Okay. All right. Now I think we're ready to get going. So, thanks everyone for joining us again, for our inaugural Guggenheim Healthcare Innovation Conference. Hopefully, it's been a productive three days for all of you, coming down the home stretch here. I'm Vamil Divan, one of the biopharma analysts here at Guggenheim, joined up here on the Guggenheim side by Danielle Crozier from the team. And next company in this room, we have Keros Therapeutics, and we have Jasbir Seehra, the CEO and Chair of the company. Company we've picked up coverage on relatively recently. It's been fun to get to know the team and get to know the story. But maybe, Jas, just for people who may be less familiar with the story, if you can just give a little overview on sort of the Keros history and where you are today, and then we'll dive into some questions on your three main programs. Sure. Keros is a company that's entirely focused on a particular pathway, the TGF-beta pathway. And I think really what's great about this pathway is that the biology translates faithfully from rodents to humans. And it's active in all tissue in during embryogenesis and for maintenance of tissue in adult. When you get aberrant signaling, it can lead to disease. Therefore, the opportunities are tremendous. And we have got three product candidates that are in clinical development. Most advanced of them is elritercept KER-050 in a hematology indication, MDS, and myelofibrosis. Our next advanced molecule is cibotercept KER-012 for treatment of pulmonary arterial hypertension. And then in phase one is KER-065, which targets myostatin and activin to increased skeletal muscle in obesity and also applications in neuromuscular diseases. Great. So I think what's been interesting, Jas, is that so elritercept's technically ahead in development, but by far the majority of the questions we've been getting is on cibotercept and just the progress you're making there. So maybe you can just talk about it as what you see and kind of the, as you've been developing this product, the unmet need. There's obviously been the entry of sotatercept into this market over the last, I guess, year or so now. But what you, where do you see cibotercept maybe filling an unmet opportunity? Yeah. I think when Acceleron, my former company, took sotaltercep into the clinic, there was a hypothesis. The hypothesis was that in pulmonary arterial hypertension, it is aberrant signaling through one arm of the pathway, the activins, increased signaling through that and reduced signaling through another arm, the bone morphogenetic protein signal. And if you rebalance that, it should provide benefit by remodeling that vasculature so that it opens it up. And I think the phase two data that came out in 2020 and subsequently the phase three data in March of 2023 provided proof of mechanism, right? It's validated. However, sotaltercep was never designed for that, this indication. It's a wild-type activin receptor. And as such, it went through a torturous development path, starting off as a drug for bone loss. But because there was this dominant pharmacology of red blood cell increases, it became an anemia drug. And then it was no longer being pursued for those indications. It was returned to Acceleron for PAH. But that dominant pharmacology was already there. So Acceleron knew that they had to titrate their drug such that the increases in red blood cells would be kept below one and a half grams per deciliter. Because when you have greater increases than that, then that could lead to stress on cardiac tissue, and regulators are gonna frown upon that. So for the, with that, they had to keep it to low doses. Those low doses were 0.3 mg and 0.7 mg. They showed a dose-dependent decrease in pulmonary vascular resistance. But even at the highest dose of 0.7 mg, you leave a lot of room for additional target engagement. So that was our foray into it in 2020, is that we can do better because we don't have an increase in hemoglobin. So we can get better target engagement and potentially better efficacy. I think one of the things that have been observed that was there in the preclinical talk studies was that there's safety signals associated with the biology of sotatercept because it is a wild-type activin receptor ligand trap. And that has now panned out over the last 20 months. It started off in the open-label extension of PULSAR, where there were these spider veins, telangiectasias that were observed. That told you that these were early signals of more serious bleeding events that will show up. In STELLA, you saw bleeding events and telangiectasias. And now in the real world, there are more and more reports of those bleeding events. So I think 20 months ago, investors, investigators all said the same thing, which is you gotta show better efficacy. Today, it's well, you can show the same efficacy, but a better safety profile, and it'll be the drug of choice. So I think, you know, there's a better appreciation of the opportunity, but also the limitations of sotatercept today than it was. And that's where 012, cibotercept company, potential for greater efficacy, doesn't have the increase in hemoglobin. There's four, it's more convenient. The hemoglobin, it increases, red blood increase come with a cost. And that cost is bleeding events along with the BMP, but also, there's thrombocytopenia that comes from that treatment. We don't have any of these with 012. So we have the potential, better efficacy, but also better