SVB Leerink 10th Annual Global Healthcare Conference

Feb 24, 2021

All right. Good afternoon, everyone. Thanks for joining us here at the SBB Leerink Global Healthcare Conference. My name is Tom Smith. I'm 1 of the senior biotech analysts here at SVB Leerink and happy to welcome our next company to the virtual stage, Caris Therapeutics and their CEO, Jaz Siro. Jaz, thanks so much for joining us. Appreciate it. Thanks, Tom, okay, for that introduction and thank you for giving us the opportunity to present the exciting story of Keyros. Cheers. So just before we jump into it, just a quick reminder for the audience here. If you have any questions for Caros, you can either ask them via the webcast portal or you can send them directly to me via email. And with that out of the way, Jazz, I think you have a couple slides you're use to give us an overview of the company and then we'll jump right into Q and A. Okay. Thank you, Tom. So before I go into the slides, okay, the usual disclaimer about forward looking statements. And what I'm going to tell you, okay, that Keyros is harnessing the powerful biology of the TGF beta superfamily. We are a clinical stage company, okay, that targets the TGF beta superfamily to develop novel therapeutics. And what's really exciting about this biology is that this has been validated with marketed products. Infuse, a bone morphogenetic protein 2 for spidinal fusion and Reblazole, okay, a modified active for treatment of anemia in beta thalassemia as well as in myelodysplastic syndrome. And really what we are able to do at Kyros is that we're able to leverage our extensive experience in the TGF beta superfamily, knowing the structures of these protein, their function and couple that with protein engineering to generate a clinical pipeline of differentiated products. So you see, okay, right, the first 3 product candidates on this slide, 50 is a modified active interceptor 2a ligand trap. And it's designed to address ineffective amatopoiesis by modulating this pathway. And based upon our Phase 1 data, we believe that it has the potential to correct multiple cytopenias in patients with ineffective hematopoiesis that includes MDS and myelofibrosis. Our second product is a small molecule kinase inhibitor targeting another member of the TGF beta superfamily, active receptor like kinase 2. And this is being developed for treatment of anemias where iron imbalance is the underlying cause. And that includes rare genetic diseases such as iron refractory iron deficiency anemia to the broad indication of iron deficiency anemia, which includes chronic inflammation in there. And then there is the opportunity for the same molecule in a very rare genetic disease called fibrodysplasia, ossugen, where following injuries skeletal muscle and tendons turn to bone. And we'll be starting Phase 2 studies with this program in 2021. And then lastly, okay, right, a preclinical asset that will be entering the clinic later. Another active in receptor ligand trapped that is being developed for treatment of disorders associated with bone loss and pulmonary to hypertension. And I think what you see here, okay, is the unique position that Keyros is in, where our discovery pipeline is yielding us multiple product candidates and we'll continue to build the pipeline in bone, muscle and pulmonary diseases. So this is a pipeline that is shown on a chart. Okay. Right. And you can see that 50 has completed its Phase 1 studies. It's in its 1st Phase 2 study in MDS patients and will report the initial data in mid-twenty 21. And we're also starting the Phase 2 study in myelofibrosis this year. And then 47, which completed its Phase 1 towards the end of last year, we'll be initiating 2 Phase 2 trials, 1 in IDA and the other in ARIDA in 2021. And then lastly, 12 will enter the clinic in the second half of 20 21. So you see a nice progression of assets, okay, advancing through the pipeline and new ones coming in to fill that pipeline. And the anticipated milestones are shown on this slide, where we will be announcing the initial data from our Phase II trial in MDS with 50 in middle of the year and then starting that myelofibrosis study in 2021. The 2 Phase 2 trials with 0.47 in 2021 and we'll be presenting data from the 12 at PAH at a major conference in 2021 and starting the clinical trial in the second half of 20 21. So with that, I want to thank you, okay, for the opportunity and leave it to you, Tom. Great. Thanks, Jazz. Really nice overview. Just and you alluded to the mechanism, I want to start with the mechanism for CAR 50 and you talked about it a little bit, but maybe if you could just go into a little bit more detail around differentiation between 50 and say luspatercept and sotadircept, the other ligand traps that most investors are familiar with? Yes. So I think all 3 molecules are derived from the active N receptors. The difference is that luspaterocept, the approved product is derived from active end receptor 2b with a single mutation in that that actually renders it incapable of binding to 1 ligand active in A. So TAROCEF binds to multiple ligands active in A, active in B, GDF8, GDF11 