Good afternoon and a warm welcome to all of you in the audience here in Stockholm today, and a warm welcome to our audience online as well. My name is Lars Frick, and I will be moderator here today. Before we delve into the presentations, there are a few groundkeeping rules. If you need Wi-Fi, log in to the Helio network, and the password is topsecret in small case as one word. If you have the agenda for today, there's a QR code which you can scan in the lower right corner, and then you will get access to the presentations online. In case you didn't receive one of these, they're available at the entrance. Today's session will be divided into, let's say, two blocks. First, an overview of corporate matters and the melanocortin receptors and presentations more on the science side of things. There will be a Q&A session around shortly after 2:00 P.M., followed by a coffee break. Coffee will be served right outside the door, and if any of you need restrooms, they're in the lower hand right corner of this reception area. There will be a second Q&A shortly before 4:00 P.M. If you have any questions, but there is, let's say, a lack of time for the first Q&A, just save it, and we'll address it later in the second Q&A. With that, a final caution, please put your phones on silent. Directors, on behalf of the entire management team in SynAct, I'm very happy to see such a big crowd today. It's our first Capital Markets Day in our company. Very nice to see all of you. I see a lot of new faces. I also see some that I met back in 2016 when we listed the company as Spotlight. It's very good to see all of you. You have been on a, I think, very exciting journey, and it is instrumental that you have been part of this journey, otherwise we wouldn't have been here today and in such a good shape as we will show you we are during the day. We have a couple of our board members present as well, Tore Kvam here on the first row and Uli Hacksell in the back row. Please feel free to grab hold of those guys during the day and have a bit of a chat. Our COO Thomas Boesen is here as well. Feel free to make contact. We have a exciting program, and I'll get back to the agenda in a second. Just a short disclaimer because we will have some forward-looking statements. On the agenda, I will have Torbjørn to present a corporate update, a bit on the company, a bit on where we're coming from, and a lot about where are we today and where do we plan to go forward. After that, Professor Mauro Perretti will take the scene and tell a lot more about the technology. Mauro have been with us for a long time. He dates back from 2010, where he was part of the Action Pharma story, and later on helped us with SynAct. Exciting stuff, and there's no doubt that we can go deep into some of the questions that you might have, especially in that part of the section. Thomas Jonassen, our CSO, and also the founder of the company, will take the stage after that, talk about the peptide programs, the acquisition of TXP, and get a good overview of what we're doing there and what the plans will be, followed by a Q&A session, as Lars alluded to. After that, we'll have a video presentation of Dr. Alan Kivitz from the U.S. Dr. Alan Kivitz have been involved in more than 1,000 clinical studies, specialized in our area. Very interesting presentation as well. Thomas will go back on stage, present a bit of an update on the programs. I can say already at this point that we are on time, and that is a nice feeling in our industry. re as well. Jim Knight, our CBO, joining us from San Diego, made the trip, arrived last night, so completely fresh and ready to give you a good update on where we can position our compounds, a bit on the business development activities that we're doing, and I'm sure that we will receive a lot of questions on that one as well. Torbjörn will wrap up, summarizing a bit on the way we're heading, the way we're going. There's a reception where we will have some nice catering, and I hope that as many of you who can do it, will stay on for some more talks. As many of you will know, I will be stepping down as a CEO here later in the months, at the AGM. I think it's 25th of May. I have had the privilege to be the CEO for nine years, being in the driving seat. I have also had the privilege to be part of the process of finding my replacement. That is a nice feeling. It's not happening every time for CEOs in biotech. I'm very confident that we together with the board have picked the right one. I have known Torbjørn for 20 years, and apart from being a good friend, I've worked with him closely. We have done 3 companies together. They all succeeded. I'm confident that Torbjørn will do a excellent job in driving SynAct forward. Being a long-term shareholder myself, I will make sure that he'll get out of bed and get it going. By that, I would like to hand over the words to Torbjørn, let's see if we can cover as much ground as possible today. Thank you very much. Here you go. Thank you. Good afternoon, everybody. This guy, under his leadership, we have taken SynAct Pharma from being a tiny small company, first a private one, then to the Spotlight, and now to the main market with more than 14,000 shareholders. I think that he would be okay that we have another applaud for the achievement of Jeppe. It's always fantastic challenging to develop a small biotech company, and we need to take the right decision all the time through. However, if like 80% of decisions are right, we're on the right spot. A big question then is: How do we further build value in SynAct Pharma? What do we do in order to be even more visible, even more established what we are doing? For us, it's quite clear. We want to establish ourself as the... Further develop the fact that we are leading company within inflammation resolution. Why is that so important? You will hear Professor Perretti talk about inflammation resolution. This is in fact a mechanism associated with a lot of different diseases. Everything from inflammation as such, autoimmune diseases, to cardiovascular and metabolic diseases. This is a uniform mechanism that makes a lot of damage for the patients, and we need to control that. We believe that AP1189 have that ability. We believe that the rest of the pipeline can have that ability too. That's how we will create value. The mission is really to further establish ourself on that. Okay? Next one is why rheumatoid arthritis as the first indication? It's a very big disease, right? 1% of the world's population do suffer from rheumatoid arthritis. Many small companies would go for small indications as easier to get through. However, we choose a very big, very large indication. However, it's a large indication with a big medical need. We see a lot of patients, and Dr. Alan Kivitz will come back to that. We see a lot of patients that are not controlled by the existing drugs. We believe that 1189 and now resomelagon is the generic name. Yeah, I didn't pronounce it correctly, but, you know, we need to practice on that one. AP1189, we believe is the right one to control that disease. We have the first clinical results, as you know from the BEGIN. We are waiting in about five months' time. We'll have the EXPAND and thereafter the first result study. If they continue to be as good as we saw in the first trial, we will have a more expanded profile of the drug. Jim will talk more about the positioning, how we see the positioning today. We have done market research. We'll put that into perspective. We are doing this because we believe that AP1189 is tailor-made for that indication. However, we also know that AP1189 could potentially be used for many other indications, and that's also an important point, and Jim will come back to that as well. 2022 was a very important year for us. First we got listed on Nasdaq stock main market. Why is that important? It attracts more investors. We will be quite focused also on attracting specialist investors and institutions into the share. That is important for us. We'll have a big focus on that. Second one was filed in open U.S., IND. Some of you might have been involved in opening an U.S., IND. That's troublesome. It's a lot of work. It's linked with a lot of risk factors. Thomas and his team managed to do so. Thomas and Thomas, yes, managed to do so with an A+, I would say. Good work on that. Initiated the Phase IIb in early severe RA. We believe that early severe RA, those that has just been diagnosed and starting on methotrexate is a very interesting group of patients. Also from a market point of view. Jim will come back to that as well. Importantly, initiated the DMARD-IR. Those patients that are not anymore responding to methotrexate, that is the first choice, can we get them into a better control of the symptoms? That's the big question on that first proof of concept study in the first phase of the DMARD-IR. Then, obviously the completion acquisitio`n of TxP Pharma. Why was that so important? It was important because it enlarges our field within resolution of inflammation with many, many more shots on goals, many, many more business opportunities. What we see at the moment is that Big Pharma and other pharmas do get their eyes open for that field. We want to, as I said, establish and further establish ourselves as the leading company within this field. It's important. It complements fantastically the AP1189. Which is, I think Willy said it last time, which is a pipeline in itself. That's important as well. The acquisition of TxP Pharma makes a lot of sense. We have not been able or we have not talked very much about it, but today we'll talk much more about it. Thomas will talk about the peptides, and Jim will talk about the market opportunities that gives for us, that gives SynAct Pharma in addition to AP1189. What's the important milestones this year? Yeah. It's quite self-explanatory, right? In about 5 months' time, we'll have the EXPAND Phase IIb, 12 weeks study. We'll know much more about the efficacy as well as the safety together with methotrexate. That's very important for us, for the potential indication for the first line of the patients. However, it's also important in potential discussions with partners that we can show those results. Really eager to do that. Then of course, the RESOLVE Phase IIa, very important also exactly for the same reason. This is a proof of concept. Can we really do something with those patients that have not any longer been response to methotrexate? That's a very important question that both we as well as our potential partners are looking forward to get the answer. Then it's the nephrotic syndrome, the Phase IIa, 12 weeks. We're recruiting into that. It's a kind of proof of concept for can we reduce the proteinuria in these patients. It's an important question to be answered. We need to develop the preclinical pipeline, push it into the clinical development in order to create more value in our mission. This is the pipeline, and this is the value. This is the value triggers of SynAct Pharma. Quite a bit now. Wow. Is a dentist here? Quite a bit of value that can be created from this pipeline. This is exactly what we're going to push forward. Your battery is running low. Yeah. Right. Maybe close that one. Okay. The hand, we take the hand away. Okay. Let me end with one slide here, and that is, oh, how is the market? How does the market, the pharmas look upon inflammation, inflammatory diseases as a target for M&A and deal making? I'm not saying that these numbers are the one at all for SynAct Pharma. What I'm saying is that we see now an increased interest in inflammatory diseases. Big Pharma has been very focused on oncology, cancer treatment for many years, now inflammation is getting there. We believe it's quite valuable to have a pipeline in Phase II with, of course, good data. The Prometheus Merck deal was the last one that came this year. This had been a very active. Batteries. I think there's no battery left. Okay. Very simple schematic. The inflammatory response start, goes to peak, and goes down. What we and others have been demonstrating the last 20+ years is that this second phase, as I said, is not passive, is active. It carries on. It comes into place because there are specific mechanisms which operate in our body, in your body, to make sure that inflammatory response stops. This is what we call physiological inflammation that we all experience, I hope to experience soon because I got a cold. Once the cold will terminate, means that my body has been dealing with infection in a nice way, and the inflammatory response stops. However, in some or when we have a traumatic, you know, event on the skin or when we have a sting of a bee and so forth. However, as we all know, inflammation can also procrastinate and becomes chronic. This means that the we can harness this biology of the resolution inflammation perhaps for pharmacological purposes. This is the scope of my 20 minutes presentation here today, to illustrate how addressing or harnessing, as I said, the biology of the resolution inflammation, which means the biology of why this line will go down and so inflammation terminates, we can try to exploit avenues, you know, to correct ongoing chronic inflammation and establish what we call resolution pharmacology. All the drugs which have been which we use as anti-inflammatory and been developed over the last 40, 50 years or actually even more recently, like the biologics, by blocking specific pro-inflammatory mediators. Antihistamine, for instance, to block the histamine receptor for allergic reaction. Eicosanoid, of course, non-steroidal anti-inflammatory drugs block the synthesis of eicosanoids. Biologics, we all know block anti-TNF, IL-1, IL-6, you name it, or IL-17 most recently. This is the approach that has been taken for drug discovery in controlled inflammation. I'll come back onto this. The other point I want to make that Torbjörn, you know, mentioned earlier is that we all know since the initial cover of the Time magazine in 2004, but actually we know more, that more and more diseases really have an inflammatory component. Not only the classical musculoskeletal diseases, rheumatoid arthritis, gout, arteritis, you know, polymyalgia rheumatica, you name it. Also clearly lung diseases, cardiovascular, cancer, and now metabolic, even brain diseases as we know for Alzheimer. I've also learned, for instance, that epilepsy as well is controlled by inflammation, not the neuronal firing, so not the epileptic attack, but the frequency of the epileptic attack is controlled by the inflammatory status of the brain. Really by studying inflammation really, we should be able by proposing novel anti-inflammatory approaches one could potentially have an effect on a variety of diseases as shown here. If you focus on RA, I declared I'm not a clinician, so later I think we'll, we hear, we'll listen to an expert in clinical trials. Even I know that there are issues with the current anti-rheumatoid arthritis approaches. There is a proportion of patients who don't not respond satisfactorily, which is ACR70, which essentially is like a remission. There are secondary effects. The most common one is immunosuppression and the re-emergence of infections. There is also, in some cases, a diminished efficacy because our body produce antibodies against the biologics, as an example. Also there are side effects, well, secondary effects associated with the disease like cardiovascular complications, which are not controlled by the current anti-rheumatic drugs. Actually, in some cases like JAK inhibitors or anti-TNF are worsened by the anti-RA therapy. There is a lot of scope, in my view, in trying to carve a or propose an innovative approach for the treatment of rheumatoid arthritis. What today I would like to illustrate, therefore, that by studying the resolution inflammation, one could propose in a therapeutic innovation in a context which will imply a variety of the pathologies based on two major innovation points in my view: integration and amplification. I'm going to demonstrate this or illustrate rather this in the next slide with a couple of schematics. I write here to promote tissue regain of homeostasis, of allostasis. Homeostasis means physiology. You can imagine a chronic inflamed tissue goes back to, you know, as if I were young. Now I start adding allostasis, which means reset up to a point where the quality of life of the patient improves. Maybe it's too much to think that we can go back. You know, if I think about my joint, can I go back to my joint in the way it was when I was 18? If my joint improves and my quality of life improves, then I think it's a good enough result. This is what we call allostasis compared to homeostasis. These are the two schematics I want to say. One is integration. Resolution pharmacology implies that one activates pathways of resolution which normally operates in our body when acute inflammation resolve as an option to control chronic inflammation. By activating, we can set in motion a variety of responses. There is no point, well up to you, to read the specific, what counts is the network. You activate a cascade of events which could re-correct ongoing chronic inflammation. The other concept is here amplification. By acting onto a cell, onto a target, onto a tissue, one can set in motion a gene reprogramming and switch the phenotype of target cell. As such, we propose, have a better chance to correct ongoing inflammation which is associated with a malfunction, if