Faron Pharmaceuticals Oy (FARN) Earnings Call Transcript & Summary

Hello, everyone. I'm Markku Jalkanen, Faron's CEO. Welcome all. We do have a record-high number of people all over the world. I really thank you all for joining us today, and I really hope also that you can feel the excitement we have, especially with the bexmarilimab program, and that's really the focus of today. Before I comment here, I need to show this mandatory disclaimer because we will have forward-looking statements. And obviously, there are reasons to show that. And we have a really busy agenda today. I will have some introductory overview on our pipeline. And then soon after that, we move on to talk with Dr. Tyler Curiel from Texas, San Antonio. This will be a chat with him and hope that you really enjoy because we are going to explore the current landscape and also really focus on ongoing unmet need we have in that area. We all recognize that already. Then we move on to have a talk from Dr. Maija Hollmén, who is one of the scientists really focusing on macrophages and their role in cancer formation and especially now in this case, also using a bexmarilimab for surrogate antibodies really to look at the mechanism involved in that regulation. And then the last speaker, I'm really proud to present Dr. Marie-Louise Fjallskog, who is our new CMO, initiated collaboration work with us on -- in January but is already really in, and she will present our plans and some recent data we have obtained, especially from the MATINS trial. And I also remind you already at this stage that you do have the opportunity really to make questions. [Operator Instructions] And at the end of the presentations, we will have a Q&A session. So do those while we are progressing with the program. So we do have 3 different target molecules we have been dealing with for years. CD73, we want to use to upregulate the breakdown of these purines, which are really a risk in our system, and also ATP and ADP. And when CD73 then breaks down the last AMP, we -- that will convert AMP to anti-inflammatory adenosine. There are a number of conditions where this could take place, and all those conditions can actually destroy our key central organs. We have recently also shown in a very dramatic conditions, which is the ruptured aorta, which is obviously a life-threatening condition. If you do not express CD73, you increase the risk of death. If you do express CD73, you actually have 100% survival possibility. But there are a number of other conditions and also within the cancer area, where the increase in number of cell-based therapies are causing the cytokine release syndrome, and we want to control that. So we are not only looking a -- infections. We are really looking the dramatic conditions where this control must be ongoing. And we believe that sometime in the near future, we have a separate R&D day really to focus on this program. Then the immuno-oncology program, Clevegen, bexmarilimab, that is the target of today, and I will save you more words about that in a minute. But then I also want to mention the Haematokine. We all know that we have a tremendous need in certain patient populations to stimulate the born of hematopoietic stem cells in order to get our cells to the blood, which can control us. And without that constant production of these cells, we run into a situation, which, again, we have a life-threatening condition. We have a way of controlling this stem cell proliferation using an inhibitor for AOC enzyme, and we are progressing with that one. We want to be sure that we have the right type of the compounds to move on because this is really a location in bone marrow, which is a really niche area, and we really need to know that the compound is active over there. But hopefully, we can report something also in that area. But then look into bexmarilimab opportunity. I don't know if you have seen this article from last December in [ New England Journal of Medicine ], which is on the left-hand side. Two significant directors, oncology directors, from FDA wrote that we already have enough what we call immuno-oncology checkpoint compounds, the anti-PD-1 and anti-PD-L1 compounds. And instead of trying to make them more and run head-to-head trials, we should actually focus on having additional tools and mode of actions and then combine those and really take them further in the patient populations. And the reason, very obvious. If you look the right-hand side, the overall responder rate is below 20% in many of the populations and in this article, is only 13%. And it was really summarizing quite a number of studies already at that time. This 87% do not benefit from these treatments, and that is very critical because we do use these compounds also on those patients. So it's rather costly to test which of the patients or who of the patients are responding and who are not. It's well appreciated that if you have a response, you have extended overall survival rate. And obviously, that is really great news, anybody who actually can respond. But we need to improve the performance of this and current treatments in order to really please the need, what we have. And obviously, that is something we really would like to now move on and discuss. And I would like to introduce Dr. Tyler Curiel from San Antonio in Texas. I also have called him from time to time Tyler curious because he is really a person who has committed his 2 careers into a -- looking for additional treatments for cancer. He has explored the experimental cancer lab, where people are working on the mechanism and testing number of different things. But then he's a clinician, so he really knows well what the needs are. And with -- he has training from Duke, Harvard and long-term experience with clinical patients and have seen -- has seen pretty much the development of these current immuno-oncology treatments from the very beginning. And with that, I'm really happy to introduce Tyler, and we will have a chat on these issues, which are related to cancer treatment landscape and ongoing unmet medical need. Welcome, Tyler.

Thank you. Good afternoon to you.

Thank you. So how -- what is your opinion or feeling why these FDA directors really came out to write this article on [ New England Journal of Medicine ]?

Well, there's been a huge focus on immune checkpoint blockade, which is reasonable up to a point, but what we really need now is not just more of the same targeting. We really need to look at additional targets, which would include additional immune checkpoints but also other strategies to treat cancer as well. So perhaps, it wasn't reasonable to say you can't develop more anti-PD-1s and PD-L1s, but I think it should be pretty clear that that's probably not the best path forward to continue to improve treatments for cancer using immunotherapy.

So in your mind, how do you feel -- what is actually preventing that they are not helping more people than actually they are at the moment?

Well, cancers are very smart, and they've come up with a multitude of strategies to evade the immune system. So your immune system is exquisitely good at detecting things that shouldn't be there and eliminating them. And cancers, by definition, are abnormal. They have many mutations, so they should be targets of immunotherapy. They should be targets of immune attack, but tumors use a very large variety of approaches to prevent them from being detected by the immune system. And blocking PD-1, blocking PD-L1, blocking CTLA-4, these were great strategies initially, and they do work in some patients and give good responses. But there are just too many other ways that tumors can throw up more defenses to prevent an effective immune attack, and you see we need to look at these other angles, these other means of defending against immunity by cancers.

People are often talking about these hot and cold tumors. How you would define those for this audience?

Well, generally speaking, what you need is for immune cells that can kill the tumor to get into it. So tumors that are infiltrated with the right kind of killing immune cells, typically T cells, those are considered hot; and tumors that aren't infiltrated well within immune cells that can kill tumors, those are considered cold. And a hot tumor is an indication that there's an active inflammation going on, a good kind of inflammation that has the right factors that can help eliminate a tumor, whereas a cold tumor is lacking those factors that are needed to eradicate it immunologically. So if you have tumors that are hot, those are the ones that tend to respond better to immune checkpoint blockade immunotherapy. The ones that are cold are less able to respond, and one trick is to try to turn a cold tumor hot to make it more likely to respond to immunotherapy.

Right. So in your mind, what are the ways we can actually do it? How do we get -- yes, please.

So one approach would be to try to find a way to make cells traffic better, so have an attractant to pull immune cells in that you want. Then that would make the tumor hotter. A second way would be to try to provoke more of the factors that produce the right kind of inflammation, and a major factor would be interferon gamma. Another approach would be to remove physical barriers that tumors have that prevent infiltration, such as collagen formation or changes in blood vessels. And another approach would be to have the cells that get in be better armored so they're protected from the immune defenses or better activated. And there are other approaches as well. Different types of immunotherapies can hit all of these different areas. There's some thought that anti-CTLA-4, for example, can increase tumor infiltration of immune cells, at least in some kind of tumors, and help turn a cold tumor hotter. That's been debated whether that really occurs and how often it occurs or as anti-PD-1, anti-PD-L1, to a much lesser extent, really increased infiltration into the tumor to make it hotter if it wasn't already hot.

