A warm welcome to this audio cast. My name is Erik Vahtola, and I'm the Chief Medical Officer at Active Biotech. Now, today we have the pleasure to hear a presentation by Rebekka Schneider, covering her preclinical research with tasquinimod. This has been the foundation for starting a clinical trial in myelofibrosis. Tasquinimod is a small molecule immunomodulator, and it's been previously studied in phase III in prostate cancer, and now it's in phase II in relapsed refractory multiple myeloma. It's studied in multiple myeloma in combination with standard oral anti-myeloma therapy. Two clinical studies in myelofibrosis are planned to start in 2024. The first one in Europe and the second in the U.S. We are excited to hear the background and rationale for starting the clinical development program in myelofibrosis from Rebekka. Rebekka is a Pathologist and Professor of Cell and Tumor Biology at the University Hospital in Aachen, Germany, and Oncode Principal Investigator at the Department of Hematology Cancer Center, Erasmus MC, in the Netherlands. Before starting her own research group at Erasmus, Rebekka worked as a postdoc researcher in Benjamin Ebert's lab at Harvard Medical School. Rebekka's research is focused on the role of the microenvironment in myeloid malignancies, and she has 93 publications in peer-reviewed journals. After the presentation, we will have some time for questions regarding her work. With that, I will hand over to Rebekka to share her presentation. Yeah, thank you very much, Erik. It's a huge pleasure to present today our work on tasquinimod in myelofibrosis. As Erik already said, I'm a professor of cell biology in Aachen, and also an Oncode Principal Investigator at Erasmus MC, and my lab really focuses on blood cancers, and here, specifically, how the environment maintains these malignant cells with a focus on myeloproliferative neoplasms. This is the disease I will talk about today. It's abbreviated, and you will see that during my talk as MPN. And so what does this stand for? Myeloproliferation means myelo means the bone marrow. Proliferation is that there are cancer cells that just grow too much, and neoplasms means that this is basically a cancer. As you can already see from the word, we are talking about the bone marrow, where you basically have too many blood cells. There are different types of the disease, and this is going quite into specifics. It's not that important for the talk, but I here want to give an overview. We can talk about polycythemia vera, abbreviated as PV, and in this disease, you have too many red blood cells. So in your blood, there's just too many cells, and it's not a fulminant leukemia, as, for example, in acute leukemia. It's kind of like more an early, early stage with a mutation in hematopoietic cells, as we will talk about later. And you can also have too many platelets in your blood, in your bone marrow, and this is called essential thrombocythemia. We will specifically talk about today about fibrosis in the bone marrow. These MPNs, they can give rise basically to too many fibers in the bone marrow. But it can also be that, for example, PV, so polycythemia vera or essential thrombocythemia, can progress into myelofibrosis. This blood cancer, MPN, is really associated with fiber formation in the bone marrow, and we will also talk about this later. The origin of this disease are hematopoietic stem cells, as you can see on the left side, and this is where the mutation happens. During the course of life, and this is a somatic mutation, the hematopoietic stem cells acquire so-called MPN driver mutation. These can be mutations in a gene called JAK2, and this is the most frequent mutation in a patient. There can be mutations in the gene called MPL or also CALR. This basically then gives rise to these kind of different phenotypes that are introduced before. The next question is, how often does MPN occur? MPN is often referred to as a rare cancer. But actually, if you look at the numbers, and this was something that was reviewed in 2020, it's obvious that MPNs are rather a massively underdiagnosed cancer. It's called rare cancer, but the prevalence might be much higher than what we think. It's quite interesting to look at across different studies, and you can see that there are quite some discrepancy, ranging from two patients per 100,000 to 92 to 120 per 100,000. So, I mean, this is something we have to keep in the back of our mind. In general, kind of like rather a rare cancer, but it might be that the prevalence is much higher than we think because of poor diagnosis. And, as Erik introduced, I'm a professor of cell and tumor biology, so we're really interested in the cells that are affected. And this picture here depicts really how the disease, and now we will talk more about bone marrow fibrosis, is initiated. So it all starts with the hematopoietic stem cell, as I said before. So this is kind of called the malignant clone. These are mutated hematopoietic stem cells, and then somehow they activate cells that are non-hematopoietic cells, and they're also not mutated, but