Welcome everyone to Cantargia's R&D day. I'm Göran Forsberg. I'm CEO of Cantargia. I'm very glad to have this event, which I think is caused by several very interesting events. We have new data in pancreatic cancer, which was disclosed during the night, and we also have new data around preclinical activities in our second product, CAN10. Before starting the activities, I would just quickly like to present what Cantargia is to put everything into context. By doing that, I'd like to show our pipeline. Cantargia is an antibody company. We are based in Sweden. We are focusing all our development on one molecular target called IL1RAP. This target is found in a large array of different cancers as well as having relevance in autoimmune inflammatory diseases. The lead asset is called CAN04 and is being developed for pancreatic cancer, non-small cell lung cancer. Most of the activities right now are focusing on combination with chemotherapy, where we are in Phase IIa in both these indications. We've also done some monotherapy to primarily get data on biomarkers, mechanism of action, and safety in a number of solid tumors. We are doing activities where we combine CAN04 with pembrolizumab in patients that have relapsed on pembrolizumab therapy, which is a Phase I trial ongoing in the U.S. We're about to start several new trials in other cancer forms, again, looking into chemotherapy combinations. The second product, CAN10, is another antibody direct against a different epitope in IL1RAP, and it's been designed for treatment of autoimmune inflammatory diseases, and the lead indications are systemic sclerosis and myositis. Behind that, we have several hundred different antibodies in a platform product called CANxx, where the idea is to fish out new antibodies which are complementing CAN04 and CAN10. To put this in a little bit more context, we are very much driven by that we have positive interim data in cancer. We have very much focused on, let's say, combination therapies, which I think is very much the way to go here. IL1RAP, it's interesting because it's a target for several different cytokines, so it's the interleukin-1, interleukin 33, and interleukin 36 pathways. This opens up lots of opportunities in lots of different diseases. We are definitely working on indications where the medical need is very high. Besides, let's say, the drug development strategy, we also have a very unique and robust patent portfolio. Besides having compositional matter patents on the CAN04 antibody valid until 2035 and a recently filed patent on CAN10, we also have a granted patent on the IL1RAP antibody target in oncology, which is valid until 2032. We're listed on the stock exchange, we have a market cap of around $400 million and a cash position which is pretty good with slightly more than $100 million on the bank end of last year. Going into today's program, I'm very excited to say that I think it's a broad and nice program where David Liberg, who is Vice President of Research at Cantargia, will start to explain more about CAN04 or nadunolimab, its mechanism of action. Professor Ahmad Awada, who has been the lead investigator for our ongoing Phase I/IIa trial of this antibody, will present the latest clinical data in pancreatic cancer. These data will then be put into context of the pancreatic cancer environment and pancreatic cancer disease by Dr. Manuel Hidalgo from New York. After that, Ignacio Garcia-Ribas, who is our Chief Medical Officer, will explain more about how we are moving our portfolio forward in cancer. After that, David Liberg will come back and present the latest on the CAN10 project. After that, we have time for questions and answers. Each presentation will be run without questions, but there will be time for one or two questions afterwards if there's an interest before we join into the next subject. Otherwise, I suggest we leave questions for the question and answer session. By that, I'm very happy to let David enter the stage and present a little bit more on CAN04 or nadunolimab and its mechanism of action. Thank you very much. It's a pleasure to introduce IL1RAP as a target in disease, which we believe is a very unique and intriguing target. We start with oncology then and the mode of action of CAN04. I'll focus on the subject of today, which is chemotherapy combinations and pancreatic cancer. IL1RAP is a protein that's found in tumors, both on cancer cells but also on other cells in the tumor vicinity that helps the tumor to grow. IL1RAP is a protein expressed on the cell surface, and it acts there as a receptor or a sensor. It picks up signals from the environment. These signals are signals of danger, of stress, of inflammation, and it relays the signal inside the cell then, and the cell has a response to this. In this way, IL1RAP scans the environment and is involved in cell survival and also, which we believe is really interesting, in resistance to therapeutic interventions. It works like this. I don't have the ability to point here now, but I'll try to guide you through these pictures. You have IL1RAP in red here to the left, and the signals it detects are called IL1 alpha and IL1 beta, which are two extremely potent inflammatory molecules, so-called cytokines. These actually interact with another receptor called IL-1 receptor 1, but once they do that, this receptor interacts with IL1RAP and signal transduction into the cell is allowed. IL1RAP is required for this interaction or this signaling. What CAN4 does, as you see to the right there, is that it binds IL1RAP, by doing that it blocks the interaction with the IL1 receptor, thereby you have no signaling. At the same time, CAN4 is an antibody, it has two parts. One, which is the binding part, which is the one binding to IL1RAP here, the other part is a part which immune cells can recognize in order to kill the cells that express IL1RAP. Actually, CAN4 is engineered so that it has a much more potent effective function like this than a normal antibody. Both of these mechanisms we believe is very important for CAN4 function. As I mentioned, CAN4 is expressed in tumors, this is of course how we found IL1RAP in the first place. We look into different tumors, these are solid tumors of different variants, we see that we haven't actually found a tumor yet that does not express IL1RAP. If we look at the cancer cells, which are the blue bars here, you see that you have a varying expression. For example, in non-small cell lung cancer to the left, you have about 80% of the tumors where the cancer cells express IL1RAP, and its varying degree in other cancer forms. What is true, though, is as well that if you look to a large extent throughout the tumor, all of them will express IL1RAP in the tumor stroma. The stroma is the surrounding tissue or the intervening tissue into the tumor, where you find, for example, blood vessel infiltrating immune cells and so on. To the left, you see a biopsy from the CAN4 study. This is non-small cell lung cancer. You see at the top and the bottom, you see tumor cells which express IL1RAP, which is in brown here, and you see the intervening sheet here which is the stroma then. You find as well there brown cells that express IL1RAP. What are these then? Well, a tumor is of course not just cancer cells. It can be described almost as a badly organized organ, which grows and contains a lot of the supportive cells you find in normal organs. For example, it requires a blood supply, so you have blood vessels growing into the tumor, which is of course what we try to target with VEGF inhibitors, for example. You have other cells like fibroblasts, the CAF cell, the red cells, which are very important, for example, in pancreatic cancer where they form a very solid environment, which is even hard to penetrate for drugs. You have infiltrating immune cells like so-called myeloid cells, macrophages, monocytes, neutrophils that are inflammatory and help to create an inflammation. Here we should say, though, that this is not a productive inflammation. This is more like it's been likened to a never-healing wound. It's a more repair mechanism trying to soothe the tissue. It helps in getting blood vessels into the tumor. It keeps the active part of the immune system out of the tumor. This is a suppressive kind of chronic tumor inflammation that is required for the tumor to grow. All of these cells express IL1RAP, the tumor cells, the fibroblasts, the myeloid cells, and the endothelial cells, and they all respond to IL-1 alpha and IL-1 beta. They communicate through this system, which is important in many aspects. One aspect where it is really important is in resistance to therapy. This is not something that we made up ourselves, of course, but this has been described in many ways, not just for chemotherapy as well but for example, EGFR inhibitors, for NF-κB inhibitors and other therapies. This is something that we are exploiting. What happens is here that chemotherapy hits the tumor cells and they start to die. They send out these stress signals I talked about in the form of IL-1 alpha. IL-1 alpha is released from the tumor cells after chemotherapy, and they will then activate these fibroblasts, the CAFs, and the infiltrating immune cells who will start producing IL-1 beta. Now you have both IL-1 alpha and IL-1 beta in the tumor communicating to IL1RAP, and this is involved in chemo resistance. It is not absolutely clear how this works, but clear is that both of these cytokines are connected to chemo resistance. We can see this as well in our preclinical systems. This is an experiment where we have a human tumor, non-small cell lung cancer that is implanted under the skin into mice and we treat with, in this case, gemcitabine and cisplatin. What you see then in A to the left is that we kill the cells. We have increased necrosis and cleaved caspase-3. These are markers for cell death. We also get an application of IL-1 alpha, which is there in the middle. At the same time, if you look to the right, you see IL-1 alpha in C in the left part of the C figure. In the right, you have these green flashes turning up in the stroma, so that's the non-cancer cell part. This is active interleukin-1 beta converted enzyme or ICE caspase-1. This protein is involved in IL-1 beta activation. This is a sign of IL-1 beta being activated by the cell. Here we have this communication. We have chemotherapy activating IL-1 alpha, killing cells in the tumor part, then activating the stroma that produce IL-1 beta. If we're adding CAN04 to this, we see that we get a better effect. Chemotherapy alone is not as good as chemotherapy plus CAN04. This goes for, in this case here, this is the same model, lung cancer, CISGEM or CARBOGEM. We've done this though in several different models, even in mice models. We've done zebrafish with