you wish, of a variety of cells, immune cells as well as stromal cells in the tissue. You need to make an agonist in order to activate these responses, in order to therefore harness the resolution of inflammation in terms of resolution pharmacology, as is shown at the bottom here. Quite a few years ago, as Torbjörn mentioned, we start working as an academic collaboration really with SynAct Pharma, and we elucidated the pharmacology or the molecular pharmacology of this compound that you all know. Before I move on this, I would like to take this cartoon from my colleague Trini Montero-Melendez in our institute, simply to say that some of you will remember from the textbook, this is the classical textbook, whereby ACTH, which is the adrenocorticotropic hormone, and we will see later also data from Jim, I think, and others. ACTH is acting by releasing cortisol from the adrenal glands, and then all the anti-inflammatory effects of ACTH are due to cortisol release. However, over the last 20 years, it has been apparent that while this circuit exists and can also exert anti-inflammatory effects downstream cortisol release, cortisol in humans, corticosteroid in experimental animals, there are also peripheral receptors. You see here several cell types like osteoblasts, osteoclast, chondrocytes, fibroblasts. These are all cells which are in the joint, as a matter of fact, as well as macrophages here. These cells express receptors. I trust you know what a receptor is, but essentially it's a target which can be activated by a drug in order to set in motion pro-resolving effects. There are glucocorticoid-independent effects of melanocortins which are not due to the stimulation of the adrenal glands, but they are due to the activation of receptor in specific target cells. When we tested the AP1189, I think Dr. Thomas Jonassen came over and said, "Okay, this molecule here seems to compete on the MC1 receptor," you can see here, "this play, but actually does not activate the receptor." However, it's anti-inflammatory. How come?" You know, because one could say it competes, this pharmacology could be an antagonist, but you would expect an antagonist of melanocortin receptor not to be anti-inflammatory. However, the classical signaling response, cyclic AMP, was not evoked by AP1189. What we found in our laboratory was that another signal response actually was activated by AP1189, shown here at the bottom, and shown better in these graphs, which essentially. I'll take you through this one as an example. Here we have α-MSH, which is the natural agonist of. Then you have AP1189. AP1189 is white and α-MSH is here. This the skew towards cyclic AMP response or towards phospho-ERK or cyclic AMP and towards calcium. Actually, sorry, I'm jumping here. Okay? You will see that AP1189 essentially is 100% not skewed towards cyclic AMP. Even a low concentration, there's no cyclic AMP formation. This is extremely important, first because demonstrate in our view how AP1189 can exert anti-inflammatory effects. It does something in the cells, but it's not what we expected. There is the important issue that increase of this secondary messenger has been associated to melanogenesis. Well, actually not has been, it is. Melanocytes get stimulated by α-MSH as a, as part of a natural response to UV lights by tanning, melanin formation. There has been an anxiety in the field of melanocortins for many years that continual activation of melanocyte might lead to melanoma, really. I don't know whether this is proven or not, but is a, you know, is a sort of red alert. Actually, AP1189 does not act as an AMP, as such will never have the risk to. It will not activate melanogenesis, and as such will never have the risk to potentially induce melanoma. Rather, will maintain the anti-inflammatory effect. I'm going to show here a couple of anti-inflammatory effects, which I'll come back to the end as well. You will see cytokines that you know which are modulated in the release from a specific cell, a macrophage, in vitro by AP1189. I would like to note that you have a what? 30% inhibition, 30%, 25% inhibition. Multiple cytokines, in this case 3 cytokines, as reduced by AP1189 by around 30%-40% inhibition, no more than that. That is important in my view. You have the activation, Activation, increase of phagocytosis, increase of efferocytosis. These are typical pro-resolving effects, which takes place into a tissue once the tissue terminates inflammation and needs to go back to normal physiology. I'm going to show you some images and, you know, data are nice but are a bit dry. These are when immune cells invade a tissue and inflammation resolves, these immune cells die by apoptosis, and they need to be removed very quickly. What you see here, you see apoptotic cells in green, and you see macrophages which have uptaken a large number of apoptotic cells. This is an important pro-resolving effect of the drug. In a context of an acute inflammatory response that resolves, if you focus on the left-hand side here, if you give AP1189 at the peak of inflammation, you accelerate the resolution as well. These effects, therefore, are linked to the really important concept that we like to stress today that AP1189 exert pro-resolving activity, and that promoting resolution is not identical to anti-inflammation. It's a completely different mode of action. It's a completely sort of philosophy, if you wish, as a way to control the inflammatory response. Finally, in our lab, very much before the clinical trial that we heard, AP1189 display antiarthritic effects which can be shown here in this animal model. What's important, I think, in my view, to focus on this data here, where you see that essentially the number of experimental animal with severe arthritis was remarkably attenuated when received the proper dose of AP1189. That I think is important considering also the unmet need. Okay, we are towards the end. Don't know if I'm being too fast or not. On the left-hand side here, we highlight the current anti-inflammatory therapy, which of course is important. You know, it would be very stupid to dismiss this. Glucocorticoids, methotrexate, you heard H1 antagonist for allergy, NSAIDs, non-steroidal inflammatory drugs, you know, for cold, in fact, as a matter of fact. All these drugs which have been developed since the seventies up to 2010, act by blocking. Blocking the synthesis of prostaglandin, blocking a specific cytokine, blocking leukocyte migration, blocking this, blocking that. Usually, I actually, my own experience, big pharma, you know, the more the merrier. The more you block, the merrier. 90% minimum, if not 100%. However, we now know that that leads to immunosuppression because, as I said at the beginning, inflammation is good. It's not bad. It's when it persists, when it's unabated, when it's uncontrolled, that is bad. On the right-hand side, you see what we propose with the resolution pharmacology, whereby, you know, there are several potential candidates like melanocortins. You can increase the phagocytosis, you can induce apoptosis. Doesn't matter what is the specific event, but I want to stress induce. You activate, you set in motion events, you don't block. This is important, in my view, which relates me to what when I highlighted the moderation of the cytokines, 30%, 40%, that, you know, 25%. It's a really a moderatory effect that these compounds have, at least in preclinical settings. That, I think, is important because the prediction, therefore, is that there will not be immunosuppression, and there will not be toxicity associated with the administration. It seems to me that the current Phase I trials at least indicate lack of toxicity, which is also important. For many years, there has been the obsession with the magic bullet. Give me a magic bullet to treat rheumatoid arthritis. Probably doesn't exist, a magic bullet. What we need, we need a combination of therapies, or we need an innovative approach to therapy, which what you see here on the right-hand side. Here I put α-MSH. It could be AP 89, it could be other molecule. By essentially activating and targeting multiple mediators, activating multiple effects as a, in order to achieve a broad action and to avoid immunosuppression. I'm afraid resolution pharmacology require an 180-degree completely different approach to drug discovery. I speak, of course, at the preclinical level because I have no clinical qualification. You know, you can see the 100% the table, we want to activate. We think that. Sorry, we want to activate the responses. Here is by no mean an exhaustive list of a variety of molecules which are based on the fundamental biology of the resolution of inflammation, which are at different level of development. I say by no mean an exhaustive list because these are things which I know, but there are other things which I don't know but still may be happening. To finish in the way I started, we have a chronic inflammation that leads to arthritic diseases, metabolic diseases, you know, cardiovascular diseases, CNS, and so forth. Far, we propose, we and others propose that not only is important what promotes inflammation, but it's important what resolves inflammation. Lack of resolution could, at least in part, contribute to ongoing chronic mechanism of inflammation during pathology. Second consideration is pharmacological. So far, for anti-inflammatory drugs, we have ignored 50% of the physiology because all the drugs which are available have been developed by blocking this or blocking that in the pro-inflammatory phase. The proposal is that we want to harness this and make resolving drugs, and by doing this, we will be exploiting the patient's own mechanism, really. That's what I wanted to say today. Thank you very much. Thank you. Thank you very much, Professor Perretti, for a very informative presentation. Now we have the pleasure to welcome CSO Thomas Jonassen to the stage to talk more about the preclinical peptides in your acquired pipeline. Welcome. Please. Thank you very much. Before I go to my own presentation, I would like to thank Mauro for a splendid presentation really. As was slightly alluded a couple times, we have been working and especially I have been working with Mauro for more than I think we started in 2009, 2010, and been working on different projects since then. It has been a privilege and really have opened up my understanding of the potential in melanocortins agonist as a potential for treating among others autoimmune diseases. I think we just briefly also have to mention that Mauro had been living in London for 30 years. He is a professor at the William Harvey Research Institute in London, which is a fantastic translational pharmacology institution originally founded by Sir John Vane, who got the Nobel Prize for his work also in the inflammatory field. Mauro has been a co-director of William Harvey Research Institute, and the last five years, I think it was, he has been and recently stepped down, has been dean of research for Barts and London School of Medicine, and published several hundred papers in this field. It has really been a privilege to work with him and also to have him on the stage today. What I'm going to say is to give you a short introduction to the peptides that we bought from TxP Pharma and where that where on a technology originally invented by Thomas Poulsen, our COO. We see as highlighted, we see opportunities in melanocortin biology beyond the possibilities and the large amount of possibilities we have with the Resomelagon or AP1189. This slide has already been shown, but it's just to say that we have the small molecule AP1189, a biased agonist for stimulating MC1 and 3 receptors present on white cells and thereby with the potential to have an oral treatment approach. And I will, after the break, come back to pharmacology and that, a little more on kinetics and others. To the program that we are running today. The peptides, they give us additional opportunities. They give us also opportunity to have in-hospital treatment of diseases where IV treatment would be specifically good. It gives us possibilities for slow-release formulations, not at least inspired from what Jim will come back to later today on the potential in what has been for years been restricted to ACTH-related therapy, but to have the same pharmacological potential of the compounds without the MC2-mediated side effects. This is another way of saying the same. The MC peptides are compared to the AP1189 compound. They are classical agonist to the receptors, meaning that they stimulate both the MC1, both the cyclic AMP way as well as the ERK phosphorylation pathway and thereby can be given as a full agonist potentially, whether that have additional pharmacological effects in some circumstances probably has. It has the potential, as I said, as going for IV and sustained release formulation, and we can apply that in severe acute inflammation. For example, the program that we ran during the pandemic with the giving AP1189 in COVID patients. Some of these patients would most probably have benefited from having the possibility to get a melanocortin receptor agonist as an IV formulation. We really see potentially in having this now and our opportunity to broaden our pipeline. The concept of the peptides is Thomas' invention of BAP technology. It stands for a Branched Amino Acid Probe, and the whole concept is that by adding a number of positive loaded peptides to the N-terminus of a given melanocortin peptide, you of course, get a new chemical entity. You also, very interesting, as I show down here, increases the binding affinity for a given compound. If you modulate α-MSH by the BAP modification, we increase binding affinity and also the efficacy of the maximum efficacy of the compound, of a given peptide, and thereby we have the potential to have a more potent compound. In addition to this is simply just a table to give different examples of what is possible. If you take TXP-35, for example, NDP-MSH is in the literature known as the most potent MC1 receptor agonist and see what we can do here by adding the BAP technology. We increase both the binding affinity as well as the potency of the compound. We have an opportunity here, and they are very stable in formulation, meaning that we can make IV formulations that can be used in the clinic, can be ready for reconstitution and in use. We can make slow-release formulations that make possible to give injections for patient groups where that would be a need, and Jim will come more back to that. Where we are and they do have the same anti-inflammatory and pro-solving effects as would be expected from alpha-MSH and a melanocortin receptor agonist. Here again, a few examples of the ability to reduce pro-inflammatory cytokines in relevant setups and we are of course continuing this development. The concept is as Jim, sorry, as Mauro said, we do not block pro-inflammatory pathway, we modulate them with the melanocortin receptor pharmacology. Here to the right from a model of acute peritonitis, just to say, to show here that this compound TXP-11, is as potent as α-MSH in this model, in this case also dexamethasone. This is a little of how you, you give dexamethasone. In this study that I ran together with the U.S. lab, we saw very nice here effects of both α-MSH and TXP-11 in this model, which is, you could say, what we would expect to see from a melanocortin receptor agonist. There is without any doubt potential in these peptides. What we currently are doing is that we are building up a full pharmacological dose response in different animal models and as well as in human tissue in order to support a first-in-man clinical trial applications. A few years ago, the guidelines for first-in-man studies was changed quite a lot. They meet quite substantial amount of pharmacology and also to define what is called minimum biological activity, pharmacological active dose ranges, and so on. That is what we are currently generating these data, so we can write it up in the investigator brochure and the clinical trial application at a later time point, where we are aiming to do that to be ready by the end of the year. So you can take these peptides, and they will be applicable in critical care. I will show a few slides from other melanocortin receptor agonists that have been tested. There is a clear market in critical care. We know that hyperinflammation is present. It's present in sepsis patients, it is present in major cardiovascular surgery, in major other kinds of surgery. It was present during the COVID-19 pandemic, and it will be present in whenever highly affected influenza patients. Compounds that can modulate this hyperinflammation and bring the homeostasis to bear back, or was it allostasis back, would be a tremendous way of large potential in treating patients where we today have an unmet medical need. In rheumatology, there is a lot of potential. We have until further we have focused in, on rheumatoid arthritis, but there is other, there is gout is a, is a brilliant example of where melanocortin receptor treatment would most likely have a very, very effective, at least in animal models, very effective way of treating. It's a disease that is driven by an acute pro-inflammatory response that you can modulate with our compounds. Then, of course, also more systemic diseases, also more rare diseases have potential with these peptides. Ophthalmology, and that's actually quite interesting because the melanocortin system is