Welcome to everybody online, in person, here in the room. A big thank you to all of you, and specifically to our presenters today, for the time and the energy you are putting behind this project. The data we'll be speaking about is 989. The data that was presented today is the first clinical data presented with this product. In fact, I was thinking of the ASH preclinical presentation that was a plenary session like two years ago, two and a half years ago. What you could wish at the time, you will see in the first 50 patients that are treated with ET, and what it would look like. Frankly, that's what makes this data so exciting, is that it looks very much like what we have seen a few minutes ago.
It will be this entire presentation will be about that subject of what the data means and where we are going to go with this project. I just want to say a word before we go into the science about why this today is an important day for Incyte as a corporation. We all know we have been facing questions about the long-term growth of our Jakafi franchise beyond 2029. That's an appropriate question to have in mind. As you know, the Jakafi franchise is made of GVHD and MPN. In GVHD, we have the launch of Niktimvo that is taking place now as we speak. We think it will be the growth driver for that part of the franchise for the long term.
Frankly, 989, what we have been discussing this morning at the late-breaking abstract session, is what is going to drive the growth of our MPN franchise beyond the sort of the Jakafi franchise itself. It is an important day for patients who are suffering from MPN. It is an important day because it is a new approach for their treatment, but it is also an important day for the company because it is a result of research programs that we have executed over the past years in many ways. We will be going through a number of presentations, and I will let Pablo introduce the scientific program for the session. Thank you very much.
Thank you, Hervé. And good morning, everyone. Good afternoon here in Milan. We have a really busy agenda for you today, so we're going to get right to it. We're going to start with an overview of essential thrombocythemia, which is the disease we're going to focus on today with the data from 989. Claire Harrison is going to give us an overview. Then Dr. Nangalia is going to talk about the biology of the CALR mutation and why this is so important. And it has really, when it was described first a little over 10 years ago, started to change the way we try to develop new medicines for this set of diseases. Patrick Mayes, our own Head of Discovery Biology at Incyte, will talk about the mechanism of action of 989, critical to understand some of the data that you're going to see. And Dr.
John Mascarenhas will talk about the data from 989 in the phase I study that he presented earlier today at the late-breaker sessions. Hopefully, we'll have time for Q&A after that. Let me spend a couple of minutes here on the introduction to our speakers. Dr. Claire Harrison is a professor of myeloproliferative neoplasms and Deputy Chief Medical Officer at Guy's and St Thomas' Hospital in London. She co-founded MPN Voice about 20 years ago and is the trustee of Blood Cancer UK. She sits on several European Hematology Association boards, very relevant to the meeting today, and is Deputy Editor in Chief of Hemasphere. The next external speaker will be Dr. Jyoti Nangalia, who discovered the CALR mutation and its importance in MPNs and published a paper in the New England Journal in 2013.
She has continued to make landmark scientific contributions across this set of diseases and provides finalized predictions outcomes in the MPN for MPNs. Her team identified other genetic drivers of myeloproliferative neoplasms, and she's also a group leader at the Wellcome Sanger Institute and Cambridge Stem Cell Institute. Dr. John Mascarenhas, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, Director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of the Tisch Cancer Institute, where he directs the adult leukemia program and he leads clinical investigations with the MPN Disorders Program. He's been a principal investigator and presenter of a lot of recent clinical investigations in MPNs and other related areas. With that, I'm going to hand it over to Dr. Claire Harrison.
She's going to tell us about ET, a disease overview, and some of the important points to remember as we start thinking about the potential role that 989 can play in these patients going forward. Claire?
Hello, everyone. It's my great pleasure to be here today to introduce you to this disease area and to give you some insights as a clinician who's looked after patients with these diseases for more than 25 years. As many of you will be aware, the MPN family consists of two more perhaps indolent diseases, although as I think I'll show you, they're not so indolent, ET, polycythemia vera, and then myelofibrosis. Focusing in specifically on ET, this is a relatively rare disease. The incidence is about one in 100,000, but the prevalence is at least 30 per 100,000. The disease has a bimodal distribution. The median age at presentation is for patients in their 60s, but many of the clinicians here today would be able to describe to you that we also have a peak in younger individuals, particularly young females.
I'm going to tell you the story of one of my patients later. The main clinical presentation is thrombosis and hemorrhage, but the risk for the patients and the thing that they're most worried about is disease progression. This is a time-related event. Disease progression is principally to myelofibrosis, which we do have some treatments for, but none of them are particularly curative, as you will know, although there's work in progress. Acute leukemia is also a risk for these patients. Zooming in in particular on mutant CALR positive ET, this represents around 30% or so of our ET patient population. What do they look like? I'm summarizing that for you on this slide. They tend to be younger. They have a higher risk of MF transformation. That's what this graph is showing. This is myelofibrosis-free survival.
These are the CALR type 1, and these are the CALR type 2. My colleagues will explain what a type 1 and a type 2 mutation is, but just focusing in on these are the patients in my ET population who are most likely to develop myelofibrosis, and they do so quite quickly. In this disease, these are pertinent points for you when you see the results later. A higher VAF tends to be the case for CALR patients compared to JAK2 positive ET, which is around 50% of the population. Specifically in the CALR population, a higher VAF is known to be associated with a higher risk of disease progression, thrombosis, and poorer outcomes. These patients also tend to have more indication for starting treatment. They tend to have a higher platelet count. That tends to be our reason for initiating treatment for these patients.
They also, as I'll show you in a subsequent slide, in some data generated by us in a study that we started in 1997, tend to be less likely to respond to treatments. If I look at a patient with ET in my clinic, or John does, or Jyoti does, or any clinician treating these diseases, these boxes here, these are the things we're trying to focus on. We're trying to minimize the impact of the disease, control the risk of thrombosis and hemorrhage, and do so in a safe way, allow them to become pregnant if that's something they want to do. We do not have, as you'll see, anything at present that we know for these patients can prevent disease progression, can restore normal hematopoiesis, and by any tractionable means reduce the clone size, which is something that we would perhaps be defining as disease modification.
Just to show you what the current treatment landscape looks like, for a high-risk patient, generally, that would be defined as either someone who's over 60, someone who's had a thrombosis, or someone who has a platelet count of over 1,000-1,500, which is where the indication for treatment for CALR comes in. These patients, we give these very old-fashioned drugs to, hydroxyurea or interferon, or in the second-line setting, a drug called anagrelide. You will have seen some data at the EHA meeting comparing these two therapies. These treatments are used by us in day-to-day practice with these three aims: control the blood count, reduce the risk of thrombosis, and reduce some symptoms. There's no evidence at present that they modify disease. Interferon, we have been using for decades in this disease setting. We never say to a patient it's going to modify their disease.
I told you that CALR positive patients tend to respond less well to standard therapies. This is data that we published before Jyoti described the CALR mutation. This is in the PT1 study, which we started in 1997 in the U.K. This is response rates to patients with hydroxyurea or hydroxycarbamide, platelet counts, which tends to be our primary target. Here you can see the JAK2 negative patients running a higher platelet count than the JAK2 positive ones. We needed more doses of hydroxyurea, and we noted more cases of resistance or intolerance to disease. I can't show you the specific data for CALR patients in this setting, but I've summarized some of the available literature. There is still unmet need for ET patients. We haven't had a new therapy for these patients since the approval of anagrelide in 2005 in Europe.
