Faron Pharmaceuticals Oy (FARN) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to the Key Opinion Leader Webinar on the potential of CLEVER-1 as a target for macrophage-guided immunotherapy hosted by Faron. [Operator Instructions] I will now hand over to the CEO of Faron, Dr. Markku Jalkanen to open the presentation. Please go ahead.

Good day, everyone. Thank you for joining us for this Faron webinar on CLEVER-1. I'm extremely pleased to have Dr. Maija Hollmén, who is one of the key opinion leaders in this field. She is an adjunct professor of Turku University in the immunobiology program and she's really expert at talking to CLEVER-1. Before we move on there, I want to remind you that we do have forward-looking statements, and this is really our disclaimer. To remind you, the antibody we have against the CLEVER-1, which is the function of blocking antibody bexmarilimab, we call often bex, is a very unique antibody being able to control the function of CLEVER-1. Bexmarilimab has already shown a single-agent activity in hard-to-treat solid cancers in condition where the patients have no options anymore. It has a very good safety and opportunity really to transform the current treatments and having a proprietary molecule up to 2037 really provides us to bring up a very interesting new treatments for these serious unmet medical needs we are dealing with on a daily basis. With that, I would like to now give the word to Dr. Maija Hollmén.

Hello to everybody. My name is Maija Hollmén, and I come from the University of Turku. And I would want to tell you today about a macrophage-targeted immunotherapy, the clinical development of bexmarilimab. My group has long been interested in studying how macrophages can be utilized to support antitumor responses of the immune system. And while we appreciate the high significance, the immune checkpoint blockage therapies have brought to the clinical cancer care, they only work to a subpopulation of patients and the majority of patients still lack benefit from the treatment. And therefore, we have to find better ways on how we can educate and support our immune responses to kill cancer. Macrophages are very important cells for our well-being, the scavenge pathogens and phagocytized apoptotic cells to maintain tissue tolerance. The cell type was highlighted in nature in their issue where they called macrophages a cell for all seasons. And I think this is a very nice description for these cells because they can perform so many functions and are very plastic. The problem arises of these cells in the tumor setting. So you can appreciate here a tumor microarray specimen that was sustained for CD68, which is a common macrophage marker. And you see the high abundance of these cells within the tumor border here. Normally, what is known nowadays is that these macrophages in the tumor side represent these into like macrophages that promote angiogenesis, support metastases or cancer cells and also suppress immune reactions toward cancer cells. These TAM-like macrophages or M2-like macrophages have immunosuppressive molecule expression, which are listed here. And these different molecules can dampen T cell responses against tumors. And the ideal situation would be that these macrophages could be reeducated as to support more of this M1-like phenotype, which is a pro-inflammatory phenotype that can activate T cells to antitumor responses and also support other immune-related functions and prevent cancer growth. Nowadays, there are many aspects how these myeloid cells could be used or utilized for immuno-oncology treatments. And what is currently under investigation is targets that can promote the depletion of macrophages, prevent their trafficking to tissues, stimulate their pro-tumor -- antitumoral functions or repolarize their M2-like phenotype towards this M1 phenotype. I have listed here the vast majority of these targets, which are currently under clinical investigation. You can see here that the macrophage colony-stimulating factor is the most investigated target. But there are many other stimuli, for example, this toll-like receptor 9 and 7 and 8 and 4 that promote these pro-inflammatory functions on macrophages. I have to emphasize here, though, that while these are very potent immuno stimuli, they are not that specific for only macrophages and they can induce a lot of side effects. For example, the STING agonist has to be injected directly into the tumor because of its vast majority of side effects. My group has a long history on investigating this CLEVER-1 molecule, which is a multifunctional scavenger and adhesion receptor expressed on immunosuppressive macrophage populations. Actually, the CLEVER name comes from common lymphatic endothelial and vascular endothelial receptor, which is also known as Stabilin-1 and FEEL-1. It's expressed, as I said, in a subpopulation of immunosuppressive macrophages where it induces tissue tolerance, resolution of inflammation and immunosuppression. It also regulates tissue homeostasis by scavenging bacteria, apoptotic cells and endogenous substances. It is also expressed on lymphatic endothelial cells and some specialized vascular endothelial cells such as liver sinusoids, spleen sinusoids and bone marrow sinusoids. On endothelial cells, CLEVER regulates the trafficking of leukocytes and lymphocytes within tissues, but it also regulates cancer cell metastasis to the lymph nodes. And on the liver, it can scavenge endogenous substances. Because CLEVER is expressed both on the vascular endothelial cells, lymphatic endothelial cells and macrophage subsets, we wanted to investigate which component was actually regulating the cancer growth impairment that was observed in 2014 in cancer research -- Clinical Cancer Research paper coauthored by [ Marika Karikoski ]. So we went further on to investigate the activation of CLEVER-1 on tumor growth retardation in mice that were either full CLEVER knockout mice, or then we utilized this macrophage specific CLEVER depletion by cross-breeding lysozyme 2-Cre mice with CLEVER floxed mice. And we implanted