active in the eye. There are some companies, for example, Palatin has tried to make a local application of a peptide in dry eye diseases. If you go in more into the ophthalmological diseases, some of them are driven by vasculitis, for example. Again, here, there is local melanocortin system in the eye, and there's without any doubt, large potential of stimulating the MC 1 and 3, and in some cases, potentially also the MC 5 receptors, and thereby have these immune modulating effects that we are trying to obtain with our melanocortin therapy. It's to say that we have different development possibilities, and we, of course, still as a small company, will do that in a smart and very efficient way. Post-operative organ dysfunction is. That was what we worked with in Action Pharma days. It was very, very interesting. We were at that time, PowerPoint, primarily focusing on kidney, on protecting kidney function. I think that without any doubt, say, from the literature, I'm still so impressed by the ability of melanocortins to modulate or to protect organs dysfunction after stress situation, including major cardiovascular surgery. From a development point of view, it's very important to be very clear on the readout. It has to be a readout that can be controlled in the clinical setting. Unfortunately, I was beginning in the Action Pharma days, I was also very advocating for doing the easy way just to look at a plasma marker and make all company, make the conclusions from there. Now you have to in very, very, very specific and well set up studies, it would for sure have the potential to help the patients because the case is that more organ dysfunction is in more severe patients. It's the lung, it's the heart, it's the kidney, and actually also the liver. When they are affected, there is highly a very high risk for more severe disease. If you have put a affection of your organs when you are admitted to ICU, intensive care unit, then the in-hospital mortality is significant. There is really potential here to make a development program set up in a smart way. I take this slide here from an old paper from Rob Staar at NIH lab. Probably the most, I mean, it's still a fantastic paper. It's more than 25 years old, what he did was or rather what they did in that lab was that they made models of ischemia-reperfusion of the kidneys, and then they treated with α-MSH, and they did that in a therapeutic approach. They induced ischemia-reperfusion, and you can see here if we concentrate here down to the right, creatinine then increases, indicating that you have severe affection of the kidneys. If you then give your compound at the time of reperfusion, meaning that you have had half an hour's insult or an hour, depending on the model you use, if you give α-MSH there, you can protect them against the development of kidney failure. That's fine, but nobody knows when it starts out in the real clinic. You with α-MSH, and it's probably the only compound I have seen so convincing and other melanocortins, you can start treatment several hours after the induction of the insult, meaning that you can apply the compounds, potentially can apply melanocortin receptors in a therapeutic fashion that is very seldomly that you or in preclinical models like this actually can obtain. In basically, what we have said for years is, as long as you start your treatment with an α-MSH analog within 6 hours from the insult in a relevant disease model, you will have full effect of the compound. This what he did, and that was what originally inspired us to set up Action Pharma and for the full journey that is now SynAct Pharma, among other. This was then from the Action Pharma days. We worked together with Rob Staar in this case here before I start working with Mauro, and we tested in a sepsis model. Here the take home message was that if we went in with the Action Pharma melanocortin receptor peptide and gave that in a delayed fashion, that means that we gave the first dose 6 after, 6 hours after induction of the disease, it worked as well as if we gave it at the time of induction of the disease. Again, we had a therapeutic window where we can start treatment. It was not only a question of reducing the kidney function, we looked at that, but the liver function was, we could modulate that, the degree of liver inflammation. We had here a very interesting splenic caspase activity that was significantly reduced, indicating that we overall modulate the immune system in a very beneficial way. We had reduced NF-κB activation, thereby a reduced systemic activation of pro-inflammatory pathway. We also here shown by reduction in circulating pro-inflammatory cytokines as TNF-alpha. In addition to that, we saw marked effect on different organs, including the kidneys and the heart. Again, large potential in melanocortin receptor agonist, and we are currently running a program to show that it's actually the same with the current compounds, which then could be taken further into clinic development. 1189 is the most advanced. We have. It's designed, as we said, with the BAP technology. We have anti-inflammatory pro-solving effects in relevant models, and we are ongoing with the program. We have developed it for IV treatment, so we have a very stable IV solution for reconstitutions. You can set up an IV infusion of the compound. We actually have tested this in toxicology. We do have the tox program, and we do have PK profile. It generate the toxicological profile that I would expect from a melanocortin receptor agonist. Also, there's no surprises here, we can set up a clinical program based on this. As I said, we do have the compound control product produced in collaboration with Bachem in Switzerland, world leading in manufacturing of drugs for peptide drugs. From that perspective, it's a very, very good hand. As I said, we are running the pharmacology program, and we'll come back to you later this year on the programs moving forward next year. With this, I think I would say thank you and come back. As I said, I'll come back to the 1189 program after the break. Thank you very much, Thomas. Perhaps you could remain as it's time for the Q&A session. If any questions, please raise your arm, and you will be handed a microphone. We start off with you, sir. Hi. Gonzalo Arteaga from ABG Sundal Collier. I have a question here for Professor Mauro Perretti. Come up and join. Hello. Hello. Yes. I mean, thank you very much for your nice presentation. It's very clear how you show the resolution of inflammation biology. My question is in the space of rheumatoid arthritis, I mean, it has been shown, I mean, you have shown in preclinical data very nice how like stimulating resolution of inflammation can play a crucial role in the development of disease. Also in human patients, it has been described that macrophages from the synovial macrophages, I mean, they have, especially in patients that are in remission, these macrophages have a pro-resolution phenotype. They have high expression of MERTK, they have high expression of CD206, and so on in this anti-inflammatory pro-resolution phenotype. I was wondering, I mean, as you say, this is not a one-shot cure, let's say, to resolution inflammation. It's a well-orchestrated process. I was wondering in this biology, the signaling through melanocortin receptors within the whole space, I mean, there are other like there's resolvins that play there. Resolvin D1 has been identified also in arthritis. Signaling through melanocortin receptors and in naturally, where does it play a role in resolution inflammation? It's more like in the late stage of the resolution at the beginning, or it's like cellular-driven macrophages, neutrophils, I mean. Good question. You are referring to the Oliver Nini paper in Nature Medicine with the MERTK subtype of macrophage, which actually have the enzymes for resolvins, as a matter of fact. To know how, you know, which phase of an ongoing inflammatory response is particularly sensitive to a pathway, I think, you know, it's not easy. I think the way to address this question is to think about knockout data with knockout animals. If you remove MC1, if you remove MC3 receptor, for instance, what happens to the arthritis? Which phase gets affected? The first paper we published in 2010 using a model of K/BxN arthritis, which also Oliver Nini and colleagues have used pre-clinically, although that study is clinical, and we see that there's the late phase. Usually, you don't get an overshoot of the inflammatory response, but you have a procrastination of inflammatory response. In absence of a melanocortin receptors, you also have a higher degree of activation, at least in our settings, of osteoclast activation, in context of arthritis. I think by basing the knowledge on the transgenic models where you lack specific pathways or elements of specific pathways, you can see which window is mainly affected. A majority of cases with a MC1-deficient mouse, which is not knockout but is a yellow mouse or MC3 knockout, you see is the late phase of the arthritis which is affected. Thank you. In the context of a rheumatoid arthritis, in a chronic disease, there are multiple pathways there. It's clear there are the cytokines, there are resolvins, there are melanocortins. It's difficult to tell what is the contribution. The point, though, resolution pharmacology is how do you intervene? One option is that you can also intervene by pushing and activating pro-resolving pathway as a way to rebalance the disease. No, very clear. Thank you very much. If I can make another one. Sure. It's same. It's okay. There's a whip fast at the same time. Okay. Sorry. Yeah. No, no. Whip fast. I mean. No, no. Sorry. Yeah. A second question now. It connects well with the first one. It's this translation animals to humans. I mean, the inflammation resolution literature now, I mean, piles up a quite substantial amount of papers, showing, yeah, a clear benefit by modulating this biology process, biologic process, let's say. In terms of clinic, we're not there yet. I mean, this is something that it's starting now. I was wondering, it's this translation between preclinical to clinical, specifically for, let's say, MC receptor, melanocortin receptors. How is the degree of homology from animals to humans? For example, for MC1, how much can we, let's say, assume that something working in mouse can later work or show some kind of effect in humans? I think that I'm biased here. Would be stupid to say that the animal model recapitulates a disease, human disease, especially if it's a chronic disease where you have multiple players. There is no doubt in my view that animal models can model specific phases of the human disease. My understanding, if you think about melanocortins in, for instance, eye disease, is that there is a huge... Sorry. There is a good degree of overlap between animal work and clinical studies in eye disease as an example. I think there is a good overlap. At the end of the day, you cannot use just a single model. The preclinical package brings together a variety of assays, as you know. That I would say with respect to preclinical model of disease and translation. There is, as you know as well nowadays, a lot of interest in 3D organoids, where you can use cells from patients. It's equally important. The FDA, I think, recently said that you may forget animal model and just do a 3D in some cases. All helps. What counts in my view is what we can push to clinical benefit. I hope before I retire to see a pro-resolving drug and to see whether it's true what we said, that drug will be a pro-resolving drug can be effective, it can be devoid of side effects. Regarding the question of resolution translation, there is a quite a fervid area, as you know. Is it going fast? Is it going slow? I think we are I am grateful to SynAct Pharma to push it. It seems to me that we need the big pharma to come in with a, with a certain strength in order to ensure that we make it to the, to the, you know, to the actual patient benefit. That probably has been missing the last 15 years. Although more recently, it seems to me that companies like J&J, Pfizer, BMS are awakening to resolution inflammation as a potential for new drug discovery. Finally, it seems to me that the melanocortin actually is probably the most translated. You know, there is I can't remember now what is the commercial name, but there are 2 or 3 Acthar. Acthar Gel, of course, but also the most recent one for that, skin disease. Acrinovals. Acrinovals. There are drugs which have been, which come out from melanocortin, research in the clinic. Thank you very much. Thank you. Professor, may I just have a follow-up? Sure. From a layman's perspective, I mean, you talked about functional selectivity in your presentation, but you're still working with the signaling pathway cascade, right? Could you give us some flavor perhaps about possible secondary effects from using this treatment? Well- ... especially since we're talking about a chronic illness, so I guess that's... I mean, the proof of the matter is the actual patients' data. It seems to me that, from Phase I clinical trials from Action Pharma, from SynAct, from actually ResoTher as well, and now BMS, I've not seen any side effects or toxicology, toxic effect to be reported. In some cases, if I think about anti-B therapeutics, there has been a, you know, a couple of volunteers which had enzyme liver elevation, but that, you know, is always a bit nebulous to see whether it's the drug or actually the volunteer is a chronic volunteer in clinical trials. That guy has received everything. My view is that the pro-resolving mediators, since that or drugs based on resolution, since that is the way we deal with it, our body, there is a fail-safe mechanism. By agonist, an agonist, you know, act up to a point, then there will be a receptor internalization, and then the signal stops. It's very difficult to overdo it, if I can say. It's very difficult to damage other organs in my view. That is my view, which is partial. The proof will be in the clinical data and see whether this is true or not. Still feels very reassuring though. Tomas, a question for you. In your slide, you mentioned you have something like 70 peptides in the portfolio. Just for clarification, the TXP-11 is the one you've chosen for moving forward with in clinic. Do you have more candidates? Like if that's 70, is that like a gross list and maybe 5 or 10 of them would be potential new molecular entities? The answer is yes. We do have several melanocortin receptor agonists produced also in gram batches. I mentioned a few others, TXP-35, where we have had where we have. Have generated work supporting that it would be feasible for slow-release formulation. I think it's also what we have said previously about that. I mentioned 59 as another example. I also, in one of the slide here, I had modification of γ-MSH, which is a variant of α-MSH. In principle, γ-MSH analogs have for many years, not at least from Mauro's lab, been described as preferably MC3 receptor selective. We have a couple of peptides there that stimulate that way around, and then the same concept is more potent than the endogen peptides. Yes, we also have the Thomas have generated or applied the technology to other targets. I think we recently reported that we had got a patent app or a very positive re-review on modulating GLP-1 peptides. The fact is that they increase by modulating, by adding the BAP technology to a given GLP-1 peptide or GLP-1 analog, including the. You have increased binding affinity and activity. We had a head-to-head with the. I think that's in public, in published in our patent applications, is that we head-to-head with the Zealand's originally GLP-1 analog. We were one decade more potent. That was mediated, modulated in a way very similar to what we do with BAP, but with their technology. Yes, we had applied that to other peptides also. There is a potential outside melanocortin receptors. If we sum up what we have done and in the patent applications and so on specific structures, we have quite a substantial number of peptides and possibilities. Perhaps this is a question for Thorbjørn then, but, looking at the overall pipeline, I mean, you have several projects in the clinical phase, and now we have the portfolio of peptides. I guess it's a matter of distributing resources to decide how much to push and... With that in mind, could you perhaps give us a little bit of background on the financial position of the company as it is today and- Yes how much you can do with the current financing? Yes. Yes, absolutely, Lars. The financial position today is quite good. We have enough resources to drive the studies to the end. Yep. Also including the work, some work on the peptides. However, as a biotech company, we would if we had more resources, we would be able to drive the pipeline even more. Right. We do not have any current plans to raise more money at this point of time. However, we are in a good position that we are expecting the data in about 5 months' time. Then, let's see. There's one fact, and that is that we need more money to drive SynAct Pharma further on. We're a biotech company. We need to be strong in any aspects when we are starting to talk to potential partners. We need to be independent all the way through. We need to drive the agenda and that is extremely important. At this point of time, we have. Yeah ...a quite a good, position. I guess after the data readout, hopefully it's