Resistance and intolerance to available treatments, I'm showing you the data here. These treatments do not have an impact on long-term disease outcomes. Indeed, there is evidence that hydroxycarbamide or hydroxyurea may well increase the risk of leukemia, and anagrelide is certainly associated with higher risk of myelofibrosis. We showed that in the PT1 study. Anagrelide, interestingly, is also associated with VAF increases for CALR. I think this is a fair summary for our current treatment landscape. No current treatment offers a cure, evidence of disease modification, or consistent change in key pathological features, VAF or resolution of marrow changes. Now I want to tell you a story of a patient who I first met in 1997. I think this story illustrates the statement I made on the last slide, that available treatments don't really modify disease course. She was 17 when I first met her.
This is her blood count. We did a biopsy. It was consistent with ET. We did some molecular workup, but in fact, in 1997, we had nothing to do. During the course of her disease, she developed a knee injury, actually while skiing in the States. She was put on anagrelide by colleagues in the Mayo Clinic to manage surgery because the platelet count was high. At that time, anagrelide was believed to be safe and was frequently used for younger patients. Subsequently, the PT1 study and other studies showed that it had these risks associated with it. Later, she planned to get pregnant. At that time, her platelet count was 1,600 plus.
We treated her with interferon alpha to reduce the risk of adverse pregnancy outcome, but she had a very poor experience with that drug, had a miscarriage, and because of her poor experience, has subsequently consistently refused to have interferon. Later, we found that she was indeed CALR positive. Around 20 years after diagnosis, she developed myelofibrosis. That is actually quite a long time. I saw a patient just last week who is 30. She has two children, and she transformed to post-GT MF with CALR positive disease within five years. It is very variable. Does reducing VAF matter for these patients? The only data we really have for CALR at the moment is this increase in VAF with anagrelide, which we know is associated with fibrosis. In an academic study, we took actually, ironically, another Incyte asset, ruxolitinib. In the U.K., we performed an academic study.
Jyoti was very heavily involved in this. We recruited 180 patients, and we treated them with ruxolitinib. In this study, we showed that molecular response, which was just a 50% reduction in VAF, but by the way, the results are the same if the threshold was 75% reduction or 25% reduction. By one year, event-free survival, and event-free survival is thrombosis, hemorrhage, transformation, or death. I think we'll all agree those are relevant outcomes. Later, Jyoti and team in this publication, which we published in JCO, we were able to show for the first time that an endpoint in MPN correlated with overall survival advantage. You can ask Jyoti the question about difference biologically between JAK2 positive disease and CALR positive disease, but I think there's a good rationale for why a reduction in VAF that might be viewed as relatively modest may have a disease implication.
In conclusion, and I'll speed up a little bit, I've shown you the distinct phenotypic profile for these patients, the limitations of our current therapies, unmet need for these patients, and that there is emergent evidence that reducing the clone size, even to a modest extent, can correlate with good outcomes for these patients. I believe that's because these clones are more indolent. They tend to increase more slowly. Anyway, thank you very much for your attention. At this point, I think, Jyoti, I'm handing over to you.
Good afternoon, everyone. Thank you, Claire, for that talk, and also to Incyte for having me here today. I'm going to talk a bit about the biology of a CALR mutation and its relevance in MPNs to set the scene for the clinical data to follow. I still remember the day in July 2013 when I first stumbled across the CALR mutation. Initially, it was confusion and intrigue. About eight hours later, after growing excitement, I emailed my PhD supervisors at the time at about 3:00 A.M. It was new. The JAK2 mutation had been discovered in 2005. Really, since then, we did not have a molecular basis for at least half of patients with ET and MF to try and understand what was driving their disease. These stories were published in the New England Journal of Medicine in December 2013.
It was really exciting for me in 2022 when Eddie Murra from the Incyte team stood up and presented the preclinical data on the first mutant CALR targeting antibody and as published in Blood soon after. What is a CALR mutation and what does it do? Along the top here is the normal protein sequence of CALR. If you take the CALR protein and stretch it out into a string, you start with one end here called the N-terminus, and you go down to here called the C-terminus, the two different ends of the protein. Just note here that the last four amino acids of the protein are K, D, E, L. K, D, E, L is a very important part of normal CALR. What does CALR do normally? We have DNA, and our DNA encodes for genes.
If you want to switch on a gene in a particular cell, you make a copy of that DNA into RNA. That RNA forms a template for making a protein. Once you've made your protein, your protein is just a long string, and you need to fold it into a particular complex shape for it to do its function. CALR is involved in helping that long string of proteins fold into whatever shape they need to be in a place in your cell called the endoplasmic reticulum. KDEL anchors CALR to the endoplasmic reticulum. It keeps it there so that as proteins traffic through, it helps it fold, and then those proteins go on their merry way to do whatever job they do in the cell. If you look at KDEL across humans, mice, zebrafish, Drosophila, KDEL is conserved.
This is the sequence of CALR across species. It is preserved within the animal kingdom. What was really exciting is when you look across all the mutations of CALR at the time, this was the most common. This was the second most common. There were a whole bunch of other things. What was really quite remarkable is that when you—I did this manually, working out what they did—the KDEL was lost in all of them, and there was this novel C-terminus sequence to the protein. Here is the structure of the protein now folded. You can see that there is a new tail. CALR has got itself a new tail. Now, why is that important? As I already mentioned, proteins go through the endoplasmic reticulum here, which is this sort of web around your nucleus.
CALR is normally there, and it helps these proteins fold. What it's doing, weirdly, is that mutant CALR specifically binds to the receptor for thrombopoietin. Thrombopoietin is a hormone that signals to our blood stem cells to make more platelets and to make megakaryocytes. It itself, as a receptor, needs to go through the to get folded into its right configuration before it goes into the cell membrane ready to receive signals from TPO. Mutant CALR binds the receptor for TPO in the. Because it's no longer docked to the, because it's lost KDEL, it goes onto the cell surface with the receptor for TPO and not only brings it to the cell surface, but activates it because it's continuously locked. Mutant CALR with TPOR in combination become this force of nature that then leads to this continuous signal in the cell to make platelets.
That's what drives ET. When that disease evolves genetically to acquire more mutations, that's what then drives myelofibrosis. The key thing here is, while type CALR is involved in normal cellular homeostasis, that mutant CALR has this particular predilection for the receptor of TPO that then single-handedly drives this disease. Even though this mutation, this protein, is found in all of our cells, it drives this disease in hematopoietic stem cells. That link to TPO becomes even more important when you're measuring its activity in your cells. Remember, every one of our stem cells that is part of the ET clone has a mutation in CALR within its DNA. Whether that mutation is active and doing anything is entirely dependent on whether that cell is a cell that normally makes the receptor for TPO.
This is a map here where we've basically taken all the different types of cells you have in your bone marrow: NK cells, T cells, B cells. These are lymphoid cells. The CD34 is a marker for your stem cells, that rare population of cells that make all of our blood cells, and the myeloid erythroid lineage, which is so typically elevated in MPNs. You'll see here that mutant CALR is specifically expressed in these compartments. When we measure VAF, we are measuring it at the DNA level, which many cells have. When you're looking at where it's active, it's only active in certain cell types. It's only then pathogenic when those cell types also express TPO. Here are the stem cells at the top of the hematopoietic tree.