safety. And if we miss on the efficacy, 'cause there is no more efficacy to be gained from this pathway, there's multiple pathways involved in vasculature development, VEGF, PDGF, TGF beta. It could well be in patients, that's all there is to be got, in which case you're still able to demonstrate better safety profile. That's a pretty good place to be. Yeah. So we thought it was interesting, obviously fully enrolled this phase two trial now, faster than I think people were expecting, which I think points to the interest, and, you know, maybe the opportunity. But I think we've gotten a lot of questions, I think more recently now as we get closer, a few months out from getting the actual data. And you sort of touched on this a little bit, but sort of what do you feel you need to show to be compelling? And I think that on the kind of from both sides, efficacy-wise, some thought that the hemoglobin increase with sotaltercep maybe helps with the six-minute walk. And so maybe are you at a little bit of disadvantage to try and match the efficacy that they've shown? And on the safety side, more awareness now from the community on these potential side effects. So could it be biased against you in some ways just 'cause people are more aware of it, looking out for these events more than they were back during the PULSAR day? So maybe you can just comment on both sides and how you're trying to sort of manage that risk and what are you hoping to see? So let's talk about the efficacy. The benefit is going to be on the Six-minute walk test with an increase in red blood cells. Better oxygenation allows you to have better performance. Good news is market didn't quantify that. In STELLA, it was in response to questions from analysts. They quantified it as four meters out of the 40. So it's a 10% effect. That's within the noise of the Six-minute walk test. On the other hand, that increase in red blood cells is also leading to increase in viscosity. Vis PVR is directly proportional to the viscosity and inversely proportional to the diameter of the blood vessel. So that will also result in the increase in hemoglobin of one and a half grams per deciliter is about 25 dyne increase in PVR out of 600. So 600 is really equivalent to 575 if you didn't have that increase anymore. So it's swinging around wild, okay, right? You gain on one, you lose on the other here. Okay? So that's on the efficacy side. Yeah. So we could see a slightly poorer six-minute walk test if all things are equal and we're only got equivalent efficacy. On the other hand, if there's better improvements in PVR, you would think that they will translate into a bigger change in six-minute walk test. So that's on the efficacy side. On the safety side, I think that's where we're very confident that we will be able to show differences. But to your point, everybody's looking for them now. They weren't looking for them two years ago, three years ago. So I think for that, you have to look at the placebo rate. There is a background of bleeding events in these patients and telangiectasias that are low, but they're there in the placebo. So if the placebo numbers are higher, that tells you everybody's looking harder. And then you gotta look at the treatment arms relative to the placebo, right? So at 24 weeks with sotaltercep, the bleeding events were 20%. In the treatment, placebo was 10%. So there's a delta of 10%, right? I think you have to look at it at a placebo-adjusted rate. Okay. Makes sense. So I think the, correct me if I'm wrong, or if you think of this differently, but it feels like the better safety profile is maybe the, like a safer sotaltercep is maybe where the more compelling, when we talk to KOLs, as opposed to a more effect, more efficacy, something that's safer is what I think really is resonating with KOLs. So I'm wondering if you agree with that or not agree. I think today that is indeed the case. Okay, right? They were delighted with the efficacy of sotatercept. But remember, okay, it's only a small percentage of the patients that had a delay in progression. Okay, right? 70% of the patients still progressed. So there's opportunity there, we believe. But the efficacy profile is good enough that if you had another drug that was same efficacy with a better safety profile, it will be the drug of choice for these physicians 'cause they're concerned about the safety at this point in time. I guess that's where my question was sort of, do you think you need to have sort of, obviously relative to placebo, like a clean safety profile, or can you still have a little bit of some of these events? As I think where people are wondering, like, how much does it just have to be better or does it have to almost be like none of these adverse events as people think about the profile relative to sotaltercep? Well, I think that's hard to say, right? Because the problem is it's a small study. In a small study, there is always a conspiracy of numbers. Sometimes things just don't work out in your favor. Okay? So you could see a numerically larger number in the treatment arm, but it's within the noise of the system. I'll just throw out numbers for the sake of it. It was 10% in the placebo in sotaltercep and 20% at 24 weeks. What if that 10% goes to 15% and now you see in the treatment 18%? Is that different? No, it's not. Okay? And I think where you also see is that with time, that window increased. So it's 20 and 10 at 24 weeks, at 32 weeks it became 30 and 10, and it continues for a