The viewers joining us here on our live stream. Today we are gathered here to watch the Capital Markets Day, hosted by SynAct Pharma. We'll have a long agenda today, and we'll hear from both management and also advisory, and even the board, speaking of which the Chairman is right beside me. Welcome, Anders Kronborg.
Thank you so much. It's a great pleasure to have you all here. Also, you are on the web. We have been looking very much forward to this arrangement since we invited you. It's also a great honor to present a company which is in very good shape and with a lot of interesting activities going on as we speak, and which you're going to hear more about today. I'm just going to run you quickly through the program, and then I'll hand over to the CEO Jeppe, which you all know. We are more or less done with the number one. Jeppe will take you to a short update on the company. The next two points, Thomas Jonassen will take us through, and then we have Professor Mauro joining from on the web, so he couldn't make it present.
Then Thomas Boesen will take us to the TXP program, and then Jeppe will come back and wrap it up. Just to repeat, it might be a little bit boring waiting with a question until the end of each session, but since we have this mic, it will be a very interruptive way to put that around all the time. We are hoping for a lot of questions and a good debate at the end. With that, Jeppe, I'll hand over to you.
Yes. Thank you very much, and thank you very much again all for coming, and also the ones joining on the web. I will head out giving a short update on where we are with the company. I will touch a bit on some of the milestones that we have completed, and I will also discuss a bit on the future milestones that we see coming over the next couple of quarters. I will also enlighten you a bit on what we are doing in terms of business development, which is, as you know, a very exciting area for us. I will conclude the presentation with a few updates on the capital raise that we have just announced today, just to give everybody a bit of overview of that transaction. For those of you who are newcomers, just a very brief update on the history of the company.
We spun out the assets that we're working with now from another company called Action Pharma back in 2013, and then basically funded the company SynAct based on those assets. We managed to list the company on Spotlight in 2016, and then shortly after initiate clinical development of AP1189, which is sort of the lead compound. We, in 2021, managed to get into a position where we got proof of concept in COVID-19 patients, and we're coming back to why that is very important today, because we have also launched a new program in the same area. We have focused very much on driving the main program forward in RA.
In 2022, we decided to do an uplift, not to First North as you normally do when you're moving away from Spotlight, but basically we took the decision to do an uplift all the way up to the main market. We have been quite happy that we did that. At the same time, we managed also to conduct and to initiate clinical studies in the U.S., and I'll come back to why that is important. It's quite critical in terms of the business development activities that we have ongoing. In 2023, we acquired some assets from a company in Switzerland called TXP Pharma, and Boesen, our COO, he will come back to that program a bit later in the presentation, showing where we are and also giving you a little bit of insights to where we think we can move the program within the next couple of quarters.
In 2023, some of you, or many of you, I think, learned that we had a big bump on the road. We did not get the clinical data that we were expected in a phase two program. It was a big surprise, big surprise to us, and it, of course, jeopardized the share price quite a bit. There was a need for change. We basically replaced the Board, got some adjustments to the management, and also managed to reduce the cost base quite a lot in the company. Immediately after, secured two financing rounds as directed issues, both of them at a premium. Got money enough into the bank in order to restart the study in a Phase 2B in RA. We have learned a lot from not getting the data that we wanted in the study.
We did a redesign to the next study, and that is our main focus right now. That study is, as I will show you a bit later, coming towards data end of this year. We have initiated and just announced not long ago that we are initiating a study in virus in a dengue indication, and we will have Professor Mauro , sorry, Mauro Teixeira. We have two professors. We have Mauro Teixeira to take us through that program a bit later on during the presentation. As announced today, we have launched an investigator-driven study in an indication called PMR, and Thomas will talk more to that one.
It's a very important decision for us because it adds a lot to our opportunity for doing a deal on our RA project, because it's more or less the same partners that we see for this indication as well. That's basically the history sort of in a nutshell. The team, I won't go too much into that. Thomas Jonassen, many of you know him. He's the Founder of the company. Jim Knight is taking care of our business development. He's based in the U.S. We have known Jim for more than 10 years. We actually did a deal with him when he was at Questcor Pharmaceuticals. Björn, who is our CFO, also here today. Then Thomas Boesen. Boesen has been part of the journey for a long time because he was also involved in Action Pharma, and Thomas is here as well today.