These stem cells sit at the top of the pyramid and make all the different blood cells. TPOR is expressed in these stem cells, as is mutant CALR. This is, fortunately, the target that you want in MPNs, and it is the target that both expresses TPO and expresses CALR. TPO and CALR are expressed down this myeloid lineage all the way down to the megakaryocytes and the platelets. Of note, these cells here will have mutant CALR in their DNA, but it will not be pathogenic. If you then look at these cells here, which were not highlighted in the slide before, these are the cells that are the daughter cells of your mutant stem cells. They do have mutant CALR, but they are not really contributing to the pathogenicity of it.
As these cells disappear, if you could get rid of them, these will go down quickly because they'll see the antibody. These will eventually disappear once their parents disappear. These might lag. If you look here, the early clinical indicators that one could have with a drug that targets the mutant CALR specifically in the cells that it's expressing TPOR with, you'll expect a reduction in platelets. You might expect a reduction in megakaryocytes because there are many mutated CALR megakaryocytes in the bone marrow and a reduction in the stem cell compartment. You'd measure that as a reduction of the number of cells that both express mutant CALR and TPO. These cells here, where they may contribute to your DNA readout of mutant CALR, will go down more slowly as their parents get eliminated, these stem cells.
In conclusions, MPNs are cancers that arrive after the acquisition of a driver mutation within your hematopoietic stem cell. Mutations in CALR that occur in those stem cells can drive ET and MF. A small fraction of cells that both express the mutant CALR and the TPO receptor will then drive the disease and be the recipients of targeted therapy. The cells that do not express TPOR will hopefully be removed later. For me, in particular, we are very interested in my lab about how these MPNs grow and what the merits might be of reducing the burden of disease. The way I see all MPNs and their growth over life is really like a compound interest on your bank account. These are slow-growing cancers. There may be a 5%-10% interest.
That goes on for 20, 30, 40 years, and you end up with millions to billions of cells that are responsible for your disease. If you could reduce that compound interest rate from 20% to 10%, I'm sure many people in the room could recognize the impact of that in 20 years' time. If you could reduce not only the burden of cells, there are less cells waiting for potential evolution to myelofibrosis. If you could also reduce the rate at which the overall clone is growing or indeed regress it, then that could push back disease by decades, potentially, which is what the last point makes. Now over to John Mascarenhas. Sorry, over to Patrick Mayes, apologies, to talk about the novel mutant CALR antibody.
Thank you, Dr. Nangalia. I'm going to spend the next few moments just to speak or provide an overview of our mutant CALR monoclonal antibody, INCA033989. 989 is a first-in-class agent which targets the mutant CALR oncogene. It is a fully human FC silent IgG1, which binds with equal affinity or high affinity to both type 1 and type 2 mutant forms of calreticulin. Upon binding, it leads to the potent inhibition of the constitutive JAK-STAT signaling that you just heard about downstream of mutant CALR interaction with TPOR. The net effect here is that you have antagonism of mutant signal while having no effect on normal cytokine signaling through TPO/TPOR. To demonstrate this selectivity, we isolated CD34 hematopoietic stem and progenitor cells from either MPN patients or human healthy donors. You can see from the upper left-hand schematic, this is what was described.
Mutant CALR interaction with TPOR leads to constitutive signal through the JAK-STAT pathway. This provides the oncogenic properties to the MPN cell. Whereas in a normal HSPC, cytokine is required to bind the cytokine receptor in order to engage and initiate signaling downstream. If we look then in the context of 989 treatment in the center graph, what you see is the potent and complete inhibition of the mutant CALR-induced JAK-STAT signaling shown in blue, while 989 has no effect on the cytokine or TPO-induced signaling through JAK-STAT shown in green. This is quite distinct from other therapies used to treat MPNs, where there is no selectivity between mutant-induced JAK-STAT signaling and wild-type or TPO-induced JAK-STAT signaling in an HSPC.
This creates an issue wherein you cannot address complete inhibition of JAK-STAT signaling in a mutant cell because of the dose-limiting toxicities associated with wild-type JAK-STAT inhibition in a normal cell. This exquisite selectivity of 989 is directly linked to the disease-modifying potential of this agent. As you heard from Dr. Nangalia, mutations in CALR arise in stem cells. This provides a clonal advantage of the mutant stem cell versus wild-type. Over time, this provides, in the bone marrow of patients, the opportunity for mutant cells to become the dominant clone in that person. However, what we know about ET is that the average mutant CALR VAF is about 30%-40%. What this means is that there is a meaningful reservoir of wild-type HSPCs that still exist in these patients.
If you think about the context of therapy with 989, as shown on the right, the antibody will bind to and eliminate the mutant form of the HSPCs while sparing activity against the wild-type, allowing for expansion of those wild-type clones, eventually over time leading to the counterbalance of decrease in mutant, increase in wild-type, and a decrease in mutant CALR VAF over time. To demonstrate this directly, we isolated CD34 HSPCs from either MPN patients with a CALR mutation or human healthy donors. These cells can then be cultured in an ex vivo liquid culture series of 989 on the survival and proliferation of these cells.
This is shown in the graph on the right, where you can see the effects of 989 resulting in dose-dependent elimination of HSPCs in a mutant CALR MPN patient sample, while 989 has no effect on HSPCs from a healthy donor in this system. This is important because it shows direct activity against the disease-initiating sustaining cells in MPN. Using a similar system, we can isolate CD34 cells and culture ex vivo in a cytokine milieu which biases towards megakaryocytes. Here we can show the direct effect of 989 on megakaryocytes in this system. You can see from the data on the right, in an MPN patient with a CALR mutation, we see very significant effects of 989 towards megakaryocytes in this patient's sample, whereas 989 has no effect on a JAK2V617F megakaryocyte patient.
This is important because, as you heard, ET is characterized by the overabundance of both megakaryocytes and platelets, which are derived from megakaryocytes. This demonstrates the ability to modify the pathological endpoints of this disease. Finally, we have tested 989 in a mutant CALR transgenic mouse model. In this model, we can knock in mutant CALR into the hematopoietic cells of these mice using an MX-1 CRE recombinase system. Following knock-in, the mice are allowed to age for four months, which allows for development of MPN disease, which, as you can see, results in extensive thrombocytosis in these mice, anemia, and megakaryocyte hyperplasia in the bone marrow. We can treat with 989 for 12 weeks. Upon treatment, look at disease endpoints.
What you can see from the graphs in the middle is significant effects on normalization of both platelet counts and white blood cell counts, as shown by the blue bars on the top graphs, as well as reversal of anemia, as shown by hematocrit and red blood cell below. If you look then in the bone marrow with the H&E plots on the far right, you can see a normalization of megakaryocyte cell numbers, both a decrease in number as well as a normalization in the morphology of those cells. All in all, showing the disease-modifying activity of 989 in this mutant CALR preclinical model. In summary, we've developed a high-affinity selective monoclonal antibody which antagonizes mutant CALR function. This is selective for the constitutive JAK-STAT signaling while sparing activity through normal cytokine-induced signaling.
As I showed you, this has direct inhibitory effects on the disease-initiating and sustaining cells within MPN as well as megakaryocytes, which are the precursors which derive platelets from and is how these diseases are identified. As I showed you in the mutant CALR conditional knock-in model, having transformational activity of the antibody leading to platelet normalization, reversal of anemia, and elimination of megakaryocyte hyperplasia in this model. Overall, the preclinical safety and pharmacology profile of 989 makes this a very promising candidate for clinical testing in mutant CALR-positive MPN patient samples. I'll stop here and hand the microphone to Dr. Mascarenhas.
