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, 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 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.
Following that, Patrick Mayes, 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 Langmuir from our group, that 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 for Q&A, so please hold your questions until the end. The way to think about Incyte today, it really is in four quadrants that you can see here. We're gonna 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 ALK2 inhibition, BET inhibition, as well as the mutant JAK2 V617F antibody. Also, important part of this plan is our once-a-day formulation ruxolitinib. But it's important to remember that we have a lot of activity at 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 a very exciting pipeline in oncology. With our anti-PD-L1, a unique program to really show that we can change a little bit how PD-L1 inhibitors are used and 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 at some point in the not-too-distant future. Just to highlight two important bispecific antibody programs, the TGF-beta receptor 2 by PD-1 and LAG-3 by PD-1, both of which are well into the clinic and will have data in the not-too-distant future as well. So oncology and hematology remain a very important part of our activities at 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 for povorcitinib, which we believe, and we've disclosed data that we think in many contexts, is best in disease, in diseases such as hidradenitis suppurativa, prurigo nodularis, and others.
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 by 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 at Incyte or collaborations, or in some cases, investigator-sponsored 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, the AGAVE, for axatilimab in patients with chronic graft-versus-host disease, was presented yesterday and we believe was very, very well received, and a number of other oral presentations, again, across our pipeline. We're gonna start with Jakafi, and as you know, this is a medicine that over the past 10+ years has really redefined the standard of care in three different diseases. When you think about it, it's 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 gonna stop there. The ways to continue to improve outcomes in patients with these illnesses is a combination therapy, and combination therapy with two are components of our pipeline, and you'll see a summary from that data from Dr. Mascarenhas, with ALK-2 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. With the introduction of two new mechanisms for the management of myeloproliferative neoplasms, a mutant CALR antibody and a V617F 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 MPNs. 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 the patients with PV, these are exclusively V617F 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 two 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 data was presented yesterday by Dr. Wolff and that Peter Langmuir will summarize in a minute. Initially, the interaction of axatilimab to patients with graft-versus-host disease would 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 III and one phase two trial, excuse me. A phase III trial in combination with steroids in first-line chronic graft-versus-host disease, and a randomized phase two 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 will provide more patient benefit and obviously is a much larger patient population for longer durational therapy as well. So a lot to have to come in the next five years or so when it comes to that left upper hand quadrant that I showed you, focused on MPNs and graft-versus-host disease. AXA, we will have the BLA submitted this year. If things go well, an approval next year is possible. We will initiate the two trials that I just described with ruxolitinib and steroids as well. For XR, I gave 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. We 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 spleen 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 JAK2 V617F inhibitor, those are just early programs. CALR is in the clinical already. We are treating patients. V617F, 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 has 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 in 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: PV, myelofibrosis, and ET, but 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 MF. 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. When I began in this field as a young investigator, in fact, during my training as an oncology fellow, my initial project was to try to begin to understand the genetic basis of these diseases, and my assignment was to see if we could find the mutant gene or genes that were relevant to these diseases. 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. 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 gave us a toehold of how to develop therapeutics. We know that this is an incredibly common mutation in about 90%+ of PV and 50%-60% of MF and ET. We know that it's constitutively 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, that 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 U.S.e of ruxolitinib in 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%-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 which 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 them.
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 aberrant signaling. But you should always think of these diseases as really JAK-STATopathies or driven JAK-STAT signaling. But what we've learned from the JAK2 VF mutation, from the seminal studies on the CALR mutation, resulting in aberrant mCALR trafficking, as well as on the MPL 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 it changes 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.
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 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. 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. That is my own opinion as someone who's studied these drugs for a long time.
We believe that this is the standard of care, but we do need to do better. I think one of the questions, and I'm really excited to see Incyte working on this so hard in the past five years, is you need to not just rest on the laurels of great success, but you gotta 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 in improving counts 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 their 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 pathway that are relevant? And can you use those therapies either as a combination partner, or would they have a role as monotherapy? And I think the questions are out there, and we have some information, and we'll get into where we think the answers to those questions are today. Then the second is: can we build on the success as a field, and can Incyte build on the success as a company of current JAK kinase inhibitors to develop really next-generation drugs? And that is obviously what we're all excited 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 activities is significant, but also seem to have preclinically significant activity in combination with a JAK inhibitor. And probably three most high profile right now are BET, which we'll hear about today in a few minutes. Bcl-2, 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 Bcl-2 and not Bcl-XL, you need a strategy to go after Bcl-XL, and that's the challenge of thrombocytopenia and threading that needle. And then ALK2, which we'll hear about.