positive data, and then, of course, that would reinforce your position versus potential partners or... Yes. We'll start talking to potential partners, and we'll start that process early on. Mm-hmm. Uh. This is maybe a little bit of a murky question, but I've heard that Big Pharma has become more interested in early-phase research in the last few years. I mean, versus like maybe 10 years ago, it was always late stage that took the big price money. Do you see this trend that perhaps, for instance, with obviously your peptide portfolio, that you could make a deal maybe even in a preclinical phase? Or do you have to move into clinic in order to commercialize the projects? As I said, the addition of TxP Pharma into SynAct Pharma was a strategic important deal for us because it increases our optionalities to do business and to do drug development within important indications. Of course, when Jim, Thomas, and I are out talking to potential partners. Mm-hmm ...we have everything in our suitcase. Yeah. Right? However, the main focus for us now is to get the data, to review the data, to talk about the data after the finish of the trials, then talk to the equity market, in parallel, talk to the potential partners. Mm-hmm. Do we have any further questions from the audience? Please raise your hand and, take the opportunity now that you have company management, available. We have a question here, please. Just a second, and you will get, a microphone. Hi. This on? Hi, Alex Holst from Carnegie Brain Ganglion. I was just wondering for your, for TXP-11, what kind of additional disease model studies are you looking to do this year? We are running acute organ failure models, both sepsis induced and ischemia induced. We are running together with Mauro in Mauro's lab, we have general inflammatory models. Also, I think a part of it is also to test some of the peptides in arthritis models to again, to benchmark them to other and to get full dose responses. Could you see, let's say, one of the peptides also then going into RA potentially, how would you expect then the sort of... Yeah, that. Safety efficacy trade-off to compare to the lead molecule you have? I would see a peptide even as a slow release formulation to be set in another setting than TXP than resomelagon. There is potential, of course, there's potential for. I mentioned gout, for example, where peptide agonist, I have a feeling that that should be specifically potent. Of course, I mean, you should never exclude it. There's also a possibility to local administration with peptides. It's used widely with glucocorticoids today to try to control more avid inflammation in single joints. We know that it's used to try to control the need for diseases and exacerbations, but we also know that it's associated with a lot of side effects. Also, recently, the rheumatologists have understood that it's not only local, which is, of course, there's always an infection risk that it didn't, you know, and immunosuppression and infection is not good, but there's also local toxic effect with, with cartilage destruction and so on. Then there's a spillover, which is systemic effect. Something, whatever that we can go in and, and, and have as tool to reduce the use of glucocorticoid would be of interest. And there melanocortin in the research agonist could play a role for sure, and should potentially could do that. That's my perspective. Got it. Thank yo u. Right. We're almost out of time, so just a final question here. Obviously, there is a CEO change coming up. Most of you who have followed SynAct, of course, know the background here, but perhaps Thorbjørn and Jeppe could just give us some idea of what preceded this change in the CEO seat. When Jeppe and I talked about the next stage of the company's development, then, you know, Jeppe and I, we are complementary in many ways. We are quite alike in some ways, but we're quite different in other ways as well. Jeppe is a entrepreneurial spirit, starting a lot of companies. I'm talking for your sake. Shout out if you don't agree. And to be nine years as a CEO in a growing company as entrepreneur, that's really, really good. As I said, he has taken it from almost nothing to where we are today. Right. Now, some other, skills are needed, and where I come in is on the equity side, talking to potential investors and but also on I've done a lot of different deals. The deal-making side is also one of my favorite items. That's, that's good. I love drug development. Mm-hmm. I'm the old grumpy pharma guy, right? In being brought up in the pharmaceutical industry. Well, thank you very much. Perhaps not so grumpy after all, Thorbjørn. Yeah, yeah. Well, maybe not. You know, we've been friends for more than 20 years, and if we do it continuously well in SynAct Pharma, we might continue to be friends. Well, let's hope so. Well, it seems like quite a logical step. Thank you very much, Thorbjørn. Thank you. and Professor Peretti. Thank you. Now it's time for coffee. I hope you all got your refreshments. In the previous presentations, we've heard more about the pathways and mechanisms of inflammation resolution, amongst other things. Now it's time for an interview with Dr. Alan Kivitz, who is a clinician working with rheumatoid arthritis patients. We will hear his view on how to treat the patients and the different, well, the panorama of the disease. Please show the film. Right. It's time to change perspective and get a clinician's view on SynAct's research and clinical benefits. I would like to welcome Dr. Alan Kivitz. Dr. Kivitz is a clinical rheumatologist and investigator from the Altoona Center for Clinical Research in Duncansville. That's in Pennsylvania, USA. Dr. Kivitz is participating in the Phase IIa portion of the RESOLVE study. Thank you for being with us today, Dr. Kivitz. Could you please tell us a little bit more about yourself and your practice? My pleasure to be with you today. I am a board-certified rheumatologist and have been involved with my private practice for 41 years. I work in a single specialty group, which has four rheumatologists and six physician assistants. We also do a lot of clinical trials and have been doing clinical trials for more than 30 years. Our center has participated in every advance in the rheumatologic field for the last several decades. All right. Thank you very much. As we mentioned, you're part of the RESOLVE study, the Phase IIa. Why do you think it's important for clinicians such as yourself to stay active as participating in clinical trials? I fell in love with clinical research decades ago. If we go back many decades, it was a revolution in rheumatology as we started to develop all of the new biologics medications that we take for granted today, such as etanercept or adalimumab. That all started in the late 1990s, early 2000s. To be a part of a revolution like that was just very exciting, and then over the years to participate in clinical trials for every new advance since then. I love the idea of being able to participate in trials and study medications that are still being investigated to see where their role will be, if they have a role, in rheumatoid arthritis patients. Right. That's interesting. Obviously the first step of treatment is to set a proper diagnosis, and that includes the presentation and management with early lines of therapy first line. In particular, could you tell us more about the patient situations in which the AP1189 is being studied and your approach to initiating therapy in this patient group? What are your treatment goals? Over the decades that I've been a rheumatologist, our treatment goals have been modified. Today in 2023, our treatment goal includes remission and also less patients for each medication that we try to judge benefit. Initially, when we have a patient who appears to have inflammatory arthritis, we will do various laboratory tests and X-rays or sometimes MRI if needed to make a diagnosis to confirm the clinical suspicion of rheumatoid arthritis. We look for those laboratory abnormalities that might indicate a more aggressive form of the disease, such as a positive ACPA or a positive rheumatoid factor or what are called erosions, which are damages by X-ray. When we diagnose rheumatoid arthritis, we try to treat immediately. Mm. Decades ago, we would start very slowly and work our way up, and now we realize that we have a window of opportunity where the more aggressively we treat patients at the beginning, the better outcome they seem to have. We will typically treat in the U.S. with methotrexate as a first-line agent. Everyone, unless there's a contraindication, will receive methotrexate. As a standard of care, it typically takes about 12 weeks to judge benefit. From there, if there's still activity of disease, we have to be more aggressive. Methotrexate does not work right away. Sometimes we have to use other temporary measures to help our patients feel better while they're waiting to judge the benefit of methotrexate. Right. It seems that it takes quite a while to evaluate the treatment. Are there any factors that you could see as indicator of a potentially poor disease prognosis or, well, prognostic indicators going through these 12 weeks of methotrexate treatment? Yes, I would say that there are mostly three poor prognostic indicators, although there could be others, but an elevated rheumatoid factor, an elevated ACPA or anti-CCP, erosive changes on X-ray, and there are other factors that can tend to worsen prognosis as well. For example, cigarette smokers who don't respond well to treatment as non-smokers. For the most part, the laboratory data and the X-rays hold the judgment of how aggressive the disease will be. In the AP-1189 BEGIN study, the recruited patients were seropositive, and they had highly active disease. This is quite similar to the patients that's been recruited into the three-month EXPAND study. Can you tell us what your experience been with initiating DMARD treatment, therapy with these patients? We tend to initiate DMARD therapy as soon as we make the diagnosis. Right. We try not to make delay. We try to treat immediately, and if there is ongoing activity of disease 12 weeks later, we'd like to look at biologic therapy, typically as add-on to methotrexate. We tend to be less patient waiting for results. We tend to make decisions after 12 weeks of a therapy. We don't want people on a therapy for a year and say, "Well, it never really worked that well." We want to be able to treat more aggressively, even if we have to make changes along the way more frequently. Right. Could you just add a little bit of flavor to the treatment and tell us how long would a standard treatment last for sort of an average patients if there are such things as average patients? There's no time limit for how long we can continue patients on treatment. For example, this afternoon in my clinic, I saw a patient who has been under my care. We look back, she started to come in September of 2003, so this will be her 20th anniversary, and she has been on the combination of methotrexate and adalimumab for most of those 20 years. There really is no time limit. Her disease is essentially in remission. There's no time limit of how long people can stay on medication if they're not having toxicity and if it's working well for them. Right. I guess the aggressiveness of treatment is, you want to achieve good results as early as possible. Does it have any long-term effects as well, like if you can suppress, for instance, the inflammatory response, that it would have a long-term effect on the, on the well-being of the patient as well? It's all a benefit-risk analysis. On the one hand, we have to consider the fact that being on a long-term biologic, for example, can have negative consequences, but then again, having active inflammation such as rheumatoid arthritis that's not adequately treated has negative consequences. For example... Mm-hmm we know that patients with rheumatoid arthritis have a higher risk of cardiovascular disease with MI and stroke, which we associate with inflammation. We also know that they tend to have some higher cancer risks, some such as lymphoma, associated with higher inflammation. Mm-hmm ... to find the balance between the medication to suppress the inflammation, versus letting inflammation be untreated, which can have its own negative consequences. Right. Well, in your opinion, Dr. Kivitz, would you say that there's a need for additional therapies in addition to what is already on the market and, well, perhaps particularly oral therapies that would be efficacious and safe for this patient population with poor prognostic indicators like high active disease? Well, yes, I do believe that there is a room for improvement. Let's look at what we have available. For oral medication, small molecules such as the JAK inhibitors, they now come with their warnings that prevent us from using them in patients before trying a TNF inhibitor that have their own warning about toxicity and indicate a particular patient profile where they may have added toxicity. Even if we are able to use those medications after a TNF inhibitor and considering the potential negative reactions that they can be associated with, they don't work equally well for everyone. You know, in rheumatology, when we judge benefit, we use various criteria. For example, we use ACR criteria in clinical trials. If we see a patient who has a 60% or 70% ACR20 response, we say, "Oh, that's a successful drug." Maybe an ACR50, a 50% improvement of maybe 40%, you have to look at it the other way. If you have an ACR20 of 70%, that means 30% of people have not even had a 20% improvement, so on and so forth. Not all patients respond. We have to consider the toxicity profile of the medication. Right. With regards to, administration, I mean, for instance, you have oral and injection right now as in the trials with SynAct. How much of a benefit is would an oral therapy be? I guess it's about patient convenience and whatnot. Yes. Considering that we have such limitations as I just described in our. Yeah ... oral therapy, a novel oral therapy that did not have the warnings that our current therapy has and the limitations of when and where we could use it, would be a welcome addition. Right. What responses do you typically get with the DMARD therapy? In a follow-up to that would be, how would you define a DMARD incomplete response? You know, every patient has a varied response. Every patient is different. For every one of my patients, like the one this afternoon, who has had 20 years of good results from the combination of methotrexate and adalimumab, I have patients who have not responded well to a number of different biologics. Every patient is different. In the future, we hope to be able to have biomarkers to predict who might respond best to what therapy. For the current time, we're mostly doing it by trial and error. There is a need for additional therapy, but some people do well, and they could stay on biologic or DMARD therapy as long as they tolerate it and do well with it without the toxicities. Again, everything is about weighing the benefit and the risk and individualizing the care for each individual patient based upon their underlying problems and their activity of disease. Right. That goes with incomplete response as well, that it's a discretionary decision with each patient and his or her situation then. Yeah. You asked what does inadequate response look like? Mm-hmm. It could look like two different things. It can either look like, they're not responding at all, or they could look like they've responded to a degree but they're not nearly in clinical remission, and we think and hope we could do better. There are some patients who would rather, stay with what they are because they're better than what they were, but other patients who are willing to accept the possibility of doing better than they are even if they've respond in part. Right. If you are successful, in the beginning with the DMARD therapy, is there a high likelihood that they will continue to respond positively to the treatment or is it a large fraction that sort of relapse under treatment? What I'm after is, like, if you have a positive response to treatment initially, do you usually tend to stay, respond, have a positive response throughout the treatment, until the end or? That's variable as well. All right. While there are some patients who will maintain their response indefinitely, there are certainly those patients who have responded for a period of time. That could be to a traditional DMARD such as methotrexate, that could be to a biologic DMARD or an oral JAK inhibitor. There are patients who, for reasons unclear, do lose their response over time, and their treatment has to be modified accordingly. Any situation that you could think of happening happens in real life, whether it be the patients who don't respond initially or patients who respond for a while and stop responding or patients who respond and keep responding. Right. It seems like, it's very much a case to case evaluation. Would you say overall that you're satisfied with the DMARD treatment options today? Are there any shortcomings? You mentioned that it would be desirable to see biomarkers on some populations that would respond better or worse on the treatment. Are there any other shortcomings you see with the current treatments that are available? I think the shortcomings are the toxicity potential of the fact that biologic and oral JAK