Incyte Corporation (INCY) Earnings Call Transcript & Summary

Good afternoon, everyone. Welcome to those here in person in San Diego and those online. Welcome to the Incyte ASH 2023 event. I am Pablo Cagnoni. I'm the Head of R&D at Incyte and it's wonderful to have you here to give you an update. Some of the programs that we have at Incyte right now that makes us very excited about our pipeline moving forward. specifically in MPNs and graft versus host disease. I will be making forward-looking statements over the course of my presentation. We have a great agenda for you today. I'll make some quick introductory remarks. After that, we'll have Dr. Ross Levine, give us a perspective on MPNs and new targets in this set of diseases. Dr. John Mascarenhas will summarize the data from our ALK inhibitor program and our BET inhibitor program. And following that, Patrick Mays, the Head of Biology at Incyte will give you what's relatively new data on our mutant CALR antibody program and a program that we're unveiling this afternoon at ASH, our V617F small molecule inhibitor. We'll close the prepared remarks with Peter Langer from our group. He will give you a summary of the AGAVE data that was presented yesterday at the plenary session as well. and we'll have plenty of time or Q&A. So please hold your questions until the end. So the way to think about Incyte today, it really is in four quadrants that you can see here. We're going to focus today most of all our attention on the upper left quadrant in myeloproliferative neoplasms and graft versus host disease. Obviously, ruxolitinib has been a cornerstone of therapy for these patients and changed the standard of care but we're very excited about our pipeline and how it evolves across a number of different mechanisms, including our 2 inhibition, BET inhibition as well as the mutant CALR V619F antibody. Also important part of this plan is our once-a-day formulation of ruxolitinib. But it's important to remember that we have a lot of activity of Incyte in a number of -- in the three other quadrants in this slide. In the bottom left, you can see just a few examples of what we think is -- is a very exciting pipeline in oncology with our Oral PD-L1, a unique program to really show that we can change a little bit how PD-1 inhibitors are used in what context in the management of patients with cancer. Our CDK2 inhibitor program that is advancing very well in the clinic, and we think we will be in a position to reveal data some point in not-to-distant future. Just to highlight two important bispecific antibody programs in TFG-beta receptor 2 by PD-1 and a LAG-3 by PD-1, both of which are well into the clinic and we'll have data in the not-to-distant future as well. So oncology and hematology remain a very important part of our activities and Incyte as well. We have a growing and very important dermatology and inflammation franchise right now represented by Opzelura, which has been approved, and it's growing commercially in atopic dermatitis and vitiligo and povorcitinib, which we believe and we've disclosed data that we think in many context, is best in diseases such as hidradenitis suppurativa, prurigo nodularis and others and we're expanding the povorcitinib plan now with study in asthma as well as another example, in inflammatory disease where we think it can have an important role. Finally, on the bottom right-hand corner, royalties, which are really important, these are from medicines that we discovered at Incyte that we have partnered over the years and have been developed several of our partners and they certainly provide important source of revenue for us to continue to expand our R&D efforts. We are having a great ASH, more than 50 abstracts accepted, these are either data generated by scientists on Incyte or collaborations or in some cases, investigator response to trials, such as those that were presented over the last couple of days, the plenary session, which we're very proud of, our colleagues from Syndax and the trial of the AGAVE for axatilimab in patients with chronic graft-versus-host disease was presented yesterday. We believe it was very, very well received and a number of other oral presentations, again, across our pipeline. We're going to start with Jakafi. And as you know, this is a medicine over the past 10-plus years has really redefined the standard of care in three different diseases. When you think about it, is a pretty extraordinary molecule. Initially, the first FDA-approved medicine for patients with MF, followed by the first ever approval in PV, followed by the first approved medicine for acute-graft-versus host disease and after that chronic graft-versus-host disease. So an extraordinary journey for Jakafi over the years, driven by efforts from Incyte and in some cases, our partner, Novartis. The way to think about Jakafi and MPNs going forward is summarized in this slide. And when you think about it today, Jakafi is really the foundation for therapy for patients with MF and PV and obviously, graft-versus-host disease as well. More than 16,000 patients are currently on therapy with Jakafi. But we're not going to stop there. There are ways to continue to improve outcomes in patients with these illnesses is a combination therapy and combination therapy, two are components of our pipeline, and you'll see a summary from that data from Dr. Mascarenhas with ALK2 inhibition and BET inhibition. We think that this can continue to improve spleen responses, continue to improve symptom responses in these patients and continue to drive better outcomes. The next stage is when it gets really, really exciting within the introduction of two new mechanisms for the management of myeloproliferative neoplasms, mutant CALR antibody and the 617F small molecule truly can transform the therapy of these diseases by driving molecular responses by reducing allele burden and potentially truly changing how these diseases are treated in the future. This will also expand our footprint across MPN. So when you think about MF, PV and ET summarized in this slide, the combination of CALR and JAK2 mutations cover about 90% of the patients with MF, 95% OF patients with PV, these are exclusively 617F mutations and about 85% of the patients with ET. So really from the group of patients that are treated with Jakafi today, we will broaden our footprint dramatically across MPNs in the future. A quick update on ruxolitinib XR, our program to switch to once a day ruxolitinib, which is a very important component of our fixed dose combination strategy with other components of our pipeline. Based on feedback from FDA, we will conduct a pharmacokinetic bridging study with a larger tablet. We expect that will take a little bit over 2 years, but we think we have a clear path here to develop ruxolitinib-XR and get it to an approval well before the expiration of LOE -- before the LOE of Jakafi. So this will be part of the plan going forward as well. And this will provide a significant benefit from patients in a range of ways by providing in combination therapy, fixed-dose combination with other components of our pipeline. A couple of words about graft-versus-host disease. When you think about it today, and the data was presented yesterday by Dr. Wolff and that Peter Langer will summarize in a minute. Initially, interaction of axatilimab to patients with graft-versus-host disease will be later lines of therapy. The AGAVE trial was done in patients that had received two prior lines of therapy for chronic graft-versus-host disease. We announced that we will now drive forward to more Phase III trial -- one Phase II and one Phase II trial, excuse me, a Phase III trial in combination with steroids in first-line chronic graft-versus-disease in a randomized Phase II trial in combination with Jakafi also in first-line chronic graft-versus-host disease. This by moving axatilimab early in the treatment paradigm, we think we'll provide more patient benefit and obviously it's a much larger patient population or longer duration of therapy as well. So a lot to have to come in the next 5 years or so when it comes to that left upper quadrant that I showed you focus on MPNs and graft versus host disease. AXA, we will have the BLA submitted this year. If things go well and approval next year is possible. We will initiate the 2(h) trials that I just described with ruxolitinib and steroids as well. For XR. I give you an idea what the next steps are. For ALK2, we expect, and you'll see the data in a few minutes, that we will have proof-of-concept data next year. Need more patients. We need more patients in treatment group C, which is in combination with rux in untreated patients. And we believe that after that, we'll have enough information to start setting up a Phase III trial. For BET, we're very close, in my opinion, to have enough data. You'll see today the strong effect on screen and symptoms. We think that with a little longer follow-up we'll be in a position next year to decide what the design of that Phase III trial is. Mutant CALR and JAKV617F inhibitor. Those are just early programs, CALR in the clinic already. We are treating patients. 617F, the IND will be filed very soon, and we'll anticipate to start treating patients early in 2024. So with that, let me stop here. I want to introduce Dr. Ross Levine, Dr. Levine, who's been involved in the space of myeloproliferative neoplasms for a very long time. We've known each other for about 15 years or so. He's made seminal contributions to our understanding of the biology of these diseases, and he will give us a view -- a point of view of where we stand today and our understanding of MPNs and targets for new therapies Ross?