Kirsten, with a strong background from Big Pharma, our CMO. A small team, a team that have worked together for quite some time. We have a very experienced board. The first three members you see on this slide, they stepped in back in 2013 when we needed to.
24, sorry. When we needed to sort of reset the strategy, and we're very grateful that they stepped in at the time. It was not an easy task, but they have done a good job. They're very close to the company. Anders Kronborg, that you have not met already. Anders has a background from, amongst others, LEO Pharma, where he's been both the CFO and also the CEO. Sten Scheibye, former chairman of Nordea Nordic, also been for quite some time the CEO of another Danish big company called Coloplast. Then Sten Sörensen . Sten is here today as well. Sten is a successful CEO of another Swedish biotech company, Cereno Scientific. Those three members have done a big job in getting things back on track and worked very closely with the company. Here recently at the AGM, we have included Jeppe Ragner.
Jeppe Ragner is the Group CEO of Sanos Group, who is also involved in the CRO business that are running our studies and also a big investor in the company. Nice to have him on the board as well, and also be able to put a bit of pressure on that they deliver the patients in the order that we want. Basically, what's one of the news for today is that we are entering into a new indication called PMR, and we are doing that as an investigator-driven study. Basically, in order to sort of just give a brief overview of where we are, we have two different tracks, and we run them in parallel.
That's a big strength for a small company like ours, especially in terms of developing the projects, but also making sure that we get into a position where we can do hopefully a deal when we have a bit more data than we have right now. Basically, one track here is focused on the autoimmune diseases. There we have a novel mode of action. We have something that we believe is very patient-friendly. As said before, we have an ongoing study in RA where we are going to include 240 patients, and we can say that that study is recruitment-wise on track and on plan. That's nice to be able to say in biotech.
As said before, we are going to focus in an investigator-driven study on PMR, and we will come back to that a bit later in the presentation today, what PMR actually is and why it fits really well into the RA indication that is our lead program. We have the other track, which is in the viral infectious, and there we have launched the dengue project, which we believe is going to be an important one as well. It is a huge indication. It is an indication which is a big problem in certain countries, and we have established a nice collaboration with local people in Brazil and managed to get this study up and running very quickly. We are waiting for recruitment. We need to see the next epidemic come into play, which we expect will happen in the autumn.
A very nice track, a very interesting path, and potentially also a path that could develop into other indications as well into the same area. With the money raised today and basically yesterday, we will have a bit more freedom. It's also an area where we believe that there's good opportunities for soft money, and we have a couple of applications ongoing. With more money in that area, we could do a lot more. We will get back to these investigator-driven studies during the presentation today, but short and short, those ones are small studies, but conducted in a way where it's relatively low cost to do such a study. We're talking about SEK 5 million-SEK 7 million in order to do a complete investigator-driven study in a Phase II.
It's a very interesting way of doing supportive clinical development and definitely an area that Big Pharma is looking into when we discuss the lead project. Strategy executed in Q1, Q2. Yes, we got the RA study into action, and we, as said before, we're on time. We have completed two capital raises, both of them at a premium raising around SEK 110 million, and we have done it in a way where the cost base on raising those money has been very low. We have, as said before, strengthened the management with Jeppe Ragner on the Board as well. Looking ahead, we plan to report on the RA study end of the year. Within the next not many months, we will have data, hopefully positive data.
We will initiate the study in dengue, as said before, and then Boesen will later on today explain what we are going to do with the compounds from TXP. They are basically ready for Phase I development, and we will initiate that as soon as we can. Some of you might remember that that project actually had been sold once before. It was acquired in an option to acquire agreement by Questcor Pharmaceuticals some years ago, but for different reasons, they were acquired. We managed to get the project back, and therefore we are now ready to take it into Phase I development in some very interesting indications as well. Full focus on PMR, get that off the ground, and then a lot of focus on business development, and I'll come back to that a bit later.
A nice pipeline, I think, for a small company with quite advanced indications, and I would say a good news flow over the next two or three quarters. Business development, basically the strategy is that we would like to do a deal up on positive data in RA. I think it would be fair to say that have we gotten the data back in 2023 that we expected, we would have done a deal. We were quite far in advanced discussions with quite a lot of bigger players, also some smaller biotechs in the U.S. primarily, but also in Europe. Have we gotten the data that we wanted, we would have done a deal, I'm pretty sure.