Okay. I want to thank Incyte for inviting me to join today to review with you the results that were just presented as a late-breaking abstract with 989. For me, it's very exciting. What I'm going to do with this talk is personalize it a little bit more to give you a sense of my own personal—and it's not just mine. I would say it's shared by the investigators who are treating patients' impression of the data beyond the podium presentation that we just gave because I really do think that this has the potential to be transformative in the field. This is the schema of the phase I study. You'll see that it is a study that is done both in the U.S. and ex U.S., but we're presenting the joint data. Today, we're just focusing in on the ET population.
You'll notice that there are MF patients, both monotherapy in combination with ruxolitinib, that are being treated. That data will be presented at a later time. Today, we're really focused on the ET cohort in a drug that's given intravenously every two weeks in a patient population that is confirmed to have ET by WHO criteria that's deemed high risk in need of therapy. These are patients who are at risk for thrombosis and progression. They're over 60 years of age. They've either had a thrombosis, they have high—or a hemorrhage, a high platelet count, maybe with acquired von Willebrand. They're in need of better therapy. By definition, they have to have thrombocytosis, so a platelet count greater than 450,000.
They could be on anagrelide or hydroxyurea, which is a standard of care for most patients worldwide, including the U.S., but are probably not succeeding to come on the study, meaning that they're on some dose. It's probably limited by toxicity, which is very common, and/or not achieving its goal at the maximally tolerated dose. This is really representing a group of patients that are in need. I point that out because it was not hard to recruit to this study for that very reason. Once you open up a study, you have to figure out which patients are in need and will they come on to a first-in-human phase I study. I've done a lot of studies.
This was a very easy study to recruit to as a first-in-human because I think it represented a group of patients that were in need and were looking for a novel immunotherapeutic-based treatment. The endpoint is safety and tolerability, characterizing the safety profile and, of course, trying to identify dose-limiting toxicities. As you'll see, we did not have DLTs, nor did we hit an MTD. What will be our recommended phase II dose will need to determine. Of course, looking at secondary endpoints, response rates. Response rates here for the purpose of this talk are going to be normalization of the platelet count, the white count. Most intriguingly, and I would say most impressively, are some of the biomarkers I'll show you that would suggest that this is not simply reducing platelet counts. We have drugs that reduce platelet counts to some extent.
This is likely modifying the disease. As Jyoti pointed out, that could have a much greater impact and profound impact on these patients over time. These are the 49 patients. These are the 49 patients that were recruited at the time of data cutoff from 24 milligrams, which was the starting dose in the U.S., all the way up to 2,500 milligrams across multiple centers. This was really a global effort, I'll just point out. It is very important. This was not one center generating data. This was many centers, many phone calls, many toxicity reviews, and a lot of confidence in what we are showing here today. This is the patient population that you would see and would expect. A median age in these diseases is usually in the 60s. Here, the median age was 60. The time from diagnosis was seven years.
I think that's also an important point. These are chronic diseases. These patients sometimes start with therapy that don't carry them the distance and need additional therapies. I'll show you that although on the right, hydroxyurea was the most common therapy, you will notice that the number doesn't add up to 100% because patients do end up cycling through therapies. That becomes a problem. They go from one therapy to the next therapy in search of a therapy that will both be tolerable, control the counts, and potentially modify the disease. Hydroxyurea and anagrelide for sure don't hold that promise. There's clear unmet need. I think this table summarizes some of that unmet need by the types of patients we're enrolling. You will notice that 57% of patients are type 1. That's the more common type. The rest were either type 2 or other.
The median VAF was around 30% with a very high platelet count. Again, this was a patient population in need. These are not patients that have polycythemia vera, which you may be more accustomed to seeing, or myelofibrosis. Their white counts were not super high. Their spleens were not super big. Their TSS may not be super high. I will tell you, from dealing with a lot of ET patients, they do have symptoms. There is a lot of anxiety that does not come across in tables like this when you live with a chronic disease. Therapies that can effectively control the disease relieve a certain degree of anxiety. I will tell you that that also makes for a much shorter office visit.
When you have controlled the disease and the patient's no longer anxious, they don't spend three hours sort of telling you about all the different complaints that they have, which are repeated. I've noticed with giving this drug, the office visits are actually shorter because patients are enjoying the benefit. The anxiety of that platelet count comes down considerably. That's not a trivial aspect. Here is the safety data, which was, I think, really beautiful. It was really beautiful in the sense that the treatment-related—so overall, any treatment emergent adverse event, 85%. Treatment-related, deemed by the investigator in a phase I, a lot of this was early on when we didn't know what to expect. It was about 61%. Grade 3 was about 1/3 of the patients, less than 1/3 of the patients. Serious events were 3, which I've outlined here.
Asymptomatic lipase increase happened very early on in a 24 milligram dose. We know that's not an effective dose. We know that this occurred in other patients but seemed to have no clinical sequelae. There were no cases of pancreatitis. There were no radiographic changes. It was transient. Often, we would check it. Claire and I have made this comment before. We don't normally check lipase in ET patients. I'm going to start doing it now because, out of curiosity, I wonder if lipase is elevated transiently for reasons I don't know. We didn't see any correlation with the drug in terms of we would see the lipase go up before the dose, and then it would come down sometimes even after the dose was given. It didn't seem to be clinically impactful.
This one patient, I did want to make this talk somewhat personal just to alleviate any concerns. If you see visceral venous thrombosis, a very common complication in MPN, splenic vein thrombosis. It could be Budd-Chiari. It could be portal vein, splenic vein. We see this frequently. In this individual, which was treated at our center, low dose, 24 milligrams by cycle five, she came in after a flu-like symptom, which might have been the precipitating event, and had extensive splenic vein thrombosis requiring hospitalization and anticoagulation. She had a history of DVT. She also had a lot of risk factors for thrombosis, including obesity. She had many explainable reasons why this could occur and very, very unlikely related to the drug, just to be very clear. The diverticulitis also happened in a patient who had had recurrent diverticulitis, also not thought to be drug-related.
I'm sorry, sorry. Dose reductions to treatment adverse events, one. Infusion interruptions, none, and no DLTs in a phase I study. Very, very clean. You see the toxicity here. I can assure you that most of these—and this is regardless of attribution, of course—most of these toxicities are toxicities that are commonly seen in the clinic in ET patients, except for the lipase, which I pointed out, which again was transient and without any significant clinical sequelae. This was a very clean study. It was one of the few studies I've participated in, and I've participated in many, where I felt very confident putting patients on in a first-in-human and letting them know that my concern about toxicity was very minimal and my hope for efficacy was quite high. That's what we saw. We saw it very obviously.
I'm highlighting here the change in platelet counts over time. This is grouped by dose of 24-250 milligrams and then 400-2,500 milligrams to make the point that in each group, we saw very dramatic reductions in platelet counts, near normalization of platelet count, even at the lower end of the dosing range within the first month of therapy. It was even more impressive in the higher range. The rapidity in which you see it is remarkable. The durability of that normalization is remarkable. We did not see thrombocytopenia, which is key because what we don't want to do is try to control counts to the detriment of inducing the alternative problem of low platelets. Any concern of that was wiped away when we saw this data. It was very satisfying to see platelet counts.
I mean, I had patients literally cry in the room because they had never seen a normal platelet count on them. It was just so anxiety-relieving. It sounds maybe unimportant, but it was actually a very big deal. Thirty-one patients did come on with either hydroxyurea or anagrelide. I think, really importantly, 65% of them were able to come off, come off because they do not need the hydroxyurea and anagrelide. The 989 study drug was clearly controlling the platelet count in the absence of that concomitant cytoreductive therapy. This plot is a swimmer's plot to maybe give you a little bit more granularity and help understand what we are really looking at. This is the 24-250 milligram treated patients. Here is the 400-2,500. The doses are listed here. The responses down here are color-coded.
