H.C. Wainwright Virtual Global Life Sciences Conference

Mar 9, 2021

Good afternoon, everyone, and thank you for joining the H. C. Wainwright 2021 Global Life Science Conference. My name is Andres Maldonado, and I'm an associate here at H. C. Wainwright. While we are virtual this year, we are confident we're going to be able to provide value to you with over 425 companies presenting at the conference as well as via your interactions through 1 on 1 meetings. H. C. Wainwright is a full service investment bank dedicated to providing corporate finance, strategic advisory and related services to public and private companies across a multitude of sectors and regions. We have a total of 18 publishing senior analysts with 4 93 companies across all sectors under our coverage. From a logistics standpoint, please make sure to reference your virtual conference online portal that provides your individual links to your meetings and all presentations. Panels and all presentations are live and on demand online March 9 through 10. With that said, I'd like you to have a productive and enjoyable day, and I'd like to introduce our presenter, CEO of Karos Therapeutics, Japsyr Sera, which is a company that specializes in the discovery, development, commercialization of novel treatments for patients suffering from hematologic and musculoskeletal disorders. Sir? Thank you, Andres. And thanks to the organizers for giving us the opportunity to present. So let me start with the usual disclaimer regarding forward looking statements that will be made in this presentation. Let me tell you about Curis. Curis is harnessing the powerful biology of the TTF beta superfamily. We're a clinical stage biopharmaceutical company that's developing these novel therapeutics that target the TGF beta superfamily. This approach has been validated with marketed products and Fuse for treatment of spinal fusion and Reblisor treatment of anemia in beta thalassemia and myelodysplastic syndrome. We're leveraging our extensive experience in the TGF beta superfamily structure and function and coupling that to our protein engineering experience to generate a pipeline of differentiated therapeutics. We're going to share with you 3 product candidates today. 50 is designed to address ineffective hematopoiesis by modulating the TGF beta superfamily and is being developed to treat multiple cytopenias in patients with MDS and myelofibrosis. Our second product candidate is actin receptor like kinase 2 inhibitor that's being developed for the treatment of anemia resulting from iron imbalance in patients including iron deficiency anemia patients and iron refractory iron deficiency anemia. And this treatment can also be used potentially in patients that have rare genetic disease called fibrodysplasia or gab progressiva. The biology on iron imbalance is also the biology that you see in anemia of chronic inflammation. Therefore, we think 47 has the potential to treat a broad range of patients, which is common underlying cause of iron imbalance. 12 is our preclinical candidate that is being developed for treatment of bone disorders as well as for pulmonary arterial hypertension. Our differentiated pipeline in hematology and musculoskeletal is shown on this slide, where you can see that our O5O has completed its Phase 1 study. We initiated the Phase 2 trial in MDS in second half of 20 20 and we'll be presenting the initial data from this study in mid-twenty 21. We're also starting the Phase 2 trial in myelofibrosis in this year and 2 trials with 47 in iron deficiency anemia as well as anemia from high hepcidin in the eryda will start in the second half of the year. And 12 will enter the clinic in the second half of the year. With that, let me move on to the most advanced program, O5OL, which is a novel treatment that addresses ineffective myelopoiesis in myelodysplastic syndromes as well as in myelofibrosis. So let me spend a few minutes talking about myelodysplastic syndromes. This is a hematologic malignancy that affects elderly patients. And as a consequence, these patients have multiple cytopenias. They have anemia, thrombocytopenia and neutropenia, all due to ineffective amylopoiesis. Roughly 15, 000 to 20, 000 patients with MDS are diagnosed each year in the U. S. And 90% of these patients are anemic and about half of them have thrombocytopenia. There are no treatments for thrombocytopenia. So all these patients can get are platelet transfusions. Anemia, there are treatments for anemia. They include red blood cell transfusions, erythropoiesis stimulating agents or ESAs and reblisor. ESAs only work at the early stages of red blood cell lineage. So as a common stem cell in the bone marrow takes its journey to be a red blood cell, erythropoietins work at the earliest stages. And in MDS patient, it only works in patients with low transfusion burden and low endogenous levels of EPO. Revluzole, which is