Incyte Corporation (INCY) Earnings Call Transcript & Summary

Okay. Good morning, everyone, and welcome. Welcome those of you here at -- in Orlando at ASH, and welcome those at the webcast. Apologies for the late start. We had to adhere to certain guidelines from ASH, and there was no way to schedule this. And 2 of our speakers were busy presenting actually scientific data at the meeting. So we were forced to start a little bit late. So thank you for your patience. I'm sure you had an opportunity to grab some lunch. We're going to spend the next 45 minutes or so reviewing data from our 989. We're going to call it 989 for short program with you. I think this data, some of it was presented in June of this year at AHA in patients with ET. And yesterday and today, you heard from 2 of our speakers today about the translational data and the data in MF. We think this is a really important moment for patients with MPNs and for Incyte. We think 989 not only has the potential to redefine the standard of care in patients with MPNs, but to really redefine the goal of therapy in these patients. You're going to see a lot of data over the presentation about the ability of 989 to not just induce impressive clinical responses, but to really normalize hematopoiesis in some of these patients. And we believe that is, over time, going to show that the goal of therapy in these patients has changed. It's not just symptomatic improvement, but it's true potential for disease eradication. So we'll walk through that data. Forward-looking statements, our agenda here today, I'll be brief, and then I'll hand it over to Dr. Claire Harrison, who's going to talk about MF to again reset where we are with this disease today. John Mascarenhas, who just presented at ASH, will go over the data for the single-agent cohort in patients with myelofibrosis and the combination with ruxolitinib and Dr. Beth Psaila will talk about the translational data, which was presented yesterday. Our CMO, Steven Stein, will talk about the next steps and how are we advancing this new medicine into pivotal trials. We'll have plenty of time for Q&A. Briefly introducing our speakers, Dr. Claire Harrison, I think many of you know her Deputy Chief Medical Officer at Guy's and Thomas' Hospital and Professor of Medicine at Guy's and Thomas' Hospital. John Mascarenhas, Director of the Center of Excellence for Blood Cancers and Myeloid Disorders and Professor of Medicine, the Icahn School of Medicine at Mount Sinai; and Bethan Psaila, Associate member of the Oxford Branch of the Ludwig Institute for Cancer Research and Professor of Hematology at the University of Oxford. Just to set things up for the next presentations, as you well know, almost all patients with myeloproliferative neoplasm have disease that is driven by 1 of 2 mutations that are mutually exclusive. That is a mutant CALR, a mutation that is about 25% of the patients with ET and 35% of mutant -- MF or a V617F mutation, which is the remaining of the ET/MF patients and almost all the patients with PV. Our goal at Incyte is by the end of this decade to have a targeted therapy for every patient with the myeloproliferative neoplasm. So what you're going to see today with 989 is the first step in that journey, a journey that will continue with a T-cell engager for CD3 and CALR with the V617F inhibitor and other programs that we're working in discovery to address the needs of every patient with an MPN. To remind everyone, I think you heard probably a couple of times this over the last 2 days, so I won't spend a long time. 989 is a mutant CALR specific antibody. Mutant CALR protein binds in a mutated form with the TPOR receptor, travels to the surface of the cell and signals, and that is an oncogenic driver signal. What the antibody does is disrupt that heterodimer, the complex is internalized and degraded. It is a specific targeted therapy for patients with mutant CALR myeloproliferative neoplasms. What you heard yesterday, today and you're going to hear tomorrow comes from these cohorts of studies. The monotherapy in patients with essential thrombocythemia will be presented tomorrow. We announced this morning that we received breakthrough designation for patients with essential thrombocythemia. We requested that from the FDA for patients with type 1 mutations. It's the data that we had at the time that was most compelling. We wanted to accelerate that approval. We received that. Now we're going to discuss with FDA the pivotal trials in patients with ET and Steven will talk more about that. You heard from John, you're going to hear again today, monotherapy in MF and combination. And importantly, we are in the process of enrolling patients with naive MF, previously untreated disease to randomization of 989 versus 989 ruxolitinib. That data, which we'll have in 2026, will inform a potential first-line pivotal trial in patients with MF. These are the abstracts. I think you heard from the 2 on the right, the one on the left, it's going to be tomorrow, which is an update of the data that we presented on ET. I will now hand this over to Dr. Harrison so we can get with the kind of the agenda, and I look forward to seeing you in a few minutes for the Q&A. Claire?

Thank you very much. So it's my job to give you a whistle-stop reminder of myelofibrosis. I think the pictures kind of say it all really. This is a disease that all 3 of the clinicians at the podium struggle with and our patients have a constant battle with. You're aware of the key characteristics, clonal driver mutations, myofibrosis, splenomegaly and symptoms. Among the MPNs, because we are also talking about ET to some extent, of course, this is the disease with the worst prognosis for patients. Anemia is a key feature of this disease, and it becomes increasingly prevalent over time. So 35% of patients at diagnosis and then by 1 year, more prevalent. What you see on the right-hand side is survival of patients stratified by the presence of anemia of different degrees. And you can see that severe anemia clearly has -- is a marker of a patient with the worst type of prognosis, 2.1 years. What we also know and have learned in recent times is that improvement of anemia is linked to survival benefit for our patients. So our management goals are controlling splenomegaly, alleviating anemia, improving symptoms, but primarily as clinicians, we want something that also is going to improve survival for our patients. The RNA isn't lost on me that in 2011, I was in a room like this with Incyte in search for stat sig offset presenting the data from the COMFORT study, which led to the approval of ruxolitinib, which is still the standard of care. At that time, I said I thought 70% to 80% of patients with myelofibrosis would get that drug. And indeed, that's true today. It's a very good drug. It prolongs survival and improves quality of life for our patients. But when they fail that drug, there are very few other options for them. And what we see is often patients are cycling through other JAK inhibitors, which have the same target and the same or indeed, definitely in the second line, less benefit for patients. Once we move from our first-line JAK inhibitor, outcomes for these patients are poor. So this is my conclusion slide. I really don't think you as an audience need an introduction to the disease, but just to set you where we are today and where we hope to be in the future. Thank you very much. So John, I think I'm handing over to you.