Thanks, Pablo. So I think what I hope to do, and I think John will then underscore this when he talks about some of the recent clinical data and then you'll hear about the programs after to sort of underscore where we are in MPNs and where we need to go. I'll remind everyone that we have three distinct classical Philadelphia-negative myeloproliferative neoplasms. P Vera, myofibrosis and ET, that PV and ET can both progress to MF, and we still don't really know or have any clear delineation that post PV, ET, MF is a different biological or therapeutically relevant entity to de novo enough? We know that these patients can develop thrombosis or hemorrhage or other problems. But the things we always worry about in these patients are progression to leukemia and the overall burden of large spleen and constitutional symptoms. This is when we see patients, the things that we talk about each and every day. And when I began in this field as a young investigator vectoring my training as an oncology fellow, my initial project was to try to begin to understand the genic basis of these diseases and my assignment was to see if we can find the mutant gene or genes that were relevant to these diseases. And so we and others did sort of large genomic landscape studies that really were aimed to find the driver mutations that were contributing to these diseases. And of course, that really resulted from a number of groups, including our work in the discovery of JAK2 mutations now remarkably about 19 years ago in February. And this was an incredibly important sort of discovery that really ushered in the modern era of both biology and give us a toehold of how to develop therapeutics. We know that this is an incredibly common mutation in about 90-plus percent of PV and 50% to 60% of MF and ET. We know that's consistently activating, and we know that it's a great marker for the disease clone. So this really, I think, was an exciting moment, and I'll just say with sort of a personal perspective, and I was very fortunate to collaborate with the team at Incyte in the latter half of that decade on some of the work that led to the use of ruxolitinib and MF, and that was really a great time where we got to really ask how the genetics would make a difference. But I will argue that in 2023, as we enter 2024, the JAK/STAT pathway and the constituents therein remain the best therapeutic target in MPN. And that's for a number of reasons. The first is that JAK2 VF mutations represent 60% to 70% of all patients. So this is the largest set of patients that have a specific driver mutation. The second is that in work that my lab did over many years, both genetics and gene expression, if you look at MPN patients, of all diagnoses of all genotypes versus normal blood cells, the only thing that distinguishes them is activated JAK/STAT signaling, if you look at gene expression, if you look at signaling. It's really the thing that distinguishes. And I want to leave you with the idea that yes, the JAK2 mutation, the CALR mutation are critical and targeting them will shut off the apparent signaling. But you should always think of these diseases as really JAK/stat-opathies are driven JAK/STAT signaling. But what we've learned from the JAK2VF mutation from the seminal studies on the CALR mutation resulting in Aberrant Mpl trafficking as well as on the Mp mutations themselves is that these mutations individually have the ability to truly flip a switch that results in qualitatively and quantitatively different signaling that activates in the vast majority of MPN patients. And I think one of the things that I want to leave you with today is the idea that if we could target as we learn into the clinic, these driver mutations, this is our best shot for truly definitive therapies. And we're very excited about that possibility. And of course, we've learned a lot in the past decade about what targeting the JAK/STAT pathway is like. And the work with ruxolitinib really was the watershed moment in the field, where it changed the standard of care. It's almost how do I put this nicely. It's almost an understatement to say changed the standard of care. I'd argue there was no standard of care, and it created it. I think that's probably the better way to think about it. That's true both because we see a reduction in spleen size, which is clearly objectively measurable as well as a significant improvement in symptoms. And if you look in studies, patients who are on ruxolitinib do live longer and have less disease progression. So we believe that this is the cornerstone of therapy still to this day for the majority of MPN patients, and it really is the first therapy to show clinical benefit in the first line. The role of other current JAK inhibitors it remains unclear. not because they're not important, valuable and interesting drugs, but fundamentally for a couple of reasons. The first is that they each really address a very specific subset or need, I'd argue. So for example, they might have less of an effect on platelets or have a modest ability to improve anemia or in many cases, they actually are hitting other targets other than JAK2, which are liabilities such that they don't bring massively different things to patients. And that is my own opinion to someone who have studied these drugs for a long time. So we believe that this is the standard of care, but we do need to do better. And I think one of the questions that I'm really excited to see the Incyte Group working on this so hard in the past 5 years is you need to not just rest on the laurels of great success, but you've got to ask how you can move the needle and develop novel mechanism-based therapeutics. And we know that the other thing, I think, that wasn't maybe appreciated when ruxolitinib was approved, but now it's become obvious as we've moved it, is that it's also a game-changing therapy for polycythemia vera, where it really is an incredibly efficacious therapy and improving accounts and symptoms and spleen and really is a therapy that can make a huge difference compared to therapies like Hydrea, interferon and other therapies, which although have efficacy are much harder to tolerate. And it's important to recognize that the MPN sort of constituency that gets these drugs is really relatively equally balanced between MF and PV. And the question will be is these new therapeutics will be not just how do you develop them in MF but what is our potential role in polycythemia vera as well, where we believe there remains a significant need to innovate. So what we believe that we're entering or we're in a new era of drug development in MPNs. And so there are some interesting questions. First is, are there additional targets or pathways that are relevant? Can you find other things other than the JAK/STAT pathways are relevant? And can you use those therapies either as a combination partner or would they have a role as a monotherapy? And I think the questions are out there, and we have some information. And we'll get into where we see the answers to those questions are today. And then the second is, can we build on the success as a field and can Insight build on the success as a company of current JAK kinase inhibitors to develop really next-generation drugs. So that is obviously what I want to think about today. So for combination therapies, I'll give you my perspective on where we are, there are compelling preclinical to clinical data suggesting that a number of different targets can be inhibited and have modest monotherapy activity is significant, but also seem to have preclinically significant activity in combination with the JAK inhibitor, probably the most -- three most time profile right now are BRD4, which we'll hear about today in a few minutes. BCL2/BCL-xL, which we won't talk much more about today, but I'll just remind you all that in MPNs Bcl-xL is massively overexpressed. So unlike in other myeloid malignancies, where you can really go after BCL2 and not BCL-xL, you need a strategy to go up to BCL-xL and that's the challenge of thrombocytopenia and threading that needle and then ALK2 which you'll hear about. And the critical thing here is that most of the data that's been generated in preclinical to clinical studies has used these therapies plus ruxolitinib. And that's what we're learning about right now. And so what are we learning about right now? I know John will also give perspective, and we both can give our thoughts and answer questions after about what we're learning from these combination studies. The first is we're beginning to see, obviously, data from large combination therapy trials. We saw data in the last 18 hours from the first BET ruxolitinib randomized Phase III trial. And so one of the questions, which I don't think we know the answer to you, I think we're going to learn is just reducing spleen length with maybe a slightly less significant improvement in symptoms going to be enough to, one, have a meaningful difference for patients; and two, for it to be approvable. And I'm not here to give a handicap or an opinion, but it is the question that needs to be answered. But the other part, which I think is critical that I would encourage all of us to pay attention will be, we need to look at all of the data from these combination studies, both the ones that are reading out and the ones that Incyte and others are leading. You can't just look at those initial primary endpoints, you need to look under the hood at things like fibrosis and pathology and cytokines and meet the whale burden and ask is there a stronger package of when you look at all those parameters that you actually think the mechanism that was studied in the lab actually borne out in the clinic? I think the other to pay attention to is toxicity and dose modification as these studies are gone. If you have to reduce either the JAK inhibitor dose or the partner or both in a significant fraction of patients, then that's a problem. And that's going to be a problem because is it better to get a combination with less of two drugs, or to be able to get the full efficacious dose of a drug like ruxolitinib. And thrombocytopenia, as you might imagine, is the one that we pay the most attention to and particularly for the BCL2/BCL-xL is the biggest challenge. And then the other question, which I don't think we know yet today is, are there subsets where combinations work better than others? I've not seen any data, for example, do high-risk mutational subsets, we have JAK plus a particular other biomarker. Would they benefit from a or a specific combination. And so what does this mean? I think ruxolitinib monotherapy will remain a preferred therapy of choice for most patients. And obviously, we're hopeful that the combination therapies will iterate and improve. But it's still going to be a significant lift to see whether that makes a difference. But I think what I'm even more excited about is going after the JAK/STAT pathway as a field even more. Current JAK inhibitors are offering significant benefit, but they just fundamentally can't turn off the driver mutations directly and specifically the same way that you might, for example, or other scenarios where mutant selective drugs have been done. And there's, therefore, a need to develop new therapeutic modalities that directly target the driver mutations. There are no drugs I'm aware of yet, that go after the mutant [indiscernible] but hopefully maybe I could convince Pablo that, that should be the next target to work on. But you'll hear today about efforts to develop therapies against mutant CALR and the JAK2 V617F mutation. So what's my perspective on where those are and where they're going. The first is that I really believe that the drug that targets the apparent gain of function of mutant CALR if it does in the clinic, what it did preclinically could be a definitive incredible therapy for the CALR mutant patients. It will obviously start myelofibrosis. But if it's incredibly efficacious in wide TI, there's no reason to think that central thrombocytosis wouldn't be on the radar and there's a significant fraction of ET patients with CALR mutations. And JAK-selective therapies are exciting. It is the driver gene in this disease. And this is an exciting discovery and development that as you have heard, is going to go into the clinic. And the idea here is that if you can develop a therapy in the clinic that targets the driver oncogene better, you'll get greater inhibition of mutant signaling without nearly as much innovation of wild-type signaling, which would give you greater efficacy and a wider therapeutic index and we hope even better efficacy than we see with current JAK inhibitors. So that's sort of my perspective of where they are, and I think I was going to turn it over. I believe Pablo is going to introduce John.

Thanks so much. Thank you, Ross. We're going to have now Dr. John Mascarenhas, who is Professor of Medicine and Head of the Adult Leukemia Program at Tisch Cancer Institute, of Mount Sinai. Dr. Mascarenhas has been part of a number of clinical trials advancing the treatment of new therapies actually for patients with MPNs. So, he's going to give us an overview of the data that we presented to date with our BET inhibitor and program ALK2 inhibitor programs and give us his perspective on that.