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. 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 that we're beginning to see, obviously, data from large combination therapy trials. We saw data in the last 18 hours from the first ruxolitinib randomized phase III trial.
So one of the questions, which I don't think we know the answer to, I think we're gonna learn, is: is just reducing spleen weight with maybe a slightly less significant improvement in symptoms, gonna be enough to, one, have a meaningful difference for patients, and two, for it to be approvable? I'm not here to give a handicapper's 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 mutant allele 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 thing to pay attention to is toxicity and dose modification as these studies are done. 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?
Thrombocytopenia, as you might imagine, is the one that we pay the most attention to, and particularly, for the Bcl-2, Bcl-XL is the biggest challenge. 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, where you have JAK plus a particular other biomarker, would they benefit from a specific combination? So what does this mean? I think ruxolitinib monotherapy will remain a preferred therapy of choice for most patients. Obviously, we're hopeful that the combination therapies will iterate and improve, but it's still gonna 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, for other scenarios where mutant-selective drugs have been done. 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 CALR, but hopefully, maybe I can 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 aberrant gain-of-function of mutant CALR, if it does in the clinic what it did pre-clinically, could be a definitive, incredible therapy for the CALR mutant patients. It will obviously start in myelofibrosis, but if it's incredibly efficacious with wide TI, there's no reason to think that essential thrombocythemia wouldn't be on the radar. There's a significant fraction of ET patients with CALR mutations. JAK2 V617F-selective therapies are exciting. It is the driver gene in this disease, and this is an exciting discovery and development that, as you'll hear, is going to go into the clinic.
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 inhibition 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. That's sort of my perspective on where they are, and I think I was going to turn it over. I believe that 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 at 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 gonna give us an overview of the data that we presented to date with our BET inhibitor program and 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 Steven Fruchtman and Paul Friedman, 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 BET inhibitor INCB057643, and of course, there's a lot of attention right now for BET inhibition, particularly in this field.
What I'll do is I'll summarize what I'm about to show you, and then we'll end up back at the same summary. So improvements in spleen size and symptom burden with the Incyte BET inhibitor INCB057643, ± ruxolitinib. Monotherapy or 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 the...
One of the main drivers behind understanding the biology of, of myelofibrosis and the contribution of JAK-STAT signaling, but also NF-κB, which multiple labs have shown that is upregulated in MF. And this provides a really unique opportunity to inhibit that BETs or epigenetic reader proteins that bind to lysine residues, either on histone or non-histone proteins, and in, in this case, facilitate the activation of NF-κB and the expression of NF-κB-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 in potently inducing responses in JAK2-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-κB, Bcl2, c-MYC, 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 Raajit Rampal, and 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 INCB057643. That's in a phase one dose-escalation study, starting at 4 mg QD. So this is dosed daily.
So, the MorphoSys drug is two weeks on, one week off, a little bit different, daily, and exploring the safety of this drug at different levels from 4-12 mg, so continuous in a 28-day cycle. In this patient population, these are patients who have relapsed/refractory myelofibrosis, but also could have other related disease, 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've failed JAK inhibitor or have overlap syndromes. In part two is where I think it starts to get even more exciting. It's combination with ruxolitinib. These are the 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 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 deserves a lot of attention. So there is 2 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.
This is a little bit different than the MorphoSys data, which is mostly intermediate-1 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 the spleens are big, particularly in the patients who in the relapse refractory setting, so 2,000 cubic centimeter spleen, so 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. This is a well-tolerated BET inhibitor. So grade three 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 mg in the monotherapy. Thrombocytopenia in an overlap syndrome patient at 12 mg. And at 6 mg, so right now it's 4 mg and 6 mg 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 transformation to AML. That's part of the natural history of the 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. I will point out that dysgeusia or alteration in taste is common across the BET inhibitor space. We saw it with the BMS compound, saw it with the pelabresib as well. This is low-grade, rarely a reason patients would stop therapy, as they usually feel globally better on these therapies. Here is the monotherapy spleen response. Again, this is color-coded, so it's dose escalation, color-coded by the dose of 7643 that was provided to the patients.