tumors who is on carcinoma tumors and triple-negative breast cancer tumors into these different mice strains and noticed that when we implanted these tumors into these macrophage depleted CLEVER mice, we could see that they cannot grow tumors at all compared to the full knockout mice that had some impairment in tumor growth, but that was not as dramatic as we see in both of these syngeneic tumor models. We wanted to investigate this more, so we looked at what was happening in the tumor site within these animals. And as you can appreciate here, we see a high infiltration of CD3 positive T cells into the tumor area. And these T cells were confirmed to be CD8 T cells by flow cytometric analysis. The CLEVER full knockout mice had a bit similar phenotype, so they increased the CD3 infiltration. But I have to mention here that, as I said earlier, that the vascular endothelial cells can regulate the trafficking of lymphocytes and leukocytes within different tissues, it might be that the impairment of CLEVER on vascular endothelium is also regulating to some extent the infiltration of these CD3 cells to the issue and, therefore, we see quite a decrease in those in this setting. So we next asked the question, how does CLEVER-1 targeting improve cytotoxic T-cell responses? And as we know, CLEVER is expressed on these immunosuppressive M2-like cells and they are known to have very poor antigen presentation. And the idea would be that we could educate these cells more to this M1 phenotype that will support antigen presentation to a similar extent, for example, with dendritic cells that are very high efficient antigen-presenting cells, which can educate T cells and induce clonal expansion of T cells, as shown in this schematic. When we looked at these tumor-associated macrophages in wild type and CLEVER knockout mice, there was a significant change in the fluoridation of these TAMs within these CLEVER knockout mice, shown here in green. So in the original setting in the wild-type mice, you see the majority of the cells being MHC Class low, so these M2-like TAMs, which are shown red in this quantification. Whereas in the CLEVER knockout mice, you see that there is a shift towards this MHC Class high cells, and you see a reduction of these M2-like TAMs. And interestingly, what is known about dendritic cells compared to these M2 macrophages is that they have a prolonged impairment in their antigen processing and presentation machineries. So when they phagocytize different antigens, they have a longer time to promote antigen processing and loading on MHC. So this is much more efficient, whereas the M2 macrophages very rapidly take the scavenge antigen inside the cell and are degraded and are not loaded on MHC molecules. So we wanted to look more deeply into what was happening inside the cell to understand how was CLEVER targeting regulating this antigen processing and presentation. So we utilized human primary macrophages that were into polarized, and we fed 2 different antibodies targeting CLEVER-1 to these cells. The other antibody was this 9-11 antibody, which finds this EGF like domain on CLEVER-1 intracellular domain. And we used this FP-1305, which is now under clinical investigation that binds the fascin in 1 domain. We directly conjugated these with different fluorochromes shown here and then we incubated these either 5 minutes or 2 hours on these macrophages. And as you can see here, the antibodies, both of them were very rapidly internalized within 5 minutes within this macrophage. And after 2 hours, we then quantify the colocalization of these 2 antibodies within these endosomal vesicles. What we could notice was that there was colocalization indicated by these white dots here, but there were some compartments that were devoid of either one of the antibody. So that prompted us to investigate where these antibodies were going and what proteins did CLEVER interact with because they were located in different areas in the macrophage. We did this antibody pull-down assays and analyzed all the proteins that were pulled down with these with mass spec analysis. Interestingly, there were only 22 common proteins that were precipitated with both antibodies, whereas either one of the antibodies produced the specific protein interacto. To see what the proteins were, we visualized them in this map and you can see here that the yellow ones within this inner circle were precipitated with FP-1305 and the outer circle with green were precipitated with 9-11. And we have highlighted this vacuolar ATPase complex proteins here that were only precipitated with 9-11. These results were confirmed with Western blot analysis by showing the pull down of these ATPase protein complex units by 9-11. And we looked at what were these proteins then mediating and what effects they had by Ingenuity Pathway Analysis. And what these proteins actually do in the macrophage is that they are regulating phagosome maturation, iron homeostasis and autophagy, for example, whereas the FP-1305 proteins were regulating mostly mTOR signaling cascade. So what we think is actually occurring here that when the VATPase complex unit is binding to this location here, FP-1305 can no longer bind and that's why we cannot precipitate these proteins by FP-1305 but only with 9-11. And so we tested this because this vacuolar ATPase is regulating the acidification of these phagolysosomes. We wanted to test whether FP-1305 can impair these effects. So we used these lysosomes for fluorescence probe, which measures how acidic are these endosomal compartments inside the cell. And after 4 hours of 9-11 or FP treatment of primary human macrophages, we see that there is a transient actually decrease in acidic environment. But after 24 hours, the acidification is totally impaired and actually reversed by FP-1305 but not with 9-11. This prompted us to investigate more of this vacuolar ATPase's activity and cross-presentation. So vacuolar ATPase is a huge protein complex that acidifies the lysosomes by this proton pump function. And as I mentioned previously, this acidification of these