Right. We also have a history of not really being very successful in generating tumor or cancer vaccines. Do you think that we may be dealing with a similar problem that we actually do not have active immune system that actually is helping us really to generate?

Yes. That's a very complicated but very important point. So tumors aren't cleared immunologically typically because you can't make a tumor-specific immune response. Most patients actually can. The problem is that once you make that tumor-specific response, the tumor-recognizing immune cells have to infiltrate the tumor and then execute their antitumor functions. And that's the concept of hot versus cold. So you make the antitumor immune response, but the tumor stays cold because the immune cells don't get in. So when you make a vaccine, you're increasing the number of anti-tumor T cells, but that doesn't necessarily solve the hot versus cold problem because those anti-tumor T cells provoked by your vaccine still have to get into the tumor. And when they get in, they still have to recognize it and then kill it. So a vaccine by itself could be -- it might not be useful, but it could be more useful if you combine it with something to reduce immune suppression, prevent these immune-evading strategies, increase the infiltration, make the tumor hotter. So there are lots of ways you could think of to use cancer vaccines more effectively. And our vaccine development technology is really good these days, so I think that's a good approach to think about.

Right. So you already mentioned that the microenvironment or the penetration of cells to the tumor actually could convert the environment to really become a more immune type. What -- are we having any ways of doing it at the moment?

Well, for -- the answer is yes. But for a long time, many investigators, including myself, were really more focused on T cells because the T cells ultimately do the -- most of the execution. But what a lot of us didn't pay enough attention to is that the tumors composed of this very complicated microenvironment that includes the tumor itself, the infiltrating anti-tumor immune cells, the bad immune cells that are immunosuppressive, fibroblasts, blood vessels and a lot of different cell types that are all conditioned by the tumor generally in a bad way to prevent an effective immune response. So we're now recognizing more that you can't just give vaccines. You can't just give immune checkpoint blockades. You also have to help condition the immune environment, the local microenvironment so it's more conducive to anti-tumor immunity. And a really big kind of revelation to the T cell immuno just like myself, with no surprise to the myeloid investigators, was that in many tumors, the main immune cell there isn't a T cell. It's a myeloid cell. And myeloid cells can account for 4 out of 5 of every immune cell in many types of important cancers. And those myeloid cells are doing a lot of damage. And there's other cells as well. So you can imagine either eliminating the myeloid cells, altering their phenotype. You can imagine changing other conditions that didn't directly affect immune cells. And there's a lot of work going on in different groups now with many approaches, small molecules, bispecific molecules, direct targeting of myeloid cells, direct killing of them and other kinds of cells to condition the local immune environment to be more conducive to anti-tumor immunity.

Do you have any idea why it has been so difficult to identify the patients who actually respond to these T cell regulators? The...

Boy, if I need that, I would just go ahead and say make your reservations for Stockholm right now. So that's the really big question. There are so many groups and my group, so many other groups that work with trying to understand why do some patients respond so spectacularly well. Some patients respond, but then the response dissipates or goes away, and most patients simply don't respond. And we don't have a good answer, but we do know that it's got to do with the tumor itself; the antigens that tumor's presenting, which your immune system may or may not be able to see; the defenses that, that tumor has put up; and factors in the environment, which -- all these microenvironmental factors that you're talking about including the tumor, the anti-tumor immune cells, the dysfunctional immune cells that you'd like to get rid of. And so understanding predictors is going to be a lot more complicated than doing something simple like a TB skin test. If it's positive, well, you've got TB, and we know how to fix it. Let's do something. It's going to be highly multifactorial, and it's probably going to be -- have to be tailored to either individual patients or small cohorts of kinds of patients that we have yet to fully understand.

Right. How do you feel about that, that people are saying that, in the future, we actually stop using the original tissue as a definition of the tumor and move on more to analyze the immune profile of the tumor in order to understand what kind of a tumor it actually is?

That day is almost upon us now. So in the U.S., we have -- I think you use it in Europe, too. We use the TNM system, where you classify tumors based on the T, which is the tumor itself; the N, which is the nodal invasion or not; and the M, which is the metastatic component. And there's discussion now to add the I component, which is the microenvironmental immune composition of the tumor. So you have a TNMI system where you take that into account. And so you can't simply biopsy a tumor and say, "Oh, is it PD-L1 positive or negative? Is it DNA damage repair sufficient or insufficient. Is it tumor mutational high or low?" All these things are important but by themselves don't really address will this particular patient with this particular tumor respond, and it's going to become a lot more complex. And biopsying and looking at these other factors is going to help. And potentially, there may someday be a way to do a peripheral less-invasive procedure like drawing a blood sample and understanding who can or can't respond, but we're still far from being able to do that today.

Right. Then one of the last thing to ask is really your opinion about these myeloid cells and which direction it actually should go, and I know that you have even done some experimentation in your lab with your group.

Right. So we've been fixated on T cells in my group for many years. But since we work in ovarian cancer, it's become clearer just as that one example of how important myeloid cells can be, and you really need to pay attention. So a lot of my colleagues who are a lot smarter than may have said, "You really need to be looking at myeloid cells and other cells." So in the last 10 years, we've been paying a lot more attention to the effects of myeloid cells and how they can affect the tumor environment. Ironically, even though I still think of myself largely as a T cell guy, SITC, the Society of Immunotherapy for Cancer, has their immunology primer workshop, and they asked me to do the myeloid cell workshop to get people acquainted with myeloid cells. And I said, "No, I want to do T cells." They said, "No, we want you to do myeloid cells." And -- but actually, I'm glad they made me do that because it really helped me take a deeper dive into the myeloid cells. They're critically important. We really need to do a better job of attacking them, either eliminating them, altering their phenotype, altering their function and reducing their immune suppressive consequences on many kinds of immunotherapy.

We are happy to have you, Tyler, building that up. So thank you very much. Would you like to say something before we let the next speaker to come in?

No. I think that -- I just want to say that understanding the tumor microenvironment is very critical. Myeloid cells are really major component of that. We haven't done a good job so far of attacking it, but we understand enough that we can do a better job going forward. So I think today is going to be a good opportunity to bring people up to speed on what. The new developments are.

Thank you, Tyler.

Thank you.

Tyler will be available for Q&A session as well. So if you have further questions really in mind, please just type it in and just send it to us. That then will be answered if time is enough really to do all the questions. So then we move on. We have a next speaker who is Dr. Maija Hollmén. Maija has a career, which is, from the very beginning, really focused on tumor environment; a PhD and then postdrug at the best Continental European University, ETH in Zurich and is now our key collaborator with our network for Faron. And not only she is curious about the macrophages. She's also curious how bexmarilimab is actually affecting them. And she will now give us a review where they are at the moment with some recent information not only for the MATINS trial but also from other tumor environments. So Maija-Leena, thank you for joining us. And please, the floor is yours.