This dark blue are the patients who had CR. The light blue are the PRs. The beige are the stable diseases. The triangles are the type 1s, the more frequent ones. The circles are the type 2 and the others. You can quickly see that even at 70 milligrams—and this was just random. We did not try to just put type 1s at the stairs, but it just happened to be—you get this very quick and durable control, even at 70 milligrams. You look at this and you say, "Okay, maybe not as durable or as impressive in the type 2s." You go to this side of the screen and you start to see that at higher doses, you are starting to see these responses with the type 2 patients as well. Particularly here, we are seeing that response as well.
I do think that there's a dose dependency. You probably need lower doses with type 1, higher doses with type 2. I would say that across the board, patients with ET that have a mutant CALR protein enjoy some degree of response rapidly and safely with this compound. Only one patient, again, discontinued treatment. All the other patients continue to receive every two-week therapy. This was really gratifying to see. We do not often check mutant CALR VAF in our patients who are not on trial because most of our therapies do not meaningfully change it. It is not something that would normally be done. In the context of a clinical trial where you are asking the question, "Is this truly stem cell directed?" you want to see some reduction in this VAF as a surrogate marker of disease burden.
I think at a very early time point, this is within six months. This is from the peripheral blood within six months of receiving therapy. These asterisks show the patients who only had up to three months, so three cycles. This is very short. For a long-term disease, where a median of seven years before they got on the study, within months, we're seeing reductions in the CALR VAF. This is shaded by dose. The darker the shade, the higher the dose. Most of these patients here were at 750 milligrams. This does include type 1 and type 2 patients. You can get a sense that there's darker blue as you move to the right. Of course, there's also less time for the patients with darker blue that have the higher dose.
We need more time to see even further reductions in this biomarker. All 18 molecular responders also achieved a hematologic response of CRPR. It was mostly CRs. Correlating very nicely, this change in biomarker with the clinical outcome measure of platelet control. From the peripheral blood in seven patients, single-cell RNA sequencing was done. By immunophenotype, this was shown in the previous slide. The HSPCs here and the myeloid erythroid lineage derived cells down here. In gold, these are the cells that are expressing mutant CALR in theory with thrombopoietin receptor. This is the targeted cell population for 989. You can see the very significant and within a short amount of time, here are the four patients that we're highlighting at the different doses and pointing out that this patient here was a type 2 patient.
You can see significant reductions in the CALR VAF in the whole blood. It is driven by reductions in this population here, the stem cell population. It is an anticlonal, anti-stem cell directed therapy. With it, you have concomitant increase in the wild type or normal cells that are CALR wild type. From the bone marrow, additional biomarker data that really, I think, is very satisfying to see with immunohistochemical staining for mutant CALR in yellow. Blue are the mutant CALR negative megakaryocytes. After six cycles of therapy, you see a more normal profile of megakaryocytes with distancing of these cells and more prominent normal blue megakaryocytes. Again, on the right, the proportion of total MKs in the bone marrow go down, again, driven primarily by these reduction in mutant cells with a concomitant increase in non-mutated megakaryocytes, what I would say is normal megakaryocytes.
Bone marrow evidence of disease modification to complement molecular evidence from the peripheral blood. In conclusion, in these two studies combined, 989 monotherapy, I think anyone would agree, very well tolerated, very satisfying to see that in the ET population of patients who were in need of therapy, relapsed refractory after cytoreductive therapy. We did not see a DLT. We did not even hit an MTD. We only had one patient drop off for reasons that I think are unrelated to the study drug. It is quite clear that you get a rapid and sustained hematologic response with this agent and probably more so with higher doses.
This biomarker evidence of reducing the clone is very satisfying for a physician who is looking to not just control counts for a thrombotic purpose but change the natural tendency of this disease to be progressive and maybe even transform to myelofibrosis or acute leukemia. These findings are of significant note. We look forward to sort of expanding the doses to continue to look at efficacy and follow safety. I do think that this represents a very simple, a very safe approach to treating mutant CALR ET patients. Thanks.
Thank you, John. Okay. I'm going to spend a few minutes now recapping some of what we've seen. Before we do that, it's very rare in drug development to see what we just witnessed over the past 10-12 years from basically discovering new biology in 2013, reporting a new driver mutation for an entire group of diseases, within designing a medicine specifically to address that problem, which is what 989 is, followed by a clinical experiment that basically replicates exactly what the preclinical data predicted we would see. Everything that John just summarized is exactly what the preclinical data for 989 predicted we would see in terms of normalization of blood counts, reduction of mutated megakaryocytes and CD34 positives in the bone marrow and the peripheral blood. It's a great story.
I hope you share excitement that we have an insight with this data and what we think this new medicine can do for patients. Real quick, what did we learn today? 989 in this patient population was very well tolerated. One out of 49 patients discontinued. It was a patient at 24 milligrams in the very first cohort. Dr. Mascarenhas described his impressions of that patient. It seems like it was a complication of the disease unrelated to the drug. Very reassuring at this point in the clinical development of 989, the safety data that we have. Normalization of platelet counts. I think it's a very important distinction between reducing platelets, which a lot of medicines can do, and normalizing platelets. What you see in the platelet count graph that John showed is that the platelet count drops.
When it gets to the normal level, it stabilizes. That is consistent with the translational biology that he showed. That is very different from having to keep the platelets there by constantly adjusting the dose of hydroxyurea or anagrelide. Patients normalize. They do not just drop. Very different. We saw rapid and sustained reductions in VAF in most patients, despite the fact that we have short follow-up. As you saw in slide 42, the patients at the highest dose cohorts have relatively short follow-up. Despite that, we believe that the VAF data will continue to look better and better over time because of the continued treatment of those patients.
It is very important to put the whole biology story together. The reduction in mutant CALR-positive megakaryocytes in the bone marrow and the reduction in mutant CALR-positive CD34-positive cells in peripheral blood really show that 989 is doing more than normalizing counts. It is basically addressing the disease at its core. What are the next steps for 989? We wanted to give you an idea of what is happening behind the scenes that we are going to hear more about over the next several months. Our goal, based on this data, and we are in the process of already expanding certain dose cohorts to understand better what the dose is for future development. That work is already ongoing. Our goal is to start pivotal trials in ET by early 2026.
We appreciate the urgency of this, the importance of bringing in true medicine that can change the natural history of the disease for ET patients. Our job now is to do this as quickly as we can. We will present as we commit data in myelofibrosis patients before the end of this year. That work is ongoing. The combination with ruxolitinib is ongoing. We mentioned before that we thought it was very important for the myelofibrosis data to have combination data with rux. Rux in myelofibrosis, as you know, improves survival. Having that data together was very important before we disclosed it. We will do that before the end of the year. We will accelerate the development of 989 as a single agent and in combination with rux in patients with MF.
We announced earlier this morning we established a collaboration with Coyogen to develop a co-diagnostic across MPNs, initial focus in CALR mutations. We are ready for that. We are moving forward with our partner now. Very importantly, the development of a subQ formulation is already ongoing. We believe that initially, the intravenous formulation every two weeks is acceptable. We will hear from our KOLs. We are already working on a subcutaneous formulation. What is the scope of this, the patients, the impact that 989 can have in patients with ET? There is a simple way to look at it, which you see summarized in this slide. If you take the entire population of patients with ET, both in the U.S. and the EU 28, you divide that by 25%, which is approximately the frequency of CALR mutations. Then you divide them in two groups broadly.