phagosomes really much depends how well these antigens are cross-presented to the surface by MHC peptide complexes. And in dendritic cells, this process is prolonged, so that these are efficiently loaded on MHC and presented. So to test this idea, we did this mixed leucocyte reaction by using macrophages from one donor and T cells from another donor and incubated them together, and there should be an MHC Class II -- I mismatch between these different donors, which results in T cell activation and proliferation. And this we can measure by cell tracker dilution of these T cells shown here. So when these T cells are -- CD8 T cells are incubated with a positive control, so anti-CD3, anti-CD28 antibodies and IL-2, we can see that the cell tracker is diluted by this proliferation, whereas negative control for FP treatment, there is no dilution and so the T cells are not proliferation. When we quantify this proliferation by these different treatments, so this was our positive control. And then we tested the capability of M1 macrophages, which were polarized with LP as an interferon gamma to support T cell activation. And we see here nicely that these M1 macrophages can also induce T cell proliferation in this mixed leukocyte reaction. Here, you also see nicely that the M2 macrophages do not support T cell activation as well as M1s. And then we treated these M2 macrophages with these different antibodies. So IgG2a and IgG4 serve as isotype controls for 9-11 and FP-1305. And here, you can see that only FP-1305 treatment can induce the T cell proliferation, but not 9-11. So it's really much dependent on what epitope you target on CLEVER-1 to get this function. We utilized also mouse to look at the antigen presentation of a known antigen. We took bone marrow-derived macrophages, differentiated them with mCSF and then polarized them by using Lewis lung carcinoma medium to make them more tumor-associated macrophage like. And then we fed these TAMs either SIINFEKL peptide, the ovalbumin protein or then cancer cells that are expressing ovalbumin, but they were irradiated to be scavenged by these macrophages. And in all of the situations that we looked, we see a higher cross-presentation of these ovalbumin peptide on MHC, which was recognized by flow cytometry using this antibody that binds specifically to this MHC SIINFEKL peptide complex. So it clearly shows that these TAMs when they lack CLEVER-1, they can have higher cross-presentation and T cell activation. I just want to go back into the historic moments of how this currently is anti-CLEVER antibody that is in clinical development, how its investigation started. And the idea with Sirpa Jalkanen was back in 2000 -- early 2000 was that she wanted to identify and discover new molecules that were regulating cell trafficking within lymph nodes. So she used human lymph nodes and did enrichment of lymphatic vessels from these lymph nodes in immunized mice with this lysate. She collected B cells from these immunized mice and made hybridomas to search for antibodies that were specifically binding to these lymphatic vessels within these human lymph nodes. They discovered this molecule that was really nicely binding to the lymphatic endothelial cells in the lymph nodes also to high endothelial venues. This antibody was named 3-372. And they figured out by investigations that this was a CLEVER protein and they named it the common lymphatic vascular and endothelial receptor. At the same time, there were 2 other groups, 1 in Germany and 1 in Korea, who also did this quite similar reporting of a scavenger receptor. That Korean Group named FEEL-1 and the German group named Stabilin-1, and that's why it has 3 names. And they were all noticed that they were investigating the same receptor. So Sirpa Jalkanen continued to investigate this receptor on the lymphatic and vascular endothelium, and they utilized this antibody in functional assays. Whereas these 2 groups more looked at the macrophage expression of this molecule and investigated that. So this continued further. So this was 2003 where this cancer research paper was reporting this new discovery of CLEVER-1. And they found out also that CLEVER-1 regulates the binding of cancer cells to lymphatic endothelium. So it will be a good strategy to also prevent metastases of cancer cells via targeting CLEVER-1. At 2007, Faron came along as a university spin of company, and they started developing this 372 antibody for clinical use. So first, they did a humanization and deimmunization with Antitope. So they changed the mouse IgG1 to human IgG4. The only part that remained mouse is the complement determining regions here and the backbone was humanized for human IgG4. And I have to emphasize here why we did a human IgG4 is that because CLEVER is expressed on also the endothelial cells. We don't want to induce any effector function, so human IgG4 has least effects on those. And then it was mutated even once more to get very low amount of binding to these Fc gamma receptors on macrophages, for example. This antibody, which is called FP-1305 or bexmarilimab in this case, has now proceeded to clinical investigation. And here is the clinical strategy plan of the trial where we first have this Part I dose finding where we used 4 different doses in melanoma, pancreatic ductal adenocarcinoma, ovarian cancer, colorectal carcinoma and hepatobiliary cancers to investigate the safety and tolerability and preliminary efficacy of bexmarilimab. After completing this, we are now in Part II expansion, where we have started the different efficacy effects on these different cancer types. And from these cancer types where we see a positive signal, we go further and expand these specific cohorts for the Part III expansion study. I will tell you now results that we have from the Part I dose-finding study. The study sites that we currently have are listed here. And the one, the study sites that were among the ones that performed the Part I are listed here in red. So these study sites participated in correcting patients and treating patients for this dose