Okay. Good morning, everyone and welcome. Welcome those of you here 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 two 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 have 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 EHA in patients with ET and yesterday and today. You heard from two 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 its 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 cohorts in patients with myelofibrosis and the combination with ruxolitinib. Dr. Bethan 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 St Thomas' Hospital and Professor of Medicine at Guy's and St Thomas' Hospital, John Mascarenhas, Director of the Center of Excellence for Blood Cancers and Myeloid Disorders and Professor of Medicine at 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 one of two mutations that are mutually exclusive. That is a mutant CALR mutation that is about 25% of the patients with ET and 35% of MF, or a V617F mutation, which is the remaining of the ET and 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 a 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 a 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 two days, so I won't spend a long time. 9A9 is a mutant CALR-specific antibody. Mutant CALR protein that binds when it's in a mutated form with the T4 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 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 this cohort 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 is 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 and MF and combination. And importantly, we are in the process of enrolling patients with naïve 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 two on the right. The one on the left is going to be tomorrow, which is an update of the data that we present at NET. I will now hand this over to Dr. Harrison so we can get with the content 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 three 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, myelofibrosis, splenomegaly and symptoms.
Among t he 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. Say, 35% of patients at diagnosis and then by one 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 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 irony isn't lost on me that in 2011 I was in a room like this with Incyte and Srdan Verstovsek presenting the data from the COMFORT-II study, which led to the approval of ruxolitinib, which is still the standard of care. At that time I said I thought 70%-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 at where we are today, 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 two phase I dose escalation trials involving 989. This is the myelofibrosis data that we literally just presented. And I just remind the group that the CALR mutations is present in at least a third 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.
This is the MF portion of this study which also includes an ET cohort. 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 of outcome measures. 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 is 36% and.
It was supposed to be a relapsed refractory group of patients. Although you could, an investigator could deem a patient ineligible for 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 1300, 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 2500 mg ex U.S.
It is, as I said, it is a super well tolerated therapy. I've done enough phase I studies that this is probably the best tolerated therapy I've seen in this setting. 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. 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 two weeks and there were no dose-limiting toxicities in this study and therefore there was no maximum 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 two weeks to get this therapy and they were obviously seeing some sort of benefit not having toxicity that would keep that retention rate that high. There were some AST elevations in 11 patients. Nine of 11 resolved. Two Grade 1s were ongoing at the time of the data cutoff.
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, importantly, there was no treatment emergent adverse event profile that was dose related. On the right you can see, 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 group the doses by low dose 24-250 and then 400-2,500, which is in the darker blue columns. The asterisks note the patients who are non-Type 1 CALR mutant. We saw at week 24, 42% of patients achieve an SVR25. That's a regulatory endpoint in the relapse-refractory setting. 33% achieved an SVR35. If you look at best SVR, 48% and 31% achieved respectively SVR25 and SVR35. Most patients' baseline assessments were performed prior to JAK inhibitor washout. 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 it's a valuable 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 from 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 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 man and less than 11 g 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 I 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 to 2024 response criteria, the response rate is 56% and that includes 10 major responses and four 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 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 one 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 C ALR VAF is 39%. The mean daily dose across ruxolitinib was 33.5. 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. 2351. 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 for 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. There was very infrequent dose reductions and infusion interruptions or really dose delays. There were no DLTs and again no MTD in combination with ruxolitinib. 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 the symptom is on the right. Again color coded by dose. Best SVR 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 it 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.
In conclusion, I feel very confident saying 989 very well tolerated monotherapy and in combination with ruxolitinib in patients who have a suboptimal response, and there is 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, 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 non-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 responsive in these non-Type 1 patients. And we did see reductions in mutant CALR VAF.
What I didn't show here with Beth is going to go over some of the correlatives, which I really think speak to the fact that 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 arise following the acquisition of a gene mutation in a blood stem cell that basically results in cytokine independent receptor signaling in a third of patients that affects the gene encoding calreticulin. This actually came as a surprise when it was first discovered, reported actually in a plenary 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 the blood malignancies before.
All known pathogenic mutations result in the same mutant specific C-terminus on the protein and that has two 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. You've heard already that INCA033989 is a first-in-class antagonist antibody being tested in the context of ET and myelofibrosis, too, first-in-human clinical trials in previously treated patients. And it's been shown to inhibit oncogenic signaling and proliferation of cells. 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 impact on life and work productivity and also an increased incidence of bleeding events and thrombosis. Then a third of patients will progress to 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, one in five patients will progress further to a secondary leukemia that unfortunately is refractory to all leukemic therapies that we have. 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. 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. One thing to note when we talk about VAF is that most patients with mutant CALR MPNs actually have a heterozygous mutation. The VAF is measuring the number of alleles and it's telling you the percentage of alleles which are mutants 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, that they're actually half of the percentage change in overall mutant cells. 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 VAFs, usually, and they also have a more normal bone marrow microenvironment. So they still have some ongoing wild-type hematopoiesis.