they give rise to fibrosis. And-... This crosstalk is really important to study how these blood cancer cells can give rise to fibrosis. As said before, there's a kind of primary myelofibrosis, so patients that directly present with fibrosis in their bone marrow, but it can also be that other forms, for example, a PV transforms, and this actually occurs in 75% of cases, so quite a high number. This is the look as a pathologist, and I'm a pathologist by background. You can see on the left side a normal bone marrow. All these pink and red dots that are here are kind of like the blood-forming cells, and what you can see in this light gray is the bone. I mean, all these blood-forming cells, they're embedded in their bony matrix. When fibrosis occurs, and this is something that you can see on the right, there's all these fibers that stain in the reticulin staining, which is the staining to highlight fibers for a pathologist. You can see there are these, like, thick fibers that are intercrossing. You can well imagine that over time, all these fibers take over the bone marrow, so there's basically no space for hematopoiesis anymore. Of course, this has quite severe consequences for the patient, and you can see this on the left side. There are quite some clinical symptoms. The moment when there's basically no space in the bone marrow anymore for blood formation, the spleen and also the liver take over the function to produce blood, and this is something that happens when we are kind of like embryos. Basically, the spleen is the hematopoiesis-producing organs, and this occurs then again in the disease. So the spleen and liver can get massively enlarged, really causing reduced quality of life for the patient. Of course, there's reduced blood cell production in the bone marrow, and patients present with, for example, too little blood cells, like they develop anemia when you don't have enough red blood cells. This all leads to a number of constitutional symptoms, and importantly, a significantly reduced quality of life. Because there are also symptoms, for example, like, itching of the skin that's associated with the disease, but also, brain, symptoms. And a lot of patients, for example, report brain fog. But importantly, fibrosis is really essential when it comes to survival in patients, and this is something that's quite, strikingly depicted on the right side. So you can see basically a patient with, pre-fibrosis still has quite a, good, a good survival, as you can see, depicted in months. But the moment fibrosis occurs, even in early fibrosis, but specifically in advanced fibrosis, the survival significantly, drops, and often it's around six months to 1.5 years, which is comparable to really aggressive cancers. So, I mean, it's important to understand how fibrosis occurs in the bone marrow, and it's even more important, and this is a high unmet clinical need, to find novel anti-fibrotic strategies. Because so far, the focus is really on the malignant blood cells, but not really on fibrosis, and so far, there's no therapy, drug therapy that focuses to get rid of all these fibers that occur in the marrow. And at the same time, it's also really important to find a specific biomarker that's available to predict fibrosis or the progression of fibrosis. And this is important because the earlier we diagnose fibrosis, the earlier we can start treating, and often patients are diagnosed when it's already too late and fibrosis is too advanced. So what are the treatment options that are available for patients at the moment? And the main treatment option for these patients is ruxolitinib, and this is like the main treatment for advanced fibrosis, and this was FDA-approved in 2011, in particular, for the treatment of patients with intermediate or high risk myelofibrosis. And it has quite significant effects on splenomegaly, and it also has some effect on myelofibrosis, and after a decade, it's still the standard of care in myelofibrosis. But of course, there are challenges and also open questions. So for example, it was reported that there's limited anticlonal activity. So this means you have your malignant hematopoiesis clone that expands, and it was first thought that ruxolitinib would completely eliminate this clone, but this is not the case, and there are still malignant and mutated cells even after treatment with ruxolitinib, which is actually a JAK inhibitor, which kind of is the downstream activated signaling in all mutations. What's really kind of like a problem for most of the patients is that ruxolitinib causes cytopenias, and in particular, anemia. And as I said before, this is one of the symptoms that most of the time occurs in patients. Once they have really advanced fibrosis, there's like too little blood formation, there's already cytopenias. So if you add drug, and then you kind of, aggravate these, cytopenias, this is a major problem, and this is why a lot of patients have to discontinue treatment with ruxolitinib, after most of the time, three to five years. And as said before, it has limited anticlonal activity, so it also