escalation Part I. And the study design was so that we started with 0.3 milligrams per kilogram and gave the first subject, the first cycle of the treatment. So each cycle was 3 weeks apart. And if no effects were seen for the first patient, we could then dose the second patient. And we were monitoring these patients for 9 weeks to look for any dose-related toxicity in these patients. If we didn't see any, we could proceed to the next study dose and continue from those. And as you can appreciate here, this takes some time to enroll all these patients and get a sufficient amount of data to indicate whether there was a maximum tolerated dose obtained or not. And I have to say here that with the 10 milligrams per kilogram, we didn't see any -- or we didn't reach maximum tolerated dose. These results from the Part I have been recently published in Clinical Cancer Research, and I will show you a brief sum-up of these results. So the first thing we wanted to do in these math inspirations that were recruited to the dose escalation part was that it's known that human circulating monocytes have high expression of CLEVER-1. So that's our first target where the antibody is binding. And therefore, we wanted to see how these monocytes were reacting to the treatment. You can appreciate here that after 1 week on treatment, there is an increase in side scatter and forward scatter of these monocytes in the circulation. So this is circulating monocytes. And there is also a transient down-regulation of CD14 on these monocytes. CLEVER levels did not dramatically reduce by the treatment and the monocytes were not depleted, which indicates that the IgG4 antibody is not inducing effector functions on these cells. Whereas the receptor occupancy, which was measured by the fluorescently-conjugated FP-1305 antibody ex vivo indicates that there is a good occupancy, but it's rather transient and gets back to normal or even increases after a certain period of time. But you have to, of course, remember that we are searching for the dose at that point and these dosing levels might not be optimal to reach full receptor occupancy, for example. We -- RNA sequence, the CD14 monocytes from the circulation to more broadly investigate what was occurring in these cells and we could identify that there was a decrease in LXR and RXR activation pathway and the PPAR signaling pathways, which indicate to us that FP-1305 was down-regulating the scavenging function of CLEVER-1 because it's known that FP-1305 can book the scavenging of acetylated LDL, which is this lipid related pathways that are down-regulated. We also wanted to look how well our therapy was inducing adaptive immune reactions in the patients. So we measured first the circulating levels of NK cells, CD8 T cells, CD4 cells and the regulatory T cells and B cells. And what we could clearly see is that after 1 cycle, so this is the maximum change during cycle 1 of these different lymphocyte subsets that as FP-1305 was able to increase the levels of NK cells and CD8 T cells in the circulation and reduce the levels of regulatory T cells. If we look more closely, and this is now mass cytometry data of circulating T cells, we could identify 22 different immune T cell populations within the MATINS patients. You can see here CD4 T cell cluster and here CD8 T cell cluster. And these are the identified different T cell subsets here. If we look now, what were the molecules that were changing on these T cells after 1 week on treatment. There is a clear induction of T cell activation indicated by CD25, CXCR3 and CD69 increased expression. Whereas we could also detect a down-regulation of negative checkpoint molecules on CD4 T cells, which is a very promising feature that we can lower the levels of these negative regulators on their circulating T cells. During the MATINS Part I trial, there was a colorectal carcinoma patient with microsatellite stable disease that had a very nice benefit from the drug. So here you can see her CT scans at predose and you appreciate the metastatic lesions in the lungs and in the lung -- lymph nodes here. And after 30 weeks on treatment, these lesions almost disappeared. Here is the quantification of the lesion size during the treatment. This patient also got some autoimmune reactions during the treatment, and that's why she had to be put on corticosteroids and, therefore, she discontinued the treatment. Her surgical biopsy was highly infiltrated with CLEVER positive macrophages. They were also CD163 positive indicating for an M2 macrophage population, but she had very low counts of CD8 T cells in her tumor. We wanted to investigate more thoroughly what was actually happening in her CD8 T cell population in the circulation. We were not able to get post-biopsy sample to investigate how the T cells were in the tumor side. But we think that by looking at her circulating CD8 T cells, we could mimic or reason that there was also activation ongoing on those that would then end up in the tumor side. So we did single cell RNA sequencing of her CD8 T cells together with T cell receptor sequencing to identify clonal activation of specific clones during her treatment period. This is showing these UMA plots for CD8 T cell population at predose, which is indicated in this red and at cycle 4, the 2 different time points on cycle 4, which are indicated here in green and blue. And when we look at the granzyme A expression, we see that these cycle 4 T cells had higher granzyme A expression compared to the ones that were found in her circulation at predose. We also noticed a nice appearance of this cell population here, which was TCF7 positive, indicating a stem-like cell type T cell population that is known to be expanding during anti-PD-1 treatment. There was also a clonal expansion of her CD8 T cells of some clones. We can show here, we have highlighted in different colors, the 10 most abundant clones at predose sample. And you can see here that the blue, green and purple or magenta colors are increasing in clonality by cycle 4. Altogether, we have completed Part I 30 patients and the Part II