Thank you, Markku. It's my pleasure to be here to tell you the recent updates on the macrophage-targeted immune therapy and the clinical development of bexmarilimab. My name is Maija Hollmén, and I'm an adjunct professor in tumor immunology and a principal investigator at the University of Turku investigating the macrophage targeting and utilizing CLEVER-1 to ignite the immune response against immunosuppressive tumors. This slide might be a bit provocative, but I'd like to picture the macrophages as key regulators of antitumor immune responses. And of course, it's -- the T cells are always needed to kill tumor cells, but the macrophages can really tell the T cells what to do. And what we know currently is that there can be 2 types of macrophages in the tumor microenvironment that regulate different responses on T cells. One of them is an antitumor macrophages, which supports cytotoxic T cell activation and tumor cell killing and they secrete high amounts of IL-12, TNF alpha and have high antigen presentation; whereas the pro-tumoral macrophages are very immunosuppressive and suppress T cell activation in tumor sites, and they have high expression of IL-10, TGF-beta and low MHC class expression. We work on CLEVER-1, which is a multifunctional scavenger and adhesion receptor, and the name comes from common lymphatic endothelial and vascular endothelial receptor 1, which is also known as Stabilin-1 and FEEL-1. On macrophages, it's expressed on these tolerogenic macrophage and immunosuppressive macrophage populations, which regulate tissue tolerance by scavenging apoptotic cells and regulating tissue remodeling. And on the endothelial side, they can -- CLEVER can regulate the entrance and exit of leukocytes and lymphocytes between tissues. And on the liver, it can regulate scavenging and lymphocyte trafficking. We have previously shown that the immunotherapy blockage of CLEVER-1 on macrophages can reactivate the T cell responses against immunosuppressive tumors. The way we're investigating these issues was that because CLEVER is expressed on macrophage subsets and on endothelium, we really wanted to pinpoint where the activity was that was actually regulating tumor growth. For this, we utilized CLEVER full knock-out mice or the mice that had a genetic depletion of CLEVER-1 on macrophage subsets. And if we implant tumors into these mice, we can see that the [ who is ] lung carcinoma or triple-negative breast cancer tumors could not grow at all in those mice that lacked CLEVER expression on macrophage subsets. When we look more closely into this situation in the tumor itself, we can see that this macrophage-specific deletion of CLEVER-1 could induce a robust infiltration of CD3 positive T cells in the tumor site. There was a bit similar reaction in the full knock-out mice. And I have to emphasize here that when CLEVER is also knocked down from endothelial cells, it might regulate how the T cells are trafficking into the tumor site as well. When we look more closely to the -- what type of T cells we could see in the tumor by flow cytometry analysis, we could see that the main population of T cells was the CD8 cytotoxic T cells. So how do we think CLEVER targeting can improve cytotoxic T-cell responses? As I explained earlier that CLEVER is expressed on these immunosuppressive macrophage populations and we think that when we block CLEVER activity, we can convert these macrophages to this M1 like type, which have higher antigen presentation capabilities similar to dendritic cells and they can activate T cells. In the lower panel, you can see an analysis of this full CLEVER knock-out mice and their tumor macrophages. And in the wild type situation, you have high abundance of these tumor-associated macrophages that are these M2-like macrophages that are immunosuppressive, which can be seen on the red bar here. But in contrast, in the CLEVER knock-out mice, there was very few of these immunosuppressive macrophages. And they had -- the macrophages in these settings had higher MHC expression. Prompted by these really interesting results, we have also developed an anti-CLEVER antibody named bexmarilimab into clinical trials to treat advanced solid tumors. Here is the trial design, which is named MATINS trial. And bexmarilimab is a human IgG4 antibody, which has 2 mutations to inhibit Fab-arm exchange and also suppress any unwanted effects on effector functions related to the Fc part of the antibody. We have now completed Part I of the clinical trial and Part II of the clinical trial, which Marie-Louise will explain in depth more in her presentation, but I just want to highlight a few very nice findings that we observed in the clinical trial patients from Part I of the trial. And this was published in clinical cancer research recently. And where we identified when looking at the T cell subsets in the circulation of the clinical trial patients by mass cytometry, we can identify that there was a clear induction of T cell activation by markers such as CD69, CXCR3 and CD25. And they were upregulated in almost all of the T cell subset that we could find with this mass cytometry approach, whereas some negative checkpoint molecules were down regulated mostly on the CD4 T cell populations. So how do we think bexmarilimab works on the macrophages? And this was also published in the Clinical Cancer Research paper, and I have simplified this for you to understand how it really works. So when we have these immunosuppressive macrophages, which are CLEVER positive, they normally scavenge apoptotic cells and take them very rapidly into degradation by phagocytosis and acidification of vesicles, and they are hidden from the tumor microenvironment so that they don't ignite an immune response. When we treat these macrophages with bexmarilimab, they can still scavenge these antigens. But what happens inside the cell is that the acidification of these phagolysosomes is impaired, and the macrophages then have more time to -- for the antigens to be loaded on MHC molecules and presented on T cells. And this is how we can ignite adaptive immune response to recognize, for example, tumor antigens. Here is a representation how it really could ignite this. So when we study bexmarilimab in this mixed leukocyte reaction, where we take macrophages from one donor and T cells from another donor and we mix them together, and what happens in this reaction is that the T cells recognize -- or the macrophage recognizes that T cells, there is an HLA mismatch, and the T cells via this HLA mismatch start proliferating. And this proliferation, we can measure with -- when we have -- cell track these T cells with a florescent label. And when they start proliferating, they lose this florescence and then we can monitor how much of these T cells have lost their florescent label. And you can see here these plots of the cell trace, violet, cell tracking probe. And the more diluted this probe goes, the more these T cells have proliferated. And when we look at the quantification of the proliferation of T cells with the different treatments, there is a positive control where we activate the T cell receptor and IL-2, and they proliferate. Almost 80% of the cells proliferate. With M1 macrophages, we can see that the T cells do proliferate also in this situation but not as actively as the positive control. Now when we test M2 macrophages, and remember, these were the M2 immunosuppressive macrophages, they really cannot support T cell activation. When we then incubate these M2 macrophages with different CLEVER-targeting antibodies or the isotype controls, we can see that bexmarilimab can ignite this immune response to the same level as an M1 macrophage can. Looking at how these patients are responding to bexmarilimab treatment. It seems that there is a 30% to 40% response rate in disease stabilization. You can see spider plots from cutaneous melanoma and gastric adenocarcinoma, and there are some patients who can really seem to develop a stable disease after they have received bexmarilimab. There are several cohorts from which we see that there is a positive response, those being cutaneous melanoma; cholangiocarcinoma; gastric cancer; hepatocellular carcinoma; and breast cancer, estrogen receptor positive breast cancer. So our question was actually how can we identify those patients who will get the benefit so that we can treat more of those patients and get better result with the drug. There was a recent publication in 2018 by Thorsson et al, who described that when they were monitoring from the TCGA database, 33 different cancer types, they can actually show that all of these cancer types fell into 6 immunological subtypes regardless of their origin or cancer type or molecular subtype, and these cancer immune subtypes are listed there. These are 6, and they are listed on the left side. And when we look at the expression level of CLEVER-1, so Stabilin-1 is the mRNA name for CLEVER-1 or the gene name for CLEVER-1. And we look at the survival curves related to the expression levels of PD-1 and Stabilin-1 in the interferon gamma dominant tumors, which is the upper Kaplan-Meier curve. We can see that PD-1 has a survival effect in interferon gamma dominant tumors, which is, of course, a biological issue because interferon gamma upregulates PD-1 and is a positive biomarker for anti-PD-1 therapy. But in this case, Stabilin mRNA doesn't have any significant effect on the overall survival of these patients. Now when we look at the lymphocyte-depleted tumors, their PD-L1 doesn't have any significance. But their Stabilin-1 mRNA, the higher you have it, the poorer prognosis you have. We also need to remember the context where we are looking at in the tumor side because it's known that the more infiltration you have in tumors of immune cells, especially T cells, the more likelihood you have for a response. And this is represented in the middle panel with the red cells. So the highest level you have T cell infiltration, the better responses you have. You might also have an excluded tumor where your T cells are around the tumor, and they don't respond that well to anti-PD-1 therapy for example. And then you might have a tumor type that doesn't have any immune cells, but it gets more complicated because even though you might have immune infiltration, the quality of the immune response within the tumor might determine actually how they respond. So even though you have high amount of T cells, you might have them exhausted, and they cannot perform well to effective antitumor responses. You might also have a high abundance of immunosuppressive myeloid cells that can control T cell activity and suppress immune responses against the tumor. So we wanted to utilize this and figure out what would be the best tumor type that we could use for targeting with bexmarilimab. For this, we use these patient-derived tumor explants, which we obtain from breast ablation surgeries. So we cultured these little tumor pieces in these wells and incubated them with bexmarilimab. You can see in the lower immunofluorescence images when we treat the explants with the fluorescently conjugated bexmarilimab, we can see that it really nicely penetrates these small tumor pieces. And it colocalizes with 9-11, which is another CLEVER antibody targeting a different epitope when we stay in afterwards of the incubation with this antibody. So there is really nice colocalization, and there are really abundant levels of CLEVER-1 positive macrophages within these breast tumors. Now when we study these tumors and the activity that bexmarilimab can ignite, we can see a lot of differences depending on what type the tumors are. And I also want to emphasize here that when we look at the macrophage subsets within these tumors, so there is single-cell RNA data represented in the left figure there. This is a UMAP plot, and each dot represents one macrophage found in these different tumor types. There are estrogen-receptor-positive tumors, HER2-positive tumors and triple-negative tumors. And there, you can clearly see that with mRNA and gene expression levels, these macrophages are totally different compared to in which tumor types they are. So keep this in mind also that to find the right targets, the targeted tumors or druggable tumors, we need to understand very much how these cells are and what's their phenotype in these. And here, you can see that the estrogen-receptor-positive macrophage tumors are much different from the triple-negative ones. And now when we look at these different tumors, so the TNBC and estrogen-receptor-positive tumors that have been treated with bexmarilimab, we can see that bexmarilimab can induce a nice effect in the estrogen receptor tumors but not that much in the triple-negative one. This is seen also in the cytokine levels. If we now measure the cytokines from our cultures, we can see that, in baseline situation, the triple-negative breast cancers secrete a lot of factors compared to the estrogen receptor one. And now when we look at the effect that bexmarilimab can induce in these tumors, we see that it can hardly do anything in the TNBC tumors, but it can induce IL-7 secretion, IL-12 and IL-13 secretion in the estrogen receptor one. When we compare these effects also with different or positive control, which is lipopolysaccharide and also with anti-CD47, which is the "don't eat me" signal inhibiting antibody, magrolimab, we can see that all of these different compounds that should ignite innate immune response don't do that much in triple-negative breast cancer, whereas in estrogen-receptor-positive cancer, we see very nice effects on interferon response genes as MX1 and other molecules and a common upregulation of CCL3, IL-1 beta and CD16 for example. So when we go back to our patient data and look at the responses that they got for upregulation of interferon gamma and CXCL10 in the circulation, there was no relation to dose in these patients. But surprisingly there, so the patients who got an upregulation of these factors in the circulation, we actually noticed that those were the patients that had the lowest baseline levels of this interferon gamma, CXCL10. So we wanted to model this more. And could we understand what was going on in these patients? So we turned to use ovarian ascites samples because here on the left upper bar, you can see that 80% or even 90% of the ascites sample macrophages were CLEVER positive. So we treated these ascites samples, which also contains cancer cells, T cells, B cells, NK cells and so on. So it's a very nice model to study the tumor microenvironment. When we treat these tumors with bexmarilimab, we can see that some of the tumors can really nicely upregulate MX1, which was also seen in the breast tumors, and this also relates to the upregulation of CXCL10 in these ascites samples. We wanted to perform single-cell RNA sequencing then to investigate what was going on there. And we can see that the ones that had the highest responses for MX1 and CXCL10 had the lowest preexisting response to interferon gamma, whereas those that didn't respond were -- or had an already preexisting interferon-related response. So altogether, what we now think is that where we want to target bexmarilimab is the ones that are cold tumors, so lymphocyte-depleted tumors that have high amounts of immunosuppressive macrophages. And by utilizing bexmarilimab to these or administrating bexmarilimab to these tumors, we can ignite the tumor microenvironment to support T cell activation, and we see interferon response genes upregulated and secretion upregulated. And as you know, interferon upregulates PD-1, which would mean that then these tumors could then regain responses to anti-PD-1 therapy for example. So I want to thank you for listening, and I'm happy to take questions. Thank you very much.