Okay, Claire. Thanks for setting the stage. Now I'll get into the preliminary efficacy and safety results. This is from 2 Phase I dose escalation trials involving 989. This is the myelofibrosis data that we literally just presented and I'll just remind the group that the CALR mutation is present in at least 1/3 of the patients with myelofibrosis. There is a link between the higher VAF and worse outcome, including more advanced disease, anemia and increasing circulating blasts. And the treatments that we have right now are mainly JAK inhibitors. They're not mutant targeted. And the reality is we have very ineffective agents for reducing VAF as a surrogate for better outcomes. So there's a lot of rationale for why treating our MF patients that are mutant CALR expressing would make sense with an antibody. And this is the MF portion of this study, which also includes an ET cohort, and we're going to be discussing the results of patients, both monotherapy and combination who get 989 with mutant CALR positive disease. Of course, it's a Phase I study, so it's DLT and treatment-emergent adverse events that are going to be characterized. We're also looking at secondary endpoints outcome measures. So what I'm going to do is focus first on the monotherapy cohort. This was 52 patients. You can see the baseline characteristics and demographics of these patients. I'll draw your attention to the distribution of types of CALR mutations that were present. The median VAF was 36%. And it was supposed to be a relapsed/refractory group of patients, although you could -- the investigator could deem a patient ineligible for a JAK inhibitor. So there were 10 patients that got on that had not seen a JAK inhibitor previously and I'll highlight that as well. And these are the baseline counts. The baseline spleen volume is 1,300, the symptom score 21. And you can see the various doses from 24 milligrams, which we started in the U.S., all the way to 2,500 milligrams ex U.S. It is -- as I said, it is a super well-tolerated therapy. I've done in our Phase I studies that this is probably the best tolerated therapy I've seen in this setting. And you can see the treatment-related adverse events were 57%, Grade 3, 4, 30% and serious were 5. I'll just mention the one serious just in case it comes up as a question, was a patient who had monoclonal B-cell lymphocytosis, which is not uncommon, and these diseases do progress. In this case, mantle cell lymphoma with the intestinal obstruction that I don't think is related to the study drug but could happen naturally in patients with myelofibrosis. There really were infrequent dose reductions and interruptions of the infusion. I should mention if it's not obvious, this is an infusion every 2 weeks. And there were no dose-limiting toxicities in this study. And therefore, there was no maximally tolerated dose noted and 86.5% of patients remain on study, which is also, I think, quite remarkable, considering this is a relapsed/refractory population, and this is an unmet need with a very well-tolerated therapy. So it speaks to the fact that patients were coming every 2 weeks to get this therapy, and they were obviously seeing some sort of benefit not having toxicity that would keep that retention rate that. There were some AST elevations in 11 patients, 9 out of the 11 resolved, 1 grade -- 2 Grade 1s were ongoing at the time of the data cutoff. And what we saw was that patients who had Grade 1 elevations at baseline, which is very common because of extramedullary hematopoiesis were more likely to have this transient up and down effect of their LFTs that wasn't clinically significant or meaningful. And this didn't really lead to dose delays or discontinuations. So there was no -- importantly, there was no treatment-emergent adverse event profile that was dose related. On the right, you can see the -- irrespective of attribution, the common adverse events of 15% or greater, very minimal Grade 3/4 toxicity and the things that you would normally expect in patients with advanced myelofibrosis including anemia and thrombocytopenia, are there at low frequency. So very well tolerated, very easy to give. We did see meaningful spleen responses with monotherapy 989 in this relapsed/refractory setting. What we've done is grouped the doses by low dose, 240 to 250 and then 400 to 2,500, which is in the darker blue columns and the asterisks note the patients who are type -- non-type 1 CALR mutant. So we saw at week 24, 42% of patients achieved an SVR25. That's a regulatory endpoint in the relapsed/refractory setting. 33% achieved an SVR35. If you look at best SVR, 48% and 31% achieved, respectively, at SVR 25 and 35. And most patients baseline assessments were performed prior to JAK inhibitor washout. So there's always that phenomenon that occurs. If you look down below at week 24 data, it's pulled out by whether patients had a prior JAK inhibitor and in this evaluable population, the denominator is 7. So the responses, not surprisingly, are higher in terms of SVR in the JAK inhibitor naive group with SVR35 of 57% and 27.6% in the relapsed/refractory setting. We also saw symptom improvement, and I can attest to this both not just the study, but the patients that I personally treated. We also saw symptom improvement that was very reproducible. 93% of patients had experienced improvement in their symptoms, 60% achieved the regulatory endpoint of TSS50. And at week 24, 39% of patients had a TSS50. And again, the asterisks show us the non-type 1 patients. And if you look at week 24, the TSS50 response of 39% for all comers is not as high as the 60% in the non -- no prior JAK inhibitor therapy, which is, again, not surprising. I think really importantly, beyond the spleen and symptom benefit, we saw anemia benefit here. This is divided by the baseline anemia. So in blue are the patients that would be deemed by IWG criteria to have anemia, less than 10 in a men and less than 11 grams per deciliter in a woman. Both green and blue curves improve pretty quickly, but I think it's quite notable that the anemic patients really have an improvement in their hemoglobin. We saw that in patients that were receiving transfusions and have a lady who's been out of the transfusion suite for over a year, and it's quite remarkable. So if you look at it from ELN-IWG 2024 response criteria, the response rate is 56%, and that includes 10 major responses and 4 minor responses. But all these responses are clinically meaningful to patients who are with myelofibrosis who are anemic. We did see VAF reduction as well. Again, it's color coded by dose range. I think what's complicated in looking in -- early in a Phase I study in a dose escalation study is that there was intra-patient dose escalation. So I don't know that we get the full picture here. But nevertheless, 90% of patients had at least 1 post-baseline VAF assessment and 10% of those patients had achieved a 25% or greater reduction in their VAF. This is the combination. So that was all monotherapy data. So this was the 20 patients who came on. They were already on ruxolitinib and then 989 was added because they were deemed suboptimal responders. So you can see the baseline characteristics here. Again, 60% type 1, meaning CALR VAF is 39%. The median -- the mean daily dose of ruxolitinib was 35. So they weren't underdosed with ruxolitinib for the most part. And you could see the baseline counts, the TSS score is 15, spleen volume is quite large, 23, 51 and then the doses that were used in this dose ramp-up. Again, very well tolerated, tolerated as monotherapy, tolerated in combination with ruxolitinib, 55% Grade 3/4 treatment-emergent adverse events, 5 that were serious. There was a patient here who developed non-Hodgkin's lymphoma. I would still argue that this is what we see in these patients with advanced disease very frequently. And there was very infrequent dose reductions, infusion interruptions or really dose delays. There were no DLTs and again, no MTD in combination with ruxolitinib. And the profile looks, I would say, rather similar to what we saw with monotherapy, what you would see with RUX treatment, maybe slightly more anemia, but only 10% thrombocytopenia Grade 3/4. Most patients did enjoy some spleen and symptom benefit, spleen is on the left and symptom is on the right. Again, color coded by dose. Best SVR at 65% achieved an SVR25 and 47% achieved an SVR35. At week 24, 50% and 25% hit those SVR25 and 35. In terms of symptoms, 81% of patients experienced a symptom improvement, 33% achieved a TSS50 at week 24. And there was -- on the right, you can see a stability in the hemoglobin curve. There was one patient who was non-transfusion dependent who did have a major anemia response by IWG criteria, but we didn't see worsening anemia at all. So in conclusion, I feel very confident in saying 989, very well tolerated monotherapy and in combination with ruxolitinib in patients who have a suboptimal response. And there was no dose-limiting toxicities, and we did not even hit an MTD with this dose escalation. 87% of the patients remain on monotherapy, 85% remain on combination therapy. That's I still think quite remarkable. And we did see rapid and robust spleen and anemia response as well as symptom improvements. And we saw at higher doses, which I didn't totally pull out here, at higher doses, we saw improvements in symptoms anemia even in the non-type 1 and type 2. So in my opinion, in my experience with some of these patients that at higher doses, you overcome what might look to be less responsiveness in these non-type 1 patients. And we did see reductions in mutant CALR VAF. What I didn't show here Beth is going to go over is some of the correlatives, which I really think speak to the this is really a potentially disease-modifying drug. So with that clear and robust proof of concept, I'm excited for Incyte to move forward with a pivotal registration study in the near future. So thank you.