good results. This is a phenomenon that we feel very confident about, that we have a potentiation of effect of chemotherapy in experimental systems. It's also interesting what you see in B and D here. Chemotherapy will induce weight loss also in mice, and especially platinum compounds. In fact, cisplatin is used as a model for cachexia in mice. What we see is that when we have this kind of weight loss, actually CAN04 counteracts this. We have a better anti-tumor effect, but we also have reduced toxicity it seems. This makes sense. This can go through inflammatory signals, it's of course something that we're really interested to have an eye on in the clinical studies as well. CAN04 and chemotherapy is a good combination. Some words about pancreatic cancer. This is extremely difficult cancer form with very poor survival, it's a difficult to treat tumor. Still, when we started some years ago to outline a strategy for development CAN04, we had pancreatic cancer as one of the main indications. This is because there is a connection between pancreatic cancer, IL-1 alpha and beta. That is very interesting. If you see in the middle graph, for example, the blue curve there is patients where tumors have low amounts of IL1RAP. The other curve, the purple curve, is where you have a high amount of IL1RAP. As you see, if you have a lot of IL1RAP, your survival is very poor, but you have a better survival if you have a low amount of IL1RAP. There may be a mechanistic explanation for this because pancreatic cancer is driven by a number of driver mutations, and perhaps the most important of these is KRAS. Over 90% of tumors, pancreatic tumors, have mutated KRAS and activating mutations, and KRAS have been shown to induce IL-1 alpha directly. Now you have a situation where KRAS drives the cancer, drives production of IL-1 alpha, which then communicates with fibroblasts, the macrophages, and these cells will start producing IL-1 beta. This inflammation has been shown to be important in pancreatic cancer. To the left there you see as well that the similar bars for KRAS compared to IL1RAP. Again, the same is true if you have high amounts of KRAS, you have a reduced survival. If you have lower amounts, you have better survival. They look very similar. This connection between IL-1 alpha produced by tumor cells, fibroblasts, which are so important to pancreatic cancer, is actually something that we can model in vitro, that is in the test tube. Bear with me, I'm aware that this is a complicated picture, but I think it's really interesting. If we grow pancreatic cancer cells here, PDAC cells, together with the cancer-associated fibroblasts or the CAFs, they form structures that almost look like a tumor in the cell culture dish. You have the cancer cell areas, and you have intervening sheets of these cancer-associated fibroblasts. If you look in the middle picture, it's shown again what I said in the last slide, that it's actually the cancer cells that produce IL-1 alpha. This is the white bar. The fibroblasts, the orange bar, they do not produce that. If you grow the cancer cells and the fibroblasts together, you have about the same amount as you have just cancer cells, showing that this is produced by the cancer cells themselves. If you look at IL-1 beta here, the right graph, then you see that pancreatic cancer cells on their own or fibroblasts on their own do not produce any IL-1 beta at all. If you put them together, now something happens and you get upregulation of IL-1 beta. This we know is driven by the cancer-associated fibroblasts, not by the tumor cells. We've looked at this in not just IL-1 alpha and beta, we looked at many different genes. We've done RNA-Seq, it's called, so it's basically looking at thousands and thousands of genes at the same time. What is quite obvious is that when you do these kinds of cultures and mix the fibroblasts and the cancer cells, you have large changes in gene expression. You have cells change, and the cells that change the most are the cancer cells with fibroblasts. The tumor cells reprogram them into something else. When we add CAN04 into this, we see to the right there that genes go up and down. This is red and blue. When we add CAN04, we have a few genes that change in these cancer cells. It's just four here, but we have a lot of genes that change in the fibroblasts. There's 230 genes that are influenced by CAN04 here. The conclusion there is then that this crosstalk between cancer cells and the stromal fibroblasts involve IL-1 alpha and beta. If you add CAN04 into this, you have a large impact on the cancer-associated fibroblasts that are so important for this tumor to grow. We can do this in vivo as well. Again, if we do this in mice, we take these cultures and we put it under the skin of the mouse, you'll start growing a tumor, as on the left here. Again, you see the same kind of pattern. You have areas of cancer cells, PDAC here. You have sheets of fibroblasts growing around, supporting the tumor to grow. This is now, of course, in three dimensions, it's the same kind of picture. What is interesting, if you just grow the cancer cells by themselves as a lump of cells without any microenvironment like fibroblasts, you don't really have any effect of treatment. Once you mix them, you have a good effect of CAN04 reducing the tumor growth in these mice. The conclusion here then is that the inhibition of tumor cell growth induced by CAN04 in this system is either mediated by cancer-associated fibroblasts, reprogramming them in some way, or we're just destroying the cancer-associated fibroblasts' ability to support the tumor. Just to sum up this a bit here. What I said was that CAN04, an immunomod, blocks IL-1 alpha and beta signaling and induces antibody-mediated cell killing of IL1RAP-expressing cells. IL1RAP is broadly expressed in solid tumors, both on the tumor cells and in the tumor stroma, the supporting cells. CAN04 targets both of these cells, both the cancer cells and the tumor stroma. Remember, you can do this by blocking IL-1 alpha and beta, but also by actually killing the cells by antibody-dependent cell killing. If we add chemotherapy, we activate the system. You get more IL-1 alpha and beta in the tumor microenvironment, this is involved in resistance to the therapy. When we add CAN04 and chemotherapy, they act in synergy to inhibit tumor growth. We believe that these effects on the tumor microenvironment are crucial, that the effects with chemo-resistance makes CAN04 an intriguing and unique compound, including then treatment of pancreatic cancer. I'll just show you how this looks in real life, so to say. These are now biopsies from the CAN04 study. The two left slides are pancreatic biopsies from CAN04, and you see on the left there, the brown cells are tumor cells, and they are brown because they stain for IL1RAP. In the middle, you see the same kind of tumor cells that are stained brown, but you see it's less tumor and more stroma. The intervening and surrounding tissue is very dense. It's fibrotic. There's not much cells there. You have these elongated cells that are cancer-associated fibroblasts that stain for IL1RAP as well. They are there. To the right, you have a liver biopsy, also from CAN04. Here you have a tumor which is weakly expressing IL1RAP. It's the top part of the picture there. You also have these cells that are brown because they express IL1RAP, and these are tumor-associated macrophages then that also sit in the stroma and mediate the tumor progression. All of these cells are important for tumor growth. We are getting a lot of this data now, so that's, I think, it's really interesting. We have biopsies that we're looking at different markers. We look at sero markers, and all of this will help us understand even better what CAN04 does in the tissue. This is ongoing, however, so we'll present this at the conference at a later stage. Okay, I think that was my last slide. Thank you very much, and I'm happy to take any question. There's no questions related to this segment, so I think we'll be able to move on. Okay. Well, I would like to ask you to stop sharing, David. Okay. Thank you ask Professor Ahmad Awada to enter the stage. professor Ahmad Awada has been the lead investigator in this trial, and we're very pleased that you will do the presentation of this updated Phase II data. I am Ahmad Awada. I am the head of Oncology Medicine Department here at Jules Bordet Institute. My task to present today to you the preliminary data from the pancreatic cancer cohort. As disclosure, I am the study coordinator of this trial. I am involved in the development of this drug from the first immune study two, three years ago. We heard really a nice introduction from David Liberg about this pathway, important in many tumor types, but particularly true in non-small cell lung cancer, as well in pancreatic cancer. We are all aware of the importance to find a new solution for pancreatic cancer because this is a medical need. So far in the clinical practice, we have only one or two regimen of chemotherapy. David explained really well to us the importance of this pathway, the IL-1 pathway, IL1RAP interaction with the immune system, introduced really well the value of this CAN04 in modulating this pathway. Of course, the best way to go in further development is not to give this drug alone, as we saw early, but in combination with chemotherapy. That's particularly true in tumor types like pancreatic cancer. In this slide, you can see basically the clinical development plan of CAN04 since the first-in-man trial, which included 48 patients, where I presented the data of this cohort, this first-in-man trial at ASCO as oral presentation. Of course, there are another study now cohort, looking to the combination of platinum and gemcitabine and CAN04 in non-small cell lung cancer, this trial is ongoing. Of course, the focus of today is the combination of one standard regimen in pancreatic cancer, gemcitabine nab-paclitaxel, in combination with CAN-04. We are taking patients stage III, IV pancreatic cancer in the first-line setting. Patient candidate for gemcitabine and ABRAXANE. We included so far 36 patients in 10 sites, where eight patients received CAN-04 at the dose of 7.5, and we go down to 5 milligrams for the following 28 patients in order to mitigate the infusion related reaction, which is particularly seen as the main, let's say, side effect in the first-in-man study, the monotherapy study. All the maximum of the patient received CAN-04 as a dose of 5 milligram per kilo and for gemcitabine ABRAXANE as a standard dose. We defined from the monotherapy study that in order to mitigate the infusion-related reaction, to start with the priming dose of 0.5 mg/kg, let's say - 7, and before to go to the combination for the majority of