and those have all been published either in peer reviewed journals or alternatively in the patents from Exelon. So the difference between sotatercept and luspatercept is that luspatercept does not bind active NA. KER-fifty binds all the same ligands that Sotelisib does, active in A, active in B, in GDF-eight and GDF-eleven. And therefore, it has some of the same biology that has been observed with Sotatercept. Sotarosap, based upon both preclinical and clinical studies that have been published, increases bone mineral density as well as increases red blood cell. Lispetercept according to all of the published work only increases red blood cells, does not have effects on the bone axis. 50 actually increases red blood cells, increases bone mineral density and reduces fibrosis. And you see begin to see some of the impact, okay, of that, that it is indeed cause increasing red blood cells in healthy volunteer studies, but also increasing platelets. And that's because there is an interplay talk, okay, right, that's ongoing in the bone marrow, but in red blood cells and platelet precursors, a megakaryocyte. So O5O is the 1st molecule that has demonstrated increases in platelets in healthy volunteers. And we think this really could be a meaningful differentiation for 50 whereby in MDS patients in the low risk to intermediate risk for developing to AML. 90% of those patients are anemic, but 30% to 40% of those patients have low platelets and or low neutrophils. So they're thrombocytopenic or neutropenic. And therefore an agent that works on multiple lineages has the potential, okay, right to correct the cytopenias that are in those patients. And some of the first line treatments in MDS are in fact the hypermetallic agents such as azacitidine, okay, right. They actually cause they relieve the anemia, but they cause thrombocytopenia. Therefore, there is a significant unmet need for a molecule that actually does treat the thrombocytopenia in patients. So we think that's a real advantage. And then sort of thinking about it in myelofibrosis. In myelofibrosis is the primary defect in the JAK STAT pathway results in actually overproduction of megakaryocyte precursors that failed to develop to platelets. And those megakaryocyte precursors breakdown, cause inflammation in the bone marrow and set off that vicious cycle where you don't get red blood cells, you don't get platelets and then eventually you end up with extra medullary hematopoiesis. Hematopoiesis in the spleen, which then causes all of the other symptoms, right. And JAK inhibitors really only treat, okay, right, the symptoms okay, right. They're not disease modifying. So if you could actually allow those megakaryocyte precursors to mature all the way to platelets, you actually reduce the inflammatory signals in the bone marrow. Therefore, there's a potential you could reduce the fibrosis and therefore opioid rights start having a disease modifying role. That to me is very, very exciting. And I think that's how 50 gets differentiated from other molecules, okay, right, that are from of similar lineage. Okay. Yes. No, I appreciate that the distinction there. And I guess if we could I'd like to go through the Phase 1 data in a little bit of detail, but if we could maybe focus on the erythropoiesis pathway. And 1 of the potential benefits here is you're acting earlier in the pathway. You think about potential application of that, perhaps you see a broader impact or an impact on anemia in a broader segment of the population. What clinical data, Jazz, or what preclinical data do you have that gives you confidence that 50 is actually acting on the earlier parts of the erythropoiesis pathway? And then similarly, how is that differentiated from either sotadocep or luspatercept? Yes. I think, okay, right, it's sporadic or small pieces of data that will give you that confidence. Okay. The first 1, okay, right, is actually the preclinical data where, okay, right, mechanistically you see what's going on. And what you see is the treatment from a single dose of 50 results in rapid increases in red blood cells. And remember that in the journey of a common myeloid cell, okay, all the way to a red blood cell, in humans that takes 21 to 28 days, whereas in rodents, it takes about 7 to 10 days. Therefore, if you see increases very, very quickly, that means that you're actually accelerating the progression of precursor cells that were already almost completing their journey. So preclinically, we see those increases as early as 12 hours. We've only looked at 12 hours. We haven't looked any earlier, but we see those increases. That means, okay, the red blood cells almost completed their journey. But then we continue to see that increase through day 14 that we published in our ASH presentation. And when you then look at the clinical data, you see the same thing, right, that you see that there are increases on day 2 in hemoglobin levels, red blood cells and radiculostat and those increases then continue. Now the Cmax of the drug in our Phase I study is achieved on day 4. So on day 4, you've got the maximum concentration of the drug. And then by day 15, where