3 patients met, you know, 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, 5 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, in which the bar is probably high, you know, 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 4 and 6, that are color-coded.
At week 24, one patient receiving the 4 mg dose hit SVR 35%, but the graph is showing you the best spleen volume responses on study. Again, you can see 1 patient in combination had a 45% reduction. These are patients again who had suboptimal responses to ruxolitinib. So you're 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, improving symptoms. So monotherapy, three patients met the regulatory endpoint of TSS 50% improvement. These are at doses 10 mg 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 BET inhibitor monotherapy.... This is in combination with ruxolitinib. So two patients hit TSS 50% at week 24, one in each cohort, four and six mg. But you can 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 a regulatory endpoint, but these 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 INCB057643 at 8 mg QD in monotherapy, but both 4 and 6 mg in combination therapy. This was well tolerated, both as monotherapy and combination. Dose escalation is with monotherapy is complete for monotherapy, but continues with combination therapy. And it's currently enrolling into the 8-mg cohort, and there's plans to open the phase III study in the second half of 2024. And again, this could be potential first-line in combination with Rux, again, salvage, with patients who are saw and 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. 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, 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 shown 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 BMP, signals through SMAD signaling intracellularly, and governs the expression of HAMP, which is a gene for hepcidin. Hepcidin is markedly elevated in these inflammatory states and chronic anemias and negatively regulates the access for erythropoiesis, access of iron for erythropoiesis through binding of the ferroportin 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 the 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, the safety and tolerability in a 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 eight weeks prior to cycle one, day one, they required at least four units of red cell transfusions. Here are the patient characteristics of 46 patients that have been enrolled to date at the study data cutoff of August first.
There is one patient that has been treated in combination in JAK inhibitor, but that's not, that's not being 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, you know, mostly higher risk, intermediate-2 and high-risk patients, who've previously seen ruxolitinib. So this is an advanced patient population. Anemia is very prevalent in these patients, and it's very troublesome. It links 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 healthcare system. So these patients had low hemoglobins. Those are high hepcidin levels, as one would expect.
This was a well-tolerated drug, as I would have anticipated. Dose escalation is ongoing. MTD has not been reached. One dose-limiting toxicity occurred of grade 3 alveolar hemorrhage, which I've 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. One treatment-related adverse event led to study drug discontinuation, which was hyperferritinemia at 200 mg add-on therapy. You could see the adverse events for monotherapy on the left and in the combination for the add-on strategy on the right. There is minimal grade 3 for toxicity here. And most...
I would, 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 rarely a reason for concern. So from my, my perspective, very well-tolerated, therapy at this point. And effectively reduced hepcidin as a pharmacodynamic readout of on-target activity, at 100, 200, and 400 mg once daily as monotherapy, and, and even, perhaps, you know, optimally at 400 mg in combination with Rux as combination therapy, and durably over the, the course of follow-up.... and improved hemoglobin. So, these lines are a little bit hard to, to sort of, follow from my perspective, but, what we're trying to show you here is the, the change from baseline in hemoglobin over function of time, from dose, from first dose in weeks.
So you can see that the dotted lines are, you know, 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 zero, so improvement in hemoglobin at different doses in the add-on strategy in these patients that are treated at 100 mg, 200 mg, and 400 mg. 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 treatment-emergent adverse events. MTD has not been reached, and the dose escalation continues with the clinical proof of concept for mid-2024. I think that's right. I'm personally excited about these therapies. I know if, if there's one company that's going to move them forward, who's been invested in this space from the beginning, it's 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, mutant CALR 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'll tell us about the two programs, and we can address questions at the end. Patrick?
Okay. I'll begin with an overview of INCA033989, 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. So CALR acts as an oncogene through rogue chaperone function, where it binds abnormally to the thrombopoietin receptor TpoR, forms a complex at the cell surface, leading to constitutive signaling through JAK-STAT, as you heard. Our antibody binds to mutant CALR and disrupts the complex of mutant CALR and 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 a 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. 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 and 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 a megakaryocyte differentiation, and you can see a significant effect of megakaryocyte differentiation in a sample with mutant CALR with INCA033989 treatment, whereas no effect is observed in an MF patient sample harboring a JAK2 V617F mutation. We went on to test INCA033989 in a genetic mouse model of ET. In this model, disease is established over an 8-week time course, at which point INCA033989 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 INCA033989 treatment on platelet counts within the blood.