year. Okay? So as we continue to monitor those patients in the open label extension, we'll see, is the window getting bigger? And if the window isn't getting bigger, then I think that is refutable support for a better safety profile. Okay. So one more question on 012, then I'll turn it to Danielle for the other assets. But just in terms of the label, your thoughts around moving beyond this indication. So we see obviously sotaltercep and others are looking at, you know, Group 3 PAH. Just your thoughts, obviously you're sort of constrained capital in terms of what you can maybe do more from a mechanistic perspective of what you'd want to pursue this product in. Are there other indications that you think could be compelling to go after? I think on one extreme, it's heart failure. But that's a completely different set of physicians that treat. It's a completely different commercial opportunity. It's not one that a biotech company like us can ever optimize. But the good news there is that we have multiple molecules that have similar profile and yet are different at amino acid sequence level. So at some point, somebody could come to us and say they want a partner. So we can deal with that situation. I think moving to earlier and earlier patients and keeping them on treatment is one in PH, moving to the group three, but also moving to perhaps IPF, right? Fibrotic lung disease, because many of the features that you see in PH are also the features there. And I think there's some of the competitive data that's coming out is very encouraging. Pliant, they're inhibiting an integrin and thereby preventing activation of TGF-beta. That's SMAD 2/3 signaling. Wherever TGF-beta is at work, activin is there. Therefore, okay, right? What you're seeing with that is a potential for sotatercept as well. Okay, right? So I think if the capital was available, there's lots of other indications that you can think about in lung diseases all the way through to IPF. Okay. All right. Danielle? Yeah, great. So maybe shifting gears to elritercept a little bit. Yeah, as we discussed, it's, you know, actually further along than sotatercept. So maybe could you discuss the data to date here, in both MDS and MF, and maybe kind of frame it among the other competitors here like luspatercept or something like that? Okay. So elritercept, we've been sharing data for a few years now. And our thesis was right from day one is that elritercept acts on all stages of erythropoiesis and thrombopoiesis. Therefore, it should be able to treat a broad patient population, RS, non-RS, and those in their early stages of their disease journey, as well as those that are more advanced where they have a more compromised bone marrow that is less able to maintain hematopoiesis. And I think what we have demonstrated to date, activity in RS and non-RS, we've shown responses in low transfusion burden patients, non-transfused patients, but importantly, in patients that have a greater disease burden, those that have a high transfusion burden, we have demonstrated a response rate of in the 40s, whereas luspatercept has a 20% response rate there. So it's a much better response rate there. In addition, we've demonstrated a more durable response in these harder to treat patients. At the last data cutoff, we had more than half the patients still on treatment with more than a year of treatment. With Luspatercept, the median duration of treatment was 30 weeks, driven primarily by the low transfusion burden patients. We hadn't reached the median duration of treatment. If everybody had dropped out immediately after the last data cutoff, it's gonna be greater than 52 weeks, right? So I think it's showing to you that more durable response because it's able to treat that bone marrow that is more, has a greater disease burden. And you see that in our baseline characteristics where we have patients that have multilineage dysplasia. They have anemia, they have thrombocytopenia, whereas most of the patients in MEDALIST were just anemic. So I think you're seeing that. And then the third point I would make is that Luspatercept provides transfusion independence. But patients feel fatigued. Some of them feel very fatigued on Luspatercept to the point where the medical reviewer in MEDALIST noted it in the medical reviews and therefore recommended against approval. But it is a common thing that we hear from physicians. The patient is on Luspatercept, they don't feel great, they're feeling fatigued, they wanna come off. And yet the physician knows that keeping that transfusions, reducing the transfusion burden is good for them. And so it's a tug of war, okay, between the patient and the physician. We have demonstrated that Elritercept actually reduces fatigue. And we see that in patients pretty quickly. And we see it in patients that don't even get transfusion independent because their bone marrow is incapable of mounting an erythroid response. So we've seen that. Great. Oh, thank you. We saw that you announced that you're presenting three abstracts at ASH next month. Maybe if you could kind of go into what we should be looking for from these data sets. So I think the data is very mature at this point in time. We shared earlier this year that we had had discussions with the regulators, FDA, and we were moving to phase three. So with that, we stopped additional recruitment of patients into the trial. So you're gonna continue to see data from the patients that are in the trial. Maybe there's a handful of