the drug levels have gone significantly lower because of the half life of the drug being 12 days, right, you still continue to see increases. In fact, those increases are occurring through day 29. And if you look carefully at the data that I've done, you see, okay, that some of the participants in that study had increased it through day 42. That means that our cells, okay, that are coming out into the bloodstream that started their journey 21, 28 days earlier because by that point, there's no drug on board. So that really does fit, okay, the preclinical data that you're acting at all stages of erythropoiesis. Furthermore, we've seen, okay, right, that with O5O, we get increases in erythropoietin in circulation in rodents. And that again means that you're helping assist okay, those cells at the earlier stages, which is being committed to go down that early. So I think that all of that data tells me that there is potential, okay, of this molecule to be working at multiple stages. And in patients with ineffective erythropoiesis, they are heterogeneous population. They don't have interruption of these pathways at 1 spot. Okay. Right. Otherwise, they would all be very, very homogeneous. And therefore, you would get a treatment, okay, right, where everybody is responding. And as a consequence, okay, I think of it as well, you have the potential where Revolut showed really nice data, okay, right, and with respect to increases in a small subset of the MDS patients, these RS patients, and they've got a response of roughly 40%. Why aren't the other patients responding? They must have other okay, right, perturbations in the pathway that are preventing the maturation of red blood cell. So I think given what we've seen, given the broad mechanism, there is a potential that we can treat RS, non RS and perhaps even have a different response rate. Okay. Yes. No, I appreciate those comments. I guess shifting to the Phase 1 results and maybe the Phase 2 study design here where you're going to have initial dose escalation data in MDS patients in kind of mid-twenty 21. If you could talk a little bit about how you're thinking about dosing and then a little bit about the design of this dose ranging study and some expectations ahead of the initial data cut, how many patients, potentially how many dose levels? Obviously, you're still running the study and collecting the data, but what's your sense for what investors should expect ahead of this data readout? Yes. So we haven't actually shared what our starting dose is, okay, right. But I think if you go back, okay, to our Phase 1 study where the lowest dose in the SAD that we detected drug in circulation was the 0.5 mgs per kg. And then the lowest drug that we tested in the MAD was 0.7. That gives you sort of the range, okay, right, for the starting dose, okay, right. We know that at those doses, we got some increases, okay, right, in reticulocytes and increases in red blood cells. Therefore, we were getting target engagement. So think of those sort of 2 numbers as sort of the starting dose. And then after that, okay, right, dose escalation is very simple. It's the usual, okay, the Fibonacci design of a study. So it's the first 1, okay, number is 1, 2, 3, 5. So your dose escalating, okay, right, where the next dose after the first 1 will be double, okay, right. And the next 1 is triple and so on. So we have 4 cohorts planned in the dose escalation. It's an open label study where there are 6 participants in each dose level, 3 RS, 3 non RS. And based upon the safety data, you'll escalate to the next dose. And in the RS in each cohort, the patients will receive 4 doses at 28 days interval over a 3 month period and then be followed for another 3 months. So that's what we the study is designed and what we're looking for in Part 1 of that study, okay, right, which is dose escalation, we're looking for signals of activity. Does this drug okay show changes in red blood cell brand? Does this drug show changes in platelets? Okay. Right. So that's the lowest level. Okay. And then when you start thinking about beyond that, how or how durable is that effect? Okay. Right. Is it a few weeks? Is it a month? Is it 2 months? Okay. Right. Because then that starts giving you information about how you're going to treat the patients. Okay. Is it monthly dosing? Is it less frequent? We believe based upon our Phase 1 data that we can dose on a monthly schedule. Kuvi's dose okay on a less frequent schedule based upon the mechanism. We don't know. We have to find that out in the patient. Then what are the doses at which we see begin to see responses in RS versus non RS? Are they different? Okay, right. And then these are patients, they are okay, right, or already have the disease. Some of them would not have seen any would not have received any transfusion, but others would have received transfusion. What about those that have received transfusion? Are you seeing, okay, the same signals of activity on the red blood cell on the platelet access, right? And if you are seeing those, okay, right, are some of them having to skip, okay, right, the transfusion, put that on. So you're