All right. I really appreciate the opportunity to be here today like Ross, I've been in this for quite some time. And I knew Incyte when it was a very small company of like 30 people. I worked in the lab with Steve Friedman and Paul Freedman, saw the whole thing go from INCB18424, to a drug that's approved. So for me, this is thrilling to see it all come to this point where we're talking about new therapies and combination approaches with the same company that was there from the beginning. So we'll start with the BET inhibitor 7643. And of course, there's a lot of attention right now for BET inhibition particularly in this in this field. Well, I'll summarize what I'm about to show you, and then we'll end up back with the same summary. So improvements in spleen size and symptom burden with the Incyte BET inhibitor 7643 plus or minus ruxolitinib. Monotherapy in combination with ruxolitinib generally well tolerated. So we'll show you some efficacy and some safety data. And then the plan for the company is to open up a Phase III study in the second half of next year with potential either in the first line in combination with ruxolitinib, add-on to ruxolitinib treated patients who are suboptimally responding or monotherapy after ruxolitinib failure, and the details for the study patient population will be provided by the company in upcoming months. So this is a slide, I probably should have really asked Ross to present because he really was one of the main drivers behind understanding the biology of myelofibrosis and the contribution of JAK/STAT signaling but also NF-kappaB. which multiple labs have shown is upregulated in MF. And this provides a really unique opportunity to inhibit BET [indiscernible] or epigenetic reader proteins that bind to lysine residues either on histone and non-histone proteins. And in this case, facilitate the activation of NF-kappaB and the expression of NF-kappaB controlled genes and there's crosstalk between these two pathways. And Ross has shown very nicely in murine modeling that the two drugs work even better than one drug alone and potently inducing responses in nipple-driven murine mice. And what we believe is that if you can hit these two pathways appropriately and synergistically, you will down-regulate TGF-beta, NF-kappaB, BCL2, CMIC, all of that, which are implicated in the pathophysiology of this disease and affect aspects of the disease. So we're really letting the science drive us and Ross was behind a lot of that science, and it's very exciting to see this play out now clinically. So you saw the MANIFEST data that was presented last night by Rajiv Rampaul, sort of validates that the combination in an upfront setting is active. And now we'll take a look at some of the early data coming out of Incyte with their BET inhibitor 7643. That's in a Phase I dose escalation study starting at 4 milligrams QD. So this is dosed daily. So the morphosis drug is 2 weeks on, 1 week off, a little bit different. daily and exploring the safety of this drug at different levels from 4 to 12 milligrams, so continues in a 28-day cycle. In this patient population, these are patients who have relapsed/refractory myelofibrosis but also could have other related diseases, MDS, CMML or other MDS MPN overlaps with a platelet count of at least 50,000, there is some on-target thrombocytopenia that you'll see. So that's often the threshold platelet count that's allowed. And in part one, it's monotherapy. So the patients who have failed JAK inhibitor or have overlap syndromes. And then part two is where I think it starts to get even more exciting is a combination with ruxolitinib. I mean these are suboptimally treated patients. These are patients who don't have the full response to ruxolitinib but don't also have progressive disease. It's a huge chunk of patients ultimately that you can find to add to this to this combination. You can see the primary endpoint is obviously in the Phase I study is safety and determination of DLT. And then the key secondary endpoints, which are regulatory endpoints, SVR 35%, TSS 50%; and then anemia response, which is dose a lot of attention. So there is two cohorts, 18 patients in the monotherapy cohort, 11 patients in the combination cohort, which I'm showing you the data here, it is the patients you would expect to see or that Ross and I would see in the clinic. These patients predominantly have higher risk disease is a little bit different than the MorphoSys data, which is mostly intermediate on risk patients. But again, there were also patients who had other related myeloid malignancies. These patients were not heavily transfusion dependent, but they had all seen some prior therapy, mostly ruxolitinib, but other JAK inhibitors, too. And you'll notice that their spleens are big, particularly in the patients who in the relapsed/refractory setting, so 2,000 cubic centimeter spleen, it's a large spleen, maybe a little bit smaller in the patients who still have the suboptimal response that need additional benefit. And these are very symptomatic patients with a score of 32 and then 23 in the combination. Those are well tolerated BET inhibitor. So Grade 3 or worse treatment-emergent adverse events occurred in 65% of patients and serious in 20%. So there were two DLTs in the dose escalation. One DLT -- so two DLTs with monotherapy and one DLT with combination therapy. So hyperbilirubinemia at the highest dose, 12 milligrams in the monotherapy, thrombocytopenia in an overlap syndrome patient at 12 milligrams and at 6 milligrams. So right now it's 4 and 6 milligrams that have been tested in combination thrombocytopenia. So you can see the distribution. I won't go through each one of them. I will just draw attention in case your eye catches the fatal treatment-emergent adverse event. This was a patient who had a transformation to AML that's part of the natural history disease. That's not a treatment-related complication. On the right, you'll see the frequency of -- and this is irrespective of attribution, the frequency of treatment-emergent adverse events, most of which are intrinsic to the disease, but can be seen at low grade levels with the addition of a BET inhibitor. And I will point out that dyscrasia or alteration taste is common across the BET inhibitor space. We saw it with the BMS compound, saw it with [indiscernible] as well. This is low grade, rarely reason patients would stop therapy as they usually feel globally better on these therapies. Here's the monotherapy spleen response. Again, this is color coded, this dose escalation, color-coded by the dose of 7643 that was provided to the patients. Three patients met the regulatory endpoint of SVR 35% at week 24. But what I'm showing you in the graph is the best spleen response at any point on trial. And you can see that there are a number of patients, five in which have at least a 25% spleen. And why do I even point that out? Well, there is data that in the second-line setting, particularly, even improvements of 25% or greater in spleen volume which the bar is probably higher to reach -- harder to reach provides benefit to the patient. So you can see that there's clear spleen volume reduction with monotherapy BET inhibitor. What about in combination? So there's fewer patients here. The doses were four and six that are color coded. At week 24, one patient receiving the 4-milligram dose hit SVR 35%, but the graph is showing you the best spleen volume responses on study. And again, you can see one patient in combination at a 45% reduction. These are patients, again, who had suboptimal responses to ruxolitinib, you are adding on beyond the ruxolitinib an additional 45%. So five patients here, again, had 25% or greater spleen volume reduction. What about symptom improvement? There's a lot of attention to symptoms and improving symptoms. So monotherapy, three patients met the regulatory endpoint of TSS 50% improvement. These are dose 10 milligrams and higher, six patients had that response at any point. So the best response -- best symptom improvement during treatment. Again, you can see the color-coded dose cohorts and degree of symptom improvement with inhibitor monotherapy. This is in combination with ruxolitinib. So two patients hit TSS 50% at week 24, one in each cohort 4 and 6 milligrams. But you could see at least six patients had that response at any time. And I would point out, and I'm sure this is obvious to everyone, there's nothing magical about week 24. And when I treat patients, I want to get the deepest response for the longest amount of time over time. and there's nothing specific about week 24, it's regulatory endpoint. But this kind of data gives you a sense of what it looks like throughout the time. So in summary, improvements in spleen size and symptoms were observed with 7643 at 8 milligrams QD in monotherapy, but both 4 and 6 milligrams in combination therapy. This was well tolerated, both as monotherapy in combination. Dose escalation is with monotherapy is complete for monotherapy, but continues with combination therapy and is currently enrolling into the 8-milligram cohort. And there's plans to open the Phase III study in the second half of 2024. And again, this could be a potential first line in combination with rux, again salvage with patients who were saw in suboptimally responding to rux or monotherapy after rux failure and those will be disclosed later. So let's talk about ALK2 inhibitor that Ross alluded to before, zilurgisertib. So, in summary, before we look at the data, goal of program is to prevent and reduce anemia is a major problem in myelofibrosis. very well understood. It has a very strong negative impact that's independent on prognosis. It worsens with disease course and many of the therapies that we give are really insufficient and don't durably improve anemia. Hepcidin is elevated in myelofibrosis [indiscernible], a very inflammatory state and negatively regulates iron availability, offers an opportunity to capitalize on that from a therapeutic potential. And this drug, again, has been trying to be generally safe and well tolerated with the data that I'm going to show you. dose escalation continues, it's early on and clinical proof of concept is anticipated by next year. So why are we talking about ALK2? ALK2 receptors expressed on hepatocytes, engages BNP, signals through SMAD signaling intracellularly and governs the expression of TAM, which is a gene for hepcidin. And hepcidin is markedly elevated in these inflammatory states in chronic anemias and negatively regulates the access for erythropoiesis, access of iron for erythropoiesis through binding of the [indiscernible] channel. So if one can reduce the elevated levels of hepcidin in myelofibrosis and relieve the sequestration of iron and provide iron for erythropoiesis that would improve anemia. And that's the concept between giving an ALK2 inhibitor in this disease state. So this is the Phase I study design of ALK2 inhibitor monotherapy in patients who've lost response, add on strategy to ruxolitinib if they've been on a stable dose for at least 12 weeks. Or eventually, it's going to be in combination in JAK inhibitor-naive patients with dose escalation and then expansion at appropriate doses. Here, primary endpoint is, of course, is safety and tolerability in the Phase I study. But the secondary key endpoint is anemia. Can we improve anemia with this ALK2 inhibitor? And then, of course, looking at PK and PD readouts as well. And these patients are all anemic, just to be very clear. So hemoglobin less than 10 or transfusion dependent, which means in the last 8 weeks prior to cycle one day 1, they acquired at least 4 units of red cell transfusions. Here, the patient characteristics of 46 patients that have enrolled to date at study -- at a data cutoff of August 1. There is one patient that is treated in combination in JAK inhibitor, but that's not something presented today. So 23 in the monotherapy cohort 22 in the combination. I won't go through each of the lines, but you can see them there. Again, these are mostly higher risk, intermediate to and high-risk patients. who've previously seen ruxolitinib. it's a vast patient population. Anemia is very prevalent in these patients, and it's very troublesome, it is linked to symptoms, it reduces quality of life, reduces functionality, ties patients to the transfusion suite and is a huge financial burden to the patients and the health care system. So these patients had low hemoglobin. Those are high hepcidin levels as one would expect. And this was a well-tolerated drug as I would have anticipated. So dose escalation is ongoing. MTD has not been reached. One dose limiting toxicity occurred of Grade 3 alveolar hemorrhage, which I reviewed that data very carefully. And I'm not clear, it's even Grade 3 alveolar hemorrhage actually and not clearly drug-related. Treatment emergent adverse events were mainly low grade without any apparent dose dependency. And one treatment-related adverse event, late-study drug discontinuation, which was hyperferritinemia at 200-milligram add-on therapy. So you could see the adverse events for monotherapy on the left and in combination for the add-on strategy on the right. There is minimal grade 3, 4 toxicity here. And most -- I'd still argue most of the toxicity that we see that's Grade 1, 2 is often associated with the disease process and is really a reason for concern. So from my perspective, very well tolerated therapy at this point. And effectively reduced hepcidin as a pharmacodynamic readout both on-target activity at 100, 200 and 400 milligrams once daily as monotherapy and even perhaps optimally 400 milligrams in combination with rux as combination therapy and durably over the course of follow-up and improved hemoglobin. So these lines are a little bit hard to sort of follow from my perspective. But what we're trying to show you here is the change from baseline in hemoglobin over a function of time. from dose -- from first dose in weeks. So you can see that the dotted lines are sort of the definition of anemia response, which is 1.5 grams per deciliter or higher and sustained for 12 weeks or a transfusion independence, not requiring transfusions for 12 weeks. So you can see that there's this upward and durable oscillation above 0. So improvement in hemoglobin at different doses in the add-on strategy in these patients that are treated at 100, 200 and 400 milligrams. So in summary, saw a reduction in hepcidin levels to credential the on-target effect of this agent. With greater control of hepcidin over time in combination with ruxolitinib at the higher doses. Preliminary improvements in anemia observed, we need to treat more patients and have a longer follow-up. The therapy -- monotherapy or in combination with rux was generally well tolerated, predominantly Grade 1, 2 treatment emergent adverse events. MTD has not been reached. and the dose escalation continues with clinical proof of concept for mid-2024. And I think that's right. I'm personally excited about these therapies. I know if there's one company that's going to move them forward who's been invested in this space from the beginning, its Incyte. So I'm proud to be here with you guys and happy to take any questions afterwards.