We're showing this here depicted as two 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 two 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.
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, a third 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 pull 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 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 two. So after only two infusions of antibody therapy, you can see it's normalized, it's reached the normal range. So that's after only two 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 for the first six months. You can also see that there are more consistent decreases in platelet counts in patients receiving these higher dosing cohorts. Then looking on the right. So this is now showing that those hematological responses are actually correlating with decreases in mutant CALR VAFs 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 high doses and correlates. So 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 plot 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.
What you can see here is that again, changes to the mutant CALR VAF correlate with SVR and or anemia response. The dynamics of this change is slightly different. You can see here that they're continuing to decrease even by after 10 or 12 cycles on therapy.
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 two different cell types. Firstly, it's the stem cells. These of course are the cancer initiating and maintaining cells, the ones which it's really crucial to hit. And then the second cell type which expresses the thrombopoietin 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 two cell types are the direct targets of antibody therapy.
Now all the other cells, so 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 targets 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 multi-omic testing on single cells isolated from the peripheral blood of a 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 two 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 film 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 this: the so-called silent carriers are really in very high abundance, so high numbers of mutant monocytes, NK cells, B cells. This is very interesting. Also actually some T cells are also mutants.
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 will also decrease 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 one, cycle four, just four months on therapy. And they 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.
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. Then we also need to assess the burden of mutant megakaryocytes. This is depicted really beautifully in these slides. To do that, you can perform immunohistochemistry on bone marrow biopsy sections. We're fortunate to have an antibody that works really specifically and only identifies it, only stains mutant CALR, doesn't stain wild-type CALR. 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. These changes here are quantified across the cohort of patients.
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 the very nice benefits 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 a clearance of these atypical circulating mutant CALR-positive erythroid progenitors that I mentioned. So they decrease.
Interestingly, we saw an increase looking in the bone marrow at CD71-positive cells reflecting erythroprogenitors. What this is reflecting is we're getting renormalization of bone marrow hematopoiesis and recovery of healthy hematopoiesis occurring within that bone marrow microenvironment. Finally, 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. 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 two patients here who have very high clonal complexity are shown for example. 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 one, ASXL1 and EZH2 for patient two 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 clonal 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 are 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.
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. Using the words extremely encouraging here may be classic British understatement given the robustness of the proof of concept you just saw. 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 a third of patients currently benefit with available therapies, thus defining the unmet need in this population. 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. 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% + 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 the 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 the typical regulatory endpoint. This was, as John pointed out, an ongoing dose escalation and expansion study. 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. In this study, 42% of patients achieved an SVR25 and 33% of patients an 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 use, 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 available 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 were seen in both Type 1 and non-Type 1 patients.
Then as Bethan just showed you, the potential for disease-modifying activity, very elegantly demonstrated by her by the decreases in mutant CALR megakaryocyte sequence 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 sub Q 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 regular 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're seeing 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 sub Q if that is ready in time, and then based on the ongoing phase I in the first line setting, which includes monotherapy989 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 sub Q 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 two 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? Yeah, we have microphones. We open the floor for Q & A and then we'll go to the webcast as well.
Okay, Alexis. Okay.
Thank you. Brian Abrahams, RBC.
First off, congrats on the data. I wanted to dig into those seven 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, is there anything you can tell us a bout 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? Thanks.
Let me touch first. The definition of ineligible was determined by investigators. Mostly 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 was included. This group of patients was included in this study because it's a 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 reason that the investigator deemed those patients ineligible was anemia, which we see frequently 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 to the patient. So I got to tell you, patients are interested in this therapy because that's the other thing that gets missed. Another thing is that I didn't think we had so many CALR mutant patients until this antibody came out. And now there's all these CALR mutant patients that come out of the woodwork and 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 to 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 get on.
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 infection. So that's often patients are very aware of this. I work in Oxford and our patients tend to be very educated. So they often come to you with the statistics about toxicities of treatment. So infection risk 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, symptom, anemia and of course then disease modification. So you may, you'd have different criteria thinking about eligibility for agents like this.
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 .
Brian, just to add what's, 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% + 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 few. Where are we going? Greg, I think.
Hi, Erik from Mizuho. Eric Lavington. Sorry. So I'm just wondering what sort of t imeline you would be looking for VAF reduction in the MF patients to get the majority of them over the 50% reduction.