Hi. So I'm going to go now over in a little bit more detail the molecular characterization of patients with myelofibrosis and ET who were treated with INCA033989. So you heard a little bit of background about the disease already from Claire and from Pablo, but just really to go over that in some detail again. So all MPNs arrive following the acquisition of a gene mutation in a blood stem cell that basically results in cytokine independent receptor signaling. In 1/3 of patients, that affects the gene encoding calreticulin. This actually came as a surprise when it was first discovered, reported actually in a pen session in 2013 at ASH because calreticulin is well known as a chaperone protein within the ER but hadn't been implicated in the context of blood malignancies before. So all known pathogenic mutations result in the same mutant-specific C-terminus on the protein, and that has 2 critical consequences. One is it changes the charge on that C-terminus, which forms an aberrant complex with a thrombopoietin receptor. And the second is that protein then loses the signal that retains it within the ER and the complex travels up to the cell surface where it induces signaling and also presents a really excellent opportunity for targeted therapies. So you've heard already that INCA033989 is a first-in-class antagonist antibody being tested in the context of ET and myelofibrosis in 2 first-in-human clinical trials in previously treated patients. And it's been shown to inhibit oncogenic signaling and proliferation of cells. So Claire was going over some of the physiology of the disease, but just to recap in a little bit on that and give you a little bit more detail. So mutant CALR MPNs result in a significant burden of morbidity and mortality. So most patients present with a condition called ET or essential thrombocythemia. Here, the mutation drives an increased number of megakaryocytes and platelets, and this causes significant symptoms that can have impacts on life and work productivity and also an increased incidence of bleeding events and thrombosis. Then 1/3 of patients will progress to a much more sinister cancer called myelofibrosis. So here, you get fibrotic remodeling of the bone marrow microenvironment and you get bone marrow failure, leading to cytopenias, in particular, anemia. And then extramedullary hematopoiesis occurs affecting the spleen primarily and patients get very painful splenomegaly and Claire showed a beautiful photo there in her image of a patient with a very large spleen. From this stage, 1 in 5 patients will progress further to a secondary leukemia that unfortunately is refractory to all leukemic therapies that we have. And patients at that stage have an incredibly poor prognosis, surviving usually 12 months after the diagnosis despite best available care. This progression occurs slowly over years or even decades and is associated with a gradual expansion of that mutant clone and evidencing this, you can see that the CALR burden at baseline, the so-called VAF or variant allele frequency is higher in the MF patients than the ET patients at baseline. So one thing to note about -- when we talk about VAF is that most patients with mutant CALR MPNs actually have a heterozygous mutation. So the VAF is measuring the number of alleles, and it's telling you the percentage of alleles, which are mutant versus wild type. So when we talk about a 40% VAF, that actually means that 90% of all hematopoietic cells are mutant positive. And if we talk about a 5% reduction in VAF, that's actually a 10% reduction in the CALR mutant cells. So it's important to bear those in mind when we're looking at VAF changes is that they're actually half of the percentage change in cells overall mutant cells overall. A second thing to highlight is that there are differences in terms of the bone marrow microenvironment and what's going on with the wild-type stem cells between patients with ET and patients with myelofibrosis. So in patients with ET, they have a lower level of VAF usually, and they also have -- they have a more normal bone marrow microenvironment. So they still have some ongoing wild-type hematopoiesis. And we're showing this here depicted as 2 taps, obviously, wild-type hematopoiesis and mutant hematopoiesis. With this therapy, you turn off the tap of the mutant clone, but the tap, which is running out the healthy cells, keeps going. Now in myelofibrosis, that tap is the wild-type tap is turned off more. And then when you turn off the mutant clone, the wild-type cells are going to take longer to recover for 2 reasons. One is because they were lower actually at baseline. And secondly, because this is happening in quite a perturbed microenvironment. The fibrosis that Claire showed is really quite profound. So it's going to take longer for that to recover because the healthy cells, they need a healthy microenvironment. So that's how we're depicting that in this image, which I quite like actually, yes? Okay. So patients with myelofibrosis, we know they have greater clonal complexity at baseline and also -- progression is also associated with the development and the acquisition of additional mutations in addition to that first primary driver. And you can see that in this cohort. So basically, in the cohort tested in these studies, 1/3 of patients with ET and almost 80% of patients with myelofibrosis had an additional co-occurring mutation. And those are shown on this plot here. And you can see that many of those mutations are in high-risk genes, so ASXL1, EZH2 and TP53, just to call out a few, and these are gene mutations associated with progression to leukemia. So this slide shows the ET efficacy data or highlights of that, that was presented or will be presented tomorrow. And what you're looking at here is the effect on the platelet count. So you can see the median platelet count here is around 1,000. That's significantly high. But within -- by cycle 2, so after only 2 infusions of antibody therapy, you can see it's normalized. It's reached the normal range. So that's after only 2 infusions. So a very rapid decline here, rapid efficacy and normalization of the platelet count. And that response then is maintained over the course of the study. And you're looking here -- the results are shown here over the first 6 months. You can also see that there are more consistent decreases in platelet counts in patients receiving these higher dosing cohorts. But looking on the right, so this is now showing that those hematological responses are actually correlating with decreases in mutant CALR VAF in the mutant clone burden, again, split by low dose and high dose. And the lines here represent individual patients. What you can see in the ET cohort is that there are these rapid decreases in mutant CALR VAF occurring by around cycle 4 and then being maintained over the first 12 months here on study. And that's more consistently seen in patients on the higher doses and correlates to see more consistently in patients who are achieving durable hematological responses. Patients with myelofibrosis. So John very nicely presented the impressive impact on spleen reductions. And here, I'm correlating again those responses with VAF reduction. So you can see again an association between clinical responses and molecular responses. So in this part, again, you're looking at individual patients in the columns and the columns are colored according to the best change in mutant CALR VAF. So the deep blues and greens are patients who've had deeper changes in their mutant CALR VAF. Again, you can see that 48% of patients achieved an SVR25 and 31% of patients achieved an SVR 35%. These are impressive responses considering this is a second-line setting. So the majority of these patients have already received ruxolitinib therapy. And again, these lines are now showing the changes in the mutant CALR VAF over time, low dose, high dose. And what you can see here is that, again, changes to the mutant CALR VAF correlate with SVR and/or anemia response. And the dynamics of this change are slightly different. You can see here that they're continuing to decrease even by -- after 10 or 12 cycles on therapy. So to dive in a little bit then in more detail. So I mentioned that the mutant CALR protein is only expressed on the cell surface of cells, which also bear the TPO receptor. Now fortunately, in the setting of MPNs, this is actually 2 different cell types. Firstly, it's the stem cells. These, of course, are the cancer initiating and maintaining cells, the ones which is really crucial to hit. And then the second cell type, which expresses the thromboprotein receptor are cells of the megakaryocyte lineage. So these are the cells which are implicated as the key drivers of fibrosis and inflammation in the bone marrow. So these 2 cell types are the direct targets of antibody therapy. Now all the other cells, are more downstream progenitors, myeloid cells, lymphoid cells, they're so-called silent mutant CALR carriers. They're mutant positive, but they don't express the protein on the cell surface, and therefore, they're not direct target of therapy, but they are major contributors to the VAF when it's measured in whole blood. And I'll go into that in a bit more detail. To drill into this then, we performed single-cell multiomic testing on single cells isolated from the peripheral blood of the subset of patients with ET and myelofibrosis. And these cells were analyzed using a platform that enables targeted immunophenotyping in parallel with genotyping. And that data is represented on these UMAP plots. So in these plots, each dot represents a single cell. The cells are then clustered and annotated according to their expression of cell surface markers that identify them as these different cell types. And then the dots are then colored according to whether they're wild-type in gray or mutant in red. And to pick out just 2 features, you can see that in the myelofibrosis patients, there are expanded populations of stem cells and these erythroid progenitor cells here. So when we -- as hematologists, when we look at the blood form of these patients, these are changes that we classically see. You see mobilization of stem cells to the peripheral blood and then you see these very aberrant nucleated red cells that aren't normally present in the peripheral blood. So those are features that represent this transition to myelofibrosis. The second thing to note then is the so-called silent carriers are really in very high abundance. So high numbers of mutant monocytes, NK cells, B cells, which is very interesting. And also actually some T cells are also mutant, yes, seen on these plots. So first, focusing then on these stem cells. These, of course, are the most important cells to hit because of the cancer initiating and maintaining cells. On the right, you can see rapid decreases with therapy in the percentage of mutant CD34-positive stem and progenitor cells over time. And you can see that the lower levels of mutant CALR HSPCs in patients with ET also decreased with therapy. So in contrast, when we look at those silent carrier cells, we see much more minimal reductions at these early time points. This is Cycle 1, Cycle 4, just 4 months on therapy, and there really are much more minimal changes in these cell types. This is what we would expect. And the important thing to note is that these cells are terminally differentiated and don't have any long-term repopulating ability. So these cells will be expected to decline with time if we're getting true targeting of the stem cells as they won't be replenished. Instead you'll be replenishing wild-type downstream cells. So then we also need to assess the burden of mutant megakaryocytes, and this is depicted really beautifully in these slides. So to do that, you can perform immunohistochemistry on bone marrow biopsy sections, and we're fortunate to have an antibody that works really specifically and only identifies only stains mutant CALR, doesn't stain wild-type CALR. So this is an exemplar image from a patient with ET. You can see these abnormal clusters, too many megakaryocytes in the bone marrow, and they're all staining positive for mutant CALR. Cycle 7, you can see a significant reduction in the mutant megakaryocytes. And these changes here are quantified across the cohort of patients, and you can see quite dramatic reductions in total megakaryocytes and mutant megakaryocytes and a really nice increase here in the percentage of megakaryocytes that are wild-type, so non-staining for mutant CALR. And that correlates very nicely with improvements in fibrosis. And of course, changes to fibrosis will take time and actually is quite a difficult thing to assess. So it's graded in these big buckets. So what about anemia? John also mentioned a very nice benefit in terms of anemia responses in the patients with myelofibrosis. So 56% of patients achieved either a major or minor anemia response. So correlating that with what's going on with disease pathophysiology, the first thing we were able to show is that these anemia responses correlated with the clearance of these atypical circulating mutant CALR-positive Erythroid Progenitors that I mentioned. So they decrease. And then interestingly, we saw an increase looking in the bone marrow at CD71 positive cells, reflecting Erythroid Progenitor. So what this is reflecting is we're getting a renormalization of bone marrow hematopoiesis and recovery of healthy hematopoiesis occurring within that bone marrow microenvironment. Finally, then perhaps most importantly, we also saw nice responses in patients who have not only the primary mutant CALR driver, but also these co-occurring mutations. So if we look at the patients with myelofibrosis who had a co-occurring mutation, 40% of those patients benefited from either a spleen volume or an anemia response. And then 2 patients here who have very high clonal complexity are shown, for example. So these are what we call fish plots. In these plots, the blue area represents the healthy wild-type hematopoiesis and then the colored areas, the mutant CALR clone is shown in orange and then the additional mutations in EZH2, SF3B1 and KRAS for patient 1, ASXL1 and EZH2 for patient 2 are shown in other colors. And you can see with treatment, this reduction in all clones and recovery of the wild-type hematopoiesis. So then to conclude, INCA033989 treatment results in rapid normalization of platelets in ET, splenomegaly symptoms and anemia in myelofibrosis. These clinical responses are associated with rapid reductions in the mutant CALR clone burden. And this is really demonstrating a speed and depth of response that hasn't previously been seen with other therapies tested in this setting. And importantly, is highlighting the VAF as a relevant and measurable endpoint. The clinical responses were also observed in patients who have co-occurring high-risk mutations, including those associated with increased risk of progression to AML and the improvements in the bone marrow really reflecting recovery of the bone marrow hematopoiesis. And this really supports the potential of INCA033989 therapy to modify the disease of patients with mutant CALR MPNs. Thank you. With that, I'll hand the podium back to Pablo for the Q&A, and thank you for your attention.