going to get a lot of data, but it's going to be a little bits of data, okay, right? Because you're going to get some patients responding, others, okay, right. And that gives you clues about how you want to start thinking about your Part 2, which is the dose confirmations of the study where you have a larger number of patients. So you start to get experience with in terms of what your response rates are and also, okay, right, you're treating now in your open label extension and you're getting your experience as to what the durability of the effects are. Right. Okay. Yes, that's really helpful. Just in terms of patient numbers, Jazz, and understand that you're still enrolling the study and you don't have perfect visibility into that, but it is an open label study. Like what's a reasonable expectation for number of patients at this initial data cut? Tom, we haven't shared that, okay, right. But what I would tell you, okay, right, is that we started the study in the second half of last year. And as you as I just shared, okay, the actual treatment period of the study and follow-up is 6 months. But prior to being dosed, okay, the patients have to be followed for 2 months so that you get the baseline characteristics for the hematology parameter. So the patients are in the study essentially 8 months. So you can imagine, here we are in February, we are moving on this. I can't tell you how many patients we'll have. But I think what I can tell you is we're progressing along that study, okay? It is an open level study, so we'll share the first of the data in mid year, but we'll continue to give additional updates, okay, right as we get more data. Okay. Okay. I appreciate that. Maybe we can talk, you mentioned also initiating the study for 50 in myelofibrosis. Maybe if you can talk to a sense of timing for kicking that off, trial design and then what you're looking for in terms of initial signals within the MF population, how that compares to MDS? Yes. So I think, first of all, okay, right, we'll be starting that study this year, okay, right. We haven't given any more guidance than that, nor have we shared the design of the study, okay, right. But I think previous okay programs have actually hinted at what that study is going to look like. It's going to be a study as a monotherapy in myelofibrosis patients as well as those that are on JAK inhibitors. And again, here, the ability to modulate platelets could be a real, real advantage for us. So in those patients, okay, right, it's going to have to be a longer treatment, okay, right, Probably 6 months and longer, okay, right. And then what you're looking for is, are you correcting the anemia? Are you actually correcting the thrombocytopenia in those patients, okay, right. And then as you progress, okay, right. What are the impacts on the bone marrow, okay, right there. And 1 of the things, okay, that happens in these patients, okay, right, is that as the abnormal bone marrow is expanding, the inflammatory signals are actually causing bone resorption, okay, right. So you get osteosoriasis. Do you okay right now begin to see okay reduction in that? You can follow that through bone biomarkers and so on. Okay, right. So we'll be looking at all of that. And I think that's where okay, right, returning that bone marrow to a more normal state has the potential, okay, right, to have a disease modifying properties to the molecule. Okay. Yes. I mean, certainly a lot of I think a lot of potential as a pancytopenia agent, particularly within MF. And so, yes, we'll be interested to see what the initial signals look like. Maybe I want to be conscious of time and make sure that we get through you guys have a number of programs, KAR-forty 7, your ALK2 inhibitor. Maybe if you can talk a little bit about the plans here in IDA and ARIDTA? And I guess also putting it in context with the Phase 1 data that you announced late last year, do you feel like you need further dose ranging here or just kind of walk us through what the how you're thinking about positioning 47 within these initial indications? Yes. So I think they looked Phase 1 data was really exciting data because for me, seeing the biology once again translate from rodents to humans is really exciting. And our Phase 1 data really showed, okay, right, that you can inhibit ALK-two as a consequence of inhibition, you get reductions in hepcidin, the master regulator of our eye and immediately you begin to see changes in serum, increases in serum. So you're mobilizing that. But then what was even more satisfying is that that iron is available for incorporation into red blood cells where we saw increases in hemoglobin content of reticosat, the newly minted red blood cells that are found in circulation. So that was all very exciting. Okay, right. So in our multiple ascending dose, our lowest dose was 50 mg dose. And even at the 50 mg dose, we saw decreases in hepcidin from that treatment. And these are normal healthy individuals. They already have low hepcidin, okay. And yet we saw decreases in that hepcidin. So as we think about going into the RADA into the iron deficiency anemia, some of these patients are going