And in fact, at this five-week time course, 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 we're pointed out with the arrows there, that are present in the bone marrow in these untreated mice 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 observe 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 post-treatment 12-week time course. So in summary, for 989, this is a potent selective antagonist of mutant CALR function. We've demonstrated here using patient samples from MF harboring a CALR mutation, as well as in multiple mouse models of MPNs with a CALR mutation. These observations provide the rationale for an ongoing clinical investigation of 989, which is occurring in MF ET patients with CALR mutations. And 989 is being explored as a monotherapy, as well as in combination with ruxolitinib in patients with MF, and as well as a monotherapy in patients with ET.
So I will transition now to an overview of INCB160058, 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 patient, 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 O58 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 JAK2, 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 through binding 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. The V617F mutation has been shown to change the conformation of JAK2 in a way that prevents auto inhibition of the active kinase from the engagement of JH1 and JH2 domains.
INCB160058 binds in a pocket in close proximity to V617F, changing the conformation 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 INCB160058 and its ability to inhibit the cytokine-independent signaling through JAK2 V617F, while 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 P.M. this afternoon, session 631, where a more extensive data set will be represented for INCB160058. You can see really the key selectivity towards V617F.
This is a demonstration of that selectivity here with cell lines on the left, MPN patient samples on the right, demonstrating the ability of O58 to inhibit JAK-STAT signaling more potently in a cell with V617F mutation, as shown in red, as compared to a cell with a 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 O58 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 intracellular form of the 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 Wilmes 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 FRET method developed by the lab of Dr. Jacob Piehler at the University of Osnabrück. Through a collaboration with the Piehler lab, we've tested O58 and our JH2 binding compounds, and what we see is a, 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, 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 JAK2 V617F cells are labeled with GFP, co-cultured together with cells that are unlabeled, and then we can treat with O58 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 showing selective functional effects on a JAK2 V617F cell survival and function in a system like this. We also tested O58 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 irradiated 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 INCB160058 in its ability to selectively inhibit the engraftment of mutant JAK2 V617F CD34 cells, while having no effect on wild type CD34 engraftment in the bone marrows of these mice. And this is distinct from a high dose of ruxolitinib, as shown here, which equally affects cell engraftment 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 INCB160058 to inhibit that pathogenic increase in cytokines is shown in blue. Whereas INCB160058 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 INCB160058, we've developed a potent and selective inhibitor of mutant JAK V617F through the binding, the novel binding, really, of the JH2 domain. And this results in the reversal of the auto inhibition of the enzyme.
Through this V617F selective function, 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 INCB160058 to reverse a cytokine-independent receptor dimerization, while sparing function against wild type JAK2. And as I said, initiation of clinical trials for INCB160058 are expected to start first quarter of next year. So I'll stop there.
Thank you, Patrick. We're gonna shift gears now to chronic graft-versus-host disease. Peter Langmuir, who's heads our Oncology Targeted Therapeutics group and oversees, has been overseeing the axatilimab program for quite some time, is gonna give us a summary of the AGAVE data that was presented at 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. Excuse me. 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 replaced one terrible disease with another. And so patients can live for years with significant complications involving just about any organ system in the body. It's the major cause of non-relapse mortality in patients more than two years out from transplant.
Though overall survival, median overall survival, is relatively long, these patients suffer significantly. They have significant contractures 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 agents. It's the moderate and 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 will have eye involvement if they're 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 hits 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. And so monocytes will differentiate into macrophages that may either have an inflammatory effect, driving the GVHD, or particularly important, a pro-fibrotic 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. 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%.
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. This was a 3-arm study looking at three doses of axatilimab. The 1 mg/kg every two weeks was the dose that was felt to be optimal from the smaller early study. We had a 3 mg/kg every four weeks to see if we could dose a higher dose less frequently, and then a 0.3 mg/kg dose every two 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 two years of age.