Given the extremely encouraging data you just saw presented by the prior speakers, Bill and Pablo get to invite me to talk about next steps. And using the words extremely encouraging here may be classic British understatement given the robustness of the proof of concept you just saw. So the mutation landscape here defines the opportunity for the development in myelofibrosis. In the United States, there are approximately 25,000 people living with myelofibrosis. CALR, as shown to you is the second most common mutation after JAK2 in myelofibrosis and occurs in approximately 35% of these patients. If you use SVR35 as a surrogate for response, only about approximately 1/3 of patients currently benefit with available therapies, thus defining the unmet need in this population. And the unmet need may be best addressed by innovative approaches targeting underlying molecular drivers like the mutant CALR mutation. Our program will focus across the board in all types of mutations, but just to point out that if you look at type 1 or type 1 like in myelofibrosis, that constitutes about 76% of the population as illustrated on the top right for you. The data shown today, and I think John defined a new term on the podium this morning, super well tolerated. I think in our world, when we say generally well tolerated, it could be like 90% febrile neutropenia, but super well tolerated, I think, really reflects the incredibly well-tolerated drug this is and then indirectly reflected by 85% plus of patients remaining on therapy in both cohorts. Just to be clear, no dose-limiting toxicities were seen and no maximum tolerated dose was defined as is common case with targeted therapies. As prior speakers just showed you, rapid and robust reductions in spleen volume in both the monotherapy and combination cohorts. The week 24 data is pointed out because that is a typical regulatory endpoint. But this was, as John pointed out, an ongoing dose escalation and expansion study, and there is some expectation that people who are given the correct dose for the right length of time may actually have increased rates of response here. But in this study, 42% of patients achieved an SVR25 and 33% of patients and SVR35 at week 24, respectively. Symptom improvement was seen in the vast majority of patients in monotherapy, 93% and the combination cohorts, 81%. And then specifically looking at the binary validated endpoint that we used, TSS50 at week 24 monotherapy in an ongoing escalation study, 39% with monotherapy and 33% with combination therapy achieved TSS50 with the caveat that this is not randomized data, obviously. Again, as shown by John, the trifecta, if you will, after spleen and symptoms seen in an unprecedented way, I would add, anemia improvements as well, with 56% of the evaluable patients by the definition, achieving an anemia response and in fact, 40%, a major response by the Tefferi criteria. At the higher doses, reductions in spleen volume, symptom improvement and anemia response was seen in both type 1 and non-type 1 patients. And then as Bethan just showed you, the potential for disease-modifying activity, very elegantly demonstrated by her by the decreases in mutant CALR megakaryocytes seen and the increase in erythroid progenitor cells, which probably then translated to the anemia improvements that we saw in the actual data. So where will we go? Next year, we will begin based on the breakthrough designation that we announced this morning, a Phase III trial, hopefully by the middle of the year in second-line ET. Because speed is of the essence here and not to wait for the subcu development to be ready, we will begin the study with an IV Q2 week of 989 first best available therapy. The actual doses, et cetera, will be determined after regulatory consultations, which are going on at the moment. The intent is also to begin a second-line myelofibrosis study based on the dose expansion you've seen going on now with dose selection being finalized over time and to begin that study in the second half of 2026. Currently, it is planned to begin with the IV therapy as well, again, given speed is of the essence, but there is some potential to use the subcu if that is ready in time. And then based on the ongoing Phase I in the first-line setting, which includes monotherapy 989 plus the combination, when those results are delivered in the second half of 2026, the intent is that will inform a first-line pivotal trial design. The subcu development, you saw the announcement, the Enable agreement is signed. The EnFuse device is going into the clinic in early 2026 in a Phase I in both ET and MF. And we will -- if we use this IV in the registration studies, we'll do a bridging study to use those in those 2 settings. With that, I'll hand the podium back to Pablo for the Q&A, and thank you for your attention.