has non-curative nature. It doesn't cure, the disease, and due to the cytopenias, there's a substantial rate of discontinuation, as also said before. And the problem at the moment is that there is no real second-line, treatment other than JAK inhibitors, so there's another JAK inhibitor, now that's, fedratinib, but there are basically no anti-fibrotic, options available for these, patients. And the only so far curative therapy is allogeneic stem cell, transplantation. So this means that the patient gets, yeah, new, fresh, hematopoietic stem cells from a donor after quite an aggressive regimen of chemotherapy. And this means that most of the patients are actually not eligible for hematopoietic stem cell or allogeneic stem cell transplantation. But what allogeneic stem cell transplantation can do is really to ameliorate fibrosis. So this, for example, so it has an effect on the bone. So again, you see this was like, for example, a bone marrow of a patient with severe grade three, that's the most severe form, bone marrow fibrosis. And then after allogeneic stem cell transplantation, you can see that basically there are only, like, a few fibers left, but this is really a potentially curative approach. And also the spleen size shrinks. So in the lower image, you can see this, like here, highlighted in white, is a spleen. And then after allogeneic stem cell transplantation, the spleen is basically normalized. But the problem really is that it's a high-risk procedure. Most of the patients are not eligible for this therapy. It is associated with a high mortality, and importantly, not all patients respond, and so far, it's not possible to predict which patient will respond and which patient will not. So there is the option of an anti-fibrotic strategy, but it's allogeneic stem cell transplantation as a really highly aggressive therapy. So that means that we need to find new therapies and need to understand how fibrosis is initiated in the bone marrow with a goal to kind of like ultimately cure it. For that, my lab started a couple of years ago to look into the bone marrow niche and to understand what cells in the bone marrow do actually make fibrosis. Because that was like an open question, even after years of research, it remained elusive what the fibrosis-driving cells actually are, and this is really something that's important to to specifically target these cells. This is an example of the bone marrow niche, which is basically the tumor microenvironment in MPNs. It's a simplified image, and there are kind of like a lot of different options, but you can see that there are a lot of, like, stroma cells in the bone marrow that could potentially give rise to fibrosis-driving cells that are either associated to the bone or that are associated to the vasculature. They all have different names. They have been studied by different groups. All of these kind of like subtypes, like P1 positive cells, LepR+ cells, and so on, they all have different, functions. There are Nestin+ cells, which are kind of like also nerve, associated. So it's quite a variety, and it wasn't, like, understood, like, a couple of years ago, which of these cells are actually activated in fibrosis. That's where our research, started, and first we got interested in a cell population that's called, GLI1. And here we use genetic fate tracing in a mouse, so we can highlight these GLI1+ cells under normal conditions and in, fibrosis. So on the left side of the image, you can see a normal bone marrow, and here with a white line depicted as the bone, and in red, you can see GLI1+ cells that nicely align the bone and can also be found in a perivascular localization. Then on the right side, you can see here we induced bone marrow fibrosis in the mouse, and these GLI1+ cells, they are activated, and they can be really found abundantly in the bone marrow. This highlighted that these cells are a key driver of bone marrow fibrosis. So this was the first important step to go kind of like towards identification of fibrosis-driving cells and to identify mechanisms. But then in the context of all these different stromal cell populations in the marrow, we were wondering: How are they related? What's the ontogeny of these different stroma cells, and so how does this actually work if you compare GLI1+ cells to LepR+ cells to OVCs? And we wanted to use single-cell RNA sequencing as a quite novel method to really say what kind of, like, cell population has what job in bone marrow fibrosis. And there are different ways to do that, so you can enrich either for a marker and then sort cells and then do single-cell RNA sequencing, where you really get resolution of, like, each cell in the bone marrow that has a specific role. And we did not want to use this approach because it's quite biased. So we would have to choose, like, a marker, and then we would have narrowed our approach to, let's say, LepR+ cells or GLI1+ cells. Here, we really decided to enrich for non-hematopoietic cells. So basically, we got rid of all the blood-forming cells and thus enriched all stromal cells in the bone marrow