the patient at 5 mg/kg. Another possibility in the mean to mitigate this infusion-related reaction, we see with this kind of a drug, is to increase also the duration of the infusion. You can see here we have 36 patients registered, but there are three patients not treated by chemotherapy or withdraw consent. We have only 33 patients available for efficacy. You can see here the patient characteristics for our study, our cohort in the CANFOUR trials. We put it here not for comparison, but only to remember for one of the pivotal trial of gemcitabine and ABRAXANE published by Von Hoff in 2013. Basically, the patient characteristic in the first-line setting are similar, except in our population, 50% of the patients received adjuvant chemotherapy. At this time, at the Von Hoff presentation, there are no standard adjuvant therapy at this time. Basically, the patient characteristic, as you can see from this slide, are similar. The patient receives the combination of chemo CAN04 and evaluated every two months by CT scan. Of course, as you know, CA 19-9 is a tumor marker in pancreatic cancer, and we follow this as also used in clinical practice. I will go directly to the main conclusion at this time from the combination of CAN04 and chemo, we observe responses as we expect with this kind of combination chemo and here in combination with CAN04, which were durable, and I will come back to that later. Promising PFS and overall survival result. Interestingly, we saw what's called in the immunology field, immunotherapy field, and that's unexpected for pancreatic cancer for immunotherapy. As you know, immunotherapy didn't emerge as a treatment in pancreatic cancer for many reason. Not here to explain, but basically no responses and even no pseudo progression. No pseudo progression described in pancreatic cancer as a whole when we go to the literature. Basically, we observed at least in five patients, five well-documented patients, a pseudo progression-like response, interestingly, which predict a longer progression-free survival. Let's go a little bit more on details. Here you can see here the evaluation of tumor shrinkage by the investigators. You can see we have 27% objective response rate, as you can see here in this slide. It's important to say also this is by local evaluation, and by central review, we observe nearly the same, but this evaluation is still ongoing. Only to remember what's mean pseudo-progression in the immunotherapy era field. This patient, when he received checkpoint inhibitor, for example, they progress at the first evaluation, for example, before the tumor shrinks later on. This is explained simply, but I think it's a simplistic explanation, but surely correct, that are probably is a result thing from immune cells infiltrating the tumor. This is the reason why instead of RECIST criteria was developed, what's called iRECIST to consider this pseudo-progression possible situation observed with checkpoint inhibitor. To our knowledge, this not described in pancreatic cancer so far. You can see here the patient with a pseudo-progression-like response in five patients. You can see the figures are really the same. At the first evaluation, we see that by CT scan, the tumor progress. Sometimes we have a new lesion before the tumor shrink. We can see in parallel to that, the CA 19-9 decrease significantly. That's true for five patients in our 33 patients, which is really an important number of patients for a small cohort of patients, which suggesting strongly this phenomenon of pseudo-progression-like response. To illustrate this by CT scan, you can see here in one patient with liver mets, after the first evaluation, there are increase in the target lesion before to decrease at three months, seven months, and 12 months. You can see in orange here the evolution of CA 19-9. Exactly the same picture from another patient with pancreatic cancer and liver metastasis. You can see at two months an increase of the target lesion by 25%, which decrease at four months, you can see the lesion is a little bit shrink and to shrink much more at five months. You can see the evolution of CA 19-9, which became normal in this patient. If we summarize here, the objective response rate by investigator, we have nine partial response, 27%. We have a pseudo-progression in 15% of the patients. We have a disease control rate of 72%. What's important to remember here, because this is really important with pancreatic cancer as well as other tumors, the median duration of response in median here is around seven months, and you can see that the range is from 2-14 months. By reference, I put here in the right part of this slide what was observed in the ABRAXANE gemcitabine alone trial. You can see here the progression-free survival by iRECIST. Why iRECIST was used here? Simply because also we saw this five cases of pseudo-progression-like response. You can see the median iPFS is 7.8 months. You can see the interval confidence here, with 55% of events. You can see that, and that's more important that PFS according to iRECIST at six months, 62%, at one year, 19%, and this evaluation is still ongoing. In my opinion, as you know, here, of course, we're doing chemotherapy and immunotherapeutic agent. As you know, by using immunotherapy alone, for example, PFS is not really the good outcome to study. Important to look what has happened at the survival level. At this time of the evaluation, the cutoff for this data is in April of this year, 2021. The median overall survival is around 13 months, with 42% of overall survival event. You can see the six-month survival rate is 71%, is not bad. One year, 55%. Of course, we need some maturation before to conclude about this small cohort of patients. Here, once again, to remember this information and to put it in the context and the benchmark with IMpassion trial, I think we cannot compare for the PFS, for overall survival, we can say it seems there are something interesting happening in this combination with chemo plus CAN04, particularly true with one-year survival, 55% for pancreatic cancer metastatic, stage III and mainly stage IV disease is something of interest to follow in larger cohort or larger randomized trial. Let's move now to the safety. We can say that as expected from the Phase I infusion-related reaction, this was observed in other drug of the same class, was seen with CAN04, neutropenia and neutropenia-related event, particularly febrile neutropenia. We observed mainly with the priming dose of 0.5 milligram per kilo, up to 44% of the patient developed mild to moderate infusion-related reaction. We saw last managed with pre-medication and prolonged first infusion when we go to the combination. More importantly, we observed more neutropenia compared to what would be expected from the pivotal Phase III trial of ABRAXANE and gemcitabine, and the Grade III febrile neutropenia was observed in this combination of CAN04 with ABRAXANE and gemcitabine in 17% of the patient. Of course, this could be managed with G-CSF and, of course, those modifications. You can see here one example of a patient, you can see in two patients, G-CSF seems to decrease the depth of the nadir of neutrophil in a patient, for example, presented here at the right part of the slide. Febrile neutropenia seems to be present higher than expected, 17% of the patient, and that could be, of course, as you know, mitigated by G-CSF and eventually in a further cycle, in the subsequent cycle by dose reduction of the chemotherapy agent. Interestingly, also the observation that still this is a small cohort of 36 patients, there seems to be less fatigue. Fatigue, as you know, is subjective. More importantly, in my opinion, less peripheral neuropathy compared to gemcitabine ABRAXANE in the Von Hoff trial, which was around 17%, and the FOLFIRINOX, where oxaliplatin is neurotoxic drug, was around 9%. Not described in the CAN04 cohort, in our CAN04 cohort. We can do a lot of hypotheses about that. Possibly IL-1 plays a role in fatigue, that's sure. Peripheral neuropathy possibly, and probably we are mitigating here by modulating the IL-1 pathway, IL-1RA, probably we are mitigating this problem of fatigue, peripheral neuropathy seen in other trial of chemotherapy-based approach. What we can conclude at this time from this pancreatic part of the CAN04 trial, that adding nadunolimab CAN04, which gemcitabine nab-paclitaxel in the first-line treatment seems to give us promising efficacy in terms of response. This story, this observation, this finding of pseudoprogression-like phenomenon, which is correlated really well with what David explained to us about the ADCC, the immune, let's say, modulation, because basically this pseudoprogression-like phenomenon in five patients, well documented, wasn't described with chemotherapy alone, for example. We know checkpoint inhibitor alone didn't show a big, or let's say, breakthrough in the treatment of this disease. I think we cannot say a lot about PFS and maybe iPFS today and overall survival because these data still need to be mature. The early data seems to be promising compared what we know from historical control. That's really, we can really give at this time still in conclusion. What we see, it's clear that neutropenia seems to be more important in this combination. We have a little bit more neutropenia related, that mainly febrile neutropenia which should be mitigated by G-CSF. It's important to know that G-CSF wasn't used as primary prophylaxis, but surely secondary prophylaxis. Those modifications according to the protocol might, to moderate infusion-related reactions CAN04, mainly in the priming Phase, and which was decreased by increasing, for example, the infusion time. That was documented already in the monotherapy arm in the first- in-man trial. That's important to follow because this is important, less neuropathy, this is something cumbersome for the patient and less fatigue, which is more subjective. That's, I think there is rationale to go to a Phase III trials combining this new approach, innovative approach, which really targeting not only the immune function from one side but also the IL-1 pathway, two important pathways in solid tumor, particularly true for pancreatic cancer, but also for non-small cell lung cancer. The non-small cell lung cancer cohort is still ongoing. With that, I would like to thank you very much for your attention. Yeah, we have a couple of questions to you regarding your presentations. The first one is, could you clarify how many confirmed and unconfirmed responses you have observed as there seems to be some sort of confusion about that? I think we can say at this time, I think what's really clear, there are at least nine partial response. We can say to my knowledge, to my evaluation, we have nine objective