Thank you, John. So we're going to transition now to the newer programs. You can call are V617F. To give us a summary of those two programs, we have Patrick Mayes, who is currently Head of Biology at Incyte and had an instrumental role in developing the mutant CALR antibody. So he will tell us about the two programs, and we can address questions at the end. Patrick?

Okay. We'll begin with an overview of INCA-33989, which is our mutant CALR antagonist antibody program. CALR is the second most frequently mutated gene in patients with MPNs accounts for approximately 35% of patients with MF and 25% of patients with ET, and CALR mutations are not found in PV. CALR acts as a oncogene through rope chaperone function, where it binds abnormally to the thrombopoietin receptor TpoR is a complex to cell surface [ leading ] the constitute of signaling through JAK/STAT as you heard. Our antibody binds to mutant CALR and disrupts the complex of mutant CALR TpoR at the cell surface. And as a result, turns off constitutive signaling through JAK-STAT. This is an example of the selective inhibition that we see of JAK/STAT signaling downstream of mutant CALR TpoR in this system, we've collected CD34 cells from MF patients with either a CALR mutation or in this instance, a JAK2 V617F mutation as well as CD34 cells from a healthy donor cultured in the presence of TPO. And what you see in the graph is a dose-dependent inhibition of JAK/STAT signaling specifically in the MF patient sample harboring a CALR mutation, no effects observed in the JAK2 V617F sample or the wild-type CD34s. The functional consequence of this selective signaling inhibition is demonstrated here again using CD34 cells from patient samples. The graph in the middle, we show in blue, a dose-dependent decrease in the hematopoietic stem progenitor cells from a patient sample harboring a CALR mutation, while we see no effect on HSPCs from CD34 cells from a healthy donor. MF is characterized by an overabundance of megakaryocytes. The graph on the right demonstrates megakaryocyte differentiation. And you can see a significant effect of megakaryocyte differentiation in a sample with mutant CALR with 99 treatment, whereas no effect is observed in an MF patient sample harboring a JAK2 V617F mutation. We went on to test 989 in a genetic mouse model of ET. And this model disease is established over an 8-week time course, at which point, 989 treatment is administered for 5 weeks. samples are collected, and we can look at disease endpoints in both the blood and the bone marrow of these mice. The graph on the bottom left, you see a significant effect of 989 treatment on platelet counts within the blood. In fact, at this 5-week time course the platelet counts are back at normal levels in a 989 treatment group. The H&E graphs on the right shows that with 989 treatment, we see a normalization of the bone marrow histology in these mice. And you see an absence of the large megakaryocytes, as I pointed out, with the arrows there that are present in the bone marrow in these untreated much with ET. Additionally, we tested 989 in a more aggressive mouse model. This is a model that harbors a homozygous deletion of mutant CALR and this presents with a disease that more closely recapitulates MF. These mice have abnormal hematopoiesis. They have enlarged spleens and extensive bone marrow fibrosis over time. This model establishes over a 4-month time course. And after the establishment of disease, 989 treatment was administered for 8 weeks, followed by stopping treatment and then monitoring for an additional 4 weeks, at which point tissues were harvested and we looked at disease endpoints in these tissues. Again, in the bottom left showing the effect on platelets. You see a significant and sustained effect of 989 treatment on platelet counts from the blood of these mice. Like in the ET model, we see a normalization of the bone marrows from these mice, complete absence of the abnormal megakaryocytes which are present in this disease model. And then the graph on the right demonstrates the significant effect we observed with 989 treatment on spleen weight. So spleen size is back to normal levels. You can see pretty quickly within 4 weeks of treatment, and that's sustained even throughout the kind of the post-treatment 12-week time course. So in summary, for 989, this is a potent selective antagonist of mutant caller function. We've demonstrated here using patient samples from MF harboring a CALR mutation. So always in multiple mouse models of MPNs with the CAL Rmutation. These observations provide the rationale for an ongoing clinical investigation of 989, which is occurring in MF patients with CALR mutations and 989 is being explored as a monotherapy as well as in combination with ruxolitinib in patients with MF as well as a monotherapy in patients with ET. So I will transition now to an overview of INCB-160058, which is our selective inhibitor of mutant JAK2 V617F. As you heard, JAK2 is the most frequently mutated gene in MPNs and represents the majority of patients with MF and ET and nearly all patients with PV. JAK2 and CALR mutations are mutually exclusive and almost never found to be co-occurring in the same patients. So these are unique subsets of patients here. I'll spend a bit of time on this slide because it overviews the key and novel mechanism of action of 058 as compared to the numerous other JAK kinase inhibitors that are either in development or approved. And the ultimate goal of the program through selective engagement and targeting of V617F is to eradicate the mutant clone, leading to molecular remissions and ultimately, disease modification as well as sparing activity against wild-type JAK 2, improving the tolerability of JAK kinase inhibition in these patients. In the bottom left is a ribbon diagram, this represents the mechanism by which this selectivity is achieved, rebinding to the JH2 or the pseudokinase domain of JAK2. Represented in the blue domain is the binding of ruxolitinib, and this binds to the ATP pocket of the active kinase domain of JAK2. also called JH1. The V617F mutation is located in the JH2 domain shown in green. V617F mutation has been shown to change the confirmation of JAK2 in a way that prevents auto inhibition of the kinase from the engagement of JH1 and JH2 domains. 058 bonds in a pocket in close proximity to V617F, changing the confirmation of JAK2 back to a wild-type state, allowing for auto inhibition of the enzyme to occur. This is schematically represented on the right showing the effect of 058 and its ability to inhibit the cytokine independent signaling through JAK2 V617F all sparing function through wild-type JAK2 in response to normal cytokine binding. So we've selected some data to present here, but I encourage you to also attend the session, which is happening at 3:00 this afternoon, Session 631, where a more extensive data set will be represented for 058, you can see really the key selectivity towards V617F. This is a demonstration of that selectivity here with cell lines on the left, MPM patient samples on the right, demonstrating the ability of 058 to inhibit JAK-STAT signaling, more potently in a cell with V617F mutation, as shown in red as compared to a cell with wild-type JAK2. The selectivity can really reach tenfold and exceed tenfold depending upon the context tested. So this is a key piece of data, which demonstrates the novel function of 058 in these JH2 binding compounds. So JAK2 requires cytokine receptor dimerization in order to function. In a wild-type state receptor dimerization occurs through cytokine binding to the extracellular portion of the cytokine receptor, which results in JAK2 dimerization on the intracellar form of a membrane, leading to signaling downstream. In a JAK2 V617F cell auto inhibition of the enzyme is lost, making these cells more susceptible to having cytokine receptor dimerization in a cytokine independent manner. This is nicely shown from the 2020 science paper from [Wilms] et al. Receptor dimerization is illustrated here by the blue signal you see in the panels on the right. And this is possible through the use of an elegant single molecule threat method developed by the lab of Dr. Jacob Peeler at the University of Osnabruck. Through a collaboration with the Peeler Lab, we've tested 058 and our JH2 binding compounds. And what we see is an ability of these JH2 binding compounds to inhibit cytokine independent receptor dimerization that occurs in these cells. And this is a unique function of these JH2 binding compounds that is not observed with ruxolitinib or JH1 binding kinase inhibitors. Here, we've utilized an isogenic Ba/F3 co-culture system. In this system, mutant JAK V617F cells are labeled with GFP, co-culture together with cells that are unlabeled and then we can treat with 058 over an extended time course in this instance, looking out through 18 days. And what we see is a disappearance of the mutant clone as labeled with GFP in this culture over time. So it showing selective functional effects on a JAK V617F cell survival and function in a system like this. We also tested 058 in a mouse model of JAK2 V617F disease. In this system, we collected CD34 cells from patients or CD34 cells from a healthy individual. These cells were then transplanted via intratibial injections into a radiated mice and then we can track the engraftment of cells either in the bone marrow and then looking subsequently at the effect of pathogenic cytokines or disease-associated cytokines in the blood. And what you can see in the graphs on the bottom left is the effect of 058 in its ability to selectively inhibit the engraftment of mutant JAK2 V617F CD34 cells, while having no effect on wild-type CD34 engrafted in the bone marrows of these mice. And this is distinct from a high dose of ruxolitinib as shown here, which equally affects engraft in both the wild type and the JAK2 V617F state. If you look then on the right, you can see the effect in the increase in pathogenic cytokines in the mice that are engrafted with V617F cells. the ability of 058 to inhibit that pathogetic increase in cytokines is shown in blue, whereas 058 has no effect on normal cytokine levels in mice that are engrafted with normal wild-type CD34 cells. Again, this being distinct from ruxolitinib at a high dose, which equally affects cytokine levels in both wild-type and V617F mice. So in summary, for 058, we've developed a potent and selective inhibitor of mutant JAK V617F through the binding -- the novel binding really, the JH2 domain, and this result in the reversal of the auto inhibition of the enzyme. Through this V617F selective function, we think this has the potential to target and eradicate mutant clones allowing for a potential disease modification in these patients. Interestingly, we show a unique ability of JH2 binding compounds in 058 to reverse a cytokine independent receptor dimerization while sparing function against wild-type JAK2. And as I said, initiation of clinical trials for 058 are expected to start first quarter of next year. So I'll stop there.