and then performed single-cell RNA sequencing. And in my lab, we have a number of different murine models. So by doing transplantation, we can induce the disease, and we can overexpress, for example, the JAK2 mutation, we can overexpress the CALR mutation, the MPL mutation, or we can overexpress thrombopoietin. And all these models give then rise to bone marrow fibrosis, as you can see as an example on the right side. So in the upper lane is the control condition. Again, all these dots are blood-forming cells that give rise to the different lineages. Then, for example, here we introduce the JAK2 VF mutation, which is the most prevalent mutation in patients. And you can see that this causes really fulminant remodeling of the bone marrow, fulminant fibrosis, as you can see with these thick, black intercrossed fibers. And even in the kind of, let's say, normal staining, this HE staining, you can see that there's new formation of bone and a lot of fibers. So we have a lot of different mouse models with different kinetics, and we then perform the single-cell RNA sequencing in these murine models... And this is an example how this looked. So our approach really enriched for our stromal cells, so there are non-hematopoietic cells, and the majority of cells that we found were so-called mesenchymal stromal cells. Under normal conditions, these mesenchymal stromal cells, they support blood formation. So they are really in direct crosstalk with hematopoietic cells to maintain the normal blood formation. Then there are also kind of like more nerve cells and bone-forming cells, but also vascular cells. On the right side, this only shows kind of the different markers that characterize these subpopulations, but you can really see that each dot here is a separate cell, and we can now see what each of these cells does when we induce bone marrow fibrosis. Our first question was, which of these cells upregulate matrix? Which of these cells make fibrosis? This is quite a complicated graph, but what you can basically see here is on the left side, the different cell populations, and then on the upper, it's core matris ome, collagens, and glycoproteins, so these are basically different types of fibers. Then we wondered if we compared control in red and fibrosis in blue, which of these cell populations upregulate these different fiber sets, so to say? You can see here that there was only a significant upregulation in mesenchymal stromal cells, populations one and two, and these are really progenitor cells of mesenchymal stromal cells, so the cells that normally support hematopoiesis. All the other cell populations did not upregulate collagen. So this was quite to our surprise, that it was quite a specific population that had upregulation of, these kind of like fibrosis, related proteins. And then with that, having, identified this, we can really dive into the mechanisms that, happen in fibrosis. And here we can look into early phases where no fibrosis is present yet, but we know the mice, for example, will, develop fibrosis, or we can look into severely fibrotic, conditions. And what you can see here on the, left side is the pre-fibrotic, condition, and you can see that in particular, in this early phase, there's an upregulation of a lot of, like, inflammatory factors, for example, TNF-alpha. Then interestingly, once there's fibrosis, the whole bone marrow is really reprogrammed. Everything is just going into a kind of like fiber formation, in particular in these MSC one and two, and there's upregulation of mostly TGF-beta, downregulation of all other pathways, and TGF-beta is known to be the master switch of fibrosis also in other organs. So this was quite interesting. Also, in the bone marrow, there's a lot of similarity to other organs, and having the single-cell sequencing now defined, we can really look into the different mechanisms that happen in each cell in the bone marrow and fibrosis. So this was in mouse models, but of course, it's also really important to look into patients. And here the challenge is that not all patients get bone marrow biopsies, but these bone marrow biopsies can also be quite tiny. So here we work together with a pathologist, because the pathologist makes the initial diagnosis that a patient has fibrosis, and then usually a biopsy is around 2 cm long. And 1.5 cm are needed for a pathologist to make the diagnosis there is actually fibrosis. And whatever was left, so the leftover material, we got into our lab, and then we developed a protocol how to kind of like process these tissues and how to get cells out of these tiny, bony fragments. And on the right side, you can see the example of one patient. In the left side, you can see a controlled bone marrow. So in an adult patient, you can see that these holes, that's actually fat cells. So it's normal, kind of the older you get. For example, it was 50 years, 50% is fat, basically, in the bone marrow, 50% is blood formation. And on the right side, you can see a patient with MPN, so myeloproliferation, too many blood cells, and fibrosis, and you can see really this