response, which lead to 27% of the objective response rate. The other question is, how concerned are you about the neutropenia frequency ahead of expansion into the FOLFIRINOX combination? To be honest, when we go to FOLFIRINOX in my practice, when I saw from the reported result, there are no so important neutropenia-related events. From my clinical practice, we saw much more, let's say, neutropenia-related events, severe neutropenia, and so on. This is the reason why I'm using FOLFIRINOX mainly for young patients, in order not to have this problem. Clearly, CAN04 seems to increase the neutropenia problem related to chemotherapy here. I think it's important to use G-CSF as prophylaxis. Now, the question, primary prophylaxis, secondary prophylaxis. If we go to the algorithm about the use of G-CSF, of ESMO, for example, when we have 10% or less, no G-CSF will be used. When we have 20% and more G-CSF should be used. We are here in between. Of course, this kind of patient, to some extent, are fragile. Basically, I am not against to only G-CSF when we go to a randomized Phase III trial. I think there's time for a couple more questions. What do you view as a clinically relevant overall survival improvement in first-line pancreatic cancer? Sorry, I didn't follow well the question. What do you view as a clinically relevant overall survival improvement in first-line pancreatic cancer? What is my opinion about survival? What could be considered, you mean, of importance? That is your question? Yeah, I think that's how you should view the question. Yep. There are two things here, in my opinion, for pancreatic cancer, and I am sure Dr. Hidalgo, which has a major experience also of pancreatic cancer, could comment on that later on. I think the median is something of importance, of course. What always, for this kind of tumor in a metastatic situation, I am looking also always the percentage of patients alive at six months, percentage of patients alive at one year. Unfortunately, this group of patients is really bad in terms of prognosis. Personally, the median of one year, that seems to be okay, but what is more interesting to me, what was observed at six months and at one year, the percentage of patients still alive. I think in the Phase III trial, in my opinion, I don't know Dr. Hidalgo what he thinks about that, should be one of the co-primary endpoints, percentage of the patients alive at one year, because it could give more information and more importance to the combination and the study. Yeah. Could you share some light on what you believe would be the sort of lowest level of overall survival rate in order for CAN04 to become a new standard of care treatment? I will look, if, let's say, if we expect to have, let's say, eight months from the standard chemotherapy, and we can increase it by 50%, I think that's something of importance. Yeah. The final question for you, could you shed some light on how representative the trial participants were of the overall first-line PDAC population? Normally, we cannot do what I did in one of my slide to put the patient characteristic of the GEM and nab-paclitaxel pivotal trial head to head. I put it only to be sure that our population are not different from the population of the pivotal trial. Basically, when we go characteristic by characteristic, we are exactly the same except for prior chemotherapy, which is not in favor of CAN04 chemo combination here, because that's still not big percentage of patients receive chemo in the adjuvant setting or neoadjuvant setting was 15%. In my opinion, it's representative. Still, we are here talking about the methodology of clinical trial. We cannot conclude from 33 patients, that give, let's say, good insight, in my opinion, to move ahead for two reason. The first reason is the data I presented, and secondly, the mechanism of action of this drug, the innovative approach of this drug, which is completely different from what we know in the immunotherapy field. We have checkpoint inhibitor, we have the antagonist, we have the agonist. It is completely something different, targeting at least two different pathway. There are some interaction, of course. I think that's a give to this drug, in my opinion, some more, let's say-Value to move it on in pancreatic cancer, a randomized trial. In any way, if we ask for 50% increase, for example, in median survival or one-year survival rate or whatever, I think we do not need thousands of patients here. I think some hundred of patients, these patients are available. There are not many competitive trial. We could have the answer very quickly, basically, about the value of this study. It could be done very quickly. In my opinion, it's not a really rare tumor. The standard of care, of course, here is used. We are adding something in order to improve. I don't think we will have a difficulty to recruit patients in this kind of trial. There are no, to my knowledge, many competitive trial in this setting. Many thanks. I think we'll keep the rest of the questions for the final Q&A session then. Thank you. You're welcome. Well, thank you so much, Ahmad. Now I'm handing over to Manuel Hidalgo from New York, who will, let's say, present more about the disease and then put the new data into context. Please go ahead. Thank you. Good morning. I may have my slides? Yes. What I thought to do this morning is to just give a brief overview of where we are in pancreatic cancer. I think a number of the questions are sort of pertinent in terms of what is meaningful improvement in outcome, how do we design studies, what are the next steps came in the prior discussion, and I'll be addressing some of those as we go. I will highlight some of the ongoing therapeutics that likely or hopefully will impact the disease, and then to spend a little bit of time on putting the data we just heard into context. If I may have the next one, please. These are my disclosures. Next. This is the problem, and this is recent data showing that really, pancreas cancer, we have not made significant progress in the past. If you look at this slide, we're expecting that by 2026, which is around the corner, pancreas cancer would be the second cause of cancer-related death, both in men and women, just beside lung cancer. A very significant problem. Next. Far, we treat this disease by surgery, if we are lucky to get it at earlier stages. Radiation therapy, which has a controversial role, but with new technologies, hopefully will be effective and helpful, particularly in patients with a locally advanced or more localized disease. Traditional chemotherapy, we heard about that, and we saw the data from the MPACT trial before, which is the main treatment strategy. Neither precision therapy nor immunotherapy really has made an impact on this disease as of yet. For that reason, the data we saw this morning about modulating the immune system and starting to see responses that are durable is quite exciting because, again, we are not there yet. Next. I'm not going to go over the entire spectrum of management of this disease, but just to highlight how little progress we have made, is the only biomarker that we have at the moment is performance status, which has been around for 50 years, maybe. We classify patients in groups depending on that. If their performance status is good, and usually those are the patients that we treat in clinical trials, we can use either gemcitabine ABRAXANE or FOLFIRINOX. Today, we saw data with GA. Data with FOLFIRINOX is being developed. Either one of these regimens are optimal standard of care, first-line treatment. There are differences in which one we apply to one patient versus the other, but they will never compare head-to-head. The belief that FOLFIRINOX is more effective is based on non-comparative data. When you look at real-world evidence, real-world data, in properly selected patients, they're quite comparable. It's good to have data with both of them, but I think either one can be a move forward as a registration strategy. On the other side, poor performance status, gemcitabine is what we use, very ineffective, and the discussion, unfortunately, with these patients is best supportive care. The group in the middle, reduced performance status, Karnofsky greater than 60, the ECOG 2, a very interesting group because it's a large group of patients. We tend to use gemcitabine or gemcitabine ABRAXANE, actually. We published data on that, showing that GA is tolerable. That, I think is, when we look at the spectrum of the disease, one thing is to develop drugs for the good performance status, which is important, and the first step to get drugs into the market. We need to also understand that many patients come to the clinic and are not candidates for those drugs, and therefore, anything we can do to improve, either change performance status by early diagnosis, by better supportive care, or applying these drugs to those patients is important. Of course, in advanced disease, we are not curing patients. It's eventually important that we move these drugs to earlier stages and that we diagnose patients at earlier stages. By increasing the number of patients and moving the drugs in those situations, likely we will be able to save more lives, which is at the end what we want. Next. Multiple agents in development. This is from a review we just wrote with Ignacio Garcia from the University of Utah a number of years ago. Very busy area, many drugs in early stages, very few advancing to late stages, really nothing at the moment that you could say, "Well, this is really outstanding. It's going to change the panorama." Still, we need to continue doing this early work, as the one we saw today, to identify new targets, new drugs that will have an impact on the disease. Next. Now, two major areas. Precision oncology, and the problem here, and I will be very brief, is that most of the cancers have RAS mutant. It's not the 12C, it's 12B, 12D. Which so far we don't have effective drugs for this tumor type, for this oncogene, and that is a major problem for precision oncology in pancreas cancer. The other genes, P53, SMAD4, P16, the same. They are not targetable as we speak. A major area of research interest is to develop drugs that work in this genetic background. Next. We have been able to pick small groups that have actionable mutations. The largest group being the DDR, the DNA damage repair-deficient, which may be up to 10% if you combine all the genes, BRCA1, BRCA2. As you know, olaparib was approved based on improvement in progression-free survival. Very important, because we're talking about how you move drugs forward. Usually, overall survival has been the predominant outcome endpoint for registration. Olaparib failed in OS, was approved based on PFS, because it helps in this selected group of