approved for treatment of anemia in a subset of the MDS patient, those that have RINX syndrome loss, iron deposits in the red blood cell precursors in the bone marrow. And that represents roughly 15% to 20% of all MDS patients. And they have a defect in the terminal maturation of red blood cell. So cells that are in late in this development to completing their journey to be a red bushel. And in Phase 3 registration trial, it was shown that 38% of the RS patients responded to red bushel compared to 13% with placebo. And the benefit is similar to ESAs in low transfusion burden patient. So we believe that an agent, okay, that works throughout the erythropoiesis pathway has the potential to treat all patients with MDS and be differentiated as a consequence. Let me share with you what O5O is, it's a modified actin receptor 2 fusion protein. Activin receptors are expressed on hematopoietic cells and modulate the differentiation of these precursor cells. And O5O is a ligand trap composed of a modified extrasolar domain fused to the F3 region of an IgG. As a consequence, treatment with O5O increases red blood cells and platelets by inhibiting signaling through these ligands that act through these actin receptors. And in preclinical studies, we demonstrated that the increases in red blood cells arise by differentiation by modulating the differentiation at multiple stages of erythropoiesis. And we observed the similar changes in platelets, again, supporting action throughout thrombopoiesis pathway. Our Phase I study recapitulated what was observed in preclinical studies, and I'll share some of that data with you. So in preclinical studies, what we observed is that a single treatment results in a rapid increase in red blood cells. In fact, you can see these increases occur as early as 12 hours, which really argues, okay, that these cells were almost at the end stage in terms of completion their journey to being a red bursal. But then you see a sustained effect on erythropoiesis throughout 14 days, which is then consistent with acting at the earlier stages of erythropoiesis where you initiate that cascade of events that allows these cells to continue their journey all the way through being the red blood cell. Interestingly, we also observed increases in erythropoietin erythropoietin in circulation, about a 2 to 3 fold increase in erythropoietin. And therefore, O5O acts at all stages of erythropoietin, including those at the earlier stage of erythropoietin. We've completed our Phase I study and like all Phase I study, it was a safety study to look at safety, tolerability and PK. But we had multiple pharmacodynamic measures incorporated into the study to look for signals of activity. What we observed was that 50 drug levels were dose proportional with a mean half life of roughly 12 days. This half life of 12 days coupled with the pharmacodynamic effects observed in this study had the potential for monthly or less frequent dosing with this therapeutic. We observed that the drug was well tolerated to the highest dose level tested, which was 4.5 mgs per kg. And the only notable adverse event in this study was reversible mild hypertension and that was observed only in the subjects with roughly 3 grams per deciliter increase in hemoglobin, common to many agents that increase red blood cells. And this data some of this data is shown on this slide, where we saw that from a single subcutaneous administration, you see rapid increases in red blood cells. This is reticulocyte red blood cells and hemoglobin. I'm only showing the hemoglobin panel here. And this is consistent with accelerating the maturation of late stage precursors. What we also observed was this sustained increase through day 29. Important to recognize that the drug levels reach a maximum on day 4 and then after that with a half life of 12 days, the drug levels are declining in the course of 29 days. Yet, we see an increase. This can only be achieved because we initiated a cascade of events whereby cells early on in their journey were started on their path to be a red blood cell. And so we believe as a consequence of this that all 5 0 treatments will be infrequent. We also observed clinically meaningful increases in platelets. And here, okay, we observed 20 to 30 times 10 to the 9 changes in 9 cells per liter increases in platelets, which are clinically meaningful because these are the increases that you're looking for when patients are at high risk of blood or bleeding events, you're looking to see an increase with transfusions of 20 to 30x10 to the 9. And once again, what we see here is that we see a rapid increase in platelets and a sustained increase in platelet. So a mechanism that is mirroring what we observed in erythropoiesis. I already said that, so what's on this slide, so I'm not going to spend a lot of time on this. But I think what 5.0 does, it works at all stages. So that differentiates