It's a good question. We're going to ask Beth to comment. We don't have a timeline 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+% improvement in anemia, we thought it was remarkable. Importantly, it does all those things not in a symptomatic way, but it just 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 is 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.
I might have called it a tap rather than a forceps, but that's okay.
The tap.
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. N ext.
Thanks.
Hey, it's Michael Schmidt with Guggenheim. Pablo, nice data readout. Congrats on 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 what about Type 1 and Type 2 patients? And could you comment? I know there was intrapatient dose escalation. And what dose did the Type 2 patients get up to in this study?
So let me separate the two scenarios here. The two 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 9A9 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 PD marker in ET that it makes the dose selection simpler. So that's where we're very close in MF with 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 OTV 2 dose selection, whether 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.
Occurred really fast after two 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's 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.
Hi, this is Kripa from Truist. Thank you so much for taking my question and congrats on the data today. So one on ET, the breakthrough designation is for a subset of ET patients. Can you remind us what % 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 one and intermediate two 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.
Yeah, 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 top of my head.
I think the difference is simply one is a combination of Jakafi, the other with single agents. The phase I study and as a first in human study, I think, you know, 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 insertions. Type 2-like mutations, the picture's 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 at 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 run in 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, three of the 10 SVR35, so it's a response rate of 30%, so this medicine works across a range of mutations. Time and dose are two variables that we need to keep in mind. The other variable we need to keep in mind is washout. Remember, these patients retreated 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 good.
Just to comment with the use momelotinib as we did in SIMPLIFY-2 with no washout, the spleen response rate was 7% and they failed on symptoms.
I was going to say but no, thank you Claire for it. Yes, 7% is a SIMPLIFY study. The MOMENTUM study at 22%, you're at 35% that had mandatory washout of two weeks. I believe the SIMPLIFY had a spleen response of 7%. When you look at these results that we just showed you, keep that number in mind.
Hi Pablo, Tazeen Ahmad. Bank of America.
How are you?
Thanks for hosting. A couple questions from me. Can you just give us a little bit of clarity on where you are in this sub Q 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. Thanks.
Let me start with the second question so I don't. First of all, that population is not a population. That's not a study we're going to do. Right. The suboptimal responders at 989 we had to do that data. It's the first in human study. The safety question about combined with ruxolitinib had to be addressed and then understand a little bit of what it does on top of Jakafi. I think the cohort that matters to Tazeen is the one we're doing now in naive patients on 989 vs. 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 was well tolerated as Jackson highlighted, but we saw stabilization of the anemia and improvements in spleen and symptom. The sub Q. 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 sub Q 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 we're accelerating that as much as possible.
I don't know who has the mic over here.
Thanks, Pablo.
Yeah, congrats on the data. Appreciate the event here. Just first question on the SVR r esponses, it looks like between the two dose cohorts that you kind of look at, it's fairly flat, but when you look at TSS, it looks like a l ittle bit more of a dose response.
Just kind of curious if you can reconcile or what you think is going on there?
And then second question, just curious on t he, you know, 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 three or four 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 1 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's some patients that perhaps did. So when you put those four 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, 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 dose intensity?
I'll try. First, I think if you saw John's slide, the mean dose delivered was, I think, 33 mg. If you look at real world use of rux in the United States, about 15 bid. So, it's consistent with how the drug's 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.
So going in it was 33, and I don't think that it dropped on studies. You know, it wasn't like they were being dose reduced. These are patients that were recruited at MF centers where we typically, you know, 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, you know, I think that the population that we see represents what we would normally see.
Hey guys.
Gavin Clark-Gardner from Evercore ISI. Hey Pablo, thanks for the presentation. So for the experts up here for the anemia benefit, I'm hearing that a lot of investors are cross comparing against m omelotinib and I guess the reality is t he way they achieve the anemia benefit is very different. Restoring hematopoiesis versus, you know, 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 three. Claire, you go first.
I definitely think it's disease modifying. We don't see this kind of benefit with the JAK inhibitor. We just don't. And on the subject of anemia response, you may remember ASH a few years ago when Steven Oh 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 forceps. Maybe not.
Beth, you want to comment on.
Just to say I completely agree they're totally different drugs. You'd use them in different settings. I think to relate to momelotinib. GSK have done some really nice analyses 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 proportion of patients who benefit from anemia. No doubt about that. But it's a different mechanism.
I would just add that there's no. Obviously the mechanism as it was highlighted by our experts is clearly different. The magnitude is completely different. I mean when you look at the momelotinib difference, a 10% difference. We just showed you 56% difference mostly in Jakafi pretreated patients. I think you have a follow up. Yeah, 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 SVR35s 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 CALRs that's driving some benefit there.
So John, Claire, Beth, if you want to address the second part, I'll come back to the TSS50 question.