is now ongoing, where we have treated roughly 110 patients altogether. Here, you can see some of the very nice responses we have seen. So here is the colorectal carcinoma that I showed previously. Then there was this cutaneous melanoma patient who got a clearance of her pleural effusion and shrinkage of her metastatic lesion in the lung. And then this ovarian cancer patient whose lesions almost disappeared during the treatment. I have to also say that these patients that we have treated, our last line in therapy, the medicine cannot offer them anything. And still, we get these very nice responses with our drug as monotherapy. For example, this cutaneous melanoma patient had received EP and nivo combo before entering our trial and they did not help. So she was refractory to current immune checkpoint blockage therapy. And the strongest results that we have observed for RECIST criteria, meaning that the disease control rate was partial response plus stable disease. We have seen in cutaneous melanoma, 3 out of 9 patients; gastric cancer, 3 out of 10 patients; cholangiocarcinoma and hepatocarcinoma. So altogether, disease control rate was 31% in this heavily treated metastatic cancer patients just by having monotherapy of anti-CLEVER-1. Here is also a progression-free survival curve in patients that I just showed you in the previous slide, who had partial response or stable disease. And all of them were alive after 6 months of therapy compared to only 30% that did not survive or did not have benefit with CLEVER -- anti-CLEVER therapy. So I have to also say that if you look at these curves in the previous line of therapy that these patients got, they are quite similar. So there is definitely a patient group that is benefiting from targeting CLEVER-1. The million dollar question is, how do we know who will benefit from the drug? Is it the ones that have the highest CLEVER expression in the tumor macrophages? Of course, this is a necessity to have so that we can target these cells. Or is it the CLEVER receptor occupancy so that we could appreciate that patients who have the best receptor occupancy would have the best results? But this is not necessarily the case since there was a publication publishing immunity in 2018, where they showed the immune landscape of cancer. They utilized this TC database, analyzing 33 different cancer types by different means. And they could actually divide all of the cancers regardless of -- in which cancer type they belong to, to these 6 different inflammatory groups listed here, which were wound healing, interferon-gamma dominant, inflammatory, lymphocyte depleted, immunologically quiet and TGF-b dominant. If we now look at CLEVER expression within these different subsets, we can clearly see that in the interferon-gamma dominant tumors, PD-1 expression has a clear survival effect. So the higher the patients have PD-1 expression, the better response they -- or the overall survival they have. Whereas Stabilin, which is the gene name for CLEVER-1, doesn't have any prognostic meaning in these type of cancers. Whereas if we look at the lymphocyte depleted tumors, here, PD-L1 expression doesn't have any significant effect on the overall survival. Where as Stabilin-1, the patients who have higher Stabilin expression have significantly poor prognosis. So are these the types that we should actually be targeting? We went back to our MATINS trial data. We measured the interferon gamma and CXCL10 levels in the circulation and saw that actually, there was -- in 7 out of 30 patients, there was a twofold increase in interferon-gamma levels by 2 weeks on treatment and 6 out of 30 patients increased also on CXCL10. Here is the area under curve for the different doses at cycle 1 of these changes in interferon gamma and there was no relation to the dose of this increase in the cytokines. But what we actually noticed was by doing this linear regression analysis was that the patients who had the lowest baseline levels of interferon gamma and CXCL10 had the highest increase of these cytokines within these few weeks on treatment. This would indicate that the ones that get the most benefit are the ones that have no underlying inflammatory reactions, and they are suppressed patients. We did an analysis of our hypothesis by utilizing the predose sample of our patients where we enriched the PBMCs, so peripheral blood mononuclear cells, and either treated these cells with LPS or without LPS and compared the full change of LPS in these cytokines within the predose sample and 24-hour sample after treating the patients with FP-1305. And interestingly, let's look at this patient #10, for example, that at predose, her PBMCs were not that responsive to LPS. You can see here that the cytokine levels are not that dramatically increased by LPS treatment. Whereas this 24-hour sample posttreatment induced high secretion of interferon alpha and beta in these patients tested, indicating to us that we can reinvigorate these patients' responses to pro-inflammatory stimuli. So the playground now where we are at is that we don't necessarily want to treat hot tumors because they have an underlying inflammatory response. And there, we don't see any benefit from adding bexmarilimab treatment. Whereas we target the cold tumors, which are known to have high amounts of M2 macrophages and exposed to T cells or no T cells at all. And we want to convert these cold tumors to hot tumors by activating their antigen or immune responses again, which would also help by inducing combination treatments of anti-PD-1 and anti-CLEVER, for example, in future clinical trials. In the end, I want to acknowledge my lab. This team has performed really, really well, and they had started CLEVER actions very broadly in macrophages and in lymphatic endothelial cells. I also want to acknowledge the funding sources and the Cancer IO consortium and InFLAMES flagship where I'm currently a principal investigator. I just want to leave you with this message, so keep calm and think CLEVER, and I'm happy to take questions. Thank you very much for your attention.