Thank you, Patrick. We're going to shift gears now to chronic graft-versus-host disease. Peter Langmuir, who is heads our oncology targeted therapeutics group and overseas -- has been overseeing axatilimab program for quite some time is going to give us a summary of the AGAVE data that was presented on the plenary session yesterday, and we'll take questions after that. Peter?

Thank you. So it's my pleasure to share with you some of the axatilimab data. Hopefully, many of you saw the plenary presentation yesterday with Professor Wolff. So I'll take you through some of those data and then obviously, we can discuss at the Q&A session. So chronic graft-versus-host disease is a major cause or the major cause of morbidity following stem cell transplant. By the time patients develop chronic graft-versus-host disease, at this point, they're often cured of their underlying cancer. But we unfortunately have replaced one terrible disease with another. And so patients can live for years with significant complications evolving just about any organ system in the body. It's the major cause of nonrelapse mortality in patients more than 2 years out from transplant, the overall survival -- median overall survival is relatively long. These patients suffer significantly. They have significant contractors of their joints. They have severe skin rashes, most severely, they can develop severe lung fibrosis, risk of infections and the treatments are also associated with considerable morbidity as well. You see the GVHD is divided into mild, moderate and severe. The mild is generally managed with topical agent. It's the moderate severe that we're most concerned with here. And you see the survival, particularly for the severe ones is significantly lower, mostly driven by lung GVHD. So as I said, GVHD can involve just about any organ in the body. The most common sites are shown here. The eye incidence is probably somewhat lower than reality just because oncologists and bone-marrow transplants are not very good at identifying eye GVHD. if you have these patients seen by an ophthalmologist, almost all of them have eye involvement there with GVHD. And that's actually true for many of these organs. If you look very carefully at the organs, they have evidence of -- early evidence of fibrosis appearing even though they may not have developed clinical symptoms. So by the time they develop symptoms, in many cases, these are irreversible or as Professor Wolff said from the podium yesterday irreversible until you have a drug that has the right target. So axatilimab, we hope will address some of these complications. Most of the GVHD therapies that are out there, certainly ones that are approved target either T cells, so drugs like ruxolitinib or belumosudil or B-cells, drugs like ibrutinib or rituximab. But one of the other key mediators of GVHD is the monocyte macrophage pathways, monocytes will differentiate into macrophages that may either have an inflammatory effect driving the GVHD or particularly important, a profibrotic effect driving the fibrosis in multiple organs. And so axatilimab is a monoclonal antibody against the CSF1 receptor that blocks maturation of monocytes into these pathogenic macrophages. And in the Phase I/II study that was presented a couple of years ago at ASH, the drug had a fairly favorable safety profile with an encouraging response rate of 67%. And so we moved into the AGAVE-201 study which was a pivotal Phase II study to demonstrate both the safety and efficacy of axatilimab in chronic GVHD. So this was a three-arm study looking at three doses of axatilimab, the 1 milligram per kilogram every 2 weeks was the dose that was felt to be optimal from the smaller early study. We had a 3-milligram per kilogram every 4 weeks to see if we could dose a higher dose less frequently and then 0.3 milligram per kilogram dose every 2 weeks to try to define a minimally effective dose. As I'll show you in a minute, sometimes your plans don't exactly work out, but I think the results speak for themselves. The eligibility was patients had to be at least 2 years of age. We did end up with a handful of pediatric patients. The youngest patient was 7 years old. Patients had to have at least two prior lines of therapy. So these were fairly refractory patients. And as I'll show you, patients that actually receive generally many more lines of therapy than this. The primary endpoint was overall response within the first 6 months of treatment. The endpoint was considered to be met if the lower bound of the 95% confidence interval exceeded 30%. Other key secondary endpoints included symptoms, duration of response, failure-free survival, overall survival and organ-specific response rates as well as safety. Here are the baseline characteristics, generally well balanced across the three arms of the study, no significant differences. A few things to highlight here, though. One is if you look at the median time from diagnosis of chronic graft- versus-host diseases it was 4 years. With one patient of 17 years of chronic graft-versus-host disease. So if you think these patients had this chronic inflammation and fibrosis going for years before they arrived onto our study. And in fact, although the study required at least 2 prior therapies, the median number of prior therapies was four and you see one patient have received actually 15 prior therapies. So these are really patients who are out of effective options for their GVHD. One of the key questions is obviously now we have three approved agents in the U.S., at least for the treatment of chronic graft-versus-host disease. And many of the patients -- most of the patients have received at least one of those treatments. So 31% have received ibrutinib, 74% have received ruxolitinib and 23% have received belumosudil. If you look also at the bottom, you can see that these patients have very extensive GVHD with multiple organs involved. The median number of organs involved was four and over half of the patients had more than four organs involved. And most of the patients, 80% had severe GVHD. So this is a pretty very heavily pretreated population. As we heard yesterday, the primary endpoint was met in all three cohorts, so that lower bound of the confidence inflow is greater than 30% in each case. But very clearly, you see that the most effective dose was the 0.3 milligram per kilogram every 2 weeks with a response rate of 74%. Compare that to a 66% response rate at the 1 milligram per kilogram every 2-week dose and 50% in the 3-milligram per kilogram every 4-week dose. Overall response was defined objectively using the NIH consensus criteria. So these used objective criteria, and I'll show you in a minute the organ-specific responses. Encouragingly, the time to response was quite quick, generally around 6 weeks. Patients actually did start to feel better before that, but it took maybe 6 weeks before they started to reach objective response, and many of them continue to improve over the course of dosing. And if you look at the durability of response, which is obviously critically important for these patients, you see that over half of the patients in each of the dose levels were still in response a year later. So that was very encouraging as well. Looking at the subgroups. We don't see any subgroup where axatilimab appears to be significantly less effective. A couple of key things to point out. You see in the red box are the responses based on whether patients had received prior FDA-approved therapies, ibrutinib, belumosudil and ruxolitinib, what you see in each of these cases as axatilimab is highly active in each of these populations as well. Axatilimab was also active in patients who had been refractory to the last prior treatment as well. Again, supporting the idea that this is a different mechanism of action that's providing benefit to these patients. Axatilimab was active in patients with severe GVHD, it was active in patients who had over four organs involved, and it was active regardless of how many lines of prior therapy you had. And this is just data for the 0.3 milligram per kilogram dose that we're showing here. These are organ-specific responses at the 0.3 dose and so you see responses observed across all of the organs involved. As you would expect in chronic GVHD especially in such a heavily pretreated long-lasting patient population who had GVHD for a long time, complete responses are uncommon, but we definitely saw some in each of the organs and what was encouraging a couple of things here. One is that in some of the organs where fibrosis is a particular complication. So things like esophageal disease, joints and fascia, lungs, you see very encouraging response rates in those settings. The skin I want to comment on and I think Professor Wolff commented on this as well. The skin looks relatively low, but this is actually not very surprising based on how the responses are assessed, that if you have any area of sclerosis, you may not be able to be counted as a response. even though your skin may feel significantly better. And so we certainly heard from investigators that skin definitely improve. And I think that's also shown by the symptomatic results that I'll show you in a second. This is a result for failure-free survival. So failure-free survival is defined as the time until either death, relapse of your underlying malignancy or need for another GVHD treatment. Remember that these patients were out of effective therapeutic options. So there are not many effective therapies available to these patients, but definitely a very encouraging medium failure-free survival of 17 months. Put that in the context with some of the other agents that are out there, the median failure-free survival for ruxolitinib in the REACH3 setting was 19 months. And for belumosudil and the RockStar study was 14 months. So this is extremely encouraging, especially again, in this very heavily pretreated population. Here are the results for the symptom improvements, a 7-point decrease is what's considered at least by the FDA as being clinically meaningful and we saw 55% of patients in the 0.3 milligram dose, having a clinically meaningful improvement in symptoms. But what you can clearly see is almost all the patients had some improvement in symptoms, which comes back to what I was saying about the response rates that the objective response rate may not be telling the entire story that most of the patients felt better even if they didn't achieve an objective response. And again, similar to response, the median time to that 7-point improvement was about 6 weeks. So patients started feeling better quickly as well as starting to have objective improvement in their disease. Overall, the drug seems to be pretty well tolerated, particularly at the 0.3 milligram per kilogram dose level. If you look at the rate of discontinuation, 6% of patients on the 0.3 milligram per kilogram dose level discontinued for adverse events. Just to put that in context with other agents in the REACH3 study for ruxolitinib was about 17%, and it was about 12% -- or sorry, 14%, I think, in the belumosudil study. So this is really a surprisingly encouraging results showing the tolerability of this drug at this dose level. The most common adverse events we see with axatilimab are elevations in liver enzymes, liver transaminases like ALT, AST and CPK. This is a result of a direct effect of the antibody on liver macrophages. It does not represent underlying liver toxicity. We've looked very closely at this and it's really just an enzymatic finding that we see and very clearly, you see a dose response here where the incidence of these liver enzyme elevations is higher at the higher doses. Probably the thing that's most notable for patients is periorbital edema, which again is related to the mechanism of action of the drug, it's something that is reversible with dose reduction, dose interruption. But encouragingly, at 0.3 milligram dose, the incidence was quite low. Other than that, most of the side effects we saw in the study were things that would be normally expected in a refractory -- in a patient population with a refractory GVHD. So in conclusion, axatilimab looks to be a potential novel therapeutic option for patients with chronic graft versus host disease. We met the endpoint across all three dose levels in this study, but very clearly, the 0.3 milligram per kilogram dose level provides the best efficacy and safety profile and the best across all of the efficacy endpoints. We've seen responses across all of the patient subgroups regardless of prior treatment and durable responses as well, which is extremely encouraging. And as I said, the adverse event profile is consistent with what you would expect in this patient population as well as what would be expected from the mechanism of action of the drug. So we're currently preparing to submit the BLA by the end of the year, which I know is in about 20 days. And -- but that is on track, and we would expect approval in 2024. And -- and then we're obviously encouraged by the next steps. So what we'd like to do is move this treatment earlier in the treatment of patients with GVHD. We don't want to wait for patients to develop that severe sclerosis and fibrosis that may take months or years to improve. We want to try to treat patients early on when they're just starting to develop this or even before they develop it to try and stop it in its tracks and reverse it early. So we're initiating two studies in the frontline treatment of chronic graft-versus-host disease, so newly diagnosed chronic graft-versus-host disease. One of these will be a Phase II combination with ruxolitinib and the other will be a Phase III combination with corticosteroids, and those studies will both start in the new year. So with that, thank you very much, and we'll move to Q&A.

