Jefferies 2021 Virtual Healthcare Conference

Jun 1, 2021

Hi, everyone. This is Yiyoon Yang, a biotech analyst at Jefferies. This is my pleasure to host a fireside chat with the Jialis Lazira, Chief Executive Officer of Keros at the Jefferies Vertura Healthcare Conference. So as a reminder, Joss will be taking questions from the audience later, so feel free to type any question you might have in the box under the video. So before we go into Q and A, Joss is going to give a quick overview, and then we'll give Q and A. Joss? Sure. Thank you, Yun. Thanks for this opportunity to have this discussion. As you know, okay, VACYROS is a developing therapy that targets the TGF beta pathway and we shared open 3 product candidates, KR-fifty in MDS and myelofibrosis, 47 in diseases where iron imbalance leads to failure to incorporate iron into hemoglobin and results in anemia. And then, 12 for treatment of bone disorders and PAH. So all 3 programs are on schedule as we've highlighted before in our filings and shared with investors. I think when I look at the preceding 5 months of 2021, I think the highlights of the year so far and be we've had multiple presentations and multiple meetings starting with the European School of Hematology. We'll have some presentations at EHA. We also had the presentation at the American Thoracic Society. And importantly for us, our foundational patent on the active immune receptors was issued. So it really provide us with a very, very strong scientific and operational stance, okay, going into the remainder of the year. And with that, I'll hand it back to you. Great. Thank you. So let's just start with a kind of a big picture question on TGF beta pathway. So you are developing potentially to initiate the product compared to Acceleron but targeting the same biological pathway. So aside from the different ligand binding properties, can you talk about how tariffs approach and know how would it be differentiated from accelerant's approach? Yes. Look, I think Acceleron's approach has really highlighted the translation of biology from lower species to higher species. They've got approved product, the REBLISIL, which is approved for treatment of anemia in MDS patients that are ring syndrome blast positive. I think the early biology with O5O shows that it not only has the impact on red blood cell production, but it is a drug that targets immunities, including platelets. So it is having an effect on the myeloid immunities and for us, okay, that's very, very exciting. Furthermore, when we look at just the lysopoiesis, Reblisil, which has been shown to have the effect on the thermal stages of differentiation, whereas 50, we've now continued to provide additional data in 2020 as well as in 2021 that it actually impacts all stages of erythropoiesis. And that, I think, gives us reasons to believe that it could work in correcting anemia in patients that are ring sicklebras as well as those that are non ring sicklebras. I think that's where the differentiation can come. It can come, okay, at the number of different levels. First of all, we're going to be treating the patients on a monthly basis. So 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. Then of course, it's ring syndrome glass versus non ring syndrome glass. Do we have the activity in both sets of patients? And that's the next level of differentiation. And then on the platelets, that's the 3rd level of differentiation. So we've got multiple opportunities to differentiate 50 from the approved reversal. Okay. So obviously, the focus is on the Phase II data, initial data for 50 expected by the end of June. So as you pointed out, there are multiple levels of differentiation that you can potentially show. So this is 1 of the 2 low dose in the cohort data, 0.75 milligram per KEGG and then 1.5. So maybe, Joss, you can talk about it's monthly dosing, but at the same time, in current Phase IIII, you have 3 additional months of follow-up after the last dose to see if you can potentially dose even lesser frequently than monthly. So can you talk about I mean, although you may not able to talk about much on what we should expect, But from those 3 key differentiating points, can you give us kind of data that you have in healthy volunteers as well as treatment and co data to support your confidence in perhaps a product to differentiate from Revozu? Yes. So you're absolutely right. Okay. We're going to be sharing data from the first 2 cohorts to the 0.7 and the 1 5 mgkg dose. And we're in the currently in the 1.5 mgkg dose. So I think the first thing is that the 0.7 mg per dose was deemed to be saved by the SRC, allowed us to dose escalate. And 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 platelet. So 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? Because then that it tells us that we have a drug that's working. And it's all about finding the right dose level at that point. So 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? And 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, right, where they don't have any significant disease or inflammation. Whereas here, these patients are very heterogeneous. So there's going to be patients that are ringed central blast, those that don't have ringed central blast. And 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. So 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, right. And the first 1 of those is indeed reticulocytes. Can you see changes in reticulocytes? And if you are, that's saying that the drug is trying to do something in those patients. And then 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, it's still functioning enough that they're making red blood cells. So do you see an increase in reticulocytes that lead to an increase in hemoglobin. And what is the magnitude of that change? So that's 1 level. And then in patients that have had 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. So now do you see a change in your tickle site