we feel confident that what we see in monkeys has a probability of success in humans. Okay. All right. You have 047. We have about a minute left. Can you talk about what should we expect with 047? Yeah, I mean, 047, okay, is the sleeping giant, okay, right, in some ways because we never get to talk very much about it. We showed the healthy volunteer data, and you'll see a number of presentations at the European Hematology Association meeting. I think the data continues to strengthen our belief that this is the best way to mobilize iron and change, okay, those iron parameters that can lead to correction of anemia. I think that what you will also see at the European Hematology Association meeting is an abstract that says that we have the potential to reverse iron load, iron overload in patients, and that's based upon the preclinical data where we created iron overload and treatment with an ALK2 inhibitor is able to reduce iron in liver, and that abstract has been published. You'll see data from that study at the European Hematology Association meeting. I think 047 continues to show the opportunity. We start the IRIDA and the IDA studies in the second half of this year. They're going to be open-label studies, so they'll start generating data once they've been started. Okay. Jas, our time is up. Thank you for the fireside chat. We look forward to the data later this month. Thank you very much for the opportunity. Yeah. As always, pleasure talking to you. Thank you. Bye