We did end up with a handful of pediatric patients. The youngest patient was seven years old. Patients had to have had at least two prior lines of therapy, so these were fairly refractory patients. As I'll show you, patients that actually received 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 have been met if the lower bounds 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 disease, it was four 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 two prior therapies, the median number of prior therapies was four, and you see one patient had received actually 15 prior therapies. So these were really patients who were 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 twenty-three percent 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, and over half the patients had more than four organs involved. And most of the patients, 80%, had severe GVHD. So this was a pretty sick, very heavily pretreated population. As we heard yesterday, the primary endpoint was met in all three cohorts, so that lower bound of the confidence interval is greater than 30% in each case. But very clearly, you see that the most effective dose was the 0.3 mg/kg every two weeks, with a response rate of 74%.
Compare that to the 66% response rate at the 1 mg/kg every 2-week dose, and 50% in the 3 mg/kg 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 continued to improve over the course of dosing. 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, so the responses based on whether patients had received prior FDA-approved therapies, ibrutinib, belumosudil, and ruxolitinib. What you see in each of these cases is 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.
This is just data for the 0.3 mg/kg dose that we're showing here. These are the 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. So we certainly heard from investigators that skin definitely improved, 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. 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 were not many effective therapies available to these patients, but definitely a very encouraging median 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 study was 19 months, and for belumosudil in 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 mg 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, the 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 mg/kg dose level. If you look at the rate of discontinuation, 6% of patients on the 0.3 mg/kg 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 result 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 a 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 mg 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 3 dose levels in this study, but very clearly, the 0.3 mg/kg dose level provides the best efficacy and safety profile, and the best, you know, 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. 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 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. Two, three, four. Okay, lots of questions. That's good.
Hi, Eva Privitera from TD Cowen. Thanks for the presentation and for taking our questions. For the ALK2 program, what, 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?
So it's interesting because I think in MF, I think obviously hepcidin is an important part of the mechanism why some of these patients 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 or anemia prevention, depending on the patient, is not quite, quite linear.
So I think it's gonna be highly variable from patient to patient, and I can't tell you there's gonna be a target that we need to reach on everybody. I don't think it's gonna be quite that straightforward. Peter, I don't know if you want to comment further. Okay, thank you. I think the second one was here, and then I'll try to... Please keep your hands up because it's gonna be hard to - Go ahead.
Hi there, Conor MacKay, associate on the Seigerman's team.
Yeah.
Thanks for taking our question.
Yeah.
I just had one on the sequencing of your combination therapies in MPNs and, you know, 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 on one of your slides, right, that you expect Rux to remain, Rux monotherapy to remain the mainstay in frontline, and then, you know, potential use of the combinations in the second line. I'm, you know, just curious, I guess, you know, why, why that's, you know, why you feel that is the case?
Yeah.
You know, sort of consistent with what I had heard the other day at another presentation and investigators say. 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? Thank you.
Yeah, so let me take the first part. So I think, there was a slide from Ross that talked about the mainstay in first line to continuous, so he should probably comment on, on how he sees that evolving. I think when you look at the data for BET inhibitor, I wouldn't rule out that we'll develop it in two different ways. It could be developed in second line, in suboptimal patients and in combination with Rux or as monotherapy. I mean, you saw the monotherapy activity, particular symptoms is pretty striking. And potentially, once we have more data, we can make a decision as to whether it's truly a first-line regimen. I think the data from, for instance, on MorphoSys, really shows that there, there might be a path there, for first line. So I wouldn't rule out first line and second line.
I think for ALK2, to answer that question more definitively, we need data from LIMBER Group C in the study, which Dr. Mascarenhas didn't show because we don't – it's still evolving. Once we have data in newly diagnosed patients in combination 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 your 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 can 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.
Will I choose it only for people where spleen is really the massive problem, subsets, other molecular subsets?" So I think when you bake those two things in, I still think there's a reasonably reasonable possibility that a lot of patients are going to begin with ruxolitinib. I am hopeful again, that we're, we're going to learn with some of these combinations, that there will be data that suggests 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.
Thank you. 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.
Hey, thanks. Michael Schmidt, 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, you know, it's interesting because symptoms are a key driver for why patients start on therapy with Jakafi, with MF particularly. And the improvement is very, very rapid. And you saw in one of Ross's slides, from the COMFORT data, just to remind everybody, the dramatic improvement in symptoms that Jakafi produces. But not everybody responds, and not everybody is asymptomatic. So there's still room, and I think there's still enough room for the right medicine to deliver symptom improvement in first line. Is that absolutely necessary for approval? Well, I think that's a conversation to have with FDA. We'll learn about that over the next few months, I predict. We'll learn more about the FDA's position on that regard. In the past, they have been pretty clear that spleen shrinkage alone is not sufficient.