Thank you, Steven. We will now -- do we have microphones? Yes, we have microphones. We open the floor for Q&A, and then we'll go to the webcast as well.

Okay. Alex to start -- okay.

Brian Abrahams, RBC. First off, congrats on the data. I wanted to dig into those 7 patients who were JAK naive or ineligible just to gauge how representative they might be for a treatment-naive population, the treatment-naive population that you're studying. Just is there anything you can tell us about the characteristics of the responders there, whether they were type 1, what doses that they were on? And then maybe for the clinicians, is this the population, a JAK ineligible CALR mutant population where you could foresee using 989 as a monotherapy in the front line? And how large is that subgroup in your practice?

So let me touch first the definition of ineligible was determined by the investigators. Most of these patients were deemed ineligible because of anemia. In terms of the future, we intend to develop 989 in all patients in first line of treatment-naive MF, not just in this cohort. This cohort is included -- this was of patients was included in the study because of the Phase I study, and we didn't want to take RUX-eligible patients. In the long run, our vision is that this medicine is going to be used in first-line MF regardless of eligibility for Jakafi. I don't know, John, Claire or one of you wants to comment on that population.

No. I mean I can just agree that the major region -- major reason that the investigator deemed those patients ineligible was anemia, which we see with CALR mutation. So I think in those cases, the thought process was that maybe a JAK inhibitor wouldn't bring the same kind of benefit and the patient -- so I got to tell you, patients are interested in this therapy. That's the other thing that gets missed in this is that I didn't think we had so much CALR mutant patients until this antibody came out. And now there's all these CALR mutant patients that come out of the woodworks in the community practice, which is where most of MF is. So my clinic is inundated with CALR mutant patients. And many of them don't understand why they would have to fail a JAK inhibitor. It doesn't make sense for them to have to wait to get it. Even though this is a first-in-human Phase I study, I mean, we had patients that were more than happy to go on. So if the patient had anemia and we weren't clear that the spleen and symptom burden was such that it would necessarily require a JAK inhibitor and the patient wanted to, and that was often the case, they could out.

Just one thing to add as well as anemia, the other risk reason can also be infection risk because, of course, JAK inhibitors do increase your risk of infections. So that's often patients are very aware of this. I work in Oxford and our patients tend to be very educated crowd. So they often come to you with the statistics about toxicities of treatment. So infection is another one. And just to echo the idea that actually our thoughts about this therapy probably eligibility for JAK inhibitor isn't necessarily how you would see eligibility for this drug because you use JAK inhibitors when you want to achieve spleen and symptom responses. Here, we're looking at spleen and symptom anemia and, of course, then disease modification. So you may -- you have different criteria thinking about eligibility for agents like this.

And then finally, just to say, we use JAK inhibitors currently in patients with pretty advanced disease. We're testing this agent in ET, which is generally a precursor for myelofibrosis. I think generally, the community tends to wait quite late to treat myelofibrosis patients. I think we would be really looking to intervene early and halt the disease.

Steven?

Yes. And Brian, just to add, what -- I think what you're alluding to and what's potentially really encouraging about this data set, though imperfect, it may be a surrogate for first line because they're JAK ineligible, 5 of 7 get SVR35, 60% plus SVR35 rate with all the caveats. Obviously, our first-line study is ongoing, but if that carries through to first line, that's truly high activity there.

Next question. Where are we going? Great, I think it's...

Erik from Mizuho, Erik Lavington, sorry. So I'm just wondering what sort of time line you'd be looking for VAF reduction in the MF patients to get the majority of them over the 50% reduction?

Well, it's a good question. We're going to ask Beth to comment. We don't have a time line for that. I would take a step back and remember what we just saw, which is that 989 impacts every relevant clinical endpoint, SVR35 symptoms and the anemia data, which I would argue is completely unprecedented in this disease for single agent in this population, the 50-plus percent improvement in anemia, we thought it was remarkable. And importantly, it does all those things, not in a symptomatic way, but it does all those things because it's literally reducing the burden of the disease in these patients. Measuring VAF, I believe, and Beth can confirm is a lagging indicator for what's going on in the bone marrow and what's going on with the cancer stem cells in peripheral blood. Over time, we're confident VAF will continue to go down. If you shut the faucet, as Beth showed, it's going to happen. We don't have a specific goal how long it should take and how low it should go. It's obviously good to see. But that -- so silent carriers will have to die out in the peripheral blood for the peripheral blood VAF to continue to go down. So I don't know, Beth, if you want to?

I might have called a tap rather than a facet, but that's okay.

The tap.

Just, yes. Yes. I think we're kind of in uncharted territory when it comes to knowing what the dynamics of the VAF changes should be and even in terms of how low you need to go and what happens when you stop therapies because actually, we don't have other therapies that reliably reduce the VAF in mutant CALR MPNs. So to relate it perhaps to interferon, which is probably the best drug we have in the context of JAK2 mutant MPNs, those reductions are incredibly slow. And often, we don't even bother measuring it until a year after someone's on therapy. And of course, that then ends up being typically very clinically meaningful. So I think we need a lot more information to understand this. So slow reductions could be very meaningful. As you were just saying, it may underrepresent when we look in whole blood, what's happening in that important stem cell compartment. And then when it comes to thinking about the depth of response that's required, that again, is uncertain. But you could argue given that we know this is a disease that evolves over years or decades that a small reduction in VAF is very meaningful because it can push the disease back by years or decades. And that is an important goal for these patients.

Once again, to emphasize, the right things are happening. We're reducing cancer initiating cells. We're reducing malignant megakaryocytes. We're reducing malignant erythroid progenitors. All those things are happening, and they're happening pretty fast. VAF, will get there. Next?