patients to decrease chemotherapies, better tolerate it, and probably easier for the patients. There's a debate in the field whether or not that is enough. The reality is that the drug was approved. Then a million of other mutations, less frequent, but when you have them, let's go to next, drugs work. This is an example recently presented for the RET fusion, very rare. Patient with RET fusion, as you can see, baseline, multiple liver metastases, then very good response, up to 40 cycles with the selpercatinib. Very interesting case, and I just want to highlight that those cases are out there, and we need to do genomic analysis to identify them. Next. This is the data I just alluded to for olaparib that increased progression-free survival and was approved first targeted agent to be developed in pancreas cancer. Next. One area, precision oncology, working on it. Second area, immunotherapy. There we face the tumor microenvironment that was alluded to before in the early mechanistic presentation, which creates this immunosuppressive tumor microenvironment. For that reason, many or none of the immune-active agents that are being approved in other tumor types have been effective in pancreas cancer. Next. Some of the drugs that are being developed or are in development or already failed, we don't need to go over this, but I'm going to make a couple of points. Checkpoint inhibitors, as we know them, they just don't work. The progression-free survival, the overall survival in these patients is very short. It's worse than with chemotherapy. It's about three months. Does not improve the outcome of patients treated with chemotherapy. That kind of gives us the ground of what immunotherapy is doing in this disease. Of course, multiple attempts to overcome that problem. I'm going to show you just three pieces of data from one of our recent studies using CXCR4 inhibition, just to illustrate where we are and how difficult and complicated this is. Next. This is a strategy of making the cancer immune-sensitive. We do that, or we try to do that by blocking CXCR4, which is a receptor that signals T cell to stay out of the tumor. The belief is that the tumor does not respond to immunotherapy for the simple reason T cells are not in close proximity to the tumor. When you block that pathway, in this case, when you block fibroblasts or eliminate fibroblasts that secrete the cytokines, and we heard about that earlier today, secrete cytokines that signals the T-cells to stay out, T-cells get in, when you then incorporate PD-1 active agents, you get a response. Next. We saw in biopsies taken in this clinical trial published last year, before treatment and after treatment, in a trial that we did with a CXCR4 inhibitor, BL-8040, plus pembrolizumab plus chemotherapy, we proved that in paired tumor biopsies, you can get an influx of T-cells. Of course, next, when you treat those patients, you start seeing response rate. In this case, the overall response rate was about, in this small cohort of 22 patients, 32% in the second-line setting. This is probably the best data that we have available, published data with immunotherapy in pancreas cancer. Still, it's not outstanding. In the second line, we will need to see what happens when we do this in a randomized clinical trial. It's positive in the sense that we were able to see some responses, but we still need to see whether or not that's going to be impacting progression-free survival and overall survival in a randomized trial. Next. Among the many targets that are important in the stroma, IL-1 is one of them, both alpha. In pancreas cancer, the most recent data would suggest that beta is the most significant one. This is a very recent paper from Dafna Bar-Sagi at NYU, in which they showed that, indeed, IL-1 beta is needed and is produced by the fibroblasts, and it fits the tumor, and you need to have it for pancreas cancer progression. Preclinically, the IL-1 pathway, I think, has been nicely validated and highlighted as a targetable or as a strategic target in this disease. Now, it's alpha, it's beta, it's the IL1RAP, those are things that, of course, we will need to sort out in the studies. The strategy that you saw today, if you remember from the prior presentation, by targeting the receptor-associated protein, it likely blocks signals from both alpha and beta, and I think that's important. Next. We saw, and I'm going to pick up a few of the slides that Dr. Awada presented before. Response rate, this is confirmed by RECIST, by investigators, and you see a number of patients with disease, with control, with partial responses. Of course, we now compare that, this is using RECIST, we compare that to the standard of care, 30 patients, non-comparative, very difficult to say this is going to be different if we were to do this in a randomized Phase II study, which in my mind should be the next step. What was very interesting and unique in this study is the pseudoprogression. As it was alluded before, we have not seen that with chemotherapy, of course, but not in the immunotherapy studies that we have run so far with the checkpoint inhibitors. This is taken from the prior presentation, a few patients that the tumor goes up, but the tumor marker comes down. If you continue treatment, they enter a response or stable disease, and that tends to be durable, which I think is an important message. They're durable. If we were to do these studies using just RECIST criteria, as we do with chemotherapy, many of those subjects would've been taken off the study just at the point of the disease progression. That it's probably what would happen in the next patient. That was one of the cases that was shown, if you can advance. Actually, I thought I have one of the CT scans, but probably I don't. I don't know if I may have it in the next one. Probably not. Oh, here it is. You see that this patient, by two months, 25%, would've been taken off the study, and then we would never know if there was benefit or not. Six months, five months later, there is basically a complete stable disease. The tumor marker has come down, and it's very likely that these patients will enjoy this disease control for a while. The problem or the limitation or how we need to be innovative here is how do we build this into the design of a clinical trial? I think we're there. We're there for a couple of reasons. First, as I mentioned before, we got olaparib in the market based on improvement in PFS. PFS is, in the right setting, can be considered a registration regulatory, primary or secondary endpoint, or maybe combined with overall survival. At the end, we want overall survival, but we need to build this stage way. If you go to the prior slide, which I'm sorry I have them flipped. This is very interesting data. This is a recent paper published by the Canadian group, these are patients treated with checkpoint inhibitors. What they did is they monitor cell-free DNA at three months. You can see here, out of 73 patients, there were about 30 patients that developed disease progression in blue and had increased cell-free DNA, and they didn't do very well. The seven patients that had disease progression and decrease in cell-free DNA in orange, they did very well. They did as good or very close to the patients that had RECIST evidence of response. The problem of a patient comes in, we have disease progression, what do we do? We continue treatment or we just stop treatment, I think can be solved now by, of course, applying the CA 19-9, but also by utilizing more sophisticated and innovative ways to monitor disease. These are elements that incorporated in the right clinical trial, I think will be helpful to move this agent along and to be able to capitalize and take advantage and to capture those patients with pseudoprogression that still benefit from the drug and should be continued on treatment. Likely, if you have up to 15% of those, that's going to increase your disease control rate in a manner that will very well show benefit as compared to chemotherapy. I think this is my last slide. We already saw this one. Thank you for your attention. A pleasure to review this data, and happy to take questions. There's no specific questions related to your presentation, so I think we can proceed. Yeah. Thank you so much. Thank you. Manuel, I'm not sure if you have time to stay on, but if you have, maybe a chance for questions later on. Yeah, I can stay for a little bit longer. Yeah. Okay. I'd like to hand over to Ignacio Garcia-Ribas, who is the Chief Medical Officer and is going to explain how we are, let's say, advancing the program. Hello. Hello, everyone. I hope you can see my screen. I'm Ignacio Garcia-Ribas, the Chief Medical Officer and medical oncologist by training, and I'm going to tell you about the current developments of CAN04 in the light of the data that you have seen in pancreatic cancer in combination with gemcitabine and nab-paclitaxel. I hope that now it's clear that we have promising data. Obviously, it's very early. What can you expect from single arm trial? We are having hints that there is good hopes for having better efficacy compared to the standard of care. The reasons to believe is what we see first, durable responses, that is not only the pseudoprogression, is those patients with response, as Professor Awada show, they stay on response for double time that it is published in Von Hoff's gemcitabine nab-paclitaxel trial from 3.5 months to 6.8 months. This is interesting, although obviously the numbers are very small. The second thing that is really what is more interesting is this pseudoprogression phenomenon about which Dr. Hidalgo has discussed quite a lot because it is not response. What is going to be evaluated by regulatory authorities as relevant clinical benefit is the time to event, in this case, progression-free survival and overall survival. This is something that is an interesting finding because it's pretty obvious that if we can generalize this in this 15% of patients in this population, it can really impact the overall outcome of a registration clinical trial. We need to investigate this more. This is not unexpected because the trial was designed to evaluate patients per RECIST criteria. We were hoping CAN04 to have an immune oncology mechanism of action, and it seems that this purpose is paying out now. The new clinical trials that you will see, I'm going to present to the best possible way, also speaks for the chemo-sensitization hypothesis, that we had it. We observed this in animals. We generate non-clinical data about it, we are seeing also some interesting results in this direction. Obviously, we have safety side effects. The first one was first presented by dr. Ahmad Awada at ASCO 2019. It's not unexpected. It's infusion-related reactions. Today, we know that