Now, how much of a symptom improvement is sufficient in addition with dramatic spleen shrinkage? I think we're going to learn about that in the next few months, so I, 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 one, two, three, four, or some order like that.
All right. Derek from Wells Fargo. Thanks for taking the question. Sticking with the theme of BET, maybe for the doc discussing the BET, just how manageable do you think the grade three thrombocytopenia is, you know, for that combination? And is that something that kind of worries you with kind of the emerging profile of that program?
Before Dr. Mascarenhas jumps in with the answer, the slide did not show the grade 3. Numbers are small. The grade 3 thrombocytopenia is about 33%, so numerical doesn't look very different from the data presented for Pella. Obviously, the numbers are very small at this point. Dr. Mascarenhas?
Yeah. So I was going to say it's manageable. So you know, I mean, there's such heterogeneity in myelofibrosis patients. You're not gonna, you know, you're not gonna, expect the same toxicity or the same reaction toxicity if you go in with someone who already has 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, you know, modification and holding. But you know, I think we need to see more data for, you know, for this agent. But, you know, I think I just want to echo that ruxolitinib remains the mainstay of treatment.
Even with the pending approvals of other agents, I don't think it's really going to change that. There's such variability in the way. So about two-thirds of MF is actually treated in the community. It's not treated by Ross and I. If you canvass 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. 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 so, you know, 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, you know, a BET inhibitor, you know, at any point, at initiation. So the data that's being generated is helpful because you can demonstrate activity, you know, upfront, suboptimal, to provide that confidence to the prescriber to use it at any point in the clinical course and adjust for thrombocytopenia.
I think there's a gentleman there, over there, who's next. I'm trying. Eric, we'll go to you next. Okay.
Thanks, Reni Benjamin, JMP Securities. You know, the combination data with the BET inhibitor showed an amelioration of certain side effects, like nausea. I was kind of curious, and that was just one, there were several others. I'm kind of curious what the mechanism of action is there for your BET inhibitor. The other is for the KOLs. You know, if... There was so much data that came out with combination studies with Rux, right? There was navitoclax, there was, you know, a ton of them. As you either advise the company or if you had these two drugs, you know, in your own company, how would you decide to move it 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 on the combinations. Go ahead, Peter.
I don't know if I have a great explanation for the safety profile. I mean, I said 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, with-
Are there any other...? We're good? Who wants to go first on the-
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 that and the Bcl-2/Bcl-XL drug, there's pretty compelling rationale that they both target apparent, biology that's distinct from the JAK2 mutations or a sort of down by-product of, the mutations. The challenge is balancing that with their therapeutic index and is 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, tense yin-yang of efficacy versus. And I think that, you know, I don't want to put words in 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, are there platelet-sparing Bcl-2, Bcl-XL strategies, like degraders 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 BETs is that we all believe that there are 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 myelo parameters, and I'm waiting to see that data in the clinical, that I believe it offers clinical benefit.
The question is that, is it enough that you'll get it as an approved therapy across all the MF patients, or are you going to be figuring out, you know, 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, you know, tractable efficacy at where they're not always kind of worried about the platelet? I'm paying attention to that one, to toxicity and dose reductions and sort of what lots of sites are experiencing. I don't know if that helps, but that's my two cents.
John, you want to comment further?
Yeah. I just want to... Obviously, I totally agree with what Ross is saying, and I'm highly biased in what I'm about to say as the study chair of the MANIFEST-2 study. But, you know, I saw that result with the BET inhibitor, both in the monotherapy in phase II, and you could see the results that were presented. The 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 to the disease process. So, you know, the data looks great from MANIFEST-2, and Ross is right. I mean, there's going to be challenge, I think, approaching the FDA because it didn't hit that key secondary endpoint of symptom improvement.