inhibitors have a risk of increasing infection, for example. I had another patient today who has had a total knee replacement, and he had an infection after his knee replacement, and he is not considered a good candidate for biologic therapy. I think that there's always room to have a medication that would have potentially a safer profile and still be efficacious for those people who need other options. Right. If we look at AP1189 and the patient population that's being studied there in RESOLVE, the assessment of the patient population has been initiated in the first part of the study. If the clinical profile of this seen in the BEGIN trial is born out in further Phase II and even P hase III assessments, do you think this could be a welcome addition to your treatment toolbox for your patients today? Very much so. In the U.S., and let's face it around the world, we are basically faced with some restrictive parameters about when we could use what treatment. As an example, we know that if a patient were to receive methotrexate plus a biologic from the day of diagnosis, that they will respond very quickly and completely in many cases. We're not able to start a biologic at the onset of disease. We must wait the 12 weeks for any U.S. payer to approve it. For 1189 to be used for early disease treatment would also require that we're able to access the drug early on as well. It's intended as first-line treatment. Am I correct in assuming that? I think that we would think that that's where it would play a role, but we don't know that at this point. We only see encouraging initial results that have to go longer in duration and then with the current clinical trials get a better sense of where it fits in. Right. Results are encouraging enough to be doing these additional trials and find out the answer to that question. Well, it's all about data in your business, doctor, so that's a very good answer. Delving slightly into the speculative area, Dr. Kivitz, but autoimmune diseases, there are unfortunately quite a lot of them. Inflammation, of course, is a big part of a big sample of that. Would you possibly see that AP1189 could be expanded into other areas as well within this field? I mean, other indications where- Of course, that would be purely speculative. However, other disease processes where there might be theoretical benefit based upon, what we know of the product, 1189 could theoretically include psoriatic arthritis, could theoretically include ankylosing spondylitis, or theoretically could even include other autoimmune diseases such as lupus or Sjögren's syndrome. I think that sums up, this interview. Thank you very much for participating, and, good luck with your trials and your patients, Dr. Kivitz. Thank you very much. My pleasure. Happy to join. Righty right. It's always nice to hear professionals in the field giving some insights into the sort of practical work as a clinician. Obviously, there is a high unmet need. Fingers crossed. Perhaps SynAct will be part of solving at least some of these problems. Now it's time to move on. Thomas Jonassen, welcome back. Now it's time to talk about AP1189. Welcome. The stage is yours. Well, thank you very much. What I will do here is to give you a update on where we are in the clinical programs. Before I do that, I would like just to go a little back to the pharmacology of the compound. Mauro, he made a brilliant introduction, including both this approach of resolution pharmacology approach, showed data in relevant disease models, including the K/BxN arthritis model, which is in many way a very fascinating model to work with. Before going there, our overall pipeline looks like this. That was not in the... Well. We have the ongoing program here in rheumatoid arthritis, severe treatment in previously treatment-naive patients. That is first-line treatment. Patients are referred to. They're referred to rheumatologists, as then Dr. Alan Kivitz highlights today. We start dosing very, very aggressively and first-line treatment is in most cases, both in the U.S. and Europe, if you're following the guideline, that is methotrexate treatment. You start, it's oral treatment. You give a tablet once weekly, and you can gradually then start in typically of seven and a half to 10 milligrams, and then gradually goes up. In Northern Europe here, we are much more aggressive with regard to go up in doses as they are in U.S. and other parts of Europe. For example, in Japan, you are never allowed to go higher than 12.5 milligrams simply because the metabolism of methotrexate is very different in Asian population than it is in European or recent population. Methotrexate is associated with quite some side effects, especially if you get up in toxic doses. The concept is these patients, they are referred to a rheumatologist, and if they are then eligible for methotrexate treatment, we have offered to them to participate in our study. The first study was the BEGIN study that we completed and reported in December, just around December 1st, 2021, where we tested at that time point, we had four weeks treatment, and I will go through the data in the presentation. What we are doing right now is to have the EXPAND study running, and I will also go into detail about that. We reported here two weeks ago that we had completed recruitment in a total of 127 patients in that study, which we are conducted here in Europe. We have also before the break, Torbjørn highlighted that we do have an open IND, meaning that we have been through all the work with setting up interaction, discussing with the FDA and filed all the files in order to be able to run clinical trials in under an IND and that means including sites in U.S. Just to put it a little in perspective, the size of such an IND file is around 1 GB i n PDF files. This is a study where it's built up in two parts. Part A, which is ongoing, where we, as in the BEGIN study, only dose for four weeks. We have the. It's like a dose range and action, so we get a grip of whether or not this compound works in this patient population. We have also the part B. It's actually so that it's fully approved. We have a fully approved Phase IIb study in the in these DMARD-IR patients. I'll come back to the design later. We have the ongoing program in nephrology. We have melanocortins receptors are present in the kidneys. My background from kidney research, well, I find it very interesting, and specifically the MC1 receptor. It's not only a question of the receptors present on the white cells in the kidneys, but it also present on a specific cell that's very, very important for the overall functionality and integrity of the kidney called podocytes. When you stimulate MC1 receptors in these podocytes, you will regain the three-dimensional structure of the cells and thereby everything else, keep the intact functionality of the kidneys. It's the patient population we are currently at dosing this compound is to being considered at least in Europe as an orphan indication. It's not a large study, and it goes steadily forward to recruit the patient and test the concept. The concept is to see whether we can reduce proteinuria. Jim will come back on the potential outside this very restricted nephrology population. The take home message at this time point is that the nephrologist, when they are presented for the concept of this, they find it very, very attractive because current treatment is almost solely some way of immunosuppression with a lot of side effects. We had the virus-induced respiratory insufficiency program running. We were stimulated by COVID-19 and had an investigator-driven study. We set up the RESOMAIR co-collaboration together with Mauro Perretti and Mauro Teixeira and Bill Hoy-Sundin in Brazil and generated some very interesting data. We of course have the preclinical pipeline as well. So to resomelagon 1189. It's an oral available drug that can be given one daily, and that's actually the intention. I will show you why. Currently in Phase II development. The concept is that we have a total of 5 different mineralocorticoid receptors. As we have discussed here earlier today, the MC2 receptors should not be stimulated. That is what ACTH stimulate, and that gives glucocorticoid release. This molecule, like the shorter peptides that we are working with, do not stimulate the MC2 receptor, which is very, very important. Just to be on the very, very safe side, we measure this in all our patients, so we can document that also in a clinical setting. The two receptors we stimulate are the MC1 and MC3, most importantly, and they are present on white cells. Mauro has explained that very much in detail. Just to repeat, in this case here, we have a macrophage. If we stimulate, in this case, an MC3 receptor in the presence of some kind of stimulus, you have a pro-inflammatory macrophage. When stimulating the receptors, we reduce this pro-inflammatory activity, thereby we see a reduced release in pro-inflammatory cytokines. At the same time, we also see that a subgroup of these macrophages, they go out and express another phenotype, a pro-resolving phenotype, a type two alike macrophage you could call it, with this ability to efferocytosis and phagocytosis. Efferocytosis is what Mauro very nicely described as the ability to clear up apoptotic neutrophils. That is one, not the only one, but that's one of the effects of our compound. That is to drive the immune system from a pro-inflammatory state to a resolving state, and then of course eventually with the hope that we can bring it back to normal homeostasis. The effect Mauro has also showed that, but the concept is that we have the ability to reduce neutrophil in disease model here to the right here. We have the ability to reduce recruitment of neutrophils, and that's important. We do never block them, and that's also important because if you block the neutrophils, then get them completely out of the equation, you will induce immunosuppression, and that is really not what we want and not benefit in any settings. We also have reduced release of pro-inflammatory cytokines. Again, never take them out. This the next here is what also Mauro showed. Perhaps just to try that one more time. If we have an acute model here, in this case, we in a disease model with acute neutrophil driven inflammation, if we take the compound on top of the inflammation, then we get the result much faster. We get rid of these pro-inflammatory cytokine. Bring them, bring the system back to homeostasis, and that's among other associated with the increased number of macrophages with the ability to engulf or eat, you could say, and what we call efferocytosis, to take up the apoptotic neutrophils. Just to highlight one more time, as it is a biased agonist, meaning that we go for alternative way intracellular in the cells, we do not stimulate melanogenesis. This is from a publication here from Trini Montero-Melendez some years ago, where we showed that α-MSH as well as NDP-MSH had this ability to stimulate melanogenesis through MC1 receptors, but our compound did not have that effect at all. That is potentially actually quite a good thing because then the risk to get skin pigmentation and in the patient is reduced. So that's just to set the setting about the compound. From a pharmacological, from a pharmacokinetic point of view, that's important as well. It's an agonist treatment, and one thing is for sure, that is if you take an agonist treatment and give high doses and continuously stimulate a receptor, you will get what is called desensitization. That means that the receptor system will be locked down and potentially you can lose complete efficacy through the systems. Whereas if in an antagonist you block the receptor, it does not work. In this case, you can take out a system and then there will be compensated by other mechanisms. In our hand, we had the target to would like to go higher than 200 ng milligram in the plasma in the blood when we gave the compound orally. We reached that here in our Phase I studies after repeated dose, we reached that level in 250 mg given once daily. Importantly, see what we also do, we, if we go up to 100 mg here, we come down through below this orange dotted line, and that is very, very important because then the likelihood to have continuously relevant receptor stimulation is significantly reduced and thereby the risk for desensitization and thereby lose of function is reduced. That is what we gain for, and that what was the aim in Phase I. That was the aim in our BEGIN study, where we used the same formulation, which in this case was a suspension that the patients had to drink. Now we have Developed, that's thanks to Thomas. A very, very nice, very efficient, and very patient efficient tablet. This is here a plasma concentration for healthy volunteers where we compare the suspension that we used in each development with our new tablet. As you can see here, the tablet is spot on with regards to plasma concentration. We can repeat this not going get fast, get fast increase in the blood so we get the compound out to the receptor. In each have the pharmacological effect then also have what we call a trough value during the 24 hours period before we give the next dose, thereby we infuse our pharmacological effect. This compound has then been, is now in rheumatoid arthritis. The BEGIN study was the first study, as I said, that we conducted during the pandemic and it was, we succeed doing that. We conducted the study. Half of the patient was, a little more than half of the patient was recruited in Denmark, Norway and Sweden, and the other half was recruited in Bulgaria and Moldova. We completed the study in 2024 and it was as it should be, a multicenter, two-part randomized double blind study where we tested the compound on top of standard therapy. When people, patients were recruited to the rheumatologist and they were eligible for methotrexate treatment, we started treatment. They were offered to participate in our study as well. Another inclusion criteria was that they should be Rheuma positive and have high disease activity and that is on a scoring system that is used widely here in the Nordic countries called CDAI scoring system to evaluate the patient's disease activity. There the threshold was 22 which is the same as defined as high disease activity as in the rheumatoid arthritis. The setting was that we had patients, high disease activity. They started methotrexate treatment. The primary readout in such a study was of course safety. It was first time we gave that to patients. The efficacy endpoint was based on the CDAI. Could we bring them from high disease activity to moderate or low disease activity or and how big effects on a reduction in disease could we show with the compound? Then of course a lot of secondary endpoints including the ACR score, that is what we are bringing in the studies here we are running now is the primary readout. We had a Part A where we tested two doses versus placebo, first 1 dose and then second dose. The reason to we did that was that was the first time we were in patients. It was a question of showing that we were cautious, that we were safe, that we would not progress too fast into patients. That was a way to control it. We had an independent safety monitoring board looking at the data and they recommended us to go further with the two, both of the doses that we had tested. What I will show you here is the result of the full data set. Importantly, this patient did not receive glucocorticoids. If they, there were a few who got that as a rescue medicine, and they were per protocol being taken out with regard to the response because if you get glucocorticoids on top of methotrexate you would of course have reduction in your disease activity and it would be very, very difficult for us then to evaluate the potential of the compound. What we saw was with regard to changes in disease activity was that the patients who were treated with methotrexate and placebo treatment had a reduction over this four weeks treatment of 9.3 points. They started up in the late 30s so it was quite severe disease and then they had a mean reduction of 9.3 points. With the 50 mg we had 12 points and on the 100 mg we had 15.5 points reduction which was significantly different from placebo treatment. What does it tell us? Well, 15.5 point reduction in disease activity over four weeks is considered a clinical meaningful response. When we then and another way to so in other words we had a clinical significant and statistically significant reduction in disease activity on our 100 mg dose compared to placebo and we had a very nice dose response. When we looked at the ACR score, ACR20 meaning that we on specific readouts make have an overall 20, more than 20% reduction in disease activity or you could say improvement of the compound treatment. 