It's Michael Schmidt with Guggenheim. Pablo. Nice data read. Congrats on the Phase I data. How are you thinking about dose selection in expansion cohorts and -- in Phase III? And are you considering different doses for ET and MF, for example? And then what about type 1 and type 2 patients? And could you comment -- I know there was intra-patient dose escalation. And what dose did the type 2 patients get up to in this study?

So let me separate the 2 scenarios here, the 2 diseases. In ET, as we announced this morning, we got breakthrough designation. We have initiated conversations with FDA already about the design of a Phase III trial and the dose selection. We're very close to the dose selection in ET. Our goal here is to develop 989 across the spectrum of mutations in both ET and MF, first of all. The dosing strategy, in order for me to give a definitive answer, I need a little bit of time. We are finalizing the dose selection for ET. We're almost there. We're very close. Platelet normalization is such a rapid and simple PD marker, if you may. It's obviously a goal of therapy, but it's also a PD marker in ET that it makes the dose selection simpler. So that's -- we're very close. In MF, a little bit more data. Particularly important there is going to be the data in naive patients that we're generating as we speak in order to lead to dose selection. Will the dose in ET and MF will be different, I can't comment right now. What I can tell you is that the pivotal plans that we are working on will encompass all types of mutations and the dosing strategy may be slightly different in ET and MF.

[indiscernible] occurred really fast after 2 cycles, I think. So for example, could you consider a low-frequency maintenance dosing in that setting?

It's a good question. The antibody has a short half-life. We haven't dosed patients with less frequent administration. It is something we've discussed and it's something we're contemplating maybe as a maintenance therapy perhaps, but we're not there yet. It's a good question.

This is Srikripa from Truist. Congrats on the data today. So one on ET. The breakthrough designation is for a subset of ET patients. Can you remind us what percent of ET patients those are? And also, how does that read through to the whole program that you have? And then for the MF, maybe a follow-up question for Brian's question. In the monotherapy, you had no high-risk patients. You only had intermediate 1 and intermediate 2 risk patients, I think. In the combination, you did have high-risk patients. How do these high-risk patients perform? If you can give any color, that would be helpful.

Yes. It's a -- the latter is a good question. We're going to have to get back to you on that. I mean we're starting to slice these groups a little bit too much for me to have those numbers on top of my head. I think the difference is simply one is a combination with Jakafi, the other a single agent is a Phase I study. And as a first-in-human study, I think high-risk patients are a little bit more difficult to treat. To the first question you asked, so about 55%, 60% of ET patients are type 1. And I think, Steven, one thing that we start thinking about is Steven showed this in his slide, there's type 1, there's type 2 and then there's others. And in the other category, there's a type 1 like and type 2 like mutations. The picture is a little bit more complex. We still believe that based on the data and the data you're going to see an update tomorrow, 989 works across a range of mutations. Maybe there's a difference in sensitivity in different mutations. But over time, responses are seen in patients with all kinds of mutations, particularly as you push the dose. The breakthrough designation was in type 1 patients because at the time when we had the submission, the data was more compelling in type 1, and we wanted to get that out of the way and engage with FDA. I see no reason why the trial will not be running all comers with all mutations. There's clear responses in patients with non-type 1 mutations across both ET and MF. And I think John showed some of that data today, and you're going to see some of that data tomorrow. In fact, if you look at the 10 patients with type 2 mutations in the waterfall that were treated with doses of 400 or higher, 3 of the 10 are SVR35. So it's a response rate of 30%. So this medicine works across a range of mutations. Time and dose are 2 variables that we need to keep in mind. The other variable we need to keep in mind is washout. Remember, these patients were treated with no mandatory washout. And that's a very important point when you look at the benchmark data. So a lot of these patients rebounded between the assessment for the study and when therapy started. As we know, when you discontinue Jakafi, some of the patients have a rebound. So keep that in mind as you look at benchmarks in the literature that these patients had no mandatory washout. I see nodding from our panel. So hopefully, we -- go ahead.

Just to comment, we use momelotinib as we did in Simplify 2 with no washout, the spleen response rate was 7%, and they failed on the symptoms, so just as...

I was going to say like thank you, [indiscernible] yes, 7% is the Simplify study. The MOMENTUM study at 22% SVR35 that had mandatory washout of 2 weeks, I believe. The Simplify had a spleen response of 7%. So when you look at these results that we just showed you, keep that number in mind.

Pablo, Tazeen Ahmad, Bank of America.

Good to see you. How are you?

A couple of questions from me. Can you just give us a little bit of clarity on where you are in the subcu formulation development, especially as it relates to ET, is that going to be particularly important in getting traction in that population in your view? And then can I ask one quick question on the combo data that you presented today? You've already guided coming into this meeting that, that level of detail would be limited. But as it relates to SVR35, I think you had 25% of patients achieving that. Can you just give a sense of what a good number would be over time as you collect more data in patients for combo?

Let me start with the second question. So I don't -- first of all, that population is not a -- that's not a study we're going to do, right? The suboptimal responders at 989. We had to do that data. It's a first-in-human study. The safety question about combining 989 with Jakafi had to be addressed and then understand a little bit of what it does on top of Jakafi. I think the cohort that matters, Tazeen, is the one we're doing now in naive patients of 989 versus 989 Jakafi. So I don't have a target in mind what that data looks like. We were pleased to see that on top of Jakafi, and these are people that were on Jakafi for at least 12 weeks and got to a level of response and did not respond further. And when we added 989, not only it was well tolerated, as John highlighted, but we saw stabilization of the anemia and improvements in spleen and symptom. The subcu, it's going to enter the clinic early 2026. The formulation we have it in hand. It's going to start being tested. We have the agreement for the device. So the idea is to incorporate that in pivotal trials as early as possible. As Steven highlighted, Likely, the ET second-line study will start with IV, and we'll do a bridging later on. We're pushing to see if we can include the subcu formulation in some of the pivotal studies that will start later in 2026. We'll have more details for you probably in the new year, but it's -- we're accelerating that as much as possible. I don't know who has the mic, over here.

Thanks. Yes, congrats on the data, and I appreciate the event here. So just first question on the SVR responses. It looks like between the 2 dose cohorts that you kind of look at, it's fairly flat. But when you look at TSS, it looks like a little bit more of a dose response. So just kind of curious if you can reconcile what you think is going on there. And then second question, just curious on the Jakafi dose intensity in the combo trial.

Yes. I'm going to go to Steven on the Jakafi dose intensity. Let me address the first part. The challenge with looking at the dose response with the data that we show you is there's 3 or 4 variables that you have to keep in mind when you look at SVR35 or any other clinical endpoint here. You have dose, you have time on therapy, which is different, particularly higher doses tend to have shorter follow-up. You have type of mutation, which we think it works across the board, but there's different sensitivity. And you have washout. Most of the patients did not have it, but there are some patients that perhaps did. So when you put those 4 factors, I think concluding that the dose response is flat, I'm not there. I do think that there's clear evidence that at the higher doses, the responses, particularly non-type 1 seem to be higher. The drug -- and to borrow John's term, again, is super well tolerated. So we believe a higher dose might be the best way to develop this across all types of mutations perhaps. Do you have a comment on the -- maybe John, on the Jakafi dose intensity?