Thank you, Maija. Maija will be available as well for the Q&A after we have finished all the presentations. We are now again back to the cold and hot tumors. And hopefully, we have further discussions on the profile of those. And this is really starting to indicate the target, really tumor types we need to really use for the bexmarilimab treatment. So then moving on. I can't be happier than this to introduce our new CMO, Marie-Louise Fjallskog, originally from Sweden, got training in Uppsala, for MD and PhD, then went to Karolinska and number of other clinical sites. So she's a real clinical oncologist even today but then suddenly wanted to do something that actually could benefit the patients even more than the treatments at that time and move on for the -- to serve the industry. Went to U.S., started with Novartis and then with number of other small biotech. And the last one in U.S. was Sensei biopharmaceuticals, where she was involved in setting up the clinical program but also with the IPO process and at the time when they raised something like 150 million for the company. She has been now with us for less than 2 months, but the reason why she is so excited, she can tell that by herself. But obviously, we are very happy to have a person with a very experienced development pathways in the past. And it's quite interesting that she has been dealing also with the myeloid cell targets in the past. So Marie-Louise, thank you joining us today, and tell us what you have learned and what kind of ideas you have really to take bexmarilimab further into a patient health.

Thank you, Markku, for your introduction. I'm very happy to be here to walk you through the clinical development plan of bex. I joined at Faron about 2 months ago, and the main reasons why I joined is the very robust scientific data on CLEVER-1 and also the clinical data showing that monotherapy bex could have antitumor activity. That's very, very exciting. So let's go to my clinical update. I will move to the next slide here. So I will walk you through Faron's studies. We have one ongoing study, and we have several studies that are planned. Let's start with MATINS. So MATINS is a Phase I/II study where we're treating patients with single A bex in advanced solid tumors. RENACOL is another study, a Phase I/II neoadjuvant study that we have decided to close down. So RENACOL has been planned for a long time, and the main objectives of the study was to look at the safety of one single dose of bex. Given that we get so much safety data from the MATINS study, we don't need any additional safety data from RENACOL. We also wanted to look at translational data, and we have made amendments to the MATINS study. So we are looking at that translational data. Therefore, we decided to close down RENACOL and focus on our combination studies. So BEXMAB is a very interesting study. It's a Phase I/II study, where we are combining bex with standard of care in AML and MDS. So AML stands for acute myeloid leukemia and MDS for myelodysplastic syndromes. So these are blood cancers. We're hoping to start this study in Q2 this year. Another very interesting study is the BEXCOMBO that we are planning to hopefully submit the IND by the end of this year and start enrolling patients by next year. This is a very exciting study -- a Phase II study looking at the efficacy of bex in combination with immunotherapy, PD-1 blockade, in solid tumors. But we also have a very important collaboration with investigators in Texas. So they are going to look at bex in combination with PD-1 blockade in a dose escalation study, and they're going to look at the combination in non-small cell lung cancer. This study is very important for us because we can get a dose for our combinations through our efficacy study. So let's start with the MATINS study. So this is a Phase I/II study. We are enrolling patients in -- at 11 sites in 6 countries. Two parts of this study are already completed, and I'll walk quickly through them. So in the first part of the study, we treated 30 patients at 4 different dose levels. I want to remind you that these patients are very heavily pretreated, all the patients received several different lines of therapy and failed them all. They are progressing going into this study. We did not see any safety concerns with bex as a single agent, but we did see some immune activation, and that is, of course, very important. When you treat patients with an immune activator, you want to see some sort of clinical science or translational data showing that you are getting the immune activation. We chose the dose that gave the most immune activation in the Phase I part and went to Part II. So in this part of the study, we enrolled 10 different indications with 10 patients in each cohort. I will update you on the safety and efficacy data soon. Right now, we are in the phase of the dose optimization. So we chose the promising indications from Part II, gastric cancer, melanoma and cholangiocarcinoma, and we're exploring higher doses and more frequent dosing. So here, I'm presenting the updated safety from the Part I and Part II of the MATINS study. So, so far, we have treated 193 patients. This therapy is very well tolerated. The majority of the adverse events that we see are grade 1, mild; or grade 2, moderate. We see very few serious adverse events like grade 3 or grade 4. The most common treatment-related adverse event is fatigue, grade 1 or 2, and this is also very commonly associated with an advanced cancer. Very importantly, we are expecting to see immune-related side effects, and we are doing that. Active immunotherapy always comes with some immune-related side effects. We see approximately the same immune activation signs as PD-1 blockers did. However, our frequency is much less. In the few patients that had some sort of more serious events, we managed this very easily by treating with steroids and withdrawal of the drug. So here, I have the efficacy part from Part II, and this is not new data. You have seen this one before. But I wanted to emphasize that we do get disease control in 30% to 40% of the patients. And what do I mean by disease control? So disease control means that you get a stabilization of the disease. Remember, these patients are progressing. They have progressed from many previous lines of therapies, and we get a stabilization. The tumor stops growing or in some few patients, we also see a tumor reduction. So to the right of the slide, you can see where we have some objective responses. So we see that the tumor lesions are shrinking. At the top, you have melanoma and at the bottom, gastric cancer. So here, we see nice shrinkages. So to get a drug approved, it's really important to show overall survival benefit. And with all the treatments like chemotherapy or small molecules, the overall response rate translates into a survival benefit. However, this is not true with immunotherapy. So there are several applications where they have gotten accelerated approval where, based upon the overall response rate, they now have been withdrawn because they didn't translate into overall survival. So that brings me to the next slide here. So if we're looking at the right part of this slide, you see the survival in these patients. So we have gathered all the patients that have stabilization or some tumor reduction in the red line. And in the blue line, you see patients that did not have a stabilization. They had a progressive disease. And as you can see, there is a huge difference in survival between these 2 different patient categories. However, in a single-arm study, you could debate that, well, maybe these patients would have done equally well if they did not have bex. So to be able to evaluate this, we went back and looked at the prior therapies. So if you look at the graph to the left, you see that the time to failure on prior therapy was the same for patients that benefited on bex and those that did not benefit. So this shows us that bex actually drives the survival benefit. Bex is doing something. It's not because we have indolent, slowly growing tumors. But as you also noticed, some patients do have very nice responses, whereas other patients do not. Their tumors continue to progress. So of course, you always want to be able to select those patients that will have benefit from your treatment because those patients that will not benefit, why would they have your drug? They can get some other kind of therapy, hopefully. So we have looked into blood tests, simple blood tests that most hospitals can perform. And these different markers that you see to the right, interferon gamma, TNF alpha and IL-6, show if you have an immune activation in the blood. So if we look at our patients that have a stabilization of disease or actually a reduction in the tumor burden, they're called DCR here, the red dots, and you compare it to the ones that did not have a stabilization of disease, you see a significant difference. And this is the same for all of these 3 different markers. You see that our patients with responses had lower immune activation, lower interferon gamma, lower TNF alpha, lower IL-6. So that made us think that maybe it would be even better to have several inflammatory markers together in different models to really try to separate the patients properly. So we have tested these 2 different models, 2 markers to the left, 4 markers to the right, using ROC curves. So these are standard ways of evaluating our diagnostic tests. If you see an area under the curve that is 1, that is 100% perfect test. So if you look at our test here with 2 markers to the left, you see that we have a value of 0.8, so it's excellent. It's a very good separation. By using those 2 markers, we can very well predict who is going to get clinical benefit from bex and who is not. And if we actually go to the curve to the right, you see that we have added 2 other markers. If we use those 4 markers together, we get an even better way of predicting the patients. The AUC is 0.9, which is outstanding. So this is very promising moving forward. But of course, we