this is similar to many other commercialized monoclonal antibodies, it's not a risk for development. The second one, neutropenia and febrile neutropenia, is not unexpected. It can be seen as pharmacologically driven. What we are learning is how to harness this. We have now G-CSF filgrastim. It's now generic, it's used in many situations. If you can show that your combination makes good benefit and has a good outcome, this should not be a barrier for treating patients. There are other potential benefits that I would like to highlight now, and we will need randomized trials for this, but it is interesting, the possibility of nadunolimab to control the ABRAXANE or maybe the oxaliplatin neuropathy, which is a big problem, the discontinuation of patients with Grade III neuropathy in the case of pancreatic cancer, even patients who are receiving benefit. Also, due to the anti-inflammatory properties of CAN04, we hope to see a good impact in cancer-related fatigue. This is the overview of the current development status. As you can see, we have made good progress. We have a number of trials that are ongoing or in preparation for 2021. In non-small cell lung cancer, I am going to present one slide of information that was previously disclosed. Recruitment is ongoing, and we plan to offer results in Q3 this year. For pancreatic cancer, the data presented by Professor Awada corresponds what we call RB. That was completed in October last year, but we have an extension Phase ongoing. We are investigating other doses, and not only for safety results, because while you know that now regulatory authorities require at end of Phase II meetings and before starting registration trials to discuss with them the dose selection strategy. We will go with enough information on several doses to agree with the agencies the best dose and the schedule. We have another ongoing trial in the U.S., the IMpassion trial, combination with pembrolizumab that may open the door for all the future combinations with pembrolizumab and immunotherapy. It's enrolling well. I will tell you a little bit more later. We have the second trial in pancreatic cancer, the other first line with modified FOLFIRINOX. The protocol is approved. It has been submitted, and the regulatory review is ongoing. We expect to have a first patient in this quarter. Triple-negative breast cancer with gemcitabine and carboplatin. This is the first trial that we planned that we are going to do in collaboration with the Spanish Breast Cancer Group. They adopted CAN04, and we are working with them, and we expect the submission also in this quarter. We have another trial that we call Basket Trial with three parallel indications. Colorectal cancer for FOLFOX, biliary tract cancer with gemcitabine and cisplatin, non-small cell lung cancer with docetaxel. We also expect to submit this quarter. Here is a little bit of non-small cell lung cancer combination. This information was disclosed in September last year. Obviously, we have more data that we cannot disclose today. These patients, as a reminder, is patients, most of them with metastatic non-small cell lung cancer that are either first-line chemotherapy or have progressed to pembrolizumab and then are eligible for the platinum doublet. We are seeing, as you can see here, six out of nine available patients at that time show objective response versus a historical control with gemcitabine and cisplatin alone of 25%. Probably, the only thing I want to say, because you have seen this before, is that the only effect that we are seeing again is neutropenia with a higher frequency, but we are treating this in the same way as in the pancreatic cancer trial. This is a little bit of information about the pembrolizumab trial. The first patient started in 2020. The enrollment is running according to plan. We expect to deliver results in the second half of this year. This trial is for patients who have received previous pembrolizumab, so we are trying to break the acquired resistance to checkpoint inhibitors. Obviously, the first intention is to investigate the safety of the combination. It's a novel combination, so we need to learn about that we are not having any other safety issues. With this trial, once we have it will be the obvious building block for future combinations, the doublets of pembrolizumab plus inotinib and chemotherapy, for example. We're including typical tumors for immunotherapy today, non-small cell lung cancer, head and neck cancer, melanoma, throat cancer. It's now up to 18 patients. We have three sites in the U.S. You have more information, ClinicalTrials.gov. These are the trials to be started that I announced in my third slide. The first one is FOLFIRINOX in pancreatic cancer. This is disclosed already in clinicaltrials.gov. 30 patients initially. We are going to do a dose escalation. We are using modified FOLFIRINOX that is less intensive, produces less neutropenia than the original FOLFIRINOX from Conroy. We are going to open nine sites in France and Spain, and we plan the first patient for 2021. I mentioned about the basket trial, the three combinations in non-small cell lung cancer, CRC, and biliary tract cancer. I will give you, in my last slides, information about the rationale for the indication selection, I'm not going to stop myself here. Again, submission is planned for this year. The triple-negative breast cancer that I mentioned for the combination of gemcitabine and carboplatin in collaboration with GEICAM. Why these indications and combinations? As you can see in our early development plan, we are trying to do many shots in goal. We are going to explore several different indications that likely are going to give us a good variety of information about the safety and potential efficacy of the CAN04 in combination. Colorectal cancer is an obvious place to go. It's a huge unmet medical need. It's the third most common tumor. You have patients after the first and second line of chemotherapy, plus AVASTIN plus cetuximab. They are in good shape and they don't have clear options. The options that they have available as monotherapies, they don't produce responses. They produce marginal survival benefit. Clearly it's an unmet need. Oxaliplatin, among the cytotoxics, is cornerstone in colorectal cancer. Immunotherapy doesn't work for 90% of the colorectal cancer, and we have data. It seems that CAN04 likes platinums. It's a place that we want also to further explore the combinability of nadunolimab with oxaliplatin, same as we are doing in the FOLFIRINOX trial. There is also data speaking for the importance of IL-1, IL-1 beta in the colorectal cancer. We hope also to have this dual mechanism of chemosensitization and, at the same time, changes in the tumor inflammation. Biliary tract cancer is a small indication. It's smaller than pancreatic cancer. Why going into this? Well, first of all, because the standard first line is gemcitabine and cisplatin. You've seen the interesting data in lung cancer with UCS in terms of responses. Almost every patient is having some tumor reduction, why not come in here? It's an unmet need. Recently, only the IDH inhibitors, there is one that has been approved for an IDH mutant intrahepatic cholangiocarcinoma. This is just 10% of biliary tract cancer. Many of these patients progress afterwards, and in the end, most of them will be candidates, if they are fit enough, to receive gemcitabine and cisplatin. This is an interesting option for us. There are some studies, it's easy to find, where IL-1 has been also implicated, this pathway, in the promotion of the biliary tract cancer. Well, in non-small cell lung cancer, we want to cover the field. It's in a small proof of concept arm in this basket trial for the combination with Taxotere. This is, as you know, docetaxel is, in the end, a common second, third line in patients with non-small cell lung cancer. Based on our chemosensitization hypothesis, this could be an interesting opportunity for nadunolimab, and we would like to take it. There is no question that the IL-1 system has been well described, its importance in non-small cell lung cancer development. Finally, is this triple-negative breast cancer. I think it could be a great opportunity for us. Breast cancer is a huge health problem. Thank God, now the incidence of metastatic breast cancer is going down. Still, it's the most common cancer in women. Triple-negative breast cancer, that is a phenotypic definition. A tumor that does not express estrogen or progesterone receptor or HER2, is still 15% of cases. It's probably one of the worst today because it affects younger women, it's more aggressive in general, and it's associated with BRCA mutations. It's a highly moving field, it's the breast cancer subtype when IL1RAP has the highest level of expression. It seems that makes sense to test IL-1 inhibition here. Interestingly, among all the breast cancer, in triple-negative is the only place where the oncologists are happy to give polychemotherapy rather than single agent, and the platinums have shown a clear anti-tumor activity. It's the only place in breast cancer where platinum is used. The gemcitabine, carboplatin combination is used as a standard of care for many of these patients. Why not? It's an excellent opportunity for us to explore this synergy. This is my last slide. We are happy to take questions from the audience. Thank you very much for your time. Yeah, there's one question related to this, and that is concerning if it would be interesting to study the response on a sub-cohort of patients with high IL-1RAP and compare that efficacy data with survival in this sub-cohort. Yeah, definitely it's a good idea always to try to identify or to verify if there are different efficacy, high versus low. IL1RAP is a very novel target. For the moment, we don't have data to separate, to make a cutoff and separate high from low, but definitely it's a good idea. Thank you. Okay. Thank you, Ignacio. Now it's time to leave the cancer area for a while and jump into autoimmunity and inflammatory disease. I would like David to take the stage again and present the latest on CAN10. Thank you very much. Okay. Let's see here. There. Let's leave oncology for a little while then. CAN10 is, of course, the little brother of CAN04, but it's a project that aims to harness the potential of IL1RAP now in inflammatory and autoimmune disease, where there are maybe obvious advantages. I'm happy to do this because I think CAN10 has advanced really well in the last years. We are, in this project, focusing on two indications, myocarditis and systemic sclerosis. These are different diseases in many ways. Myocarditis is inflammation of the heart that can be fatal. It's characterized by an acute inflammation that leads to fibrosis and loss of heart function. Systemic