I could tell you a story about one of my patients that's on the combination. 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 two ASXL1 mutations.
He's a very anxious man. He ran out of the hospital halfway through his conditioning for bone marrow transplant.
He is on 25 mg 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 mg his spleen is almost unpalpable and his transfusions have almost but not quite disappeared. So I definitely think there is a n added benefit. Whether it's synergy or not. I think biologically it's difficult to say, but I think it's nicely illustrated by a patient's story. Only symptoms are better as well.
The preclinical data that we presented clearly shows that these two 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, I think, and obviously we know what the side effects of JAK2 Jakafi 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 unequal follow-up. Some of them have very few assessments.
Ashwani 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 equipotent across the two.
If you look at the patients in the waterfall that receive 400 or higher, the SVR35 in those patients is 30%. In the whole population 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 from Deutsche Bank, thank you for hosting. Will the pivotal studies include stratification for Type 1 versus Type 2? Second question is how long for the pivotal ET trial to enroll and read out. And third, for the panelists, recognize 99 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? Thank you.
Let me, before we ask, so the details you're asking, the design and timelines for pivotal trials, we'll disclose over time.
You know, 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 finding, analyzing the dose selection for ET and the data were generated 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 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 reactions happening when that happens. All but two patients recovered on study. One of those two had it at baseline and both are Grade 1. The last one is still going, but is a Grade 1 AST elevation. 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 a very clinically concerning signal, and from a clinical investigative 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, you know, there was a lot of text in some of the slides. It was a patient that had 50 mg. The one Grade 3 AST elevation happened at 50 mg. The patient was.
The dose was suspended, it recovered, the patient was re-challenged. It's now currently dosed at 1500 mg. No reoccurrence of the LFT. So that's another important point to make.
Yeah, I was going to make a similar anecdote actually about a patient in the combo cohort who was entered in a relatively low dose, did have transaminitis and then since her disease has improved, her extramedullary hematopoiesis has improved and she's since dose escalated without any toxicity.
Reni 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 you know that might be coming out?
The 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 two studies that were looking at phase I, but there were really two studies. And the reason for that was we were allowed to start a lower dose or higher doses, we should say, in Australia as opposed to the U.S. and if you go back two years and some of you remember these conversations, there was a concern, a hypothetical concern that because 989 would eliminate the malignant clone in 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 t he co-occurring mutations decrease over time as well? Or are you noticing, you know, any certain co-mutation clones that might be compensating?
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. By the way, I would comment. You have patients in CML with eight, 10 years of therapy and with this mutation still in BCR-ABL, there are no secondary mutations or resistance.
In that case, just to echo that, I think the data that the FISH plots 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 from Barclays, I realized the goal here is to sort of move mCALR to frontline. But just curious, in your immunophenotyping genotyping w orks 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 t o understand, if you will, the activity i n the JAK sort of naive versus JAK pre-exposed patients and the differences t hat you've noticed there.
In terms of that?
Yeah, mCALR levels like the expression levels in pre-exposed versus JAKi-naïve.
Just understanding the difference in activity.
No. Yeah, we do not. No.
Matt Phipps, William Blair. T hanks for all the info. I want to come back to the anemia benefit. Do you have the level of anemia benefit in those JAKi-naïve patients? 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 k ind of contrast those two?
So the first question, the benefit is consistent. I don't have the actual number for you, Matt, but the benefit is consistent. The JAKi-naïve 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 six, seven, eight months, the hemoglobin keeps going up. That is not a JAK rebound e ffect.
Hi 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 r efractory.
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. You know, 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. This is something that's never been seen in MF, and really bringing these to patients as quickly as possible, I think it's really important, so we'll have that conversation. Whether it'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 from the anemia. You've talked recently about proposing anemia and SVR35 as endpoint. 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 is clinically relevant. I think it's time to have a conversation with FDA and see if we can adjust the end points, whether it's all three, 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. I think it's important for patients. I think it's important for treating physician.
Good.
One more question.
Okay. Yeah.
Steve Willey rom Stifel, thanks for squeezing me in. Maybe for Pablo, can you just speak to the appetite for potentially integrating a c ompanion diagnostic into the development plan for t yping 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 front line trial that looks to displace hydroxyurea? And maybe the physicians c ould comment on what they perceive to be the value proposition of 989 in frontline ET.
In June of this year we signed an agreement with Qiagen for the companion diagnostics, and 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, that what we're seeing today is we're not discounting doing a first line trial in ET. This is the highest priority. Separate second line ET and then the two 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.
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 true disease-modifying drug that normalizes platelets and doesn't require those adjustments like hydroxyurea 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.
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 up front 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 sub Q administration, 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.