When we reformulated the strategy, we made sure that we kept contact with all those potential buyers, and that has been an ongoing thing for the last 12-18 months to keep them updated to make sure that they are still on their toes. I can assure you that the interest is definitely still there. I think we can say that we have added another three or four to the list that potentially could be a partner for such a project. As said before, PMR lies within sort of the same area of interest as RA, and that means that the ones we are talking RA with, they are also interested in PMR. It would be fair to say that quite often in those discussions, it has been suggested, why do not you go that way?
It is our idea, but it's quite stimulated by partner discussions that we have had in the last couple of 18 months. Dengue virus, we have ongoing discussions with local partners. I think there's a reasonable chance that we can do some sort of a deal in the autumn. It's not going to be a huge one. It's going to be some sort of collaboration type of thing where they will do some work locally. As said before, there might be some soft money involved in that part of it as well. We are going, like many other biotechs, to the next event, which is Bio International in the U.S. It's probably more or less the biggest event during the year, and we are going there for people. Jim is currently busy setting up the meetings.
I think we have more or less 35 meetings confirmed already. Busy week. Then we have three, four partnering events the rest of the year that we are focusing on. I think when we get the data, we should be ready. I think it's fair to say that the team have done a number of deals in the past. I think we are sort of reasonably dressed for getting to the table. As announced yesterday and this morning, we have conducted a direct issue thanks to some very supportive existing investors, Hunter Capital, Sanos Group, Ringberg, Jonas Schild, and other investors as well. I would say that we have been very happy to be able to do this. We have done it at a small premium as well with good support from these people.
We have managed to establish a credit line provided by Hunter Capital. We have done that at a very low-cost structure, no collateral, no obligation to redraw on the loan, and the loan is valid until the end of 2026. I think all up, a nice financing that I believe will create some stability around the company because we have 18 months to do a lot of work without thinking too much about financing. I think actually those SEK 65 million + what we have in the bank now will take us definitely to the end of 2026, probably a little bit into 2027. A nice position to be in, in what can be described as a slightly difficult market.
One of the main reasons for taking and applying this model is also to create some sort of a strength on our part in the business development discussions. We will sit at the table, hopefully in Q1, a bit more safe and a bit more confident talking to Big Pharma. They always have sort of the question, how much money do we have in the bank? Now we're in a nice situation. I think we are well dressed for taking up those sort of discussions. That sort of concludes a little bit of an update on the company. I know it's a little bit quick, but basically where we are. Thank you very much. Yeah. I was curious, you mentioned a lot of deals. Could you tell us more of what you sort of imagine those deals to be? What sort of deals can you strike?
Yeah. It's a question that we get quite often from shareholders. Are you selling the company? Are you doing a licensing deal? Or what are you doing? It's difficult to say and predict, but I think ranging from full acquisition to maybe option to acquire is probably the span. You have everything in between. A licensing deal would be a nice one as well for SynAct. I think to do some sort of a deal where they pay some of the future development could be a model that would work. I think we will keep an open mind. What we have learned from past experience is that different companies have different ways of doing deals. As said before, I think we are reasonably prepared for taking those discussions.
Of course, in all interests of all shareholders, we need to make sure that we do the optimal deal, but sometimes you also need to take it when it's on the table. I think adding PMR is going to make the dealing easier and more attractive for the buyer because they can see that there's other indications. They know that already, but they can see that we have taken the first steps. We might be able to produce some data that we can support the discussion. You did also mention local partners, local deals. Are you looking for the same thing there or something? We have considered different kinds of regional deals.
I think that if we end up doing something in that line, it might be on the virus project because that sort of fits in and does not jeopardize the bigger deal that we hope that we will be able to do mainly on the RA. Today's press releases were regarding mostly financing, the credit facility, as well as the directed shares issue. Let's begin with the credit facility. You mentioned that it was to a lower interest rate than the market rate for other biotech companies. By how much? Yeah. I think the deal structure in total is an attractive one. We have had good discussions with Hunter Capital and good understanding of where we are with the company. They are also a main shareholder. So they have a good understanding on where we are and what we need.
We have looked into other options that have been available, also with bigger amounts, but I think that this model fitted in with the company very well. I am very happy that we were able to do this in conjunction with a directed issue as well. The press release mentioned that the current financing paves the way for financial runway all the way until the end of 2026. What sort of milestones and achievements do you expect to reach by then? Yeah. Basically, our main focus is that we need to get the RA study completed. We need to do that end of this year. That is sort of the main one. We need to show progress on the dengue project and on the PMR to show that we are there.