also want to look into the patient's tumor because it makes sense that the patient's tumor need to have the target for the patient to respond. So we set up an assay that has been validated, and this can assess the CLEVER-1 expression. So what you see here are tumor biopsies from 3 different patients. The brown dots are the staining for CLEVER-1 expression. So this is a routine method that is performed at every pathology department, and the results come within a few days. Preliminary data from our analysis show that the patients that had a stabilization of the disease or a tumor shrinkage have a higher CLEVER-1 positivity than those that only progressed. This makes sense, and we're very excited to evaluate this further. So it was a very high -- it is a very high priority to evaluate patient selection. Another very, very high priority is the determination of the Phase II dosing regimen moving forward. So what do we need to determine a good dosing regimen? Well, we need to understand what happens to the drug in the body. We also need to understand how is the drug affecting the body. Do we see immune activation in the blood? So we're measuring interferon gamma, TNF alpha, et cetera. We take the blood before treatment, and we take blood during treatment and then we compare. But we also want to change the tumor microenvironment. So we're taking biopsies before treatment and during treatment, and we are very excited about soon going to look at 60 pairs of these biopsies because we want to see, are we getting those changes in the tumor microenvironment that we want. Anyway, if we get immune activation but no clinical responses, that is not really interesting. So we also need to look at the stabilization of diseases and the duration. So if we have all this data together, we have a very comprehensive dataset that will help us to choose the dosing regimen that is the best for the patient. We're hoping to get a lot of this data by Q2. And then, of course, we need to do some data analysis. By Q3, we are hoping to set the Phase II dose regimen moving forward and have a meeting with FDA where we can confirm that they agree with our rationale for choosing the dosing regimen and also how to move forward. After having the Phase II dose regimen, of course, we need to narrow down on the indications. We have some very interesting data on refractory melanoma showing that this could potentially be an indication of interest. So refractory melanomas are patients that have received immunotherapy but they no longer respond. So if you look at the 3 images to the top left, you see a patient, so these are images from his tumor. This patient received immunotherapy and did no longer respond to the treatment. However, when we gave the patient bex, we achieved stabilization of his disease. So let's look at his tumor. To the left, we have -- the brown dots represent stainings for M2 macrophages. So Maija already mentioned the M2 macrophages as being immune suppressive. So this is the tumor with lots of M2 macrophages immune suppressed. In the middle, you see some stainings for the target CLEVER-1 and is positive. So we do have the target in this tumor. And to the right, the very few brown dots that you can see are stainings for T cells. So this tumor is very low in T cells, low T cells, low interferon gamma, typical cold tumor. So if we go down below, we can see 5 different melanoma patients treated with bex. The 3 patients to the left did not observe an interferon gamma increase in the blood. However, the 2 patients to the right did have this very interesting interferon gamma increase. The patients to the right, the red patients, they had stabilization of the disease. And as I showed you before, also in melanoma, if you look to the right, those patients with disease control, the red patients had a very nice survival compared to those blue patients. So very interesting indication moving forward. So what are we going to do when we have the recommended Phase II dosing regimen established? There are 2 options. So we could continue with a single-arm study if we observe more partial or complete responses. So the FDA guidance is very clear on how to get a drug approved. If you want to continue with a single-arm study, your overall response rates need to be very high. And in refractory melanoma, I would guess 30% to 40%. If you have very nice overall survival benefit, you still need to have a randomization against whatever drug the investigator would like to treat the patient with if they didn't get bex. So the way our data look right now, we see that we may need to move forward with a randomized study. But we have plenty of patients to evaluate yet, so a definitive path to move forward will not be decided until Q3. So that was a lot of data on the MATINS study and our plans to move forward. So let's go into another very interesting coming study. So this is the BEXMAB study. So here, we're treating blood cancers, AML and MDS, with bex in combination with the standard of care. So one of the reasons for choosing AML and MDS is that these are very aggressive diseases. There is a high unmet medical need. But of course, it's also important that if you look to the right, you see that we have a very high CLEVER-1 expression. To the left, you can see a graph showing that patients with high CLEVER-1 expression has a much poor survival than those with a low CLEVER-1 expression. There is also data out there showing that the standard of cares probably will benefit very well from the additional bex. We get a better enhanced antigen presentation, and we also can potentially reverse the resistance to venetoclax. So there is a lot of good rationale for combining bex with azacitidine or the combination with venetoclax. So on this slide, you see the study design. So to the left, you see the diseases. So the doublet will be evaluated in the blood cancers, AML and MDS. We will evaluate approximately 4 different dose levels. As soon as we have cleared the first dosing level, we can start enrolling into the triplet. When we have decided on the dose to move forward with, we can open up an efficacy evaluation phase. So here, we can treat patients of 15 to 35 per indication. What is very interesting here is that we already have Fimea's approval to start the study, and Fimea is the Finnish Health Authorities. We will submit an IND in Q1 2022, and hopefully, we can start the study in the U.S. soon as well. We're hoping to treat the first patients in Q2 2022. So let's move to our next combination study. So the other combination study that we're planning and hoping to start later this year, beginning of next year is our combination of bex with immunotherapy, PD-1 blockade. So why would we want to do that? Well, we know that most patients treated with PD-1 blockers do not respond to a single agent. And if you look to the right, we also know that for patients to respond to PD-1 blockade, you need to have a preexisting immune activation. So that means an interferon gamma high tumor. As you can see here, the patients with the preexisting immune activation do much better than those that do not have this activation. If you look at the bottom of this page, you see the 2 melanoma patients that I showed before. This shows that bex induces the interferon gamma levels that are required for PD-1 blockade response. So what we want to do is to take those colder tumors with a low interferon gamma, treat them with bex, get the ignition of the immune system and then add the PD-1 blockade so we can get a very good combination effect. And there are many different indications where single-agent PD-1 blockade does not perform sufficiently well. So let's go to the study design here. So this study design is going to be very flexible. We are going into CLEVER-1-positive indications. We want to come up a little bit earlier into the therapies here, so we want to go into the first or second line metastatic setting. We know that immunotherapy has a much better effect the earlier you come in and treat the patients. We are also going into patients that did not have PD-1 blockade before. So the combination dose will be set when we start this study, and we will probably start going into head/neck cancer, which is a very interesting disease with approximately 20% responses to single-agent PD-1, but I think we have a lot more to give here if we add bex. The study design is flexible. So we can decide to start with one indication or we can decide to start with several or at any time in the study, we can expand. So this study can rapidly change and become a bigger study. So here's an overview of the bex clinical development plan. So starting at the top, we have the MATINS study. During the year -- at the end of the year, we need to make a decision on option 1 or option 2 for our continued development on bex single agent. We have a very interesting study with our investigators and non-small cell lung cancer in combination with PD-1 blockade. Then we have our own going into several indications. And then we also have our blood cancer combination study, Phase I/II study in AML and MDS, combining bex with standard of care. So just to summarize what I have shown you so far, bex is definitely well tolerated, and the safety profile is very good. This is really important. The patient population we're going into is last line patients that do not have a very long survival. It is really important to have a good quality of life. It is also important with the good safety profile to be able to combine with other drugs. Otherwise, it would be much less straightforward. We do see some monotherapy efficacy with tumor shrinkage and long-standing disease controls that seem to translate into enhanced survival. We have a lot of interesting tasks this year and interesting happenings. We have to determine the dosing regimen and patient selection. We're also starting 2 combo studies and hoping to see FDA in Q3 to agree on the dosing regimen and the proposed plan moving forward. So with that, I would like to thank you for listening and hand over the word to Markku. Thank you.