Thank you, Dr. Hollmén. Really great presentation. Thank you very much. It's really clear from the science and the slides that CLEVER-1 really has a role in the control of the tumor growth and the metastasis. We are extremely interested in really learning more about the molecular mechanisms. But even more interested, we are in the data what we already have obtained from the MATINS trial, which is becoming a platform from us. In that group, we already have had 10 different cancer cohorts tested and some of them are really showing very interesting results. As Dr. Hollmén already presented, the overall survival rate is significantly increased in those patients who are responding to the treatment. You can see some of these groups on the left-hand side, especially many of them we have seen in the gastric cancer, cholangiocarcinoma and in melanoma. And keep in mind that these patients have no options anymore for any other treatments. So these patients have a clinical benefit observed already in a stabilized tumor growth or already shrinking tumor, which is a clear also in many of the diseased lesions obtained from these patients. So having early efficacy benefit like so seen here, we also have a very good safety profile as shown on the right-hand side. The patients, roughly 140, we have very few treatment-related adverse events. Grade III and IV, nonexisting; Grade I and II, nonexisting. And this is totally unusual for current other immuno-oncology treatments. So we are really making a good progress with all these findings, and we accumulate additional data while I speak here. Then on top of it, we have some significant plans to move on. We want to take a gastric melanoma and cholangiocarcinoma to the pivotal space. That means that we go back to the regulators, especially to FDA, towards the end of this year to really ask what size of the trials are needed in order to get a conditional permission. And that size could be within the hundreds, maybe less than 100 depending on this response rate. But if we get continuously the same result, having a 3 out of 4 or more, that is a very favorable position also in the eyes of the regulators. We also would like to continue with the additional trials. Those are a neoadjuvant study in a colorectal group and renal carcinoma. A lung combination with the PD-1 in the first line. This is a very exciting clinical trial setup as well. And then very first hematological malignancy and that is a acute myeloid leukemia. The reason why we are there is very simple to the myeloid background of these cells. They do express CLEVER-1, and that is a very important really learn to control in those patients. With this, we already have produced a very exciting data this year. We started with a 3-week interval dosing. We are increasing that and also making combination with increased dose and increased frequency. That data will come later on this year. With that data, we will move on and have a meeting with FDA in order to really design the pivotal stage. This all means that towards the end of this year and early next year, we would be really ready to expand these key cohorts into the pivotal stage. And that would make us a very interesting move towards the market as well. All this, we just believe that the bexmarilimab will have a very transformative power to really bring in additional treatment efficacy to our existing treatments, but maybe also look for brand new ones. So with all of these, I really would like to now stop here and allow people to have questions and turn back to the operator.