One group that basically is managed with watch and wait, which is about 1/3-1/4 of the patients, and a group that is actively treated with cytoreductive therapy. It's about 40,000 patients, give or take. Just to put that in perspective, the total number of patients in the U.S. treated with Jakafi in 2024 across all indications was 28,000 patients. This gives you an idea how many patients could potentially benefit from 989 once it's available to them. Just to mention real quick, our commitment and Incyte for patients of MPN as leaders in this space continues. Our goal is to develop medicines for every single patient with myeloproliferative neoplasms. We're not done with 989. We introduced a T cell engager bispecific. The data was presented today at the EHA conference. It will enter the clinic very soon.
Of course, many of you know the V617F inhibitor for the other most frequent driver mutation in MPNs. Just to repeat, our goal at Incyte is to have a solution for every single patient with a myeloproliferative neoplasm in the future. Let me just close with something I read short at the beginning of the year, which was a very rich set of catalysts that we committed to you to deliver in 2025. If you look as the first half is coming to a close, we have, I believe, done an excellent job delivering on those catalysts on time and across a range of indications that is in the process of, we defined at the beginning of the year, to transform our pipeline. With that, let me stop. We'll be happy to take questions from the room and online. Thank you.
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Yeah. Hi, Steve Willey from Stifel. Great data. Thanks for hosting. I noticed in the cell types that harbor mutant CALR, it also looks like there's some positive NK cells and plasmacytoid dendritic cells. Just curious if you're depleting PDCs, if you would be concerned about antiviral immunity risk, and would you have to maybe prophylax these patients if you are indeed depleting that cell type?
Can you hear me? Yes? Yep. Great. No? Yes. Now you can. Brilliant. Yeah, that's interesting. Clinically, we do not see that these patients have anything beyond the sort of myeloproliferative phenotype. We do not see any NK or dendritic cell phenotype. That aspect of the expression profile needs to be looked at. For example, we need to look to see whether those cells actually express TPOR or not. Because that map that was shown is purely of mutant CALR-expressing cells as opposed to cells that also express TPOR. You can imagine that if they do not express TPOR, then the mutant CALR expression may not do anything. That is work to be done. At the moment, there is not a clinical indication as to why that might be a concern. It is something to be checked.
I think that's correct. Right? The key point here is that there's cells that carry the mutant form of CALR, but it's nonfunctional. Right? Even though you saw positivity of mutant CALR on the UMAP in other cell types, the key slide that Dr. Nangalia showed where those cells will survive as long as the parent making that cell survives. When you ablate or eliminate the mutant clone upstream, those cells will eventually disappear as well. It is a slower process. It'll happen across the natural half-life of that cell population. Even though CALR is there, you see it visualized in that UMAP, it's nonfunctional in those cells.
Maybe just a quick question regarding potential phase III trial design. There's obviously a couple of analogs that we've seen where you could run, I guess, kind of a post-hydroxyurea trial, just look at platelet normalization. I believe there's also a phase III study of another drug going head to head against hydroxyurea where you'd have to look at events, I'm assuming. That would be a much longer study. Just curious as to how you're currently thinking about what the development pathway might look like here. Thanks.
Sure. We have, as you mentioned, actually, to summarize, we have a couple of different options. We could test 989 in patients previously untreated, or we could test it in patients that have received prior cytoreductive therapy, whether they either were inadequately controlled or they were intolerant. As I think John mentioned, there's plenty of those patients, unfortunately, to enroll those trials. It's a little bit early for me to comment on the specific design. I think that some of the designs you mentioned are pretty straightforward. Their ELN criteria for hematologic response is well established, something that some of our competitors have used in the past. However, I think it's important to understand that this medicine is different from everything else that has been tested in this disease. The VAF reduction that we saw today in a very short period of time is much more pronounced.
We expect will continue to deepen over time that what has been seen with other drug candidates in this disease. That tells me that there is room to have a conversation with health authorities about looking at endpoints in a different way. We will have those conversations in the near future. Depending on that, we will design those studies appropriately. It is a little bit too soon to commit to one path or another. We could develop this in both first and second line ET and with traditional endpoints or with newer endpoints incorporating VAF in some way. Any other questions in the room?
We'll take some questions online, Pablo. Next question is from Brian Abrahams, RBC. Looks like there's a modestly higher proportion of non-responders in the type 2, particularly at lower doses. For the company, would you anticipate different doses to be applicable for different mutation types?
As I mentioned in my closing remarks, we are in the process of expanding certain dose levels to understand the efficacy in a larger group of patients. I think it is very important when one looks at the data, particularly if you look at slide 42, that the 1,500 and 2,500 milligram cohorts have very short follow-up. To conclude that a certain mutation needs a certain dose or not, I think it is too early to decide that. What we have seen, to be clear, is responses in type 1 and non-type 1 patients. I think that is clear from the data that John summarized. We believe that higher doses with longer follow-up will clarify a little bit what the design of future studies should be. For now, our commitment is obviously to develop 989 in all patients with ET, regardless of mutation type.
We think that the data that we've seen, including the translational data, supports the role of 989 across the spectrum of the disease.
A follow-up for Claire, John, and Jyoti. Given the differences in prognosis and possible potency, how would you anticipate potentially using 989 in type 1 versus non-type 1 patients?
I mean, I think as per the answer to the last question, we still do not really know whether there really is a difference. For me, the slide that showed the changes in the hematopoietic cell compartment, there were patients with type 1 and type 2. There was a type 2 patient there who responded beautifully at quite a low dose. I think we do not know yet. I think it is interesting to note that type 1 patients are the ones that have the higher risk of myelofibrosis. I have treated patients with this disease for nearly 30 years. I have three patients on this study. I have eight patients waiting to go on this study. My patients are keen to be on the study. They are keen, even if they have to come every two weeks for a one-hour infusion.
If it becomes a subcut preparation, that's just the same as giving interferon, effectively. I don't think we would treat them any differently at the present time. Thank you.
Next question is from Ash Verma, UBS. Looking at the Q2 weekly or Q2W dosing, do you think that this is a barrier for patients? This is for the KOLs.
No. I do not think it is a barrier. I think what Claire pointed out is exactly right. I think if it was a barrier, we would not have put 49 patients on like that. If it was a barrier, we would not have a list that we fight over to get our patients on. I have physician patients with mutant CALR that are coming in to get treated knowing it is a Q2 week. I think this data, if anything, reinforces the value despite a Q2 week infusion. I think if we saw a lot of infusion-related reactions or toxicity, that might be a different issue. It is a very well-tolerated infusion. As Claire pointed out, perhaps if it was a subcutaneous delivered agent, it would make it even slightly more attractive than that. No, the answer is no.
A few questions coming from Jess Fye from JP Morgan. What is the hypothesized mechanism behind the lipase increase? Do you believe that this is on target or off target?
I'm going to ask Patrick to comment about the hypothetical mechanism, although I'm not sure we have a hypothesis yet. I want to emphasize this lipase increase is where asymptomatic, they did not require dose adjustments, dose reductions. None of them led to dose discontinuation. There were laboratory observations without any, and they resolved spontaneously on drug. I think we need to understand that. No dose dependency, no discontinuations, and they resolved spontaneously on drug and no symptoms of any related illness.