50 mean 50% improvement and 70 mean 70%. That is the American College of Rheumatology scoring system that is widely used in clinical trials and what we're using moving forward. What we saw there was a placebo treatment, in other words, methotrexate plus placebo. We had 33% who qualified for MC, for ACR20 and we went up to more than 60% on the 100 mg dose. Again also with a larger number they are reaching ACR50 and 70 compared to placebo treatment. Is this clinical relevant? First of all, it was statistically significant compared to placebo treatment and importantly it was also a response that was if we try to put that in perspective, the JAK inhibitors that have been mentioned sometimes today, they are some of the most potent compounds. They have been reported in large Phase III studies that as a monotherapy, they after four weeks can reduce, can have a scoring rate about 60% comparable to what we see here. It was a monotherapy but actually when you look into the patients many of them had some kind of glucocorticoid treatment on top of that so up to 40% of these patients. I don't know whether we can, we can say anything else but this is actually a very, very good response after four weeks. We are now continuing development here in the EXPAND study. Of other readouts, we also looked at those, the fraction of patients. It's more exploratory readout. The fraction of patients who also had high disease activity on another scoring system called DAS28-CRP. The reason to why they were not the full data sets or all the patient is that CRP in this patient in many cases are not increased in. CRP is something that is released from the liver and it, released when there is circulating inflammatory markers that can stimulate that. In many cases, up to half the patients, early arthritis patients do not have increased circulating CRP, and therefore they of course score a little lower in DAS28. For those who had a high disease activity with DAS, we saw this very, very nice increases in response rate to bring them to more controlled, to a lower degree of disease compared to placebo. When we look at the fatigue score, which is a scoring system to evaluate the patient's daily handling, especially fatigue more than anything else, we had this very, very nice also a high dose response study and an improvement here at scoring of eight points is actually quite significant in even though from a clinical point of view, on a short treatment. All in all, very encouraging data from the study that of course brought us in a situation we would like to bring it further. Well, from a safety perspective, we had, we looked and then this of course is the full number of patients that was included in the study. We did not see any serious adverse events during the four -week treatment. We saw adverse events, and this is a total number of adverse event that was reported during the full study. We saw somewhat higher numbers in the two active groups compared to placebo. The intensity and what you can see here is that the vast majority on the 100 mg were mild intensity and the two more severe we saw of this treatment emergent adverse event was presented in the placebo group. Just to say that we did not have any with regard to number and the severe and the intensity of the adverse event, it actually looked quite good. You can see the number of AE per person. Some reported more than other and but importantly, we also have very few discontinuation due to study medicine. We had one that we had to discontinue simply because the patient when we got blood pressure from the baseline level, it told us that there were a liver infection before we even started treating this patient, so we took them out. The other was a patient where the investigator could not continue treatment due to development of herpes zoster, which is a not uncommon side effect to methotrexate. From that perspective, it also looked from a safety perspective, it actually when we then look at the most common adverse events, it was nausea. Without any doubt, it was nausea that was present in all three groups. Nausea is something you see in methotrexate-treated patients. It's also something you see if you give patients or give a volunteer something like a suspension as we worked with here. It's not a surprise that we had nausea in the groups. We had headache in the active group, not in the placebo group. In the first and main study, we saw headache in all different groups. So until further, that is the most common finding. Then ALAT, aminotransferases, increases in aminotransferases. We know that methotrexate can induce and will induce, and it is dose limiting in patients that aminotransferases, which is a marker for liver function, is increased. We saw increases in the placebo group. We saw increases in 50 milligram group. We saw nothing in the 100 mg group. If that is a real finding that we can repeat in the ongoing study, then it's really interesting. Of course it was extremely encouraging from our point of view that our highest effective dose were without any effects on liver function. I actually saw like potentially could have protected effect. That was the outcome from the study for the BEGIN study. Based on that, we set up the EXPAND study where we have 12 weeks dosing in previous treatment-naive patients. The same patient population as in the BEGIN study. Now we just dose for 12 weeks and we use the tablets instead of the suspension. We completed recruitment in April, two weeks ago, and we plan for having, we can expect to have high level data in five months' time. The setting is that it's very similar patient population, high disease activity, previously treatment-naive, either treated with our compound or with placebo, and in all cases in combination with methotrexate. 12 weeks dosing, designed to have 60 patients in each group, and, the power calculation has made in a, in a way so we also can have some discontinuations, which will always take place in a 12-week study. We meant to randomize, and we could do that within the protocol 127. For a small company and us, we are specifically proud that we actually managed to have the full recruitment ahead of our original planning. Primary readout with the ACR score, for 12 week compared to placebo. There will of course also be reporting of how fast ACR20 will be reached and the level of ACR scores at the different time points. Secondary endpoints will be like CDAI score, DAS score, fatigue and other. we have a number of exploratory readouts in addition to that. importantly, we have a sub study with MR where we evaluate synovial fluid inflammation, the vascularization using state-of-the-art MRI. We normally call that MR evaluation. we have an MRI prior to treatment at the end of the treatment, and then we can look at potentially beneficial or treatment effects within the joints on the degree of inflammation. That's the EXPAND study. We have the RESOLVE study. That's as I said, it's a two-part study. The first part is a four weeks dose range study, and the second part is a 12 weeks Phase IIb study, and it's run under an IND. Here, the patient population is somewhat different. It's conducted under a US IND, and we are currently recruiting both at European sites and US site, including Dr. Kivitz's sites. The Part 1, the Part A is a four weeks study. We test three doses of the compound. We keep it in a way, so we do not dose extremely high because we still have this orange dotted orange line that I would really like to have a trough value below that. We do not go extremely low because from the BEGIN study, we had the feeling that four weeks treatment was potentially not enough to show the full potential of compound, especially not 50 mg. We had responders, we had not responders, we had some who came in slow. In any case, the PK profile of the compound indicates that we would be in therapeutic level after 1, when we went up to steady state, which means that probably not had limited effect the 1st week. We have a relatively narrow dose range here, but it would give us a lot of information that then can be brought into the 2nd part of the study, where we have the option to go up to three doses versus placebo. Then it dimension spot on, head on to what has been done with the JAK inhibitors. The inclusion, exclusion criterias are very, very similar to what AbbVie, Pfizer, Galapagos, and now I think I forgot one of the companies. Nevertheless, the way they, the way these large companies have set up their development in these patient. The concept is, of course, that the patient has been on methotrexate for at least 3 months and still have uncontrolled disease activity. Here defined, we need a minimum of six swollen or tender joint and or increased CRP and documented incomplete response. That is really so we can benchmark our studies to what previously have been done in the and out there in the literature. The P art 1 is 30 patient of each group. We are well ongoing here with the study, we have approval to kinda go on with 75, up to, in other words, up to 300 in Part B of the study. Again, the ACR response is the primary readout. The same readouts in the second part of the study with CDAI, DAS, and FATIGUE, and so on. We do not have MR in the first part of the study because four week study is probably too short a period to actually to see anything. It will be implemented, I can assure you, do we have indication of activity after Part A and the EXPAND study, MRI will be a part of that. Which always also will give us a possibility then to look up potentially inhibition of erosion, further erosions and so on in these patients. This is the Part A, is a study we look very much forward to report, and it will be reported in the second half of the year. Yeah, that is what I would say about this study at this time point. Very briefly just mention that we do have this nephrology study ongoing. I think it's extremely interesting from what I mentioned in the beginning with this potential to modulate the physical barrier in the kidneys and thereby reduce proteinuria. There without any doubt is a medical need for something in the nephrology space who is not immunosuppressive. We generated some data here in the animal studies in a relevant membranous nephropathy model, it's called Passive Heymann nephritis. It has circulating antibody who binds to this basal membrane and the podocytes, very similar to what you see in immune in autoimmune diseases that affect in the kidney glomeruli. What we saw here was that we reduced our compound given when at top of the disease started, meaning after two weeks development of disease, when we gave the compound, we reduced proteinuria quite significantly in treatment where the placebo in animal study normally called vehicle treatment were without effect. We also ran 1 study head to head with ACTH because ACTH is very effective in these patients. It was the first studies who showed that was from Lund, seen a later Gothenburg here in Sweden, where they showed nice treatment effects of ACTH. Very interesting is that ACTH works in patients who do not respond to glucocorticoids. That is one of the very important signals that melanocortin receptors agonist are active in diseases like this. As the component mediated through the glucocorticoid re-release of ACTH, how should that work if pharmacological doses of glucocorticoids do not work? In other words, ACTH indicate most likely have an effects on this disease through MC1 receptors. What we saw was that we in that case here our compound given seems to be more effective than ACTH. That's not the same as it's more effective out in the clinic, but in this case it looks very, very good. From that, we have set up this study together with a nephrologist in the Nordic countries. We started in a very, very humble way. We had the suspension. We only had four weeks treatment. We simply decided to redesign the study completely. Now we have the possibility. Now we dose for three months. The setting is that the patient has to be on ACE inhibitors as first-line treatment, so you have control of blood pressure. Then we start, then we dose either way, placebo or active for three months, then we have one-month follow-up. The readout is potential reduction in proteinuria. With this, I think I would say thank you, as that would give you an overview of where we are in our clinical programs. Thank you very much. Thomas. All right. Jim, welcome to the stage. Why, thank you. It's all yours. Is it separate? First, I'm Jim Knight. I've been with the company for a couple years now, but it's my first opportunity to be in front of you today, I'm excited for that opportunity. I have the pleasure, distinct pleasure I would say, of being able to tie together a few of the pieces that have been talked about today. Both in terms of the unmet needs and the patient situations that we're trying to develop, and as well as share our views on how AP1189, as well as the linacorin peptides can really help address, practically, you know, a wide swath of patients, patient types, patient situations, moving forward. Let's, we'll start off with AP1189, and let's get into it. You know, this whole conversation really focuses around a discussion of the emerging clinical profile for AP1189 and how well that lines up with the unmet needs such as Dr. Kivitz had shared with us earlier. You know, we know that if this does not work. We know I'll avoid using the giant hand. We know that we have oral once daily dosing, and that's fantastic, right? It's all about patient convenience. You know, there are some oral products that are available now, but you know, it's not the reason to be, but it's a nice solidifying pin all of our other aspects as well. The quick onset of action, that's actually something that's inherent with the mechanism itself. We see this with Alpha MSH. You see this with ACTH drugs like Acthar that I used to work on. It's a very quick onset of action. We're seeing that at the earliest time points that we looked at in the BEGIN study at two weeks, and even in the hospitalized COVID-19 study, we started seeing onset of action effects within the 1st day of those hospitalized patients. The mechanism itself has that nice quick onset of action, which physicians do enjoy. The JAK inhibitors have that as well, so it's nice that we have, you know, both oral, and the quick onset of action, that share similar with the JAKs. High degree of efficacy, Thomas went through that. you know, when we look at sort of the JAK inhibitors and their phase III trials in the same populations, the BEGIN data falls right in that range. We like to say that we have data from the BEGIN study that looks to be in the same range as the JAK inhibitors, and we hope that continues obviously as we go through it and into the EXPAND study as well. When you get to safety and tolerability, that's where we start getting some differentiation from all the approved products, including the JAK inhibitors. I'll have a slide a little bit later on that shows you the extent of the black box warnings for all of the key top RA brands, and it's pretty extensive. Steroid-free mechanism of action, Thomas went over a little of that as well. You know, what's nice about having the oral dosing, the quick onset of action, is that, being steroid-free, is that you know, the melanocortin mechanism allows you, I think as Mauro had, Professor Perretti had said before, these both direct and indirect, right? The indirect mechanism for melanocortin, if you're an ACTH product is to stimulate the melanocortin two receptor, to have Cortisol, and Cortisol gets to work, right? It's a powerful, natural immunosuppressive, if you will. The beauty from our standpoint is that without having that MCr piece, we're able to have all the direct effects that Mauro had gone over, from melanocortin, the stimulation, especially on receptors one and three. Bypassing the need to use steroids but having those quick and robust effects that you see with steroids. Compatible with MTX, with methotrexate. Obviously, we've shown that in the BEGIN study. We believe that's continuing through now with whoa, okay, steal my thunder. Continuing through now with the EXPAND study as well. You know, we've initially, you know, taken this profile and said, "Okay, where are the unmet needs in rheumatoid arthritis?" We've, we focused pretty much on the early lines of therapy. We think that the clinical profile matches up well with that. The oral, the particularly the safety and the high degree of efficacy. That's where we started, but as we go through this, there are multiple other potential positioning opportunities as well. you know, while the individual parameters, if you will, of that profile are quite striking and important in some ways, it's the combination of those that really gives us the biggest probably differentiation over the existing therapies. This whole mode that we've been talking about today of being able to deliver immune regulation or resolve inflammation without inducing immunosuppression, right? Again, I'll show you a slide in a few here of the other top RA therapies. All of them are immunosuppressive, right? They all have black box warnings related to immunosuppression of serious, sometimes fatal opportunistic infections and things of that nature. You know, being able to come into this early line of therapy, give oral convenience, giving a high degree of efficacy, without inducing all of those potential side effects and toxicities, is obviously something that, you know, would be, I believe well accepted in the marketplace. We'll show you data in a few moments that rheumatologists agree with us in that regard. We focused our efforts initially, as I said, on early sorts of stages in the highly active naive population, and DMARD-IR, so patients that have been on probably three to six months, probably closer to three months, according to Dr. Kivitz, in regard to, if they had a complete or incomplete response. There were even positions we have this one here, this disease activity flares. That was sort of the Acthar Gel positioning, which was, you know, do a short course of Acthar whenever a patient, regardless of what therapy