myeloproliferation, so the bone marrow is full of cells, and at the same time, you can also see all these fibers. Then, when we did single-cell RNA sequencing here, we again recovered exactly the populations that we had in our mouse. So we had mesenchymal and stroma cell population. We also had fibroblast populations and Schwann cells, but here we also captured some hematopoietic cells, so the cells with the mutation, which is important. And then we wondered, we're having all these data sets, these murine data sets and human data sets, what are conserved mechanisms? Are there genes that are upregulated really specific for the disease? And what's quite striking for us, that we found the alarmins S100A8 and S100A9 upregulated specifically in the fibrosis-driving cells, and they're not expressed under normal conditions. So again, like a similar graph, and red is the control. So here in MSC one and two, under normal conditions, there's really no expression of these alarmins. But as you can see with this peak, once you have fibrosis, there's a significant upregulation of these alarmins, specifically in the fibrosis-causing cells. And we had exactly the same finding then also in the patient. Under normal conditions, no expression, but upregulation in fibrosis, which shows that alarmins are disease-specific and are not co-expressed in control bone marrows, which is very important if you think about therapies, because you don't want to target normal cells, you want to target basically disease-specific mechanisms. Then having these single-cell RNA sequencing data, we want to kind of like understand how the cells, how these alarmins work. And here we use biocomputational tools that help us to see how cells talk to each other in bone marrow fibrosis. So this here now depicts the comparison between a normal bone marrow and a fibrosis, and this is the malignant clone, so the hematopoietic cells with a mutation. You can see in red, there's upregulation of alarmins in fibrosis, and there's more crosstalk really starting from the hematopoietic clone, the malignant clone, to mesenchymal stromal cells as fibrosis-driving cells, but also to other stromal cell populations as fibroblasts. It really seems that this is, like, an important mechanism in the marrow, and the malignant clone has a specific way, basically, of talking to the fibrosis-driving, fibrosis-driving cells. We can look at the downstream mechanisms, and at this point, this was important to us because we wanted to understand or wanted to see if we can specifically stop this crosstalk. Basically, stop these cells from talking to the fibrosis-driving cells, and then we looked into kind of like the downstream mechanism. Here you can see that the alarmins S100A8, S100A9, bind to the receptor TLR4, which then activates a downstream cascade and leads to pro-inflammatory responses. So this really leads to inflammation in the bone marrow, and we thought this is quite an interesting therapeutic target. At the same time, we also wanted to see if this could be an attractive biomarker, because as said before, it's very difficult to say that a patient is at risk to develop bone marrow fibrosis. So far, you always had to take a bone marrow biopsy to actually say that there are fibers in the bone marrow. But here we looked into the blood, and we could see that S100A8, for example, is significantly increased in patients with MPN in the blood, but also that these alarmins correlate to the severity of fibrosis. So this indicates that these alarmins could be an early biomarker to see that there is a start of fibrosis, for example, in a patient that did not have fibrosis before. Yeah, so then we specifically wanted to target this mechanism, and then found this drug, tasquinimod, by Active Biotech. And it was quite attractive to us because it was already tested in clinical phase three trials in prostate cancer, and it was well-tolerated in patients. And so we decided to test this actually in our JAK2 mouse model. And again, JAK2 is the most prevalent mutation in patients. So here we transplanted cells with a JAK2 mutation, and then actually in two cycles with our treatment, administered tasquinimod to the mice. The results were really striking, and this was, like, already obvious when you looked at the blood counts. Already over time, the blood counts kind of like normalized in the group that received tasquinimod compared to vehicle. The most striking finding for us at first was really the size of the spleen. In this mouse model, this really nicely recapitulates the disease of patients. Here you have the JAK2 mutation in the spleens. As you can see, in comparison to all other spleens, they get really gigantic. Then, when we treated with tasquinimod, you can see that there was really a normalization of the spleen size, and this was already very striking to us. Then importantly, when we further looked into the bone marrow, there was a significant reduction of bone marrow fibrosis. So here in the upper lane, you see the vehicle control, on the right side, the JAK2 mutation, and you can see all these like