Hopefully, we will be able to do some sort of a deal or be in sort of deep discussions when we hopefully get the right amount of data. We'll now open the floor in case anyone has any question from our live audience. No. All right. Yes, one question.
Maybe we come back to polymyalgia rheumatica, PMR. I'm in no way an expert of this disease, but I think it's a tricky diagnosis with a lot of variation with the same patient and between different patients. Any study needs to take account for this huge difference between different patients.
Yeah. We agree to that. It has been into the consideration from the very beginning that this variation is big.
I think Thomas will show you a bit more about what we are focusing on and what sort of endpoints that we hope that we'll be able to prove. I think why we go that way is also closely related to that we have learned a lot over the years with the compound from the other studies that we have done. We think that there's a really nice window for what the compound actually can do. Let's get back to that a bit later when we get deeper into that part of it. We'll now hand over to Thomas Jonassen as we head to more about resomelagon.
Thank you. Yeah. Inflammatory autoimmune diseases, they are, I think what you could say is in most cases, we don't have any curative treatments.
We have a lot of treatment options, but most of them are, or if not all of them, are addressed on the disease in a way. They inhibit and in many cases suppress the immune system, which is associated with side effects. In addition to that, many of the diseases can only be controlled by use of glucocorticoids. That is what I will try to show in some of the next slides here or the next presentation here is a major challenge out of the clinic. We believe very much in our concept of resolution therapy that we could potentially be a changer in the way that you treat these diseases. As you highlighted, we have decided to go for two tracks.
The inflammatory autoimmune diseases where our main focus is on rheumatoid arthritis, where we intend to set up additional studies through our network of collaborators and investigators in polymyalgia rheumatica. I will come back to how we, with our investigators and in collaboration with them, are sure that we will find a very actually quite homogeneous group of patients with the common goal of the study is to show that the compound has the potential to reduce the use of glucocorticoids, which is a major issue in these patients. That is, you could say, the main focus area right now. The other one is the host-directed therapy in environmental infections, where Mauro will give a longer presentation. Mauro Teixeira will give a longer presentation where I'll briefly address that.
The pipeline, as Jeppe shows, I do not think I need to repeat it, but what I can say about the rheumatoid arthritis is that we are very focused on first-line treatment. Our treatment approach are developed and are a very feasible and very attractive way of treating active inflammation, meaning that early intervention in rheumatoid arthritis, potentially you could go into flares, meaning exacerbation, at later time points. That is really what we are doing and focusing on in our different programs, whether that is due to inflammatory autoimmune diseases or whether it is in virus. In addition to that, we have the TXP program where we have the possibility, finally, I would say, to come into Phase I next year. It has been a question of prioritizing our resources.
We have a clear ambition to complete the pharmacology program so we can be Phase I ready next year. Thomas will come more into that. Basically, you could say that it is a treatment that could be developed for in-hospital treatment. You could say in those patients who would benefit more from more aggressive IV treatment than from tablet treatment, as we have with resomelagon. Yeah. Next slide, inflammatory diseases, rheumatoid arthritis, polymyalgia, I will come into that. We also had a program in nephrology. It is a rare indication, very, very rare disease, idiopathic membranous nephropathy. We have decided to continue recruitment within the sites we have opened without putting extra resources into that, but simply to see how many patients we can get in that in the end would benefit for the overall pipeline development.
We started the development in rheumatoid arthritis some years ago, and I'll come back to that in a little more detail. What we learned from the development so far was that this compound should be given to patients who have active disease. The most attractive way to do that is to go in early. Within a few months from diagnosis, when the disease activity is high and when you have signs of systemic inflammation, this compound is very active and addresses the disease in a very attractive way, as it has a very nice side effect profile and at the same time can be given in combination with methotrexate and thereby be applied as a first-line treatment.
To the right on this slide here, I highlight the potential and from the subset of the patients in the EXPAND study who were newly diagnosed and with signs of systemic inflammation at the initiation of treatment. It showed a very, very nice treatment effect of DAS28, which is an indication of disease activity and as well also here on HAQ, indicating that is a measurement of quality of life where we had quite striking effects of the compound. The other track is in the host-directed therapy. There, as Jeppe mentioned, in 2021, reported data from a single-site study we ran in Belo Horizonte Center with Professor Mauro Teixeira, who is going to present the concept of host-directed therapy with our compounds a little later today.