sclerosis is a disease which is a chronic autoimmune disorder that leads to fibrosis of the skin and internal organs, and often the cause of death in this disease is lung disease or heart disease, actually. Even though these are quite different, there are some connections. Vascular inflammation is important in systemic sclerosis, and heart failure is one reason for death in this disease. In myocarditis then, fibrosis of the heart is a reason why you lose contractile function. The rationale for CAN10 is now that IL1RAP, as we talked about before, it interacts and is crucial for signaling from IL-1 alpha and beta. Actually, IL1RAP can also interact with the IL-33 and IL-36 receptors. In this way, it's required for signaling through three different signaling systems. These are all exploited by different approaches, so there's drug development in these different systems. The opportunity for us then is, of course, that if we can find an antibody that binds IL1RAP in a way that blocks all of these pathways, we can do something more, and this is what CAN10 does. We've developed an antibody which is a potent blocker of all of these pathways. Like CAN04, you see to the right there's a part that binds IL1RAP and inhibits signaling. The other part that we amplified with CAN04 is here now silent. This is a pure blocker. It does not kill any cells. We've done some conceptual studies with CAN10 just to try to understand the potential of IL1RAP targeting, and this is a simple inflammatory model. You basically inject MSU crystals. This is monosodium urate. This is what creates inflammation in gout, for example. Inject this IP in mice, and what happens is you get inflammation, you get cells into the peritoneum, which is the left graph, and you get cytokines as well that you can measure as a sign of inflammation. What you see here that we've compared here to anakinra or IL-1RA, which is an IL-1 alpha and beta blocker. If you look to the left on the neutrophils entering the peritoneum, you see that IL-1RA has an effect, and CAN10 or a murine surrogate here, an antibody that targets murine IL1RAP, it does the same thing. We do get an anti-inflammatory effect. We see effects on cell infiltration into the peritoneum of the mice. At the same time, we see as well a reduction in certain cytokines. G-CSF, for example, we talked about, is reduced both by IL-1RA and CAN10. IL-6 as well. You also see that for IL-6, IL-5, and Eotaxin, three different cytokines, you have a much stronger effect by CAN10 compared to IL-1RA. This was very important for us to look at this because this shows that IL1RAP blockade is not the same as IL-1 blockade. It has additional value, and it's a stronger anti-inflammatory treatment. The fact that we had a similar efficacy as anakinra as well on, for example, G-CSF and neutrophil is also good because anakinra is a very potent IL-1 blocker. This is another set of data I'll run through, but this is also a conceptual study. This is a psoriasis model, and the reason we looked at skin is because in this tissue, this is where you find IL-1, IL-33, and IL-36. It's all been described, and it's all been described as relevant for example, psoriasis, but also for other skin inflammation. Here we see that if we take, for example, the graph to the left, the orange bar is anti-IL1RAP treatment, and we compare here to anti-IL1B, which is in green, which has no effect. Again, if we use our antibody, we do see a good effect on disease score. This model is a bit different. You have topical administration, so you basically put imiquimod, an irritating agent, on the skin of the mice, and you measure redness and flaking as you go along. The control here is dexamethasone, so that's steroids applied to the skin directly every day. It's a different control. We see after seven days, we have a similar effect. This again shows that IL1RAP inhibition is a potent anti-inflammatory treatment. Okay, the reason we chose systemic sclerosis and myocarditis is we did an exercise with a company called Cello Health to run through, I think it was 154 different indications, looking at disease severity, medical need, patient populations, market size, regulatory feasibility, and so on. Going through loads of parameters to select a few because we realized we need to focus. These turned out as the best indications. I won't mention about systemic sclerosis at this time, since the data we have presented now concern myocarditis. I'll tell you that in systemic sclerosis, you find clear connections between all of these IL-1, IL-33, and IL-36 cytokines to the disease, to fibrosis. That's certainly not an issue there. The models are quite difficult. There's no really good model for systemic sclerosis, but we are working with both human tissue and animal models, and this is something that we will present at the scientific conference at a later stage. Now, when it comes to myocarditis then, I think it's quite clear that IL1 is involved in this disease. IL1B blockade has been quite extensively investigated in cardiovascular inflammation. Also, anakinra IL-1RA has been tested. The reasoning here is a bit similar to what I described before in the tumor, that you have dying cells in the heart that release IL-1 alpha as a danger signal. This is processed by macrophages, for example, in the tissue that release IL-1 beta. This leads to an enhanced inflammation, more cell death, and a vicious circle that propagates this inflammation. By blocking them with anti-IL1, you can alleviate this. There's also an ongoing clinical trial here with anakinra in patients with acute myocarditis. There's less known here about IL-33 and IL-36. There are papers saying that putting IL-33 here and having a role in myocarditis as well, it's not necessarily described. I think one of the main questions for us was to show that IL1RAP has an additional benefit to just IL-1 blockade. Here we have good models. This is an experimental autoimmune myocarditis. Basically what you do, the blue bars in the top at day zero and day seven, is that you immunize the mice with heart protein. You create an autoimmune reaction to the heart, and you get the peak inflammation about 14 days after the first immunization, and then after a while, you get fibrosis, and the heart function deteriorates. You can measure this, as you see in the lower left, by doing echocardiography. You measure, in this case, the main parameters is left ventricular ejection fraction, how much blood the heart pumps out. As you see here, if we start treating, this is from day seven, with our antibody, which is the orange line, we see in this experiment, we hardly lose any in the heart function while the control is going down. You see anti-beta in the green is not as good as well here. We seem to have an additional benefit here as well. It's the same data from day 14 there to the right, showing that our antibody is actually superior to anti-beta in this case. The reason why we get this effect is that we decrease inflammation. This is to the left here. We see fewer cells infiltrating the heart. To the right, you see that we also decrease fibrosis. This makes sense from an anti-inflammatory treatment. What's also good about these experiments here is that it's actually treatment from day 14. Here is when you have the massive inflammation, you don't start treatment until then, and you still have good effects. There's more data from this on the poster, but what we say there is that CAN10 blocks not only IL-1 alpha beta, but also IL-33 and IL-36 alpha beta gamma. Six different cytokines that signal through IL1RAP. Blocking IL1RAP then is a potent anti-inflammatory strategy, and importantly, it is qualitatively different from pure IL-1 alpha and beta blockade. It's not the same thing. IL1RAP blockade counteracts inflammation, fibrosis, and the decrease in heart function, and has additional value compared to IL-1 blockade, and actually prednisone as well. Those data on the poster, but comparing to even anakinra or prednisone, we have a better effect with our antibody. The model, I think, has to be adjusted a bit. As we saw before, dying cells release IL-1 alpha, but they actually can release IL-33 as well, and the cardiomyocyte, at least on RNA level, express IL-33. Endothelium and macrophages can respond to this and produce IL-1 beta as before. Endothelium actually responds to IL-1, but also to IL-33. If you have both of these cytokines there, you will have a stronger signal. Infiltrating cells like granulocytes, if it's eosinophils, they will also react to IL-33 and participate in the inflammation. By blocking IL-1 alpha, IL-33, IL-1 beta, and possibly IL-36, we believe we have a more potent effect here also in myocarditis. Where is CAN10 now? Well, we're doing CMC development and we're doing production, but for safety and clinical studies, that's ongoing very well. We will, during this year, complete the safety program. We communicated that we did the first tox assay already, showing no issues up to, I think it was 15 milligrams per kilogram. We will do further studies during the year to prepare for the clinical part. We will also have interactions with health authorities to go through our clinical program. Next year, we will have the CTA submissions, and we will start the clinical studies. We will also prepare for further clinical development in myocarditis and systemic sclerosis. That was my last slide of this presentation. Thank you very much. Yeah, there's one question related to your presentation, David. Yeah. It revolves around if you're able to elaborate on why IL1RAP blockade would be superior to anti-TNF in the proposed indications. That's a more difficult one, but it's a good question. Anti-TNF, it's a more specific molecule, so it interacts, and it's amplifying inflammation in a way. The IL-1, 33, and 36 will be much broader. IL-1 will induce TNF, for example. Those often goes hand in hand. If you reduce TNF, you will still have IL-1 there, and you certainly will have IL-33 and 36. Again, this would be a broader effect. We may imagine that by blocking IL1RAP, we'll have reduced TNF levels as well. I don't think it will be the opposite. Thank you. If I understand correctly, there are no more direct questions to CAN10. I think we have reached the end of the presentations, and we now have some minutes left for additional questions and answers if there is anything that has come in here or if there's anything that anyone would like to ask. Just a couple of questions. One is regarding if you will be able to identify methods to pretest patients that will react positively for the treatment and also identify non-reacting patients in order to make the treatment more successful. Yes, I think in the cancer field, so I guess this is for pancreatic cancer, definitely it seems that this