Thank you very much, Marie-Louise. It's a really exciting time for us, and thank you again joining Faron. I think we have really good plans really to move forward. So those were the longer presentations, but we have one more to go because a lot of people are asking us often what are the patient populations you may be targeting. And for that, I ask our Chief Operating Officer, who was appointed in January, Dr. Juho Jalkanen really to go over the next slide, which is really briefing in you on what kind of a potential all these treatments may have in those populations we have been talking today. Juho, please.

Thank you, Markku. This is basically summing up everything we've already heard today, but a bit more in numbers. Already from the start, as presented by Dr. Curiel, there's a big unmet need in patients that fail their anti-PD-1 therapy because after that, there isn't usually much to revert to. It's either standard chemo, which is not that good, or a combination of checkpoint inhibitors like ipi/nivo, which then again are relatively toxic treatments with a lot of immune-related adverse events. So after failing a PD-1, there's really not much more there for patients, and we need something because it's estimated that up to 160,000 patients each year in the main markets, U.S. and Europe, fail their anti-PD-1 treatment. So that's a lot of patients. Just to summarize what would that mean in monetary terms, currently, the checkpoint refractory market isn't big because it mainly consists of standard chemo. But for example, 20,000 melanoma patients annually generate sales of approximately USD 2 billion and 58,000 lung cancer patients are forecasted to generate sales of $4.2 billion in the U.S. alone. And as presented today, what really seems to dictate, are you responsive to anti-PD-1 or checkpoint inhibitors, is ongoing inflammation interferon gamma responses, and checkpoint inhibitors do not seem to work unless there is preexisting inflammation. And then again, bexmarilimab seems to work where there is no preexisting inflammation, but it will give it, setting the stage for checkpoint inhibitors and possibly helping patients in this need. Thank you.

Thank you, Juho. All right. That is everything I wanted to present to you today, and it's now time really to move on to Q&A. And I ask the operator really to provide us questions, which I hope you have sent already to them. You can keep on typing them while we are answering the first ones, and I try to guide, if they are not directly pointed out to one of the speakers, who actually would be the best one to answer. So please?

Yes. Markku, it's Eric. I've been taking a look at the questions that have come in. There's quite a few. So I tried to sort of group them by theme, and the first is really around biomarkers. So there's a couple, but I'll start with the correlation of biomarkers to clinical benefit looks strong with bexmarilimab. Can you give us an idea of what proportion of early, meaning first-line and late-stage patients similar to or part of the MATINS trial would present with these characteristics of low interferon gamma and low tumor necrosis factor alpha?