We just had a quick discussion, actually. Jyoti and I were discussing that too. Lipase, Jyoti and I both work in hospitals that have EPIC. We have a lot of pre-embedded tests for our patients. We started seeing that actually many MPN patients, lipase goes up and down. Maybe it is related to the platelet count. Maybe it is something else. For my patients, it is not meaningful. I will hand to Patrick in a minute. I do not think there is really a clear mechanism unless it is some antibody interference we were conjecturing the other day with an assay. It is totally asymptomatic. Patrick?
Completely agree. It is not related with kind of the stage of dosing. It is not related to dose cycle. I think it is potentially something to do with the biology of the disease and it is being measured here. Right? There is extramedullary hematopoiesis happening in various tissues throughout the body. If those cells are responding in a meaningful way to this therapy, you may see blips like this. I think it is in line with the points that have been made so far.
Follow-up question. Can you compare and contrast the profile we're seeing with 989 to what has been shown with other competitors such as Bomedemstat?
I think totally different. Bomedemstat, which is an LSD1 inhibitor, is a drug that has to be dosed per platelet count. It's actually a more complex way. It's a very interesting drug. It's a rational approach. I would say completely different, different therapeutic, different delivery, and different expectations. If you were to ask me, ET is primarily treated in the community practice. In the U.S. community, practitioners probably treat 2/3 of ET patients. What you want to do for a disease like this is have a therapy that's simple, simple to deliver without a lot of need for dose adjustments or calculations like that. What's really nice about 989 is it's an infusion, basically probably going to be at the same dose at intervals that don't require one to dose adjust.
That's attractive when you're trying to avoid toxicity and maintain efficacy in the community setting. To me, that separates this drug from almost all the other drugs that we use in the field.
Maybe I could also add, having treated a lot of patients with Bomedemstat, they get dysgeusia. They also get arthralgia. There is no evidence at the present that that drug changes anything in terms of disease pathology. There is no reduction in VAF. There is no normalization of the bone marrow. Do not get me wrong. It represents an important alternative for these patients who do not have other options. It is not disease targeted, and it is not well tolerated.
The only other thing that I would add is that I have never seen a drug in a phase I study target the origin of the disease, the stem cell clone, and reduce VAF. I mean, the graph that we showed, the waterfall plot of reduction in VAF, you don't do those kinds of graphs in phase I studies. You hope for something like that in a phase III. It is completely different in how it targets the origin of the disease.
One last follow-up for our KOLs. Putting aside the VAF changes, can you talk about the clinical significance of a PR as it relates to platelets? Can you describe how the 600 threshold may be associated with reduced rates of thromboembolic events and/or transformation? Should we focus on CR and normalization of platelets?
I need to think about that. I am one of the authors on the ELN response criteria. I would say that those response criteria are developed on the basis of expert opinion, which is the worst level of evidence. I mean, they are worthwhile, but they are generally developed after a meeting like this in a room where we all vote consecutively. If we do not reach consensus, we cannot leave the room. It is reasonable. The first ever randomized study that was done in ET was done not far away from here in Bergamo. In that study, randomizing patients to reducing the platelet count to less than 600 versus not produced a significant reduction in events. We have not yet bettered that with another treatment. I think it is reasonable to say less than 600. There is no evidence that 400 versus 600 is actually better in ET.
In PV, which is JAK2 driven, we just have some emerging data that might be the case. I think the biology of CALR disease is different. John, you want to add?
I totally agree. I'll just add the other point. If the question is, is 600 meaning getting an answer? And it is for some patients. One of the phenomena that you see with thrombocytosis can be twofold. One are microvascular complications like headaches and brain fog and things like that that do improve when you reduce the platelet count even below 600,000. What's not captured here is sometimes the patients feel better with a lower platelet count. Obviously, for some of the patients that we had that had really extreme thrombocytosis with an acquired von Willebrand, particularly menstruating women that might have very heavy periods or people who have to go for surgery, you want to get that platelet count lower.
Getting under 600 usually removes the acquired von Willebrand, usually resolves the headaches that plague these patients sometimes for years before the diagnosis is made. Even beyond the fact that there is Italian data demonstrating reduction in thrombosis, there's also a lot of quality of life and practicality issues with bringing the platelet count below 600,000. To be honest, I like it under 400,000. I think that does.
Next question is from Malcolm Hoffman, BMO. Given the data we've seen so far in ET, what aspect of this data makes you most confident for the upcoming MF data later this year? What should our expectations be going into later years?
Let me tell you the way I look at it. I was asking Dr. Nangalia to maybe comment as the expert on this mutation. They're very different diseases, ET and MF. The molecular basis here is the same in terms of what mutation, the CALR, and the mutated protein does in terms of binding to TPOR receptor, going to a cell surface, driving oncogenic signal. That's the same phenomenon.
Whatever preconception one had about the probability of success in MF before the data that we saw today, particularly translational data that shows an impact on the CD34 positive population and on mutated megakaryocytes, whatever preconception one has has to be that probability of success has to go up because of the data we just saw. That's at least my opinion. And maybe Dr. Nangalia and it looks like Dr. Harrison.
I mean, I would say actually the data for clonal reduction in MF is perhaps closer to the clinic. John has shown with Imetelstat, we've shown with Navitoclax a 10%-20% reduction in VAF, actually reads out to overall survival advantage for MF patients. This year, there was a nice New England Journal paper showing the only other treatment we have for MF that cures patients. It is very toxic as transplantation. Clearance of the clone after transplant also led to benefit. A more modest reduction, which may become even deeper over time, is also likely to be significant. I think both of us are already also treating patients with MF and have got very good experience. I don't know whether either of you want to add anything.
I would add, from a biological perspective, myelofibrosis is also a stem cell-driven disease. 30% of patients will have the CALR mutation. But many of those patients with MF have now accumulated additional driving mutations, making the clone a much more faster-growing clone and therefore associated with far greater complications and disease burden. So if in myelofibrosis you could also target the stem cell clone to significant levels like we're potentially seeing here with the ET data, that would be particularly exciting. And there's no reason to believe that that won't happen provided that the CALR and the TPOR are on the cell surface. The second thing I would be interested in seeing is the trajectory of reduction. Because again, in those situations, I'm very interested in, one, how many mutant cells you have and the disease burden. But two, how fast is that clone growing?
If you could again reduce the number of cells and reduce how quickly they are growing, then you might be on a path and a journey towards protection from your disease. I'd be interested in reduction of the stem cell clone in the MF data and trajectory of reduction. However slow or fast that is, I think as long as you're heading in the right direction, that will be a bonus.
To make one additional point, I think the genetic evidence is clear. Even in the setting of a secondary mutation that may make the clone more aggressive, those cells are still fully dependent upon CALR, that initial driver mutation. That is very evident. The ability to antagonize that, showing the clinical evidence of that in ET, should translate fully to MF based upon the genetic evidence there.
Next question is from Derek Archila, Wells Fargo. This is for Pablo and Patrick. Which patients may be better suited for the monoclonal antibody versus the bispecific?
The answer to that question, first of all, would depend on more data than we have so far. It also depends very importantly on the T cell engager. Not every T cell engager is the same. We have designed our T cell engager in a very specific way with a CALR arm that binds to a different epitope than 9A9. What that means is it can potentially address the needs of patients that for some reason do not respond to 9A9 or that progress after 9A9 therapy. That indeed happens, which obviously will take more time to determine. That is the thought process behind the T cell engager that we designed at Incyte. Other T cell engagers have differences with that. I cannot generalize that answer.