[Operator Instructions] Okay. You do have an audio question and your first question comes from the line of Miles Dixon from Peel Hunt.

I guess my first question, just to clear, summing up on the receptor occupancy versus expression, can you confirm that it is actually an upregulation of the receptor in tumor-associated macrophages rather than just seeing a much greater volume of co-opted MTs in the tumor?

That's still under the analysis because not all the patients have completely analyzed to the point where we can draw a final conclusion. Maija, would you like to comment on this occupancy question as well?

So occupancy was measured from circulating monocytes because it was impossible to measure from the tumor side itself. And so what we think is that the occupancy depends, of course, on the dose, but there are other sources where CLEVER can bind or the antibody can bind and, therefore, it can somehow regulate how much we see occupancy on the monocyte subsets compared to, for example, if it's binding to the endothelial cell compartment, which is taking up the antibody. So we -- I think we just have to figure out still the dose and the optimal receptor occupancy, meaning that do we need 100% receptor occupancy to get the results that we need for immune activation, for example. And I have to also note that the antibody is very efficiently taken inside the monocyte. So the occupancy there might be prolonged compared to what we see on the cell surface because this is done on the cell surface itself and on the molecules that are on the cell surface.

Great. And if I can just ask one more. You've mentioned that somewhere in the middle of your presentation around the other kind of TAM targeting strategies that haven't necessarily worked, whether it be depletion or recruitment. On the other available proposed therapies, if you like, for repolarization, whether that be PI3 kinase inhibitors or such like. Is one of the reasons that they're not so good is because largely they're the repurposed drugs from other indications?

Right. And not only that, we are looking at a very specific population of these macrophages, which are only CLEVER-1 positive. If you start to remove all the macrophages just having a general effect on them, you actually may run into a problem that you reduced the spending capacity of our immune system and cause more damage than benefits related to these patients. So the unique role and expression pattern of CLEVER-1 is really favoring us really to produce the results. That's our opinion.

Great. And then just one last one, if I may. The soluble CLEVER-1 is particularly interesting. What's your perspective on what the source might be from the CLEVER-1? Do you think it's almost entirely from tumor-associated macrophages? Or do you think it's upregulation as for other tissue as in the macrophages, too?

We obviously first thought that it's only macrophages, but then when you start to look at some of the tumors, they built this very special venues, which have endothelial cells, which are also positive for CLEVER-1. So is this so performed really backed by the tumor themselves and put in the circulation is a very interesting idea. And obviously, we are really keen to learn that. Anyway, we have learned that if you have this soluble CLEVER-1 around, it can directly control the activation of the T cells. That would be a marvelous tool for a tumor to reduce the immune capacity also in the remote locations and that would aid the metastasis activity of the tumor. So very interesting battlefield for us really. And every day, we learn more. And that's the reason why this project is so TAM exciting.

Okay. There are no further questions on the conference line. I will now hand over to the presentation to the management team for written questions.

This is Eric Van Zanten. This is primarily, I guess, for Dr. Hollmén. There was a question that came in and said, you talked about targeting cold tumors and what you often see with cold tumors is lack of infiltration of CD8 into the tumor. How can we know if that increases infiltration and not just accumulation of CD8 outside the tumor?

Maija, do you want to take that one?