Thank you. That's a really good one. I think it's really Marie-Louise, Juho and perhaps even Tyler could comment on this because this is really critical when we move forward. Marie-Louise, would you like to start?

Yes. Thank you. That is a great question. So I would say that the data that we have in the later lines, approximately -- well, around 20% would be defined as low interferon gamma. The earlier lines, I actually don't know, and maybe I can get some help from the rest of the team here.

Yes, I can fill in on that. So the earlier line is definitely the ones that are initially nonresponsive to checkpoint inhibitors, initially refractory. So they don't develop the resistance to it, but they don't respond to it at all. That's the population. Again, it's around 30. Or maybe Tyler probably knows even better treating these patients, done a lot of the research in the field.

No, I don't have anything further to add.

Thank you. But it is absolutely something that we need to really globally start to look more carefully because, obviously, we all want to have an improved treatment for all the cancer patients, not just some proportion of them. Maybe we could move on to the next one, please. Eric, next one. Hello?

Eric is muted, it looks like.

Could somebody -- yes. Eric, you're muted.

We lost him.

I can see the questions here if we lost Eric here. It's Juho. So a follow-up question on that is similar biomarkers, for example, used for checkpoint inhibitors, for example, interferon gamma. Marie-Louise, if I spell out the question, maybe I don't want to be answering it. But I can if you feel...

Yes. I think Tyler could even -- he could respond to this question better. But I mean, as of today, we're using the PD-L1 staining in the tumors to guide us on the patients that have higher probabilities of responding to immunotherapy alone or if we need to add chemotherapy. But lots of research is ongoing of course.

Yes. I wish I had something really intelligent to add. That's about the state of the art now. I hope that, over the course of the trial, as more data accrues, we can get a better handle on what's going to make a good biomarker beyond what we've said.

Thank you. So Juho, maybe you continue if Eric is...

Yes. Sorry, I got bounced off, but I am back, and I apologize for that. So I did hear the end of Dr. Curiel. So I guess, did he address the question around sort of the rationale behind combining bex with anti-PD-1? Is the rationale that you might be able to help patients not currently benefiting from anti-PD-1 monotherapy? Or are you really hoping to enhance the benefit of those who are currently responding?

So my current strategy is to go into those patients that -- there is an echo here -- to go into those patients that do not respond to PD-1 blockers. So those that respond to PD-1 blockers, they usually have like a hot tumor or a warmer tumor. That means a higher interferon gamma production. And since we work best in the interferon gamma low tumor environment, I would like to try to go into that population and get an ignition of the immune system and then to add PD-1 blockade. So that would be my first strategy, even though the -- what you mentioned is interesting too, but this would be the first.

Okay. And then there was just another one biomarker related. Are there -- have pro-inflammatory markers been used predictively elsewhere in the therapeutic landscape?

Can I go ahead and say something about that?

Yes, please.

As an EMA- or FDA-approved indication, the answer is no. But in the exploratory way, the answer is yes. So high interferon gamma is a strong predictor of immune checkpoint blockade response. It's been used in clinical trials, but there's no approved -- regulatory approval for that in Europe as far as I know and certainly not in the U.S., but it's being looked into, along with other markers.

Thank you. But we definitely are heading somewhere with these markers. They will come in sooner or later. Maybe the next one then, please. Did we lose Eric again? Sorry for these technical problems. Juho, maybe you can pick up one again.

Yes. While Eric is having issues, we can follow up with biomarkers with some histological questions. For example, there's a question, do we follow it and what do we see on histology. Yes, we do follow that, and that's actually work in progress currently. And hopefully, we'll be revealing some data on that soon. For example, we do look at PD-L1, which is a histological marker used for checkpoint inhibitors and as we are evaluating how does that correspond with responsiveness to bex.

All right. And then next?

Yes, go ahead, Eric.

Sorry, I bounced off again. I have no idea what's going on. But -- so I guess, a couple more science related, the deeper science related. Are macrophages a physical barrier? Or is it just bexmarilimab's ability to upregulate interferon gamma that will benefit immunotherapy?

Maybe Maija would be proper person to answer that one.

Yes. I could possibly give my ideas on this one. So I think macrophages generally serve as physiological barriers in the tumor marginal to prevent T cells from infiltrating the tumor. But when bex -- when we treat the tumors with bex, they are activated to kind of awaken the T cells and therefore, support their activation and most likely also contribute to the infiltration into tumors. So this is my idea about that because then when you get an interferon response, you get infiltration also of NK cells and other antitumor supporting cells there.

One very interesting physiological situation where the same CLEVER-positive myeloid cells are involved is pregnancy. And again, there, in placenta, they really convert the environment to an immune-suppressive one. And again, we don't precisely know is there a barrier or it's just maintaining the phenotype that actually could protect the embryo against the host, mother host immune system. But it could be a very similar situation, and it would be really smart by the tumors really to use this [ and missing ] now really being able to go away in the eyes of the immune system. And whatever the way is, we just believe that is it breaking down the barrier or just reprogramming the macrophages, which are known to be very plastic. That should help really to activate the immune system. Eric, next one.

Yes. So there's 1 about thoughts on why bex worked in certain tumor types and not others as part of the original 10 different tumor types that were studied in the MATINS trial.

This will be most likely guessing who -- Juho, you would like to guess?

Yes. Well, for example, if we take pancreatic cancer, which is very difficult, it seems to be for everybody. There, I think the issue would be getting penetration to the tumor as pancreatic cancer is known to have a [ byproduct ] surface to some extent. And then also when they come onto the trial, they have a 3-week washout period without any drugs, and then we already see that the growth of the tumor is accelerating, and then it's very hard to hold it back with bex alone after it's really started progressing. And I think this is the issue with, for example, then we go to [ UL ] melanoma, similar issues. It's a rapidly progressive disease, even though it's known to have high CLEVER amounts. These were highly advanced with liver metastasis and again perhaps penetration issues for T cells into these liver metastasis, which is a known problem for IO therapies.

Marie-Louise, would you like to add anything?

Did you say me?

Marie-Louise.

Oh, sorry.

I will pass it to Tyler. Go ahead, Tyler.

No, I agree with what's been said. The really -- the numbers aren't big enough yet. There's so much variability, and there's been so many times where we've seen a really exceptional response in one patient with one kind of cancer in the early phase trials that I've been involved in that I think it's just really too early to make any clear predictions. I'm hoping we can learn from those responders, but there's nothing we've learned yet that would be conclusive.

Thank you.

So the next one is really around dosing frequency. You're looking for data on dosing frequency for submission to the FDA. What doses are now being tested? And what range of frequencies and on how many patients?

Marie-Louise?

Yes. So that's a good question. The dose that we moved into, the Part II, is 1 mg per kg, 1 milligram per kilogram every 3 weeks. We are testing weekly dosing. We are testing 2 weekly dosing, and the dosing range is from 1 to 10 up to certain mix. We are testing about -- we want to have data from 5 to 10 patients for each dosing regimen to be able to compare properly.

Thank you.

And then there were a couple about sort of potential regulatory milestones, one of which is with discussions happening with the FDA later this year, do you expect a single clinical trial to be sufficient for approval. Or are multiple trials likely to be required?

Marie-Louise?

Yes. So the way I would tackle this is that we would -- I think that with the current data, we would need to have a randomized study. I would define a study that is a Phase II study that can be turned into a Phase III pivotal trial. So I would say that one study is needed, but it will be quite big. It would be comprehensive.