Thank you, Peter. We're going to open now for Q&A. We have all the speakers ready to answer questions. There's one back there 2, 3, 4 Okay, let's take questions. That's good.

Eva Xia Privitera from TD Cowen. So for the ALK2 program, what level of hepcidin reduction do you expect to translate to hemoglobin benefit and transfusion independence? Is it a pretty direct relationship or are there factors to consider?

It's interesting because I think in MF, I think obviously, hepcidin is an important part of the mechanism why some of the persons have anemia, but it's not the only one. And so a direct correlation, it's going to be hard to draw because of other potential reasons for these patients to be anemic, including hypersplenism, bone marrow fibrosis and others. I think the goal and it depends also on the starting level of hepcidin, what I would say is what we've seen so far is that there is a hepcidin reduction that is roughly correlated with exposure to the ALK2 inhibitor, number one. And number two, that the correlation between hepcidin reduction and anemia improvement to anemia prevention, depending on the patient, is not quite linear. So I think it's going to be highly variable from patient to patient and I can't tell you that's going to be a target that we need to reach on everybody. I don't think it's going to be quite straightforward. Peter, I don't know if you want to comment further. Okay, I think the second one was here. And then I'll try to please keep your hands up because it's going to be hard to -- Go ahead.

Conor MacKay, Associate on [indiscernible] team. I just had one on the sequencing of your combination therapies in MPNs and I guess, how you see that landscape evolving sort of keeping in mind, right, the limited clinical data we have at this point. I think you had mentioned in one of your slides, right, that you expect rux to remain -- RUX monotherapy to remain the mainstay in front line and then potential use of the combinations in the second line. I'm just curious, I guess, why that's -- why you feel that is the case? And inconsistent with what I had heard the other day at another presentation investigator say, and then I'm also curious about the additional 8,000 patients you noted on one of your slides. How much of that is rux-refractory? And is any frontline capture baked into that?

Yes. So let me take the first part. So I think there was a slide from Ross that talked about the mainstream first line to continue. So he should probably comment on how you see that evolving. I think when you look at the data for our BET inhibitor, I wouldn't rule out that we'll develop it in two different ways. It could be developing second line in suboptimal patients. And in combination with rux or as monotherapy. I mean, you saw the monotherapy activity, particularly symptoms and pre-striking. And potentially, once we have more data, we can make the decision as to whether it's truly a first-line regimen, I think the data from our friends on MorphoSys really shows that the there might be a path there for first line. So I wouldn't rule out the first time and second line. I think for ALK2 to answer that question more definitively, we need data from treatment Group C in the study, which Dr. Mascarenhas didn't show because we don't -- that's still evolving. Once we have data in newly diagnosed patient community with drugs, then we'll make a decision how the ALK2 inhibitor will be developed, whether it's first line or second line. So I hope that answers the question, Ross, I don't know if you want to comment further on how this -- the landscape is going to evolve.

I mean I think it's a tough question, and it's probably more an opinion than fact. I mean the reality is that there's a few factors we don't know. The first thing we don't know is whether the combination data with the BET MorphoSys, rux or with other BETs that follow will be sufficiently compelling enough to actually get regulatory approval. So I think you could bake in some uncertainty there. And then the second part of uncertainty will be what fraction of patients who get frontline therapy, even if it's approved, will physicians reach for the combination versus say, I'll begin with ruxolitinib. Well, I choose it only for people whose spleen is really the massive problem, subsets, other molecular subsetgs. So I think when you take those two things in, I still think there's a reasonable possibility that a lot of patients are going to begin with ruxolitinib. I am hopeful again that we're going to learn with some of these combinations that there will be data that suggests that there is meaningful demonstrable additive benefit with this orthogonal therapy, and that the combinations will move forward. But I still think that they have things to demonstrate before we get there.

And the 8,000 patients, that's the group of patients are, we believe, currently are suboptimally managed with ruxolitinib. So that's sort of the next wave of expansion. So let's go Michael over there.

Mike Schmidt with Guggenheim. A follow-up question on the BET inhibitor combination. We've all seen the MANIFEST-2 Data yesterday. In your opinion, how much room is there to improve symptoms over what Jakafi is doing already? And do you believe you need to hit both spleen and symptom improvements to obtain regulatory approval in your planned Phase III study?

So it's interesting because symptoms are a key driver for why patients start on therapy with Jakafi. With the [indiscernible] particularly. And the improvement is very, very rapid. And you saw in one of Ross' slides from the COMFORT data, just to remind everyone, the dramatic improvement seems as the Jakafi produces. But not everybody responds and then everybody say symptomatic. So there's still room. And I think there's still enough room for the right medicine to deliver a symptom improvement in first line. Is that absolutely necessary for approval? Well, I think that's a conversation we have with the FDA. We'll learn about that over the next few months, I predict. We'll learn more about the FDA's decision in that regard. In the past, they have been pretty clear that plain shrinkage alone is not sufficient. Now how much of a symptom improvement is sufficient in addition with dramatic spleen shrinkage? I think we can learn about that in the next few months. So I'd rather not make any predictions. I think the person that was in front of you was next, and then we're going to go 1, 2, 3, 4 some words like that.

Derek from Wells Fargo. Sticking with the theme of BET maybe for the doc discussing the BET. How manageable do you think the grade 3 thrombocytopenia is for that combination? And is that something that kind of worries you with kind of the emerging profile of that program?

Before Dr. Mascarenhas jumped in with the answer, the slide did not show the Grade 3. Numbers are small. The grade 3 thromobocytopenia is about 33%. So numerical, it doesn't look very different from the data percent of Propella. Obviously, the numbers are very small at this point, Dr. Mascarenhas?