I'll try first. I think if you saw John's slide, the mean dose delivered was, I think, 33 milligrams. If you look at real-world use of RUX in the United States, about 15 BID. So they get in what consistent with how the drug is used real world and then guidance per label on how to dose reduce, et cetera. I don't know if John wants to comment further.

Yes, I mean so going in, it was 33, and I don't think that, that dropped on study. So it wasn't like they were being dose reduced. And this was -- these are patients that recruited at MF centers where we typically maximize the dose, it's going to be different than what you see in the community where it's typically lower doses. So from my perspective, I think that, that population that we see represents what we would normally see.

Guys, Gavin Clark-Gartner from Evercore ISI. So for the experts up here, for the anemia benefit, I'm hearing that a lot of investors are cross comparing against momelotinib. And I guess the reality is the way they achieve the anemia benefit is very different, restoring hematopoiesis versus getting a boost from the ACVR1. Do you think we can cross compare those benefits across both therapies? I guess based on the data we have today, do you believe mCALR is disease-modifying?

Let's go all 3. Claire, you go first.

I definitely think it's disease modifying. We don't see this kind of benefit with a JAK inhibitor. We just don't. And on the subject of anemia response, you may remember at ASH a few years ago when Steven and I presented the data on bone marrow fibrosis, difference between momelotinib and ruxolitinib. I think we don't see the mechanism of anemia response here is different. And maybe momelotinib just has different affinity to JAK2 and therefore, causes less anemia. I think we're comparing apples and pears or taps and facets, maybe not.

Beth, do you want to comment on...?

Just to say I completely agree. They're totally different drugs. We use them in different settings. I think to relate to momelotinib, GSK have done some really nice analysis actually correlating overall survival with anemia benefits and achieving transfusion independence. I think that data is relevant to this setting as well. So the impact of improving anemia is relevant to do the comparison, but the mechanisms here are completely different. This drug is disease-modifying. We're getting recovery of hematopoiesis, healthy hematopoiesis with this drug. Momelotinib is working very differently, does have clear benefits for the portion of patients who benefit from anemia, no doubt about that, but it's a different mechanism.

I would just add that it's not obviously the mechanism, as it was highlighted by our experts clearly different. The magnitude is completely different. I mean when you look at the momelotinib difference, a 10% difference, which just showed you a 56% difference mostly in Jakafi pretreated patients. I think you have a follow-up.

Yes. Just a follow-up. Did you disclose the percent of patients who had SVR35 or an anemia response? Like were those co-occurring in the same patients? Or there are like groups of patients who are spleen responders versus anemia responders?

There is a high degree of overlap between the SVR35 and anemia responders. It's not 100%, but there is, yes.

Marc Frahm from TD Cowen. Maybe on the TSS, there's a pretty big gap between the best TSS50 number of up to like 60% versus the at 24-week time point. Can you just comment on how much of that is purely driven by limited follow-up for those incremental patients versus some of the patients potentially losing their TSS50 at longer follow-up? And then maybe for the physicians, I think one thing a lot of people are struggling with is exactly how to interpret that combo. And are there any real signs in there that you would point to of a clear sign that there's synergy or additive efficacy happening opposed to it's really just the monotherapy CALR that's driving some benefit there?

So John, Claire or Beth, if you want to address the second part, and then I'll come back to the TSS50 question.

So I could tell you a story about one of my patients that's on the combination. I maybe misunderstood your question about synergy, but I have a patient whose father died of myelofibrosis the year before we started testing ruxolitinib. And he had, had a thrombocytosis for many years, came to us, had a CALR mutation. He's also got 2 ASXL1 mutations. He's a very anxious man. He ran to the hospital halfway through his conditioning for bone marrow transplant. He had a -- he is on 25 milligrams twice daily of ruxolitinib, so maximum dose and was transfusion-dependent coming into the study. His spleen was all the way across his abdomen. We added 989 at 750 milligrams. His spleen is almost unpalpable and his transfusions have almost but not quite disappeared. So I definitely think there is an added benefit. Whether it's synergy or not, I think biologically, it's difficult to say, but I think it's nicely illustrated by patient story. Only symptoms are better as well.

The preclinical data that we presented clearly shows that these 2 are synergistic. I think the question as we move forward with the first-line study is one of the most impressive things we've seen is the impact of 989 on anemia, I think. And obviously, we know what the side effects of Jakafi are and whether that suppression of hematopoiesis will impair the ability of 989 to deliver full benefit on anemia in first line is something we need to assess. That's the cohort that's ongoing right now. On the TSS50 question, it's a follow-up issue, Marc. It's just some of the patients have an equal follow-up. Some of them have very few assessments. All right.

Ash Verma at UBS. So I know you mentioned a few times about the sensitivity between type 1 and type 2 patients. Like is it possible that your very strong efficacy in type 1 versus not as much in type 2, whereas the prelude molecule I've heard they have characterized it as equally potent across the 2?

If you look at the patients in the waterfall that received 400 or higher, the SVR35 in those patients is 30%. In the whole population, the SVR35 is 32%. I think that tells you clearly that at slightly higher doses, the responses in SVR35 -- the responses in non-type 1 or type 2 in that case are there. Some of the patients may need a higher dose, some of the patients may need a slightly longer therapy to get there. But I think we have clear evidence in this presentation, both in ET tomorrow and in MF today that 989 works across mutations.

James Shin, Deutsche Bank. Will the pivotal studies include stratification for type 1 versus type 2?

What's that?

Stratification for type 1 versus type 2.

Yes.

Second question is how long for the pivotal ET trial to enroll and read out? And third, for the panelists, I recognize 989 is super well tolerated, but have ALT and AST signals in other second-line MF trials been seen? And any hypothesis on what caused the signal? Were there any baseline features or comorbidities that may have contributed?

Let me before we ask -- so the details you're asking on the design and time lines for pivotal trials we will disclose over time. I'm not in a position today to tell you exactly. I think that the broad terms are, we will enroll patients across a range of mutations. We are finalizing the dose selection for AT and the data we're generating in naive patients with MF will lead to the dose selection. We'll discuss those with FDA, and then we'll provide further details on that. Before I ask John to talk about the LFTs, when you look at the AST elevations in the MF, the single-agent cohort, I think it's important to remember a couple of things. One, half of the elevations were present at baseline, okay? That tells you that there's a background rate of AST elevation in these patients. 65% of patients with MF have extramedullary hematopoiesis in the liver. So there's something going on there. And we are killing those cells. You should expect that some inflammatory reaction is happening when that happens. All but 2 patients recovered on study. One of those 2 had it at baseline and both are Grade 1. The last one is still going, but it's a grade 1 AST elevation. So there's no reason to believe mechanistically that 989 produces liver toxicity. And I think the LFTs are largely explainable as a result of the background of the disease. John, I don't know if you want to comment further.

I don't know that I could add anything beyond that. I mean it didn't seem to be very clinically concerning signal. And from a clinical investigator standpoint, doesn't stop me from saying super well tolerated.

Let me make one more comment. It was in the slide, but perhaps it was a lot of text in some of the slides. It was a patient that had -- the one Grade 3 AST elevation happened at 50 milligrams. That patient was the dose was suspended. It recovered. The patient was rechallenged. It's now currently at 1,500 milligrams, no reoccurrence of the LFT. So that's another important point to make. Beth?