it all stages of erythropoiesis. Therefore, it differentiates it from agents that work at the early stages or at the terminal stages of red blood cell m actuation. And in addition, the platelet changes are also meaningful, clinically meaningful for O5O to be differentiated from other agents that only affect red blood cells. With this, we have initiated our Phase II trial in MDS patients. This is an open label Phase II trial in 2 parts, a dose escalation followed by a dose confirmation where we're looking for changes in hematology parameters in patients with MDS. So these are red blood cell parameters as well as in platelets. In this study, patients will receive 12 weeks of treatment. That's 4 doses at 28 day interval followed by a 12 week follow-up. And here we are evaluating all patients with MDS. So in the dose escalation, what we're looking to see is what are the doses at which RS patients respond and the non Rheincedroblast patients respond. And we will take those doses into the dose confirmation part of the study Part 2, where we'll increase the number of patients so that that study becomes the study that informs us about the design of our Phase 3 registration trial. In Part 1, we have equal number of rynxed roblasts and non ringcitroblast patients in this study. O5-0 is also a potential treatment for ineffective amylopoiesis in myelofibrosis and myelofibrosis is characterized by molecular abnormalities in the JAK STAT pathway. And these molecular abnormalities result in expansion of red blood cell and precursor that results in ineffective hematopoiesis. It is the accumulation of these megakaryocyte precursors that breakdown that results in inflammation in the bone marrow and subsequent bone marrow fibrosis and scarring. 50 increased both red blood cells and platelets by accelerating their development and we'll be starting a Phase 2 study in myelofibrosis in 2021. And we believe that potential to correct the hemolymphective amatopoiesis, helping those precursors to advance to platelets and thereby reduce the breakdown of those platelet precursors, which results in the inflammation and fibrosis, therefore reducing the inflammation of fibrosis. And in myelofibrosis, roughly 50% of the patients are anemic and are transfusion dependent and have thrombocytopenic. Furthermore, the current treatment, Jakafi, results in Grade 3 for anemia whereby the doses of Jakafi had to be adjusted. So being able to correct both the anemia and thrombocythemine has a potential for this therapy. In the remaining time, I want to talk about the other 2 programs, 47, which is a treatment for anemia, iron deficiency anemia, RADA, as well as for FOP. It is a small molecule kinase inhibitor that targets ALK2. It is high potency with low nanomolar IC50s. It's highly selective over other kinases, but also within the TGF beta superfamily, where it is selective against structurally similar receptors. And the PK ADM properties of the drug are suitable for once a day oral dosing. So let me tell you a little bit about ALK2 and its control of iron. ALK2 regulates hepcidin, which is the master regulator of iron homeostasis. And it is ALK2 signaling that controls this hepcidin expression. And excessive signaling through the ALK2 pathway results in high hepcidin and this hepcidin results in iron being locked up in storage tissue and not being available for incorporation into red blood cells and resulting anemia. ALK2 signal requires a number of components. It requires the ligands, the BMPs. It requires a co receptor for the action of BMPs. It is a tightly regulated system with feedback loop whereby when hepcidin levels increase, it results in increased expression of a regulatory protease on the cell surface called MT2. And this MT2 clears components of the signaling pathway, thereby reducing L2 signaling and hence reducing hepcidin. When there is loss of MT2 function, you get uncontrolled signaling through the L2 pathway with constitutively high levels of upside. And this is observed in a disease where the genetic mutations in the MT2 gene lead to what is called iron refractory iron deficiency anemia. This high hepcidin has also been observed in chronic inflammation and where the high hepcidin can result in anemia in patients. So we believe ALK2 signal will normalize high upside and therefore will mediate anemia. And this can be seen in a mouse model where when you take the gene that codes for MT2, If you now knock it out as we did in the study where upon administration of an siRNA that knocks down this gene in the liver, you get increases in hepcide and you get a reduction in hemoglobin levels in the blood. When you then treat with an ALK2 inhibitor, following treatment with the siRNA, you're able to reduce the hepcidin and correct the anemia in this mouse model. So we believe that our IL-two inhibitors will have benefit in patients with high hepcidin. And we completed our