Yes. So I was going to say, it's manageable. So I mean, there's such heterogeneity in myelofibrosis patients. You're not going to expect the same toxicity or the same reaction toxicity if you go in with someone who already has a low platelets. So if you have the cushion there, you can manage -- we're good at managing thrombocytopenia. I think the FDA is more worried about thrombocytopenia than we are. So sometimes it's dose modification and holding. But I think we need to see more data for this agent. But I think -- I would just want to echo that ruxolitinib remains the mainstay of treatment. And even with the pending approvals of other agents, I don't think it's really going to change that. And there's such variability in the way -- so about 2/3 of MF is actually treated in the community. It's not treated by Ross and I. And if you can canvas those doctors and ask them how they treat myelofibrosis, the way in which they approach it is very varied. But there's one unifying thing. They love ruxolitinib and it remains the mainstay of therapy. And even if you show them data of emerging therapies, they'll still tell you ruxolitinib is going to remain my main drug. And it will be somewhat random in terms of how they'll determine who's going to get that combination and when they're going to get it. It's really going to be I think, variable. So rux remains there, and I could see adding a BET inhibitor at any point at initiation. So the data that's being generated is helpful because you can demonstrate activity upfront, suboptimal to provide that confidence to the prescriber to use it at any point in the clinical course and adjust for thormacytopenia.

I think there's a gentleman there over there, Eric, we'll go to you next.

Reni Benjamin, JMP Securities. The combination data with the BET inhibitor showed amelioration of certain side effects like nausea. I was kind of curious, I was just on there or several others. I'm kind of curious what the mechanism of action is there for your BET inhibitor? The other is for the KOLs, there was so much data that came out with combination studies with rux, right? There was [indiscernible]. There was a ton of them. As you either advise the company or as you had these two drugs in your own company, how do you decide to move forward? What kind of metrics would you be looking at to decide whether or not to move the drug forward.

So I'm going to ask Peter to comment on the safety profile of the BET, then Doctors Levine and Mascarenhas can comment on their views and the combinations. Go ahead, Peter.

I don't know if I have a great explanation for the safety profile, we're still adding more patients on and learning more about it, but I think it's certainly encouraging that obviously, we see the thrombocytopenia with [Technical Difficulty].

So I think that's a great question. I mean I think that if one looks at sort of the mechanism of these combination partners in the case of both BET and the Bcl-2/Bcl-xL drug, there's pretty compelling rationale that they both target aberrant biology that's distinct from the JAK mutations or a sort of byproduct of the mutations. The challenge is balancing that with the therapeutic index and the benefit risk. I think for the Bcl-2/Bcl-xL as I said in my talk, although I believe the biology Bcl-2/Bcl-xL is very compelling in these diseases. Because the BcL-xL has an on-target thrombocytopenia risk, you're always in this like intense yin-yang of efficacy versus. And I think that I don't want to home work. The company, I think they have to make a thoughtful decision of whether that yin-yang is something that clinicians will actually be able to do in practice. Because if so, they should pursue it. But if they say it's just too narrow, then they shouldn't -- and we should ask whether, for example, the platelets sparring Bcl-2/Bcl-xL strategies like [craters] that are being developed that might ultimately solve that -- that's a question, I guess, for the makers of that one. I think the challenge with the BET is that we all believe that they're preclinical to clinical, that significant reduction in spleen weight and the improvement in some of the symptoms and preclinically, as I've said, there's improvement in fibrosis and even micro parameters that I'm waiting to see that data in the clinical. I believe it offers clinical benefit. The question is, is it enough that you'll get it as an approved therapy across all of the MF patients or are you going to be figuring out where it's most beneficial. And so I think that one, I really do believe it's got to move forward. I'm hopeful. But the navitoclax, I think they have a choice, and they have to do the gut-check and ask can they thread that needle where they can really get a tractable efficacy where they're not always kind of worried about the platelets. I'm paying attention to that one to toxicity and dose reductions and sort of what lots of sites are experience, I don't know if that helps.

John, do you want to comment further?

I just want to -- obviously, I totally agree with what Ross is saying. And I'm highly biased and what I'm about to say is the side share of the MANIFEST-2 study. But I saw that both in the monotherapy in Phase II, and you could see the results that were presented. BET inhibition is clearly active in this area. I mean it's clearly active. I don't think we have long-term follow-up to understand what it's really doing ultimately through the disease process. So the data looks great from MANIFEST-2. And Ross is right. I mean there's going to be a challenge, I think, approaching the FDA because it didn't hit that key secondary endpoint of symptom improvement. But I think the deltas in the detail, start looking at the subpopulations of patients, which I know might be problematic with the FDA, but you realize it's a [ 431 ] patient up for study, 400 of which were intermediate 1 and intermediate 2. So lower risk patients than in transform 1 with navitoclax, those are a high-risk patient population. And I do think that there's still a road forward for any inhibitor here. And we don't have enough data yet to get the full sense of what Incyte compound is going to do. But I think it's going to be used -- if it gets approved to be used in various ways, and we need to go back and look at whether there are any predictive biomarkers that would identify the subpopulation in the MANIFEST that might be best. And the most important endpoint in the MANIFEST-2 hasn't been read out yet, which is durability of response. And so regulatory endpoints aside for physician treating, what we want to know is are we actually effectively changing the course of disease. Are we prolonging the median duration of response. We know that the median duration with rux is about 2 to 3 years. We know five independent studies, the median survival about 1 year, 1.5 years of rux. It's a pretty bad situation. So we need therapies that not just hit spleen and symptom -- symptom is important. And I think the conversation with the FDA are ongoing to sort of redirect them away from this idea that it always has to be TSS 50 at 24 weeks. I don't think it has to be. You ask anyone who treats MF, if a patient feels better, patients feel better on rux. Why do you have to beat it on that? Why can't it be -- you get the deepest spleen response you can. It has not correlated with survival. They've shown that with COMFORT study, we believe it as a community. And then you don't compromise a symptom or you at least match symptom improvement with rux and have a toxicity profile that's not worse and even anemia benefit, which was shown, 1/3 of the patients with reduction in bone marrow fibrosis, I think you're going to see that with this drug. So I think it's the totality of the data that actually makes the difference. And can you keep patients on long on that.

Thanks, Paul. Maybe a question on 058, Patrick, you showed differential activity for the compound on the mutant form versus wild-type JAK2, but you didn't show any comparisons to rux. So I'm kind of trying to wonder whether you're actually aiming for greater OTC inhibition versus rux or lesser wild-type activity that might lead to better side effects in the Phase I study in a genotype patients, I assume?

So the second question first, no, there won't be -- there will be genotyping, and so retrospectively, we'll look, obviously, we'll know from the patients, and we'll be monitoring the burden in those patients. well. In terms of the comparisons with rux, it's forthcoming in the presentation today. So this is just a small sample of the data here.with the embargo, we decided to keep all the ASH presentations separate. So I encourage you to go through [indiscernible] data there. We'll see comparisons in terms of VF selectivity against rux. So the short answer is yes. We see distinct profile. We see temporal greater selectivity with this compound, rux is completely nonselective. Every JAK kinase inhibitor we test has no select selectivity for VF clone over a [indiscernible].

Jess Fye, JPMorgan. A few more on the BET. First, what was the average dose of rux used in those combo patients that you showed? Second, what specific learnings from the ongoing work in the clinic are going to point you toward Phase III design over the other, i.e., versus frontline suboptimal or monotherapy and rux failures? How do you expect your BET to differentiate from MorphoSys and others? And lastly, any thoughts on a triple combo with the ALK2 bet and Jakafi.

Okay. So let me take the second and third, and I'll ask Peter to comment on the design of the study. In terms of differentiation from Pella, look, they had a large randomized trial, we have a couple of dozen patients treated. So it's a little bit hard at this point. But there's a couple of -- our drug is more potent. That's pretty clear from the doses we're using compared with the dose of Pella. The relevance of that will be determining the clinic. I think the dosing could be a difference. And Dr. Mascarenhas highlighted this in his presentation. We dosed continuously. They dose 2 out of every 3 weeks, and that potentially could have an impact on symptoms in the long run, right? Because you're off therapy for a week. And if you think of the PET inhibitors, we show the single-agent data has a clear impact on symptoms, maybe that will lead to even better symptom improvement with our BET in combination. Obviously, those are at this point, hypothetical, but we need to keep that in mind. Sorry, the third question was the? The rux, no, the triple -- it's a little bit early for me to tell you. I mean, there's some overlapping toxicities when it comes to hematologic it's certainly something we could test once we have the recommended dose for both BET and ALK2 combination with ruxolitinib. So it could be something that we explore in the future. And Peter, the first one is for you, the dose of rux and the BET combination study.

[indiscernible].

Okay. I think there was one here. Who else your head point Yes.

Thanks very much. I actually have an axatilimab question to be a little different. You mentioned that you're looking to move axatilimab potentially earlier in treatment. But I'm just curious because in the presentation yesterday, there was a slight bias for patients as a negative prognostic indicator for patients who had less than four lines of treatment. So I was wondering if you have any thoughts about that.