Focused on the one that we're introducing in the clinic, that's the plan to be designed to treat patients that progress or do not respond to 9A9. I don't know, Patrick, if you want to comment further.
Next question is from Paul Jang, Guggenheim. How are you thinking about long-term dosing strategy for mutant CALR in ET once initial platelet normalization and molecular responses are observed? Is there potential to explore a lower maintenance dose or different dosing frequency? Are there any differences in how you might think about dosing moving forward in ET versus MF?
Three great questions. Long-term dosing strategy, lower maintenance dose or frequency, or difference between ET and MF. Obviously, we haven't reviewed the MF data. I can't comment on that. For the other two, we need time. We need to follow these patients for a longer period of time. I think it's important to remember what we're trying to achieve here. What we're trying to provide patients with MPNs with 9A9 is a path to a cure. This is not just about normalizing platelets. It's a path to a cure. That requires profound VAF responses. We'll continue to treat these patients in the studies. We'll continue with the higher doses to see if we can get to that point.
We will have to discuss with our KOLs what the next steps in terms of testing this frequent dosing or not are appropriate at a certain point in the future.
Next question is from Kripa Devarakonda. What are the timelines for the development of the subQ? Are you doing this in-house or in collaboration?
I'm not going to provide timelines today. Development of subQ has been done. The formulation development is done in-house. The potential need for a device like an autoinjector, for example, will be done with a collaborator. Those conversations are already ongoing. We're looking for every possible way to accelerate the development of the subQ formulation. We understand the importance in this population.
Next question from Jess from JPMorgan. Did you see any difference in response between mCALR exon 1 versus exon 2 patients?
Type 1 versus type 2. I'll refer back to the preclinical data that we've publicly disclosed. You can refer to the Blood paper. This is an active drug against type 2 patient samples in the work that we've done. I mentioned the binding affinity. This antibody binds with very high affinity to both type 1 and type 2. There is a subtle difference in binding, three and a half fold, but still a single digit nanomolar binder to type 2. This binds to and is active towards type 2 samples. We collected preclinically eight type 2 patient cell samples, tested those in an ex vivo culture system. Six of the eight responded very well at the mid-dose that they were tested. This concentration relates to the dose range that we're covering in this study outlined here. This is an active drug against type 2.
I think all the points raised around dose intensity, duration of treatment, et cetera, I think is what we're going to have to just follow and see how it plays out there.
Next question from Brian Abrahams, RBC. Looking at the safety profile, could you elaborate a bit more on the rates of TEAEs for the therapeutic dose level greater than 400 milligrams?
I don't have the breakdown here for the different doses. I would emphasize some of the comments I made earlier. The only drug discontinuation happened at 24 milligrams. There was no dose-dependent increase in adverse events. Patients continued on drug. There were no dose reductions. As we mentioned a few times, only one patient discontinued drug in a phase I study. Maybe John and Claire, from your direct experience with patients' different dose levels, you can comment. So far, we have not seen any trend that seems to point to a dose dependency on any of the adverse events.
No. To even add a little bit more color to that, even in this trial, there is intrapatient dose escalation allowed, which allows us to understand in a given individual whether we would see a change in toxicity profile as one increases the dose. Even in patients who increase the dose, I did not see any new treatment emergent adverse events in those patients. I think that is a pretty good test within a given patient that there really was not a dose-dependent TEAE profile. I mean, I have said it before, and I will say it again. This was really well tolerated. Even the treatment adverse events that you see there are classic clinical trial. A patient comes in and reports something. The CRCs record it necessarily. Attribution is provided.
Those are mostly grade one, two things that often can be explained by the disease or concurrent illnesses, likely unrelated to 989.
I mean, in Europe, we've been using very high doses. I have a patient on the top dose. My patients are doing well. That patient that's on the top dose walks 15 flights of stairs to get to the infusion facility. Fatigue is a symptom that 90% of MPN patients complain of. It is really not worse for these patients. I think it is actually surprisingly very well tolerated, personally.
Next question coming from Kripa Devarakonda from Truist. It's a two-part question for our KOLs. What do you think is the relevant significance of symptom improvement? For example, in MF, there's a lot of focus on TSS50. Would you say there's similar contribution focus in ET?
In general, there's less symptomatology in ET than MF, which is a much more inflammatory-driven disease, although some patients with ET clearly do. Some of those are vasomotor symptoms. You didn't need a specific TSS score to get on to this study. It makes it a little bit challenging to formally evaluate and report in a dose escalation study what the symptom improvements are here. I will tell you anecdotally from the patients I treated, we definitely didn't see worsening of symptoms. If anything, for a lot of the symptoms, particularly headache-related symptoms, they got better.
I don't really have anything to add other than to say I think interferon recently got approved in ET without a symptom endpoint. It's much less prevalent in myelofibrosis than in ET. Yeah, many of the symptoms do relate to the height of the platelet count. I think we shouldn't underestimate. If you remember the patient story I told you, the emotional and psychological burden of living with a chronic incurable disease and not having an available treatment that can address that disease, that leads to a kind of chronic morbidity or chronic stress state for a patient. Slightly unrelated, but I just want to put that point across.
I took apart the debates point up again because it never comes up in these kinds of slides. Actually, what I witnessed were patients who were more re-engaged in life, actually, in ways that I had not seen them before. There is something about reducing the platelet count that provides a certain degree of confidence in going out in the world doing things that they probably were afraid to do or were depressed about. There was a huge psychological component of this that does not read out on those slides nicely.
The only thing I'd like to add is telling patients you aren't going to do anything about their platelet count because their vascular risk is low and they're young and that they have to live with it is a very big demotivator. Telling them that you can offer them something that can reduce their disease burden, potentially in the future a path to cure, is incredibly motivating. That's why stem cell transplants are an option. They don't improve your symptoms, but they offer you a chance of cure. Making people feel better, but being able to prolong their survival and reduce their risk of transformation is a powerful motivator for using a drug in a condition.
Second part of the question and the last question online. Beyond platelet count and reduction in VAF, what would you see as additional metrics that strengthen the potential of disease-modifying activity?
I was really hoping disease modification would come up. It has kind of beautiful symmetry for me. Last year, I closed EHA in the presidential session with a very difficult question. Are we ready to disease-modify MPN? There is kind of a beautiful symmetry for me to be now talking today and hearing the data beautifully presented by John. I think, okay, controlling the platelet count, but reducing the VAF and then seeing those really powerful images of the marrow morphology with the yellow CALR megakaryocytes disappearing and the non-mutant megakaryocytes reappearing and the changes in the progenitor cells. I think that's a really powerful indication of disease modification. We also showed that with the MAGIC PV data, actually, the progenitor cells change. I think that's really powerful. I will hand over to my colleagues to also make a comment.
I couldn't agree with you more. For someone who, I spend a lot of time with the pathologist looking at the bone marrows of every patient I see, and seeing those changes in the bone marrow, to me, would signify that there is a fundamental difference in the pathophysiology of the disease. I have to believe that that ultimately pays off not just from a prettier looking marrow, but a better outcome for the patients.
Any questions in the room? Okay. With that, we'll close the meeting. Thank you, everybody. Thank you, everybody online, for attending on a very early Sunday morning in the U.S. We look forward to keeping you updated on the progress of this program in the next few months. Thanks again.