Yes. So we don't know that surely about it, but in some patients where we could obtain pre and post biopsy pairs, we could see that the peritumoral T cells were infiltrating the tumor bed, and they were both granzyme B positive. So to us, it would indicate that these CD8 T cells are in some patients getting inside the tumor and doing their job killing the tumor cells. So I don't think -- I think we just need to find the right patients where we can induce this indication. But I, of course, can see that it's not in all patients where we see this response.

All right. So I have one -- a couple of others that came in. Is there a biomarker for CLEVER-1? And if so, do you have a biomarker strategy for the MATINS trial?

That is very important to learn if we can really enrich the population and learn to understand what it really requires to get this clinical benefit after bexmarilimab administration. That is ongoing, and I'm assuming that now we have the group populations large enough really to get a better understanding is the soluble CLEVER-1 a good marker or do we need to add that in combination with some other biomarkers. We have some thoughts over there, but we need to confirm that. And I'm very looking forward to learn more about that. And as soon as we have learned, we definitely will tell that story to the rest of the world as well.

All right. So here's one, and I guess this is going to be your best guess, but so 31% response rate for the cancer types you mentioned as the last line of treatment is really impressive. But what sort of success rate do you think you'd have if it was a first-line treatment?

Yes, I will guess now like you said. We are now treating patients who have gone through maybe up to 6, 7 lines of treatments. Many of them have been chemo treatments, and those are known to really reduce the immune capacity of those patients. They often also receive a cortico -- dexamethasone or corticosteroids. And that's reduced the immune capacity even further. Our bet is that if we can climb up earlier with these patients first or second line, their immune system would be more intact at that time. And our capacities definitely would be better. What would be the most optimal combination? You can think many of them by class. You could combine maybe with the anti-kinase, anti-TGF, anti-PD-L1. But we just need to move on and get that understanding from the clinical data what we are obtaining now and especially in the future.

All right. And one more. How should we be thinking about the competitive landscape? Why isn't anyone else looking at CLEVER-1? And if they are, why haven't we heard as much about it?

Well, from time to time, there are some unusual discoveries. People may really have difficulties to take it immediately. And this scavenger nature of CLEVER-1 probably has prevented the other companies really to focus on that. Having said that, we know that this field is just activating itself really tremendously at the moment. We do have a very good proprietary position for CLEVER-1 as I have indicated, and the latest one was really to get the coverage for the CLEVER-1 Antitope and the bexmarilimab side that will last almost 2 decades. And that is really important for us because that actually should keep out all the biosimilar development. Would there be some additional target molecules on surface of the macrophages? I'm pretty sure that people are looking for those. And this is now recognized with big pharma as well, just looking at the commercial IDs closed during the last 12 months or so.

Okay. Those were the questions we have received through the e-mail.

Thank you very much for those questions, and I'm very thankful and thank you for joining us and especially Dr. Hollmén, having her presentation, which was really great. Hopefully, we'll convince that the science behind this CLEVER-1 project is really important one, and we are really looking forward to provide additional data as we can be able to cater that. Thank you very much and looking forward...

Dr. Jalkanen, there seems to be one additional audio question in line. If you can wait for a minute.

I can wait. Absolutely.

Okay. Yes, a question has just come in from Julie Simmonds from Panmure Gordon.

I was just wondering, with the different expression that you see in CLEVER-1 in the various different cancer types, how do you think -- do you think you're going to end up needing different dosing for different cancer types because of the sort of situation as far as the CLEVER-1 expression is concerned? Or do you think you'll be able to find one that works consistently for all of them?

I have a feeling that we may end up of having even different dosing. And this CLEVER-1 may be also indicating that the immune type that is controlling that tumor may vary, and it's not necessarily disease specific. So the quantity and combination with some other biomarkers, they could take us really to the point that we may even need to look at different dosing regimens for different various cancers. And just to give you one example is this acute myeloid leukemia, where we already know that the CLEVER-1 is heavily expressed on the surfaces and is predicting the outcome of those patients. Maybe there, we may have a totally different dosing regimen than with colorectal cancer, which we would like to demonstrate that we can convert the cold PD-1 resistant tumor hot first and then think about what the additional treatments really would be. So too early really to fix the dosing. We have to be flexible at this point. Really good point. Thank you. Anything else? If not, then I thank again. Looking forward to see you again soon.

Thank you. Everyone, that does conclude your conference call for today. You may now disconnect. Thank you for joining, and enjoy the rest of your day.