Yes. You're talking about the [ forest plot ] by different -- yes, [ forest plots ] are directional interesting, but you they're not -- those subgroups have not designed for real statistical comparisons. What I would say is in every subgroup we looked at, there is a treatment effect some with small sample sizes, those bars move a little bit too much one direction or another. So I'm honestly not concerned about that. I think that the mechanism of action of the drug, the safety profile and the efficacy we've seen all point out to the fact that it should work better in earlier lines of therapy. and we intend to test that starting next year. Back there, and then we'll come back here.

[indiscernible] on Salveen Richter's team at Goldman Sachs. Just wanted to dig a little bit deeper on the first question that was asked as part of the QA. You talked about the correlation with ALK2 -- with the ALK2 inhibitor dose level in hepcidin. I'm just wondering if there's any correlation with hepcidin and hemoglobin levels? Hepcidin levels and hemoglobin levels?

No, that we've seen -- when you see the -- when we looked at the patients with the best hemoglobin response, not all of them had the best hepcidin response. I think that's what I can say at this point from the data that we have. And I think that from my perspective is to be expected because I think the anemia in these patients is multifactorial, we're fixing 1 problem. I think with rux we fix other part of the problem, which is shrinking the spleen, for example. So altogether, that's what we expect to see. But direct correlations with those could be -- I think they're going to be difficult to find.

And just one quick question on 058. In the xenograft mouse models, you showed the impact of the drug on the mutant clones and then comparison to rux alone. Just wondering if you also did that in combination as 058 in combination with rux and given that rux was already pretty low, do you think there could be an added benefit or maybe you're approaching a floor effect there?

Yes. So a few caveats with rux in those models, we're using, at least in that example, doses of ruxolitinib that probably aren't clinically achievable for patients, but I think it's just to show the effect of the ability of a potent JAK2 inhibitor to eliminate outcomes of dose high enough. And your second question around combinations, we're starting to explore now. There was no combination test in that model, but it's something we're considering and exploring.

We have time for one or two more. Let's go here. I'll just several. We'll try to get to everyone 1, 2, 3, 4, we'll go from the front to the back.

This is Vikram Purohit with Morgan Stanley. So we had one on the ALK2 program. We'd appreciate a munition viewpoint on. So for nontransfusion-dependent patients, what level of anemia would trigger the use of an agent like zilurgisertib? And what level of clinical benefit would you need to see to keep patients on the ALK2-rux combo going chronically?

That's a tricky question. So anemia is a sliding scale and every patient is quite different and their ability to tolerate anemia is quite different. So typically, by design, we say less than 10 is anemic. But we have patients that walk around with the move them to 7.5, and they're not cardiovascular stressed by it. Typically, with transfusing patients if they're less than 7, if they're between 7 and 8 and have symptoms using the -- so those are clinically meaningful levels of anemia. We do anemia of less than 10 up scores a person from a risk scoring perspective, but it's been a higher risk score. So it has a -- it has a meaning from a prognostic standpoint, that's not totally clear. And there is some data for it is that if you correct me, we do improve outcomes. So with momelotinib, for example, there was this correlation between transfusion independence and survival study and maybe a hint of it in momentum at 24 weeks, but then there was crossover. So there's two aspects. It's the here and now improving hemoglobin and improving performance in symptomatology, which doesn't always correlate. So sometimes you can transfuse MF patients with 13 they'll still tell you fatigue and unwell. So there's not a direct correlation as been said multi times. The problem here is that anemia is multifactorial complex. It's not all dependent. -- symptoms are multi -- anemia is multifactorial like symptoms or multifactorial complex and they're not always tied neatly together. So for our purposes, when we write trials in new trials, usually hemoglobin in 10, less than 10 is considered where we're going to intervene. But in the community, can matter. It really depends on the patient and the situation.

Leonid here on for Brian Abrahams RBC Capital Markets. I just wanted to go back to axatilimab. Maybe you can walk us through your thinking on the regulatory process there, how the FDA might be looking at the [indiscernible] response curve when you file if they want to have a better understanding of potentially what's driving that mechanistically? And I guess to the extent to which the higher dose data where you saw lower responses, essentially more safety events can actually be supportive of proving the lower dose or whether you're going to try to keep those separate?

Yes. I would look at it a little bit differently. I don't think we have an inverse, a [ true inverse response ] effect. I think we have high dose, less frequent. -- and the less frequent is key there. The 3-milligram per kilo dose was given every 4 weeks. And I think that -- I think one thing we can learn from the study is that, that schedule wasn't as good as the every other week schedule. The other two arms are every other week. Then you look at 0.3 and 1 in efficacy, they're not that far apart. numerically, they're pretty close. And the safety is clearly better for 0.3. So I think that, for me, solves the problem with FDA. I'm honestly not concerned. We tested three doses, one less frequently, that didn't work very well and it was toxic. The other 2 every 2 weeks, the 0.3 is numerically better and significantly safer. So in a way, that's exactly what you want to be able to determine. It's almost really a good determination of the optimal dose of axatilamab in this setting. So I'm not too concerned what the regulatory to be honest with you. There was another one over there and then one in the back. And we're going to have to stop there.

Stephen Willey from Stifel. Maybe a question for the company and maybe the clinicians as well because I think Dr. Mascarenhas has done some work on JAK1. But just curious as to what the thoughts are around contribution of symptom improvement in myelofibrosis that comes from JAK1? And to what extent you might be losing some of that by dialing in at an 058?

Yes. Look, no question of JAK1 inhibition leads to rapid symptom improvement business of the math, and that's part of the story, which I think over time, eliminate malignant clone may lead to the same effect. One question that we'll have to determine in the clinic is whether in some patients, you start with the combination sort of an induction with rux plus 1 of the newer agents, and then you taper the rux and you continue with one of the newer agents. But I don't know if Ross or John wants to comment further on that.

Ross I can comment from a biologic and from a clinical perspective, I can think about what we see when we give other JAK inhibitors that are in relatively spare JAK1. So the create, for example, utterly [indiscernible] JAK1 driving it for the most part, does too. You get -- you can get significant symptom improvement. I will say, and I think most of the treatment agree, Rux still gives you the best symptom improvement. I mean that's where you get probably the deepest and best reductions -- durable reduction in symptoms. So you can selectively target JAK2 with those other agents and get symptom improvement.

Yes. Maybe not a lot to add, but maybe to just were Pablo said. I think that in a scenario where the mutant cells remain there in significant fractions the idea that you can target both JAK1 and JAK2 allows you not only to impact the mutant cells biology directly, but the mutant cells are producing cytokines that then activate JAK2 and JAK1 signaling, not only in themselves, but in the entire microenvironment. So I think a dual JAK1/JAK2 inhibitor does have the ability to block sort of broad inflammatory signaling, which I think is part of the symptom improvement. But if you had a drug that could specifically deplete the immune cells more potently like 058 is designed and the hope is that it will do. You would imagine that over time that, that loop would get broken and that you wouldn't need the same amount of JAK1 activity.

We have two more, one on the line and then gentleman in the back. So it's Greg going to read it. Are we connecting or? Yes, you are on the line.

Our phone question comes from Jay Olson with Oppenheimer & Company.

Congratulate on the progress, and thank you for providing this update. For your BET inhibitor 643, can you talk about any changes you observed in hemoglobin levels Also, did you test for fibrosis improvement? And then are there any broad learnings from manifest that you would apply to your own clinical development plans. Specifically, can you talk about your views on the use of the absolute change of TSS versus TSS50 as an endpoint for a pivotal trial?

Yes. We have not -- we don't have the data for fibrosis yet. So I'm not going to comment on that. When it comes to the regulatory endpoints, basically, I'm sorry, is the same answer, which is -- at the time, when we're ready, which we expect will be in 2024, we'll have a conversation with FDA on the design of a pivotal trial. And I think historically, FDA has, as we discussed, as for spleen reduction, size reduction and symptom improvement. Whether it's one of the two endpoints that we heard about yesterday, I think it's something we'll discuss directly with the FDA. And as I mentioned earlier in the Q&A, we'll learn from experience of our friends at MorphoSys, whether the change your thinking in the FDA as to how to assess symptoms. Do you want a comment on anemia or...

Just we haven't seen any significant changes yet, which is interesting. But obviously, we're continuing to follow that over time.

Yes. And last, we're going to have to end with...

[indiscernible] Securities. We were wondering about the kinetics of the anemia response in the ALK2 trial. We noticed the patient had a response at 48 weeks. So like how long do you think some of these patients in your experience could be on treatment before they see one of those responses? And are there any sort of symptomatic or biomarker readouts that you could see along the way that would indicate they might have a later response?

Yes. It's a good question. I don't think we have enough data to answer the pattern and timing of response ALK2 inhibition. I think when it comes to hemoglobin, you see some of the changes relatively early, which probably is because of the quick effect on hepcidin suppression that you saw in the presentation. But I think we need more patients, more data, particularly in treatment-naive patients in combination with rux to determine what's the pattern of response after ALK2 inhibition. So I think time will tell. We're going to have to stop there. Thank you, everyone, for coming. I encourage everyone to attend JAK V617F presentation later today. There's additional data there. I hope that you got a glimpse of why we remain more than excited about, not just the current way that we can manage MPNs and graft-versus-host disease with our existing molecules, but the path for the next few years as we introduce novel ways to treat patients with both MPN and chronic graft-versus-host disease. Thank you, everyone, for coming. Have a great rest of ASH and safe travels home.