to have much higher levels of hepcidin. So when you have high hepcidin, okay, right, do you actually get a bigger response? Do you actually need lower doses, okay, of the drug? So in some ways, okay, right, knowing, okay, that we have seen changes at 50 tells you you've got target engagement and you're initiating all of the downstream biology. So I think, okay, right, exploring lower doses in patients that have high hepcidin is warranted for those reasons because you may end up, okay, right, seeing a similar or bigger effects in patients even at lower doses. And as you well know, the lower your dose, okay, right, the better okay, right, in the long run-in terms of safety observation. So I think it is warranted that we explore a lower dose, okay, right, in the patient. How many doses, okay, right, I'm not sure, okay, that we need to explore too many doses there. So it is likely, okay, that in the RIDA patients that will do a open label study, okay, right, similar sort of in concept to the MDS study where you look at dose escalation, so that you can see changes in these red bars of family in a patient population that have high upside. And that then actually sort of feeds into what we do in the IDA as well. Okay. Okay. That makes sense. Maybe if we could switch gears just quickly on CAR-twelve. It's a compound I've been getting increasing number of inbound questions around and we've seen some of the success with sotatercept in PAH. I think there's obviously increasing enthusiasm around that approach. Maybe if you could just kind of walk us through how 012 is differentiated versus sotatercept? And you've talked about, I guess, filing an IND for 12 later this year, maybe how you're thinking about the initial clinical approach here? Yes. So look, 12 is based upon the activin receptor 2b, whereas sotatercept is based upon the active in receptor 2a. And that doesn't mean too much, okay, right. It's just they have different origins, okay, right. But I think where, okay, right, there is a difference is that when we were trying to come up with another molecule, we were looking for a molecule that would increase bone mineral density without increasing red blood cells. Sotatercept has demonstrated both in preclinically as well as clinically that increases bone mineral density, but also increases red blood cells. And in fact, okay, right, the clinical development of that program was that in Phase 1 study, okay, right, it was looking at bone as well as red blood cells. And the red blood cell effects was large enough, okay, right, that it became an anemia drug. More recently, it's pivoted to PAH because the biology suggests that could have a benefit. But I think and that's where the excitement is because Exelon did a really nice job of demonstrating the role of TGF beta signaling in PAH. But there is a limitation to the sotatercept. And in their Phase 2 study, they showed, okay, really nice response in terms of the 6 minute walk test, the PVR, which is catalyzing their progression to a Phase 3 study, but they also saw increases in hemoglobin content, okay, right, in red blood And that increase at the higher dose, the highest dose, the 0.7 was 1.5 grams per deciliter, a mean change of 1.5 grams per deciliter. And their lead, okay, right, clinician investigator did say that she wants to use the higher dose. But I'd ask the question, what about patients, okay, right, that may need a higher dose? Could you dose them, okay, right, higher, not with sotatercept? And that I think is where, 12 has the advantage, okay, that it does not have that effect on red blood cell axis. And we were looking for a molecule from day 1 that would have the effects of sotatercept on bone axis without the red blood cell. And we published that data at ASPMR in September with respect to the bone and then in the updated S1, we shared, okay, that we're seeing the activity in the PAH model. So this makes me very excited. And I think given, okay, that we've got multiple indications that we could eventually go into, again, warrants, okay, us going into a healthy volunteer study, all right, establishing what are the safe doses, okay, and the efficacious dose. The thing here is by having that effect on bone axis, we can measure that. We can measure that to bone biomarkers, right, in circulation. We can measure that to imaging techniques and so on. So you can actually get a feel for what the drug is doing pharmacologically as well as determining the safety. Okay. Right. And then that allows you to pivot in all the indications that you want to go in. PAH, okay, right, bone indications such as osteogenesis imperfecta. Got it. Got it. And so, yes, we'll be looking for those initial early signals, it sounds like probably at some point in 2022. All right, Jack. Well, look, we're unfortunately, we're up against the time here. But thank you so much for spending the time sharing your insights and we'll stay tuned here. Certainly, a lot of interest ahead of the initial MDS data coming up in mid-twenty 21. Thank you everybody for joining us and hope everyone has a great rest of the day. Thank you, Tom, for the opportunity. Appreciate it.