And then the next is are there any thoughts or potential synergy between tumor antigens with CLEVER-1 and other antigens to prevent the "hide me" signal?

Well, that's a good one. Maija, what is your prediction?

I think it depends on the tumor microenvironment per se, so depending on the antigen load. Of course, not necessarily one needs to have. But what we have seen and observed with bexmarilimab treatment is that it can change how the antigens are presented on the macrophage, and so we can support the variability on the presenting peptide on MHCs. So I believe that it has kind of a broader spectrum on how we can ignite the immune system. And we have tested similar other macrophage targeting therapies in our tumor models that I explained previously for these patients around explant cultures. And we have tested, for example, anti-CD47, which is a "don't eat me" signal igniter. And it seems that it has also common mechanisms or we see similar effects with that compared to bexmarilimab, but we also have another signature, which we get only with bexmarilimab. So I think this is quite promising in a way that we can also give additional macrophage signals to the immune system that, for example, the "don't eat me" signal will not give.

Thank you.

Yes, if I could add to that because I see a question also on CD47 and leukemia and goes a bit with antigen presentation, and the question is, is it a competitor. How do we feel about it? It's actually -- to us, it's not a direct competitor. It's -- they could be very synergistic with together because anti-CD47 allows cancer cells to be eaten and then bexmarilimab allows cancer cells to be presented. So in that way, they could be very synergistic, not competitive with each other. And that's actually a possible future combination we have some early discussions of.

Thank you.

So maybe another quick one for Maija. So what's the benefit of changing converting macrophages from M2 to M1 as opposed to killing them?

So what we have observed from our mouse studies is that if we have a conversion with CLEVER-1 in our animal model but then we deplete the macrophages, we can actually increase tumor growth. So the macrophages that are converted with blocking CLEVER-1, they become M1 supporting antitumor responses. And if you deplete those macrophages, they cannot actually help the tumor. This means that then you can get tumor overgrowth. So I think in the macrophage population, there are beneficial macrophages that we need to support antitumor responses. And if we go and deplete all of them, then it's a bad thing. And for depleting the macrophages in our animal models, we use anti-CSFR1 (sic) [ anti-CSF1R ], which is also clinically tested and hasn't been very beneficial as monotherapy, and that's actually, in our models, depleted the macrophages totally. So then we can really see that there is a beneficial population for these antitumor responses.

Thank you.

Yes. Another quick one here, which is, as you noted in PD-1 trials, an immune active tumor microenvironment has been associated with response. How closely does the magnitude of the bex response bring it in line with this immune-activated tumor microenvironment?

I think actually quite nicely. So I think in our animal models that we see also when we have treated bexmarilimab or the surrogate antibody for CLEVER-1 together with anti-PD-1, in those tumors that are not responsive to anti-PD-1 alone, the anti-CLEVER addition can really support the infiltration of CD8 T cells and ignite the immune response. So I think it is synergistic also in combination and can turn the tumor microenvironment with signals that are needed for them to become responsive for anti-PD-1 therapy.

Okay. And then maybe one for Juho or Markku. So Faron has at least 3 bexmarilimab-related patents published but not yet granted. Any update on this? And what would be the meaning of those patents being granted to the treatment opportunities?

I can start with the -- with older ones. The key patent that is really protecting the epitope binding of an antibody, meaning that it also should prevent any biosimilars to come into the market, has been accepted in U.S. We have other ones later from Europe. It will be soon. We'll print it out. We have patent in Japan, in South Korea and is looking good also in China and then some additional territories. That now runs up to 2037, and there is a possibility even extend that even further. So we believe that we have very good protection for the antibody itself. Then Juho can explore a little bit further what kind of other filings we have done during the recent last 2 years. Not all of them have been published yet. But just to give an idea, how much we have really spent time to look at the mechanism and try to protect everything we discover out of that research.

Yes. As Markku highlighted, the key patent has been granted. That's the composition of matter patent, which also refers to the epitope where bexmarilimab binds to because you can have a lot of anti-CLEVER antibodies, but depending on where they bind to on CLEVER-1, they have different actions and different functions. So that's why the most important patent is well in the bank, so to say. These additional patents that's -- as we generate a lot of data, a lot of science, we try to patent the field as proactively as we can. These are not that way the published patent applications, which haven't been granted. They are not that important. But we, of course, we wish to, I would say, mine the field as much as we can before competitors eventually will come into this space. But hopefully, we'll have everything covered by that.

Yes. And Juho, just a follow-up for you, unrelated to that one. But there -- any news to share in terms of potential partnerships or discussions, ongoing discussions with big pharma in terms of helping drive the, in particular, combination opportunities forward?

Yes, these are always discussions we are constantly having and juggling on when the time is right. For us now having Marie-Louise, for example, onboard and real oncology drug development experience, we really would want to take this to the next bigger value inflection, which would be Phase II data because it's a whole different ballgame for us as a company, partnering them instead of now. But that's a constant discussion and balance we have, and I see there was a question on funding and licensing, when to do it, but that's a constant struggle and discussion we have. But we have the ambition to take this a bit further maybe even to the end, but we'll see.

And then this one came in a couple of times. So assuming everything goes as planned, when would be the earliest possible time that bex could be to market?

That is so much data driven. It's kind of difficult really to estimate.

Well, maybe I can add into that. The combo studies that are now beginning with -- in AML with aza and venetoclax and also then the anti-PD-1 combo studies, they can bring that significant value. Inflection -- significant responses is seen in those studies. They can really rapidly take us into that direction. Again, it will be dependent on the data. Can't really give you time lines. But single agent last line is going to be dependent on survival data, which is, again, it takes a bit longer, generating that survival data. But the studies Marie-Louise has brought together and brought to you today, they look very exciting to me.

So maybe one for you, Markku or Juho. What are your thoughts to increase presence or personnel in the U.S. to drive these studies forward? And what size of the organization in the U.S. or globally do you anticipate there being at this point next year?

It's very important for us that we get more close to the sites, we get more close to the regulators and also to the commercial markets. And we anticipate a year from now, maybe to have 5 to 10 people. We already have a location in Boston and obviously are really keen to grow that to a unit that actually could really coordinate the activities on the U.S. side. Having said that, obviously, the -- one of the reasons we have now Chief Operating Officer is really to coordinate also the whole activities at the company, also including we do in Europe. So really planning to really grow the company so that the operations are global.

That covers all of the questions that have come in through the chat function. So I think unless there's any others that come in, that would do it.

All right. Well, thank you, all the speakers, the audience also. I would like to just really give this final summary. I believe that bexmarilimab is really excellent candidate really to improve the future of immunotherapies. So we already have a clinical benefit zone, especially rather high in some of the indications I already discussed today. That, with the fact that we have a well-tolerated cancer treatment, which is not really often the case, it's actually the opposite, we believe that, that combination with the biomarker could really push us to the direction where we really would please the regulators to approve, the marketing approval as well. And having this safe profile, we believe that the combinations are much more easy to do, and that's what we have discussed already. And if we can really ignite the immune activation in those patients who have a cold tumor, they could then become responsive to PD-1 blockade. So obviously, that is a very important avenue to follow. And we do have very ambitious, really, goals for this year, and we are hiring more people and competent people really to move on and execute those goals we have this year. So with this, I thank you all being with us today. We'll let you know when we have additional information really to provide and looking forward to have maybe another R&D Day also on our other target molecules. Thank you again. Bye now.