they were on, was having, you know, breakthrough disease activity. We'll start looking at both of these populations. We'll start with the highly active, naive. Here's some data from research, as well as from the literature, that we asked physicians, you know, what percentage of your patients that are coming in, these, you know, again, similar to the trial, these treatment naive, newly diagnosed patients, what percent of those present to you with what we call poor prognostic indicators or factors or signs that that patient probably will have a more serious or severe course of disease? It's about almost 50%. In the research we just conducted, 47% of patients, the physicians had said, had 1 or more of these poor prognostic indicators available. Of all the poor prognostic indicators, high disease activity is the one that's in both the European as well as the American treatment guidelines and recommendations, right? It's recognized that if you're coming in very hot, especially early on in the disease, we really wanna get that under control 'cause I believe, as Dr. Kivitz alluded to, that, you know, that there's a belief that there's a one or two-year window, right? If you come in, you get diagnosed with RA, you got a one to two-year window to really get it under control. If not, during those two years, that's when the, you know, sort of the erosions start really building. That's when you really start getting, you know, this loss of function and mobility and abilities over time. You know, also what Dr. Kivitz said, I mean, access is key. And don't disagree with him whatsoever. But what's nice about a situation like this, the data we had in Begin, if that continues through with Expand, it's gonna be hard to resist access for a product with that sort of profile. Switching up and looking at the DMARD IR piece. This is when you start looking at the data from this perspective, it was enlightening. I knew that there were some issues with methotrexate, but not to the degree as we started getting into this a bit more. The graph here on the pie chart shows, you know, what is the outcome at, say, one year from methotrexate therapy. Again, this data comes from the recent research we did with high volume rheumatologists. You can see... Oops, sorry. You can see after one year, only about 30% of patients that are initiated on methotrexate still have a, what's defined as a durable response. All right? The rest of the 70% fall into a somewhat nebulous defined bucket called, you know, DMARD IR or DMARD incomplete responders. Okay. That takes sort of two pieces. There's an early piece to that, which is shown in the, in the bar graph here. There's about 54% of the patients started on methotrexate, will have either no response or will have a, you know, a partial response that the physician, patients agree, is not sufficient for what they, for what they need in their degree of disease activity. 54% of those patients, within zero to six months will have that situation. Another, 16% of all patients started on methotrexate will initially have a response, and over the course of a year will lose that response. Those are also falling into this DMARD-IR, patient category. you know, even we get down to, you know, the standpoint of these patients that are still on. Oh, Lordy, that was not good. Sorry. Nope. Nope, nope. Nope, nope, nope. Let me entertain you. Sorry. We stopped now. Thank you. I'll try to be more technologically savvy. I apologize. Even the patients that do stay on methotrexate, and Dr. Kivitz had mentioned this, that, you know, they can be on therapy for a long period of time. Mentioned the one patient he had that's been on multiple years of methotrexate and HUMIRA combination therapy. That's great, right? I mean, that's what everyone's really after is trying to get that efficacy back, trying to get some degree of functionality back that might have been lost over time. The issue is even on long-term therapy, there's a significant tolerance that patients have to have for the side effects that are still associated with methotrexate. you know, bottom bullet point here is that after five years of therapy, you know, over 20% of methotrexate long-term patients are still dealing with daily side effect and tolerability issues. Most notably, that comes so pretty pronounced nausea, other GI side effects, let alone all of the other sort of acute and more, you know, more of an issue problems that can come up with methotrexate therapy. Still on the phone. you know, we really think that for both this highly active disease population as well as DMARD-IR, that, you know, our product profile that we shared with you I think really matches well up with unmet needs and what we can bring to bear. I believe that rheumatologists, at least the ones we’ve spoken to so far, do agree with us on this. This is some market research we’ve done a couple different rounds that we’ve done since the BEGIN study had come out. Here we’re looking at, you know, this is restricted to the U.S., but it’s high volume or high volume of patient rheumatologists, such as Dr. Kivitz. He was not one of the interviewees, by the way. What you see is they have both a degree of interest on different positions as well as their anticipated use if the product was available today. First you ask them about their own experiences with DMARDs and how what their unmet needs look like, you know, similar to what Dr. Kivitz took us through. Then we get to the point, well, how interested would you be? You know, we show them a profile of AP1189 based upon the BEGIN study. Then we say, "Well, how interested would you be in having that product available for use in DMARD-IR?" They said about 87%. Physicians tend to be a bit high, hard graders, so 87% been doing this way too long. 87% is definitely on the high end of interest levels. That's nice, solid interest, right? When they come out and say the anticipated use, I was quite surprised to see 52%, and that's 52% of a very large number. That's about DMARD-IR, just a real ballpark guess, total patients every year. Even the new onset patients is about 300,000 patients between about 150 about 300,000, sorry, newly diagnosed patients every year. Running the math through, you get about 150,000 or so of those that will be DMARD-IR by the end of that point in time in the year. 52% of that is a very large number to pull through, you know, on an annual basis. That being said, the other nice thing about being oral and being safe and everything else is that you start early, and you have the ability to be almost a foundational therapy, right? Which is what with methotrexate. Most often not, especially if there's no toxicity or tolerability issues, a patient will be started on methotrexate, and they will continue on that. If the patient's disease progresses, they need another therapy currently now that's most likely usually an anti-TNF agent gets added on to it'll be added on to methotrexate and not taken off. You know, this ability of starting early, you know, gives you a longer period of time with that patient as well. We also asked about other positions. I said before, you know, we really think that, you know, that is AP1189 very well suited for this early, these early points in therapy. Physicians are interested in multiple uses. You know, sort of the interest for TNF IR or incomplete responders or loss of response, patients that have been on anti-TNF but lost response, that's another big opportunity that clinicians are really interested in. You know, the anticipated use is a lot lower, but there are probably, I think, 12 different agents, right? Different biologics, JAK inhibitors that are all competing for that piece of the pie. Even with all those drugs and everything there, they're still seeing a need for another new treatment modality. Now to that slide I was mentioning. Here are the top RA brands. You have a little bit of it there, you know, back to 2021 sort of individual indication sales. But here they are. Right here are the top brands. First couple points I'd like to make from this is one, out of those 10 brands, seven came from external innovation, right. Really pointing out the importance of business development or, you know, working collaborations, partnerships, outside of, outside of their own, de novo, you know, pipelines, et cetera, or, you know, invented here pipelines. The other thing is to point out is that, you know, look at the number of indications in the last column. All of these products, despite the boxed warnings, so, you know, the anti-TNFs all have serious infections, and it says on the label, some of which can be fatal, right. As well as malignancy, right. All the anti-TNFs and most of the biologics have that same sort of label. It gets even worse for the JAK inhibitors, right. You know, U.S. guy and, you know, some U.S. guy. I remember some of the first commercials. The first JAK inhibitor was from Pfizer. It's called XELJANZ, right? Their whole marketing campaign for the first five years or so was we're the uninjection, right? They were marketing purely almost on the fact that they weren't oral and not an injectable, right? You know, they were doing that on the basis they had really good data, right? They had, you know, and they were oral, right? Lo and behold, you know, these sorts of things come up of serious infections. Same with the biologics. malignancy probably worse, but same as the biologics. MACE or major adverse cardiovascular events, some of which are fatal, happen as well as thrombosis, right? Can lead both to, you know, pulmonary hypertension as well as stroke, et cetera. Despite all of these serious safety concerns, you know, the, you know, the HUMIRA's got nine indications. RINVOQ, which, you know, this is again old data. That's sort of the middle of the table there, about $1.4 billion, back in 2021. By a lot of analysts, that's gonna be the leading drug, probably before long, or they expect it to be the leading drug before long. Despite its kind of caustic-looking, if you will, black box warnings, it's already in six indications, and the work is growing to bring in others. You know, as we talked about today, you know, there's a lot of potential in the melanocortin system, which hopefully you've all received today, you know, beyond what we're doing here in RA. It's gonna be home on us to really showcase that potential as we move forward and continue our partner discussions. I should say from a business development perspective, I don't want to get any obviously specific conversations, but suffice to say that we are or have been and will maintain conversations with every company listed on this slide. We are definitely covering the waterfront of the right partners to be looking at. We asked the same clinicians in the research, and similar to the responses that Dr. Kivitz shared with us today, this is unsolicited. It's, "Hey, you know, if this product were approved, where else would you be interested in using it?" Right? Psoriatic arthritis came up, lupus came up, as well as ankylosing spondylitis, and you can see a few other mentions there as well. What's interesting about psoriatic arthritis, lupus, ankylosing spondylitis, and I think pretty much every other condition up there is that same position, that same position that we're trying to occupy with AP1189 and RA, that early therapy, that DMARD-IR space, which I think is very well suited for the product profile to the marriage to the unmet needs, exists in all these conditions, right? Same sort of situation, psoriatic arthritis, a bunch of earlier, you know, psoriatic standpoint, you know, DMARD therapies that applied, about the same success rate. It doesn't work any better in psoriatic arthritis than it does in arthritis, right? Lupus is probably even worse. It's all steroids, right? There are a few approved biologics. They do get reserved for later stage patients, and patients are on, you know, steroids, which a lot of RA patients are too. In lupus, the doses can get quite high, 30, 40, even higher, milligrams of prednisone a day. Not a situation anyone wants to be in or should be in pretty long term. Ankylosing spondylitis, again, that same idea where you have these, you know, first-line therapies that are fairly ineffective in a general sense. You know, it gives you a nice picture, and all these obviously fall within rheumatology as well. Especially the audience we're already talking to are starting to get some interest with. But going back to, you know, points made before about nephrology, right? This is the point, right? I mean, for years and decades, right, everyone's been worried about the function of the kidney and measuring the function of the kidney from, you know, serum creatinine and things of different nature that Thomas had shared with us. But the real issue is proteinuria, right? This slide, you know, in a sort of crude way, but high-highlights the 40 million or so patients currently in the U.S., spread between China, Japan, U.S., and Europe, that have chronic kidney disease and are at a high risk or a very high risk of progressing. The reason they're at a high risk or a very high risk of progressing is because of the level of proteinuria, right? If a product, like 1189, could be developed that would actually safely, like, decrease the level of proteinuria, that was oral and well-tolerated, could be quite a game changer, frankly, in the field of nephrology. You know, we're excited. You know, that trial is with a lot of yeoman's work is doing well. We'll hope to see that by the end of the year as well. It's really gonna be looking, as Thomas had said, looking at the level of inhibition of proteinuria and really see, you know, how is that gonna toggle off to potentially larger diseases such as chronic kidney disease or diabetic nephropathy. On to the peptides. I know Thomas has shared don't wanna spend too time. you know, what's nice about the peptide portfolio is that they have, you know, with 70 or so different assets, there's a bunch of different sort of receptor profiles, and Thomas had shared that with you. you know, we have the ability of potentially, you know, picking and selecting a peptide for certain conditions, such as, you know, for the joints, you know, melanocortin 1 and 3 receptors tend to be important. In the eye, as Thomas had said, you know, a little bit of melanocortin 5 is sometime more important. we have the ability of selecting a peptide based upon its receptor profile. again, favorable profile. formulation flexibility, Thomas mentioned we, you know, there's IV formulation. We've done some early work on a sustained-release formulation, which is encouraging. We got the formulation flexibility, et cetera. Let's see here. I'll try not to spend much time on this busy flower slide. This is one of my previous lives here. This is sort of you see on the right-hand side here? Yeah, right-hand side. The Acthar Gel. Inside that red circle are all the approved Acthar Gel indications. There's, you know, they're summarized on here. There were 19 of them. Okay? Acthar is typically delivered by a twice-a-week subQ injection, right? One of the points I like to make is that from a twice-a-week subQ injection, right, an injection similar to how our MC peptides will be delivered, Acthar was able to have efficacy in ophthalmology, right, rheumatology, nephrology, neurology, and pulmonology, right? From that simple little subQ injection. Trying to show you the potential that these peptides really have to interdict in a wide range of disease states. Here's a little bit more, as Thomas has shared on the first thoughts for TXP-11. You know, surgery in general, or major surgery in general, is associated with a very high rate of sort of organ dysfunction, damage, and even in some cases failure. Here, cardiac surgery is, you know, probably the best studied of these. You can see, you know, in this up to, you know, 50% of patients will have issues with kidney functioning. You know, 28% will have atrial fibrillation. You'll have up to 20% get acute respiratory distress syndrome. Stroke in up to 5%. There's a huge issue that's driven by an inflammatory reaction to the surgery, where melanocortins can potentially have a good place to interdict in these diseases. We're excited to see that program progress. Here a little bit on the sustained release. We've done some early work on sustained release of some of the peptides. You know, good work to do thus far. We've got some prototype formulations which have about a one-month release profile, which is fantastic for so early on. Additional work to do to optimize that. That gets us in the realm of being able to tackle all those diseases that I showed you before, but tackle those all with a, you know, in once or twice monthly subQ injection. Talk about sort of rheumatology and orphan diseases. We talked about this a little bit. You know, lupus, again, another fantastic opportunity from a standpoint of the injectables. You know, smaller indication, not as big as RA obviously. While there are some biologic therapies, they are pretty way down on the treatment algorithm and really don't bring a lot of efficacy. The interesting part too is that, you know, there's lupus, there's lupus nephritis, which is, you know, more in the kidney, and then there's systemic lupus, where you can get, you know, heart involvement, kidney involvement, brain involvement, obviously joint involvement as well. These systemic diseases, right, with a systemic formulation really match up well, and they match up well back with Acthar, and it's gonna match up really well with our peptides as well. What's nice about this is there are also no shortage of orphan opportunities for some of these injectables as well. There were seven, I think, orphan indications on the Acthar on the Acthar label. One of these was the inflammatory myopathies, which is really polymyositis and dermatomyositis, two smaller, again, orphan conditions. The only things improved in the U.S., and I believe in Europe as well, are steroids and IVIG, right? Neither work particularly well. This is an indication where ACTH works gangbusters, right? It was, you see some of the responses we saw in very refractory patients, these are patients that have burned through all of their really treatment options. To see the responses we saw, particularly in these conditions with ACTH was frankly one of the more highlights of my career in seeing some of that, some of that data, being able to bring relief to patients that really haven't had any relief for decades, frankly, with the disease. You know, that's first one we put, and as spoken about earlier, ophthalmology. Ophthalmology is, as Thomas shared with us, you know, interesting place in regard to the immune court system. α-MSH is very much involved, you know, the sort of immune privilege, if you will, of the eye. there's obviously a lot of big diseases here. We'll talk about age-related macular degeneration. clearly, you know, the anti-VEGF therapies are about this is 2021, so a little bit older data, about $7.5 billion, right? you know, there are 50 million diagnosed patients, however, which shows you get about treatment rate about 4%, right? 