But I think the devil's in the details. You start looking at the subpopulations of patients, which I know might be problematic with the FDA, but you realize it's a 431-patient population study, 400 of which were intermediate-1 and intermediate-2, so lower-risk patients than in TRANSFORM-1 with navitoclax. Those are higher-risk patient population. And I do think that there's still a road forward for any BET inhibitor here, and we don't have enough data yet to get the full sense of what the in-house compound's going to do.
But you know, I think, I think it's going 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 subpopulations, you know, in the MANIFEST that might be best. And the most important next endpoint in the MANIFEST-2 hasn't been read out yet, which is durability of response. And you know, so regulatory endpoints aside, for a physician treating, what we want to know is, are we actually effectively changing the course of disease? Are we prolonging the median, you know, duration of response? We know that the median duration with Rux is about 2-3 years. We know 5 independent studies, the median survival is about 1 year, 1.5 years when they fail Rux.
It's a pretty bad situation. So we need therapies that not just, you know, hit spleen and symptoms. Symptoms are important, and I think the conversation with the FDA are ongoing to sort of re-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 any patient, anyone who treats MF, you know, if the patient feels better, patients feel better on Rux. Why do you have to beat it on Rux? Why can't it be, you know, you get the deepest spleen response you can. It hasn't correlated with survival. They've shown that with COMFORT study. We believe it as a community, and then you don't compromise symptom burden. You at least match symptom improvement with Rux, and have a toxicity profile that's not worse.
And even, you know, anemia benefit, which was shown. A third 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 in can you keep patients on long enough?
Thanks, Pablo. Maybe a question on INCB160058. 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 potency inhibition versus Rux or lesser wild-type activity that might lead to better side effects. And in the phase I study, you're going to genotype patients, I assume? Thank you.
So the second question first. No, there won't be no—there will be genotyping, and so retrospectively, we'll look, obviously, and we'll know from the patients, and we'll be monitoring allele burden in those patients as well. In terms of the comparisons with Rux, with Rux, it's forthcoming in the presentation today. So this was 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 the talk, see the data there. You'll see comparisons in terms of VF selectivity against Rux. So the short answer is yes. We see a distinct profile. We see tenfold greater selectivity with this compound. Rux is completely non-selective. Every JAK kinase inhibitor we test has no selectivity for VF clone over wild type.
Hey, Jesse, J.P. Morgan. 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 one 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, on the design of the study. In terms of differentiation from Pela, look, they had a large randomized trial. We have, you know, a couple dozen patients treated, so it's, it's a little bit hard at this point. Our drug is more potent. That's pretty clear from the doses we're using compared with the dose of Pela. The relevance of that, you know, will be determined in the clinic. I think the dosing could be a difference, and Dr. Mascarenhas highlighted this in his presentation. We dose continuously, they dose two out of every three weeks, and that potentially could have an impact on symptoms in the long run, right? Because you're off therapy for a week.
If you think of the BET 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... Oh, the Rux, no, the triple. Yeah, well-
The triple.
The triple. It's a little bit early for me to tell you. I mean, I... 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 ALK in 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.
Yeah, I have that right here, but I think I can range the doses that were allowed in the study.
Okay, I think there was one here. Who else? You had one? Yeah.
Thanks very much. I actually have an axatilimab question, just to be a little different.
Sure.
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.
Yeah, you're talking about the forest plot by different. Yeah, those, you know, forest plots are directionally interesting, but you shouldn't. They're not. Those subgroups are not designed for real statistical comparisons. What I would say is, in every subgroup we looked at, there is a treatment effect. In 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 that 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.
Anoumid Vaziri, 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 and hepcidin. Just wondering if there's any correlation with hepcidin and its hemoglobin levels?
With what, I'm sorry?
hepcidin levels and hemoglobin levels.
...I know that we've seen it in the study. No, 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 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, honestly, because I think the anemia in this patient is multifactorial. We're fixing one 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.
Thank you. Just one quick question on 058.
Mm-hmm.
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 in zero five eight 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 mutant clones if dosed high enough. And your second question around combinations, we're starting to explore now. There was no combination tested 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 toggle. We'll try to get to everyone. One, two, three, four. We'll go from the front to the back.
Hi, thanks for taking our question. This is Vikram Purohit with Morgan Stanley. So we had one on the ALK-2 program. We'd appreciate a clinician viewpoint on. So for non-transfusion-dependent patients, what level of anemia would trigger the U.S.e of an agent like selumetinib? And what level of clinical benefit would you need to see to keep patients on the ALK-2 Rux combo going chronically?