intercrossing, intercrossing fibers. But then when we treated with tasquinimod, there was a significant reduction of fibrosis, and we could show that tasquinimod really has anti-fibrotic properties in MPN. And these findings, they were so striking to us, so we discussed it with multiple clinicians in our network, and then also together with Active Biotech and also the Oncode Institute. We thought we have to move this forward and push this forward to translation in patients. And as Erik already introduced, we will now start a proof of concept clinical trial, and here specifically in patients, as a second line therapy. This is really a high unmet clinical need, as I said before, because there are not a lot of, or basically no other options for these patients at this time point. Here we will look specifically at the Spleen Volume Response, abbreviated as SVR. To see kind of like how the spleen shrinks with a treatment, as we know that this is a good surrogate marker for fibrosis in the bone marrow. Once patients have reduction of fibrosis in the bone marrow, the spleen size also normalizes. This study will start by next year, end of next year, and we hope that we can really see similar results as we have also seen in our mice. With this, I come to the conclusion of my talk. So here we really started with preclinical and basic research, with the idea to identify fibrosis-driving cells in the bone marrow. This is something that we could do by using new technologies like single-cell RNA sequencing, and we did this both in murine models but also in patient samples. We identified these alarmins as an attractive marker that we validated also in patients for the induction of fibrosis. But more importantly, at the same time, we identified tasquinimod to be an optimal treatment to reduce the spleen size and importantly, also reduce fibrosis in the bone marrow... and these results that started really with basic research were then translated into a clinical trial. And here, this is really, like more drug repurposing, and all this way from pre-clinical research to now initiation of a clinical trial, worked within less than five years, so this is quite, quite a fast translation. So here we use single-cell transcriptomics, identified fibrosis-driving cells, alarmins as an actionable biomarker, and tasquinimod targeting alarmins as a potential novel anti-fibrotic, fibrotic strategy. And with this, I would like to thank you for your attention, and I'm looking forward to the discussion with also thanking my team. Thank you very much, Rebekka, for a very interesting presentation. I especially like that this has many important findings in your research with potentially significant clinical importance as well. We have a time for a few questions. Well, you partly already answered this, but maybe just elaborate a bit on how you originally started to use tasquinimod. How did you find tasquinimod to your research? Yeah. Yeah. Mm-hmm. Yeah, so I mean, we, as I said, we were specifically looking into, mechanisms and genes, that were, upregulated quite specifically in fibrosis. And, there are always, like, different options if you then want to validate a pathway and also kind of like see if it's attractive for a, potential therapy. And one thing that we commonly do in the lab, for example, is we would use genetic knockout mice. So you can knock out this particular gene you're interested in and then see what kind of effect it has on the genotype. We use, for example, CRISPR-Cas9 gene editing, to knock out a gene, and so on, but these are all kind of, like, more lab methods. At the same time, we wanted to find something that we can also translate into a patient, and, here I have to say that we literally started by doing a Google search if there are already drugs targeting this specific pathway, and that's how we identified tasquinimod. Okay. Yeah, thanks. So could you just, very briefly still summarize, your key findings, from your research with tasquinimod? Yeah. So I mean, the first findings that we had was really in the blood of the mice. So I mean, if you like, as in a patient, for the mice, you can also do a blood counts and draw blood in between. And we already saw that the blood counts of mice with a JAK2 mutation that usually have too many blood cells, they were normalized. They really looked like control mice, like normal mice. And then the most striking finding for us was really the significant reduction of spleen size. So that wasn't like just a 30% reduction in the spleen size, it was really a normalization of the spleen, and that's that was really striking. And then at the same time, of course, when we processed the bone marrow to see a reduction of bone marrow fibrosis. Right. Yeah. So, going to these, alarmins, S100A8 and A9, as far as I know, there are no biomarkers that would predict treatment response or, or even be used in, in the clinic for patients with myelofibrosis. But do you think that the alarmins could become a biomarker corresponding to treatment response? Yeah, absolutely. And this is work that was also funded by an ERC Proof of