The take-home message is that in viral infections, when you have a certain level of activation of the immune system, you could say that it was hyperactive. We consider our treatment as a novel option to control that and that way around treat or protect against development of more severe diseases and organ failure. We showed that in COVID-19, and we intend to show that in the other indications that we are moving into. The concept of the compound is that we induce resolution. If we look at this slide, inflammation is per se an endogene pharmacological response to maintain tissue protection. There you typically have an onset phase, what's called number one, and a resolution phase called number two in this case. This resolution phase was for many years considered passive, but it's very highly regulated.
That is where we, with our compound, can do something that hardly any other compounds in development can do, especially not for all treatment, that we can promote resolution. We can do specific pathways that help up clearing the inflammation. If we have a more accelerated response, a pathological response, as here highlighted as number three, you will develop symptoms. You will get organ affection. You will get tissue affection. If you do not get that in control, you will go into chronic disease and a chronic inflammation, which is always associated with irreversible loss of function. We have a compound of resomelagon working in the way that it has some anti-inflammatory effect, but importantly, also stimulate resolution pathway. Thereby, we take the inflammation to a new set point. We do not suppress it.
We move it from one set point to another set point for the benefit of the patient. The way we do that is to stimulate melanocortin receptors. The cartoon here shows how a macrophage, a critical cell in many diseases, including rheumatoid arthritis and COVID-19, for example, how that, if they go into a pro-inflammatory state by stimulating receptors on the surface of these cells, we reduce the pro-inflammatory activity so they become less, you could say, violent. At the same time, a subset of the cells go to a provisional pathway where the ability to help to clear out the inflammation, what we call efferocytosis. That is a very important and very profound way of looking into this system that we believe that the melanocortin system is there in man, in tissue, in nature to help control the inflammatory system.
You can pharmacologically benefit from treating these receptors in the right circumstances to bring the inflammatory system to a new set point. This we show here on this slide very fast is our model system of an experimental inflammation where we show exactly what we are looking for. We reduce the pro-inflammatory activity, but we never take it out. We get less neutrophil influx. We get less release of pro-inflammatory cytokines. Importantly, to what we are showing down to the right, we boost these provisional pathways by having the ability to clear up the neutrophils and thereby bringing the disease to a faster recovery to a new state of balance in the immune system. The receptor, the way we do that is as a biased agonist. That is also the first. We are the first who can do, who has a biased agonist for the melanocortin system.
That is associated with some important effects. First of all, it does not stimulate. If it had been a classic agonist, we would have had a compound that would stimulate pigmentation. It would give skin pigmentation, which would be an unwanted side effect. The compound works as a biased agonist, meaning that it goes for an alternative pathway when you stimulate the receptor, the hERG phosphorylation rather than classical cyclic AMP. From Thomas Boesen's work with the compound, we have identified that the compound most likely binds to an allosteric binding site on the receptors and thereby have this alternative stimulation. When you give this compound, it has a T half-life of around 18 hours, 16-18 hours in man. The formulation we are using, we started with a suspension, and we now have a very, very nice tablet.
We have a very steep increase in concentration. That's important because we are working with an agonist. So we stimulate the receptors. When we give the compound, we reach the maximum concentration in blood within one to two hours. We have the stimulation of the receptors for some hours, and then gradually it disappears. Very importantly, we come below a certain level concentration of the compound in the blood. We do not have stimulation of the receptor all 24 hours during the day. That's very, very important because if we had that, the likelihood of getting, you could say, desensitization of the system was high. We have a very attractive way of giving this compound by a tablet. It gives a very steep increase in plasma concentration and stimulates receptors as they should.
In other words, we can give it once daily. If we look at the newly diagnosed rheumatoid arthritis patients, and that's where our lead indication is, we know that if we look at the big 16 markets, approximately 900,000 new cases are seen every year developing rheumatoid arthritis, typically middle-aged with higher likelihood for seeing that in women than in men. If you look at U.S. and Europe and Europe 5 alone, it's more than 300,000. I will come back to that, that of these patients, approximately a little more than half of them will have high disease activity and thereby per se fits into our treatment algorithm. It's also expected, and we know from Western lifestyle and so on, that the number of patients most likely will increase over the years.