Yeah, that's a tricky question. So, you know, 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, you know, we have patients that can walk around with hemoglobin of 7.5, and they're not cardiovascularly stressed by it. You know, typically, we're transfusing patients if they're less than 7. If they're between 7 and 8 and have symptoms, we're transfusing them. So those are clinically meaningful levels of anemia. You know, with anemia of less than 10, you know, up scores a person from a risk-scoring perspective, puts them in a higher risk score. So it has a meaning from a prognostic standpoint.
What's not totally clear, and there is some data for it, is that if you correct anemia, do you improve outcomes? So with momelotinib, for example, there, you know, there was this correlation between transfusion independence and survival in the Simplify 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 status and symptomatology, which doesn't always correlate. So sometimes you can transfuse MF patients with 13, they'll still tell you they feel fatigued and unwell. So there's not a direct correlation, as has been said multiple times. The problem here is that anemia is multifactorial and complex. It's not all dependent. You know, anemia is multifactorial and complex.
Symptoms like fatigue are multifactorial and complex, and they're not always tied neatly together. So, you know, for our purposes, when we write trials and do trials, usually hemoglobin at 10, less than 10, is considered, you know, where we're going to intervene. But in the community, it can vary. It really depends on the patient and the situation.
Second.
Thanks. Leonid here on for Brian Abrams at RBC Capital Markets. 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 inverse dose 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 and potentially more safety events, can actually be supportive of proving the lower dose, or whether you're going to try to keep those separate.
Yeah. 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, right? 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 other, every other week schedule. The other 2 arms are every other week. Then when you look at the 0.3 and the 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 don't... I'm honestly not concerned.
We tested three doses, one less frequently, that didn't work very well, and it was toxic. The other two, every two 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 axatilimab in this setting. So, I'm not, I'm not too concerned about the regulatory path, to be honest with you. And there was another one over there and then one in the back, and we're going to have to stop there.
Yeah, Steve 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.
Mm-hmm.
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 it out in INCB160058?
Yes. Look, there's no question that JAK1 inhibition leads to rapid symptom improvement versus the MF, and that's part of the story, which, I think over time, eliminating the 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 a combination and sort of an induction with Rux plus one 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?
... We're asking comments from a biologic standpoint. From a clinical perspective, I can think about what we see when we give other JAK inhibitors that are, you know, relatively sparing JAK1. So pacritinib, for example, utterly spares JAK1. Fedratinib, for the most part, does, too. You can get significant symptom improvement. I, you know, I will say, and I think most of the field will agree, ruxolitinib still gives you the best symptom improvement. I mean, that's where you get the, probably the deepest and best, durable reductions in symptoms. So you can selectively target JAK2 with those other agents and get symptom improvement.
Yeah, and maybe not a lot to add, but maybe to underscore what Pablo said. I think that, you know, 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 mutant cells more potently, like INCB160058 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 a gentleman in the back. So is Greg going to read it? Who's going to...? Are we connecting or-
Thank you.
Okay. Yes, you're on the line.
Our phone question comes from Jay Olson with Oppenheimer and Company. Your line is open. Oh, hey, congrats 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 U.S.e of the absolute change of TSS versus TSS 50 as an endpoint for a pivotal trial? Thank you.
Yeah, 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, it was 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 after the design of a pivotal trial. And I think historically, FDA has, as we discussed, asked 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 FDA. And as I mentioned earlier in the Q&A, we'll learn from the experience of our friends at MorphoSys, whether there's a change of thinking in the FDA as to how to assess symptoms.
You want to comment on anemia, or?
Just we haven't seen any significant changes yet, which is sort of, which is interesting, but obviously, we're continuing to follow that over time.
Yeah. Last, we're going to have to end with-
Hello?
Yeah.
Hi, Billal Jahangiri here. I work with Kripa at Truist Securities. We're wondering about the kinetics of the anemia response in the ALK2 trial. We noticed a 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?
Yeah, it's a good question. I don't think we have enough data to answer the pattern and timing of responses to ALK-2 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 ALK-2 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 the JAK2 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 MPNs and chronic graft-versus-host disease. Thank you, everyone, for coming. Have a great rest of ASH, and safe travels home.