and does that tickle site increase then lead to either an increase in hemoglobin or maintenance of hemoglobin. And that would be a measure of early indicator of transfusion reduction or transfusion independent. So 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 population. And now it's a matter of what's the dose, okay, that's optimal for each patient population. And it could well be that the dose that's optimal for RS and the dose that's optimal for non harvest is different, okay, right? And so remember, okay, that this is a Phase 2 dose escalation study with the primary endpoint of safety. But because you can see changes in red blood cell and platelets rapidly, you're actually getting data about the response in these patients. Do you expect to see so okay, RS and non RS patients, okay, so you want to see the hematologic changes, but at the same time, next stage is determining what the optimal dose would be. But for patients on transfusion versus non transfusion patients, do you expect to see differences there as well in terms of the dosing potential dosing requirement? I don't know. Okay, right. I think, okay, right. 1 of the things, okay, that you can see from the data that was there with sotatercept and with the splotatercept, there were patients that did not have any transfusions that were pretty strong responders, okay, right, because it depends on where you are on the journey, right. I mean, when we talk about transfusion independent patients, those that haven't had any transfusion, they're still heterogeneous, okay, right? Those that you catch early on in the disease, those that you catch a little bit further along. So what is the response? Don't know, okay, right, how to characterize that. We have to see that, okay, right. And it may well be that some patients are responding at a lower dose and others require a higher dose. And that could be both for RS and non RS. After all, when you look at, okay, how Revolizole is being treated, they start at a lower dose with the dose escalation, okay, right, even in the RS patient. So you don't have to dose at the higher dose if the patient is responding. But I would suspect that as the patient progress in the disease, you're going to have to modify that dose. Okay. So earlier, Josh, you mentioned that currently, you are at 1.5 milligram dose, 2nd cohort in the trial. I don't know if you have disclosed, but we're now moving to the 3rd dose in the same cohort, which is at 2.25, right, Olibrand? Yes. So the next bill is okay, right? It will be determined by the SRC and it is following the Fibonacci rules, okay, whereby the first dose dose escalation is 2 times the first dose and then it's 3 times that for the next. So it should be 2.25 subject to the SRC modifying it. Okay. Right. They always have the ability to modify and that depends upon whether they consider it will be safe if they're seeing the response or not, okay, right? So there's always that modification, but 2.25 was what was planned as the next dose level subject to modification by an SRC. So when are you moving to that dosing cohort, start of the dosing cohort? We have not shared that. Okay. Right. But look, the study is ongoing. We'll progress, okay, to that dose level. And when it's considered to be if when it's considered to be safe, we'll move to that. And then if that's safe, okay, 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 this year. Okay. So then question to you is, you said it depends so initially, you said certain doses, but it depends on the safety profile before you move into the next dose. So let's just say, 1.5 is just safe and it's efficacious, so you're going to move on to the next dose. But then can you go above 2.25 milligram at a third of dosing? Yes, we could, okay. Yes, we could. Okay, right. Yes, look, this is a safety study, okay, 1st and foremost. So this is our opportunity to look at what is the maximum dose, okay, right, that we can go to where we see an effect, right? I mean, it could well be that you see a response in at different dose levels in different patients. And therefore, okay, right, you want to know what is the dose that you can go to if you need in order to treat a patient. So this is our opportunity to do that. And if there's no dose limiting talks, then you want to do that and go up as high as you can as long as it's safe, right, and you're not putting patients at risk, this is your opportunity to test that. I see. So let's just say you chose let's say, hypothetically, you choose a third of those in cohort as a 2.25 milligram, the next cohort is, I think, at 3.75. So if you see really good efficacy at 2.25, then do you feel that you need to go to the first dosing cohort or we can potentially stop before that? Yes. So you're really talking about starting Part 2. Okay, right. Okay, right. I think that's what you're asking. And the answer, okay, right to that is we have not shared that publicly. But 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. Doesn't mean, okay, that you have to wait for the entire data set from the highest dose in order to stop Part 2. But you should really try and find out, okay, the maximum information that you can get because it is highly likely that even in Part 2, you're not going to start everybody at the highest dose, okay? There is going to be some dose titration. Okay. So let's just say you found the Phase III dose. So when you start the Phase III, obviously, it's going to be sometime next year. Do you think that you would need to compare 50 to last quarter set? Or do you think you can compare placebo in Phase III? Yes, I think in the U. S, okay, right, it is likely, okay, 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, then I think certainly in Europe, okay, right, it is going to have to be a comparator arm, okay, right, there. I think in the U. S, it's not necessary. The FDA doesn't require it, but payers, okay, right, may want that. So we have to look at that. I think this