Yes. I was going to make a similar anecdote actually about a patient in the combo cohort who was on -- entered in a relatively low dose, did have a transaminitis. And then since her disease has improved, extramedullary hematopoiesis has improved and just since dose escalated without any toxicity so.

Yes.

Pablo, Ren Benjamin from Citizens. I don't think I've ever seen this range of a dose exploration before. And so I'm kind of curious, if you separate out the lower dose ranges from the higher dose ranges, is there a signal in the side effect profile that might be coming out?

A signal?

And the side effect profile, right, that might be coming out.

I mean -- no right now. Let me make a comment on why the range of doses. First of all, there were 2 studies that we're looking at as one, but there were really 2 studies. And the reason for that was we were allowed to start at a lower dose or a higher dose, I should say, in Australia as opposed to the U.S. And if you go back 2 years, and some of you remember these conversations, there was a concern, a hypothetical concern that because 989 will eliminate the malignant clone and patients have a very small residual wild-type clone, the drug will lead to profound cytopenias. That clearly hasn't happened. The opposite is happening. In fact, patients' anemia is getting better and better over time. So because of that, we started low. We would have started the dose higher. The drug have a perfectly clean tox profile. So there's no pattern in terms of dose dependency of any of the side effects at this point. That's why we kept pushing the dose.

And just as a follow-up, do the co-occurring mutations decrease over time as well? Or are you noticing any certain co-mutation clones that might be compensated?

We have not. I think this is a question that has come up. We have no evidence in our hands in the patients that we looked at that there is an emergence of new mutations that are driver mutations in this disease. I don't know if Beth wants to comment on that, but we just have not seen it.

Yes.

And by the way, I would comment, you have patients in CML with 8, 10 years of therapy. And with this mutation still in BCR-ABL, there's no secondary mutations that lead to resistance in that case.

Just to echo that, I think the data -- the fish box I was showing were showing reductions in both the mutant CALR clone and high-risk mutations as well, including one patient had a KRAS mutation. That's very significant, also decreasing with therapy. And the vast majority of patients with MF have their co-mutations in the same clone as the mutant CALR. You will get some rare patients where they're in separate clones, but the vast majority are in the same.

Okay. Etzer Darout, Barclays. I realize the goal here is to sort of move mCALR to frontline. But just curious in your immunophenotyping genotyping work if in ET and MF patients, if you've looked at what impact prior JAK exposure has on levels of mCALR or other relevant markers. And just trying to understand, if you will, the activity in the JAK sort of naive versus JAK pre-exposed patients and the differences that you've noticed there.

In terms of that or...?

Yes, mCALR levels, like the expression levels in pre-exposed versus JAK-naive patients, just understanding the difference in activity.

Okay. No. We do not. No.

Okay. Matt Phipps, William Blair. I want to come back to the anemia benefit. Do you have the level of anemia benefit in those JAK-naive patients? I realize there's not a ton of patients there, but given they were probably anemic. And then a little bit surprised to not really see an anemia benefit in the JAK combo. So I guess when you're looking at the total patients, I guess, for the docs, maybe if you think about a patient coming off of a JAK, could this be a bit of a rebound as you're not pressuring JAK2 as RUX washes out, I guess. How do you kind of contrast the 2...?

So the first question, the benefit is consistent. I don't have the actual number for you, Matt, but the benefit is consistent with the JAK naive, maybe a little bit better. I think the mechanism is what tells you that's not the case because what's happening is, as Beth elegantly showed, we're reducing malignant erythroid progenitors. We are increasing wild-type erythroid progenitors. And then when you look at the curve over time, past 6, 7, 8 months, the hemoglobin keeps going up. That is not a JAK rebound effect.

Pablo, congratulations on the data. Imogen Mansfield from Cantor. I was wondering how you're thinking about the development path in the patients with an inadequate response to ruxolitinib compared to those who are relapsed/refractory. And is that a group where you could potentially get this therapy to patients sooner given that most patients don't have an adequate response to ruxolitinib?

That is a really good question. They're clearly not the same. The data we showed you, we separated ineligible ones because they're naive, but the others are all in one group. Quite honestly, we're going to have a conversation with FDA about some of these topics to see if we can bring 989 to market faster in some subset of patients. I think that is a great point. I think that it's particularly striking the benefit in anemia. I mean this is something that's never been seen in MF and really bringing this to patients as quickly as possible, I think it is really important. So we'll have that conversation. Whether there's a subset of patients with particularly poor prognosis, we can do this faster, we're certainly going to explore that. Thank you for that question.

I guess just one quick follow-up on the anemia. You've talked recently about proposing anemia and SVR35 as endpoints. Is that both for the first and second-line groups? And then why not include symptoms when they also look good?

Look, SVR is in. I think we all agree. SVR35 is in. We all know how we got here with symptoms. That started with Jakafi, and it was designed for what Jakafi does well, which is this rapid symptom improvement. I think we have in our hands a novel endpoint here at least in MF, which is not just stabilization, but improvement in anemia. It's objective, it's easy to measure and it's clinically relevant. I think it's time to have a conversation with FDA and see if we can adjust the endpoints, whether it's all 3, how we find the hierarchy of those, those are all regulatory conversations, quite honestly. But we intend to have a conversation with FDA about incorporating anemia improvement as an endpoint in these patients. I think it's important for patients. I think it's important for treating physicians. We good?

One more question.

Okay.

Maybe for Pablo, can you just speak to the appetite for potentially integrating a companion diagnostic into the development plan for typing mutations at baseline. That seems like an easy way to get around the dosing conundrum. And then how are you thinking about the ROI of a frontline ET trial that looks to displace hydroxyurea and maybe the physicians can comment on what they perceive to be the value proposition of 989 in frontline ET?

So in June of this year, we signed an agreement with QIAGEN for the companion diagnostics. So our work is ongoing with them. I think it's an important part of the story. I think if we develop 989 as we intend across mutations, the specificity of the mutation is less important, but we certainly have the tools if we need to go in that direction, if we happen to need to go in that direction. Before I ask our experts to talk about first-line ET, what we're seeing today is we're not discounting doing a first-line trial in ET. It's just the highest priority, second-line ET and then the 2 MF trials. The reason, quite honestly, is, as you all know, first-line treatment for ET is largely hydroxyurea. It's not a great drug. So basically, the idea is giving a drug that is toxic to platelets to reduce the platelets, but it has certain drawbacks. We believe that if 989 was available in the second line, the pressure to switch patients from hydroxyurea to a truly disease-modifying drug that normalizes platelets and doesn't require dose adjustments like HYDREA does for white cell counts, we think it's going to be very intense. But we haven't discounted doing a first-line trial in ET yet. So I don't know if John, Claire or Beth want to comment on ET?

Yes, I mean the only thing I would add to that, as a clinician who cares for these patients, I think if this was -- if 989 was commercially available, I wouldn't hesitate to use it upfront in ET patients even without hydroxyurea exposure. So although one could give Hydrea and say, you're failing the drug and move on. most of my patients would much prefer to get a monoclonal antibody than the chemotherapeutic that holds that stigma. So I think it would be an easy -- obviously, with the subcu administration, an easy sell and an easy discussion with patients.

Okay. I think is that all the time we have. Thanks again. Thank you all for joining us today. We look forward to keeping you updated. Thank you.