'Cause again, these therapies are expensive, and they're being reserved for the, you know, most severe patients, right? They tend to get reserved until patients, in this case, it's wet AMD, right? You get neovascularization and a leakage of blood. They tend to get reserved till patients are almost partially blind, right, before they get these therapies most often than not. Being able to have, again, a more attractive agent, in this case, you know, a subQ agent that can be given once or twice a month, would provide, I would believe, a nice convenience factor over having to go in and get an intraocular injection into your eyeball or both eyes every month, which is sort of the standard of care right now for those therapies. Again, other attractive targets like dry eye disease fall in there as well, and a variety of other sort of small orphan conditions fit in there as well. I think that's what I have for you today. Again, we're really excited about the opportunities that we can address with AP1189. For my own self, it's I feel like I've almost caught lightning in a bottle. I was able to go through this once with Acthar and really roll out all those indications where we could have an introduction. To be able to do that again with AP1189 is frankly an honor, and the peptides frankly an honor. I thank you for your time today. Thank you very much, James Knight, CBO here at SynAct. We have a few minutes left before Torbjörn Bjerke, Chairman, will round up the CMD. If you have any questions, please raise your hand, and we will distribute microphones. We'll start back here and then further to you. Yes. I have a question. I think it would go for Jim. Yes. It's interesting to see that doctors consider to use your drug in the first-line setting. I mean, they consider it interesting in that setting. One of the important points, it's reimbursement. Mm-hmm. From the talk before from Dr. Kivitz, we hear that it's not that easy to crack the algorithm for treatment in RA. What kind of data do you have to show in your study now, in the EXPAND study, in order to really have a chance there to get like positive reimbursement decisions in the U.S., also, I mean, in Europe, if you have a view there? That's a great question. It's true, right? I mean, access is an issue, and it's definitely an issue in the U.S., but it is an issue Europe and globally as well, right? Part of that is it's more what you're bringing, right? I'll give you the current situation right now, right? You try DMARD therapies. As we saw, they don't work that well, especially in a large swath of patients. You're left, "What's my next alternative," right? Right now, that's either a biologic, and it's usually an anti-TNF, both the U.S. or Europe. In Europe, you have the choice of the ability to also use a JAK inhibitor in that piece, right? You just went from... I'll use US dollars because I'm a little more comfortable with that. I apologize. About, you know, anywhere from $3,000-$5,000 for, you know, depending on how you're dosed with methotrexate a year, up to $60,000-$80,000 or higher a year for an anti-TNF or another biologic agent. Even the JAK inhibitors, the last pricing I saw for RINVOQ, which is the newest product, is about $110 per pill. That's $110 of therapy per day, right? Now, it's way too early for us to speculate on what the pricing would be for AP1189. Someone's gonna go up and do probably a couple million dollars, right, worth of work on pricing. You know, back to your point about what data do you need. If you look at the JAK inhibitors are probably some of the most efficacious products that are known in RA. They've actually done their phase II trials as you know, as Thomas showed, you know, from the BEGIN study and now into EXPAND. They've done similar trials in their phase III programs. They have data that looks to be as good in DMARD-IR as it looks in previous patients as well. What's nice about those trials is they also brought in HUMIRA, right? They had a biologic comparator. Across all those trials, HUMIRA is a good step down from what they're seeing with the JAKs, right? In there lies the possibility for the data that's really needed from the payer standpoint, which is pharmacoeconomic analyses, right? If you can go in and which is what the JAKs did. They kept their price as high as they did because they were able to show that they had a benefit over going to HUMIRA in this case, right? You know, our ability to go in and show that we have data better than an anti-TNF, you know, remains to be seen, but we believe that would be the case, will allow us to have that sort of positive pharmacoeconomic, which will help with pricing decisions as well. For the first line specifically, I mean... Yeah how does it look there? If you look at, you know, so these highly active sort of naive patients from BEGIN and EXPAND, if you look at the current treatment guidelines, Europe and U.S., they're pretty aligned on this in that if the patients come with high disease activity, it's basically a message of treat aggressively, right? You know, I forget exactly how they word, but it's move pretty quickly to another therapy if the first-line therapies aren't working, right? That's, you know, a position. Even the you know, in the research we did, you know, physicians don't say it's particularly or particularly easy, but they are accustomed to using and trying to get access to biologics for some of these really severe patients that come in. You know, it changes a little bit, but I think when you keep coming with datasets that are as meaningful as BEGIN, and hopefully that continues through in EXPAND, it's gonna be hard to say no, right? Especially if you have the EMA and the FDA granting an indication for that spot. That, the other part, the biologics and the JAK inhibitors are indicated for use there, except in the U.S. where they're now have to use behind an anti-TNF, but they don't have specific indications for that piece. All right? They don't have enough data they filed for to get specific for use at start of therapy or in the DMARD-IR piece. Proactively, if the data keeps continuing, you'll have the ability to make an argument for specific indication, possibly in that population as well. Okay. If I can do a short one. I mean, you said before that it's still early to talk about pricing- Mm-hmm ... how would be like a. Yeah. I mean- Like second line and first line. Is there any difference there in terms of pricing? No, I didn't wanna, you know, like, cop out, if you will, on the pricing piece, but I think what's important for a product like ours in Phase II, right, is the ability, what do we think the pricing flexibility will be in that space, right? You know, we have flexibility from, you know, that $5,000 or so for the DMARDs up to the $80,000 for the biologic, right? There's a large range of pricing points in there. I didn't mean to be glib saying that someone's gonna spend a couple million dollars. They will to price this out because somewhere in there is a sweet spot, right? About the price that could be charged for AP1189 that will allow it to be broadly used without pushing a lot of the price controls. There are the, 'cause a lot of the access controls you hear about are price-based, right? It's a payer saying, "I don't wanna pay that until I absolutely have to." Right? You know, there's gonna be a sweet spot there where there's plenty of room to find the right price that maximizes the amount of patients that can get the therapy as well as maximizes clearly revenue from that standpoint. Great. Thank you very much. Welcome. All right. I have a further question here from the second row, please. to higher. Rutgers Smith. I just want to raise the rather boring but important topic of patents. What is the situation? Right. The situation for the AP1189 is actually very good. A part of what we have done here over the last years is to get further understanding on the polymorphism of the compound, of the compound as well as the use of different salts in specific formulations. We are in a position where we consider, and everyone who had looked at that in big pharma companies as well, that we have a very good position to the other side of 2040. It actually, it's a really good position for the resomelagon. That's the first answer. For the peptides, we are now working with them. We have the... The original application was filed, I think it was 2013. There we have to work and we will work to secure that we have control and exclusivity well out in the future. I think that's the short answer. The only part on top of that for the peptides, you know, if we do are successful with the sustained formulation, a piece that we're looking at, you know, that's with proprietary technology. Pardon me. We would probably get, you know, extension beyond, and I think we're out past 2040, for the sustained release peptides as well. it is to do with formulations rather than- Yeah ... compounds. Yeah. Yeah. I think that would give us about 10 years of added exclusivity with the sustained release or more. At least a minimum of 10 years beyond what we have today. Right. Do you have any further questions from the audience? Please raise your hand. Please. Hi. Thank you. I was just wondering for the RESOLVE study, what kind of level of efficacy would you look for to be able to continue in part B? The RESOLVE study? Yeah. Or at least the I, you know. Okay. Yeah. Got it. I mean, the decision will of course be like a combination of what we see in EXPAND and as well as in RESOLVE. Let's say that we have an indication of efficacy of a compound, compared to the placebo treatment. That could be either that we have some kind of dose response or we have actually, we have a significant effect of let's say the highest dose or the combined doses compared to placebo. Of course we will move on. I mean, the. Importantly, if it's well-tolerated and we have indication of some kind of efficacy, then we will move on because the study is not dimensioned to show statistically significant effects in the patient population. If we look at from the literature and try to benchmark us to other compounds, then a four weeks response, as we saw in the, as we saw with the 60%, more than 60% ACR score after four weeks treatment, that is not to be expected in DMARD-IR patients. Meaning that you would have in general, the placebo responses in DMARD-IR are also lower than in the treatment name. It would be a lower response rate that we could expect. Of course, if we see something else, it would be fantastic. What we of course... If it's completely flat and not tolerated at all, we of course have to say, "Well, what was that?" I'm... That would be highly unlikely from what we have seen in the BEGIN study so far. Any, you could say, indication of efficacy compared to good tolerability and of course also efficacy EXPAND study, we will move on. A bit of a similar question to the nephropathy study. What would you consider a, say, robust enough proof of concept there to kind of have discussions about next steps? That's really a good question. First of all, we again, there have safety and tolerability. We need to have some indication of efficacy. Whether what we know from ACTH has been shown to be specifically effective in idiopathic membranous nephropathy patients. Some of them have, if you look into that's typically small studies that have been reported. What we can see is that the full efficacy is not present after 3 months, but you often have to treat for six or 12 months to see a full efficacy. For sure we should see some kind of effect like. It would be difficult for me to say percentages of that. If we end up in a indicating that we have a good effect moving from 4 weeks, 12 in the right direction, then I think it would be logic to say this is interesting. Then of course we have to position it. Is as Jim very said, there is potential in larger indications in other patient populations. This is really a proof of concept to see whether or not we actually do have this effect mediated through the MC1 receptors that we cross fingers have. Got it. Thank you. Thank you. I'm afraid we're out of time. That concludes the Q&A session. There will be a reception soon, so I'm sure you can buttonhole some of the members of management if you have any questions that you want to ask privately. Now it's time for Chairman Torbjörn Bjerke to sign off here. Thank you. Thank you very much. This was our first Capital Markets Day in SynAct Pharma, and I hope we were able to convey a couple of messages to you guys. One is that definitely SynAct Pharma is on the move. We have a very exciting compound product opportunity in 1189 with two proof of concept studies, positive, both of course in RA being our primary focus, but also in the inflammation seen in the COVID-19 pulmonary inflammation. We didn't talk much about that, but for us this is also a proof of concept. We have two proof of concept in two different inflammation. The way we're doing it, as Mauro talked about, is really inflammation resolution. That is a totally new way of treating inflammatory diseases. Not as what is on the market today to take out certain substances that are causing some of the inflammation, but rather balancing the inflammation in a very intelligent way. I normally compare it to the way that the new cancer treatment is, the immunotherapy in cancer. You're helping your own immune system to fight the cancer. This is the way that we are doing it. We are up for proof. You know, we need to show to potential partners and the world that this is the way we're doing it. The results we have so far is really, really good in terms of anti-inflammatory. It's balancing, and then the pro-resolution phase, which is so important. As Mauro said, it's a very active phase, we are helping the body to take away the debris from the inflammation, which hopefully will cut off the more chronic phase in the inflammation and in the disease, and hopefully also result in remission of the patients. We heard Dr. Kivitz say that remission or partly remission is really the goal. We believe that the profile of 1189 is the right one for that. We also believe that for many years to come, the treatment in Rheumatoid arthritis and other immuno-related diseases or inflammation-related diseases will be combination therapy. With our, so far, very, very good safety profile and very promising efficacy, this treatment could come in in different ways. We heard Jim talk about the how to position a drug. Of course, it's quite early stage. If we can continue to show what we have shown so far, this is a very, very attractive profile of a drug treating inflammatory diseases. Obviously, we heard about the other opportunities that 1189 do have in other diseases and how important the inflammation is in so many different diseases. We talked a little bit about, for example, Lupus, and we talked about spondylitis and so on, which could definitely enlarge the pipeline of 1189 as such. With the acquisition of TxP Pharma, we got a totally new group of compounds that I believe will be quite determined also for our future, all focusing on the same element that is inflammation resolution. We can add in different other indications and disease areas. The hospital segment, which is a even very attractive segment for a smaller company, We'll have the opportunity also to go towards other orphan indications. I think the important thing is that this will establish ourself as an even more attractive partner and player in the field of resolution of inflammation. I would like to thank you so much for coming. We're so grateful that you have been taking quite some time out of your schedule today. We also had, I think, around 250, 300 people listening in from the computer. I guess now it's time for the reception. Thank you so much for coming. Thank you.