phenomenon of pseudoprogression could be something predictive. Obviously one of the attempts that we are trying is to identify clinical factors to potentially enrich the patient population to increase the success rate. Thanks. Regarding the PDAC study, this is a specific one regarding how many were defined as in Stage III and how many in Stage IV. Yeah. 90% of patients were Stage IV metastatic. There just were a few, I don't remember if a couple of patients were S tage III and resectable. Yeah, a follow-up question to that would be, do you think there is any value for CAN04 in earlier stages of pancreatic cancer? Well, it's early to say, but the normal development, for example, gemcitabine ABRAXANE was first registered in metastatic pancreatic cancer, that is the majority of patients, and then it's moving to neoadjuvant or adjuvant treatment. This could be the natural development path. Yeah. There's a couple of questions regarding the future plans for PDAC. They are mainly focusing on whether you will apply for a Phase III study in the near future, or if there's any other plan for this indication going forward. I can start. Then you can fill in if you like. Obviously we are very encouraged by what we've seen so far. Obviously we're going to take this program forward. As Ignacio said, there are some aspects like we need to have more data on various dose levels before we can go into Phase III. It's things that are ongoing right now to fill that gap. We are recruiting patients. We expect the last patient to enter this part of the trial within a few months from now. Then we are ready for having complete discussions with the regulatory authorities. In parallel, we are doing everything we can to prepare our files and have a suggestion for them. I think we need to be humble to say that next steps is not really controlled by us. It is really in an interaction with what regulatory authorities think. We can be clear, but we are definitely going to advance this program, and then exact details we need to come back with. We have no desire to sit and wait and let time go by. We understand that there is a time pressure here to advance the program. Thank you so much. Is there anything you would like to add on that, Ignacio? No. Thank you. Thank you. I'll move on to another question then. Do you believe you will need to show an OS benefit from the Phase III trial for approval, or will you believe a PFS alone benefit would be sufficient, provided that there are only quality improvements? Yes. Traditionally, in pancreatic cancer registrations, until the PARP inhibitor has been based on survival, among other things, because unfortunately the survival event happens very quickly. It's not one of these tumors like ovarian cancer or pancreatic cancer that PFS is an accepted registration endpoint, among other things, because the disease is very long. Patients have many lines of treatment. There is a lot of confounding factors. Traditionally, in pancreatic cancer, it has not been like this with a median survival time shorter than one year. I believe, but this is just my personal opinion, that the still survival is going to be the registration endpoint. Maybe, in the case of PARP inhibitors, when you go into very small, very focused, targeted treatment, when you have already a clinical proof of concept in indications in breast cancer, in ovarian cancer, I would say that regulators should feel comfortable by doing so. I'm not so clear that this is going to be generalized to every drug. In any case, as Göran mentioned before, our plans are going to the regulatory authorities with these kind of questions. Thank you. Moving on. We've recently seen other companies with IL-1 targeting assets initiating clinical trials for pancreatic cancer. Could you please elaborate a bit on the differences between those studies and the study you have been conducting? Yeah. I can start, and then if you'd like to fill in. We're well aware about the study that Manuel Hidalgo presented earlier on showing the relevance of interleukin-1 beta in the context of enhancing PD-1 reactive antibodies in this field. There are trials ongoing where PD-1 or PD-L1 antibodies actually combined with chemotherapy and an IL-1 beta antibody is being tested in the first line setting. We're also aware about second line trials using an interleukin-1 alpha antibody, which are just starting. To be very clear, we are well ahead of those development programs right now and clearly believe that our competitive edge is around the chemosensitization and counteracting chemo resistance. We believe that we have big advantages, even though with full respect of those programs. Thank you. Moving on. The fact that you've been using a different protocol for the pancreatic study compared to historical data that you've been benchmarking against, do you think that that could be a complication when interacting with regulatory agencies? Well, I'm not sure if I get the question about the protocol. It's concerning the RECIST criteria. Okay. RECIST criteria. Now I get it. Well, obviously every novelty. requires a new regulatory consideration. We don't know to what extent in other indications with other drugs, FDA or EMA or national authorities have been discussing the situation. Definitely, it is for the good. It is not really changing the endpoint. Imagine if the endpoint is going to be survival, that is the classic, is not affected by this directly. It's only the conduct of the trials. We all understand that in the minds of authorities and everyone is to maximize the benefit of participants in the clinical trials. Here it will be even an ethical dilemma to say that you need to discontinue patients that may have prolonged benefit, as we are showing. It's a discussion that I'm happy to take. Thank you. I think this should have been sort of the main message of this session. There's questions regarding how do you view your own results that you were able to present yesterday evening? Are you happy with the results? Well, all three of us can join to say that, yeah, I think it's been pretty clear that we're very happy. Yeah. That was my view as well. Going on, Yeah. Do you see any early hypothesis generating biomarker from biomarker signatures that could indicate some patients that are more likely to benefit from CAN04 than others? Well, I don't know. Maybe David should explain what we're doing in this field. Yeah. This is something that we're actually looking at, and what we're doing is two things. First of all, we're measuring soluble serum biomarkers in there, we can look at factors, and we can follow through treatment, how they change. That's something we're going to do, of course, or that we are doing. The second one is to look at biopsies from tumors, and there for patients, we have biopsies before and after treatment. There we're of course looking at changes as well to follow. We're also looking at how do the biopsies look when the patients go in the study, and which patients then respond best. If we get any clear data out of that will tell us, it will guide us, we'll see. It's some really interesting analysis that's ongoing now. We will look at that definitely. Do you have any timeframe for when you will be able to sort of disclose more information on that? Yeah, I don't think so. I think we need to come back. There has been, let's say logistically, it's been more complicated to validate all these analyses than we planned for originally. Since patients are still on treatment, we're getting more and more information, so we need to come back on that. Yeah. We want to have all the information. Again, we like to be transparent, so whenever we have something which we feel is robust, we will communicate it. Thank you. Getting back to the Phase III issue, could you give any sort of flavor on the potential design and dimensions of a Phase III design within this field? Ignacio. Well, obviously, a Phase III is something that, at least with FDA, you go to an end of Phase meeting, and you not negotiate because it's quite clear and transparent, but there are some unique things that are necessary. One is the discussion about the dose, what to do with these patients with pseudoprogression, the follow-up of patients, the safety management team, things like this. So far, the Phase III design in pancreatic cancer has been relatively simple, unless you've been selecting patients for some very well-defined mechanism of action as PARP inhibitors. It's a randomized trial, two arms, one to one, and normally it has been classically 400 patients in total. This is what is published for others. I don't think that there are reasons to think that FDA or EMA or competent authorities are raising the bar for efficacy with hazard ratios more stringent than the old ones of 0.75 because still, this disease, most drugs fail. It's a field that has been difficult to advance, as you all know. Thank you. Finally, could you say something about the first human study within CAN10? Will it be a trial in healthy volunteers, or are there any thoughts on that? Should I start and then you can fill in, David? Sure. Basically, there are a few different options on the table now. Since we're now, let's say, addressing autoimmune inflammatory diseases, it's not like cancer where you automatically go directly to patients. Healthy volunteers is one option. You can have some kind of patients, all comer being a different option. You can have patients with some kind of dermatological disease or relevance, or you can do some kind of mixture of everything where you start with healthy volunteers and then let's say bridge over to these type of patients. No, the final decision has not been taken exactly how to do this. Thank you. We just got one additional question. Do you have any explanation on the deterioration in objective response rate? What was announced in October last year about 40% and now showing a 27% rate for that? I can take that one. It wasn't really a deterioration. What we announced was that we had 40% confirmed and unconfirmed, and it was 30% confirmed. Now it's 27% confirmed. I don't think there's a major, and obviously there are some unconfirmed patients here as well. I think what has happened after that communication where we said there are more and more patients with pseudoprogression instead. I think if you add responses and pseudoprogression events, it's been fairly constant all through the trial. Great. I think we have been running through all the questions that have been coming through this afternoon. Thank you. Well, in that case, I’d like to thank the audience for listening to us. I hope this has been very rewarding. I would like to thank Ignacio, David, and Ahmad Awada and Manuel Hidalgo for taking part in this and finally for the organizers who made this possible. Thank you so much.