Phase 1 study in healthy volunteers. This was a study with single ascending dose as well as multiple ascending dose. And in this study, we were again looking for safety, tolerability and PK, but we also again incorporated multiple pharmacodynamic markers that will give us signals of activity. And in this study, what we observed was changes in these biomarkers. What we observed was that as a consequence of inhibition of ALK2, we do indeed observe the reduction in hepcidin. And this reduction in hepcidin results in rapid and dose dependent increases in serum ion and transferrin saturation. Furthermore, these increases in serum ion are available. This increased serum iron is available for incorporation into red blood cells. And the way we looked at it was to look at the hemoglobin content of the newly produced red blood cells, reticulocyte, and we saw increases in those. There were no serious adverse events reported in this trial and therefore we are ready now to move this program into Phase 2 study. 2 studies, the iron deficiency anemia and iron refractory iron deficiency anemia will give us proof of concept for treatment of anemia and these studies will start in this year in 2021. This is also a treatment potentially for FOP. FOP is a rare genetic disease in which skeletal muscle and connective tissue transform into bone falling injury. There are no cures or effective treatment for this devastating disease and patients become confined to a wheelchair and then will have a life expectancy of roughly 40 years. It's caused by a single mutation in the ARK2 gene that result in a gain of function. And this gain of function when it's introduced into mice, you recapitulate every aspect of the disease. So following injury, skeletal muscle in rodents, carrying this mutation turns into bone as shown here in green. And in a dose dependent manner, ALT-two is able to reduce the bone that it forms. So we think this is a treatment for FOP as well. Finally, KR-twelve, our preclinical program for treatment of bone disorders and for pulmonary arterial hypertension. It is a proprietary selective active in receptor ligand tract that is in preclinical development for PAH and bone disorder. And in our preclinical study, 12 has shown that it has high affinity and importantly inhibits the ligands involved in regulation of bone homeostasis. Treatment with 12 increased bone mineral density, trabecular bone in both wild type mice as well as those that had established osteoporosis. Very important, this therapy does not increase red blood cell production in cynomol rich monkeys, which is 1 of the limitations of other programs where you see similar programs showing increases in bone mineral density, but also have dose limiting pharmacology on the rampers of access. We've taken this molecule into that models of PAH and show that in PAH models, we're able to prevent the right ventricle wall thickening that occurs as a consequence of PAH. And in PAH, where you have hypoxia induced in that animal model, there is bone loss associated with that hypoxia and we were able to prevent that bone loss as well. So we believe that O12 has a potential to increase bone morphogenic protein signaling by inhibiting the active end signaling and therefore is consequently a treatment for PAH where reduced BNP C monozygous of death. So in summary, what I've shared with you is that Keyros is positioned for clinical and commercial success. We're focused on developing novel therapies for TGF beta superfamily, where the biology has been validated in the clinic. We have a pipeline that allows Akiris to be harness the potential of this TGF beta superfamily with 50 in Phase II studies in MDS and in myelofibrosis starting this year. 47 entering multiple Phase II studies and 12 entering the clinic later this year. And our discovery approach has the potential to identify additional molecules with differentiated profile that treat bone, muscle and pulmonary disorders. Finally, these are the anticipated milestones in 2021 where 50, the initial data from Phase II trial that's ongoing will be presented in the middle of this year and additional updates will be available in the course of the year. And we'll be initiating the Phase II trial in myelofibrosis with 50 with 47, both studies start this year and 12 preclinical data will be presented at a major conference and then the Phase II Phase I study starting in the second half of 20 21. With that, thank you for your time. Thank you, Jesper, for that very productive and informative presentation. We look forward to future updates from Carus. And I'd like to take this time to thank you for the time and effort that went into preparing your presentation. And hopefully, your next conference could be held in person rather than virtually. But in the meantime, we're grateful for your flexibility and thank you for your presence this year. Thank you again. Thank you as well.