Concept grant. So, I mean, we have to do more patients to really robustly say it's a good biomarker, but all the results we have so far show that these alarmin levels really correlate to the fibrosis grade. And there is already quite an upregulation in patients that develop fibrosis later, but at that time point, they were still diagnosed at myelofibrosis grade zero, so basically no fibrosis. So it could be really an early indicator of fibrosis, and then definitely because so far you have to take bone marrow biopsies, which is quite an invasive diagnostic measure. I mean, the hope would really be that with every visit of a patient, you could look into alarmin levels and then see if there's, like, potential progression, and depending on that, maybe do a biopsy as a validation. But already kind of like see this over time because these patients, they see their doctor on a regular basis, routine appointments, and then always, like, get these alarmin levels. Yeah. And, so what do you think, are the key aspects that differentiate tasquinimod from, let's say, present and also upcoming treatments or therapies in, in myelofibrosis? So, as I kind of like also showed in the talk, there's quite a crosstalk between the malignant hematopoietic cells with the fibrosis-driving cells, and this is alarmin-mediated. So what we're targeting here is really how the malignant hematopoietic cell talks to the stroma, activates the stroma, and this is like what's inhibited, and that's why it has both an effect on the malignant cells but also on the stroma cells, and I think that's quite an attractive approach. And so far, a lot of the mechanisms or a lot of the drugs were focused, let's say, on the malignant hematopoietic stem cell, which also makes sense. It's a disease-initiating cell, so to say. But I think here, if you really kind of then target how fibrosis is activated, this will be, will be important, and at the same time, we could also show, for example, that there's a decrease in these mutant cells. So at the same time, you would basically have anti-cancer properties, but also anti-fibrotic properties. So, kind of like a disease-modifying treatment? Yeah. Yeah. Mm-hmm. Moving on maybe more into the clinical development. Looking at the present drugs in myelofibrosis, you brought up the JAK inhibitors. Where would you think that tasquinimod would fit in this treatment algorithm? Would it be a good combination partner with, yeah, with a JAK inhibitor or as a single agent, and in what lines of treatment? Yeah, I think based on the results we have so far, and this is, like, also still ongoing research, but I think it would be attractive, for example, to combine it with ruxolitinib, so the first-line treatment. And I think in particular in this disease, as we are kind of like have to target the fibrosis-driving cells and the mutated cells, having a combinatorial strategy in general makes sense, and I would see it in particular there in combination. And what's kind of like, of course, kind of much harder to study in a clinical trial is to start treating earlier in patients. So, for example, I mean, so far, we start treating patients with intermediate to advanced bone marrow fibrosis, and if we could start at, yeah, more kind of like earlier stages and then not even get to this stage. But of course, everything that includes progression and so on is harder to kind of like study in a clinical trial, but from what we know, this would make sense and would be quite attractive. Mm-hmm. In particular, as I mean, with all the data that tasquinimod doesn't have, like, a lot of side effects, quite well tolerated, this would be an option. Yeah. So now that we are going to start the clinical trial next year, could you just summarize or give your view on what the key goals and the most exciting data that you think will come from this study? Yeah. I mean, I'm very much looking forward already to seeing the spleen size, because that was, like, something that was so significantly affected in our murine model. And this is also something that on one hand is read out for bone marrow fibrosis, but at the same time, it's also something that really impairs the quality of life of patients. So I hope that we are already kind of early on, when we do our MRI, look at spleen size, that we can see differences there. And in particular, also, kind of we have, like, multiple blood counts that we can see a normalization of these, like, too many cells that you usually see in the blood, that you already see this kind of, like, going to normal, normal level. So I hope that kind of early after treatment, we already see effects. Yes. Okay. So I think these are all the questions I had, and at this point I just want to give a sincere thank you, Rebekka, for your time here and for sharing these exciting results. And I'm really looking forward to continuing our collaboration as well, in the new year, and also, of course, to start the clinical trial, and I think it's safe to say that 2024 will be a very exciting year for all of us. So thank you so much, Rebekka. Yeah, thank you very much.