is why our Phase 2 study is designed to really understand the drug. And therefore, our hope and desire is to go right from the beginning as a frontline therapy as opposed to having to do a comparator. So we're seeing activity in RS and non RS. We're seeing changes in platelets as well, okay, right. Then we design a Phase III study that is basically a frontline therapy, okay, right. And as you know, in the U. S, that is still a lithopoietin, okay, right. MDS patients get treated with is anemic with retropoietin. So it would be a placebo controlled study under those circumstances, but it might be also 1, okay, right, where you do it in comparison to support early days, okay, right. I think we need to see the data. Okay. So let's just say you have shown efficacy in RSV patients as well as upon RSV patients. Then would you actually run 2 different registrational trials of RS and non RS patients? Or it's going to be a combined 1 trial? I think we have not made a decision on that, Okura, as yet. But it behooves us to really look at a study that includes both groups so that you minimize, okay, the size of this study. I mean, if you go back and you look at the REBRISIL study, right, it basically has roughly speaking 300 patients in it. If you did a placebo controlled study in RS and non RS, a separate study, then potentially that could be, you'll get twice that side. On the other hand, if it's the same placebo group, okay, right, then okay, right, the study will be smaller than twice that size. I see. Okay. So this initial Phase 2 data coming out at the end of this month, it sounds like based on healthy volunteers' data, as well as the preclinical data, you seem quite confident that you as a show changes in histologic parameters. But in terms of dosing, we're dosing monthly. As I mentioned, you have additional 3 months of follow-up after the last dose. So do we be able to see your ability to dose less frequently than once and luckily in the initial data? Well, I think the first thing is, okay, is the data supportive of our decision to go on a monthly basis? That's the first thing. Okay, right. Then the second thing indeed is, as we continue to understand the drug in that follow-up period, okay, right. Are you able to dose less frequently than monthly, every 6 weeks or every 8 weeks? Because you want to do it on that 2 week cycle where patients are actually used to having 2 visits, okay, every 2 weeks. So we'll have to see what the data shows. It may well be that you will only get that, okay, right and at a higher dose. So you may not see it at the lowest doses and you may have to go to the higher dose to see that less frequency. I see. Okay. And then another activin receptor 12 in PAH, you have additional proof of data at ATS, and then you are moving into Phase 1 in second half of this year. So the Phase 1 initiation, is would that be in healthy volunteers? It will be healthy volunteer study. Yes. Okay. So there, we are looking for whether you have increases in number of levels of other cells in terms of safety? What should we look for in that Phase I study data? Yes. So look, I think we showed, okay, with the 50 beyond the hematologic changes, okay, right, changes in FSH and bone biomarkers, right? So remember, this is a drug that is going to target the same biology as sotatercept, but lacks okay, the red blood cell effect. So we can go into healthy volunteer studies postmenopausal women. We can look at changes in FSA and those changes in FSA will tell us how much target engagement we get. When you get a 50% reduction in FS8 in postmenopausal women, That is equivalent to 100% target engagement in terms of active in the pituitary. So that would really provide us with where we are in terms of target engagement as we dose Aeschylate. Furthermore, looking at bone biomarkers, which is a slower change, okay, right, that's a change, okay, that's as a result of kicking off the biology. And therefore, you'll see that over a period of time. The bone biomarkers also tell you what the changes in what the consequence of that target engagement are. So we have shared that we'll start the study in the second half of 20 21. And we'll share data from Part 1 of that study in the first half of 20 22. And what is first in Part 1? Part 1 is a single ascending dose, okay, right, a component of that. And we believe, okay, right, from that information would get an idea of where we are in terms of target engagement. We'll also be able to confirm that what we saw preclinically 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. And based upon all of the experience with multiple active receptor ligand traps, we feel confident that what we see in monkeys has a probability of success in humans. Okay. All right. And then you have a 047, so we have about a million, so can you talk about what should we expect with the 047? Yes. I mean, 047, okay, is the sleeping giant, okay, right, in some ways, because we never get to talk very much about it. But 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 those iron parameters that can lead to correction of anemia. I think what you will also see at the European Hematology Association meeting is an abstract that said that we have the potential to reverse ion overload in patients, and that's based upon the preclinical data where we created iron overload and treatment with an ALT-two inhibitor is able to reduce iron in liver and that abstract has been published. So you'll see data from that study at the European Hematology Association meeting. So I think, 0.47 continues to show the opportunities. We start the ARIDA and the IDA studies in the second half of this year. And they're going to be open label studies. So they'll start generating data once they've been started. Okay. Jos, our time is up. Thank you for the fireside chat, and we look forward to the data towards end of this month. Thank you very much for the opportunity. As always, pleasure talking to you. Thank you. Bye.