additional patients, but it ain't many. So what's the focus? The focus really is on that durability of response. We had not reached the median duration of treatment. We wanna look at that. And then the other thing that we wanna look at is this quality of life. We were seeing improvements in fatigue score, passive fatigue. And it's more than a dozen questions where you're asked how well you can do normal activities. So we're gonna dig more deeply into that. And then in the non-transfused patients, we have not shared what the changes in hemoglobin levels are, platelets, et cetera, et cetera. We're gonna share that with you because we think that in those patients that are early on in their disease where they respond to ESAs and luspatercept, they're gonna respond equally as well with elritercept, but they're gonna remain on it longer, okay, whereas their disease progresses even into where Rytelo takes over. So we think, okay, right, there's an opportunity. And so showing that data is important at this meeting. And then in myelofibrosis, we're gonna continue to add to the data that we had at EHA where we show amelioration of the anemia and thrombocytopenia and showed that some of the patients are actually getting a reduction in spleen size as well as a reduction in symptom score. And we continue to see that trend? If we are, then really in 2025, we will have enough patients with 24 weeks of treatment to make the decision to engage with the regulators on treatment of myelofibrosis as opposed to treatment of the symptoms of myelofibrosis and of the treatments of myelofibrosis Rux, which is anemia and thrombocytopenia. Okay, great. We don't have too much time, but I do wanna touch on 065 briefly if we can. Maybe if you could discuss the current status of the phase one trial and maybe like exactly like what data should we be expecting in the first quarter of next year? Yeah, we are moving forward with the phase one trial. We are in the MAD, and we announced a little while ago that we're dosing at two mg per kg, and then there's additional cohorts, but we have said that we will have data readout in the first quarter of 2025. And what can you anticipate? I think what I wanna demonstrate is an increase in muscle lean mass, a decrease in fat mass. It's a short-term treatment in the MAD of three months. You're not gonna see reductions in body weight. Mechanism of these kind of drugs is that you're putting on muscle, which then burns off fat. So initially, you're actually going to put on weight. And in small studies, you're not gonna see a difference, okay, right? So I think you have to look at directionally, are we seeing changes in lean upwards, decreases in fat? Previously, with molecules like this in postmenopausal women, we have demonstrated both at Acceleron and at Keros that you get improvements in bone mineral density. This is a study in men of 18-55, BMI in the range of 27-33. I don't know whether we'll be able to demonstrate that, but we'll be looking for that as well. I think given what we've seen with semaglutide updated label where there's increased fracture rate there, what we heard in the last 24-48 hours about Amgen and so on, I think a drug that can improve lean mass, reduce fat mass, and potentially improve bone health, it is unique. I think that makes it exciting. So maybe just one last question I could get in the last, you know, 30, 40 seconds here, and it's gonna take longer to answer than that, but just your vision. You have a lot of different programs going on. You're still a relatively small company. What's your plan in terms of are these things Keros is looking to commercialize going forward, or what are the decision points on what you might do with these going forward? I think obesity we cannot commercialize, right? It would be delusional for me to tell you that we can commercialize that because it's the outcomes, and those require very large studies. Therefore, an awful lot of capital. We can commercialize hematology, we can commercialize PH. I think we've brought clarity on the MDS, what the potential is. I think over the next six months, we're gonna get to clarity on MF. For a partner that might be interested in MDS and MF, we're gonna have that clarity. It's possible to partner that. Similar, in the same timeframe, we're gonna get the data from sotatercept. This puts us in a unique position to be able to partner an asset, bring in capital that we can then plow back into the rest of the pipeline, including things that we haven't talked about. You know, as you will recall, with 065, we did talk about the potential of it in neuromuscular indication. I think the Scholar Rock recently has got investors excited about those neuromuscular indications, which I've always believed are really something that these approaches can provide benefit to those patients. That's something that we could commercialize on our own as well. Okay. The vision hasn't changed from the day I thought about the company, which is we're gonna be a commercial company. But knowing that pathway takes you into lots of different area therapeutically, we cannot be a company that develops every single therapeutic area on our own. Some of these are partnership opportunities. Okay. And at the end of the day, it's always about partner. Do they share the vision for the drug with you? And then it comes down to economics. Okay. All right, great. Congrats on all the progress. Obviously, an exciting year ahead for you, and we look forward to following.