It's estimated that more than 1 million patients in a few years will develop rheumatoid arthritis every year and potentially then go even higher in another 15 years from there. If you look, and that's very important when you look into a disease as rheumatoid arthritis, we have the large scientific clinical societies, the European Rheumatological Society and the American. They every second year come with guidelines to how to treat rheumatoid arthritis. This is from the 2022 version of these guidelines, European. Target is maximum response as fast as possible and as safe as possible. That's the target for treatment with rheumatoid arthritis. When you use glucocorticoids, which you often have to do in order to control the disease, you should minimize the use and for sure try to get out of treatment within three months.
The current treatment, including methotrexate, which is the first-line treatment in these patients, they do all have immunosuppression effects, and they are associated with safety risks. The current treatments are all associated with immunosuppression, all means that you have increased risk of infections that you, in some of the compounds, even associate with increased risk of malignancy. From some of them, also induce cardiovascular disease. There is a large need for immune modulatory treatment is really needed. That's where we see ourselves. If we look at these slides here, it looks very good because you get very, very fast recovery in a number of patients. At least you reach ACR20 very, very fast if you give a lot of glucocorticoids. You can give that locally in joints.
It's very time-consuming and something you can do if you have a lot of money in your health system and you are willing to put them into hours of hours with the patients. That's not the way you do in most countries. The problem is that you can't expect that even the most aggressive treatment will get disease control within what is defined from the guidelines to be within three, max six months. You will all, in many, many cases, end up giving glucocorticoids. When you have given that for a period, you can't get out of that again. Importantly, the biologics, the TNF- blockers and so on, their side effect profile is to a degree that you can't apply them as first-line treatment. This just to say, we have a lot of we hear that it's a competitive market.
Yes, there is a lot of programs in development. If you look at all the phase three programs, they all are, you could say, have the same profile as the already existing compounds as they have the potential to induce immune suppression. We are one of the very few programs who has the possibility to go in early to do a difference at an early stage. We can act that because we have a much better safety profile than most other compounds. Why is it so important? It is so important to treat rheumatoid arthritis as fast as possible because if you look out to the right, if you look three years after the indication had been made, the diagnosis had been set, more than 95% of all the patients have been treated with glucocorticoids. Many of the patients have been shifting between different treatments.
You can see to the right that only a third of the patients have actually been exposed to biologics. They are effective. They are expensive. They are associated with side effects. Importantly, they are expensive to a level that many can't afford them. What you could say is it's much, and then if you have high disease activity, you have a high likelihood to develop early irreversible loss of function in the joints. Going early is very, very important. Patient perspective, autoimmune disease, chronic inflammation, symptoms in newly diagnosed are high. That's what you know, 10+ 1 joints. The physician's perspective is early diagnosis is what we are looking for. We would like to treat them so we get control by the latest after three months. The problem is in many cases, you don't get the patients into a rheumatologist very fast.
In some countries, the physicians are told, don't send the patient to the rheumatologist. Try to do something by yourself because it's too expensive. You end up giving glucocorticoids. Eventually, you can come into methotrexate. That was actually one of the reasons why we did not really get the right patients in the previous studies, that we got a lot of patients who had never been treated according to the guidelines but have had disease for a long time. You could say early diagnosis and effective treatment is really what we are looking for. Convenient treatment, once daily a tablet. You could preserve joint function by going in early. You could then thereby maintain daily living and ability to work. We believe we can do that with glucocorticoids, not with glucocorticoids, but with our compound resomelagon.
From a physician point of view, more safe treatment, yes. More effective initial treatment, yes, we do have that. We cannot take out the glucocorticoids from day one. They are very effective. If we could end up in a situation where you, for example, gave glucocorticoids once and not for three months with a risk to continue for life or at least for years, we would have made a big difference. Steroid sparing is really, you could say, what we look for. That is also why we think that pulmonology, as I come back to, is interesting. Rheumatoid arthritis is characterized by a very organized synovial membrane. Synovial is the tissue around the joints that produces the liquid in the joints. It is also an organ that clears and secures normal functionality of the joint.
It has a lining where you have macrophages, the target cells of our compound. That is disrupted, as you can see on the cartoon here. It is disrupted very early in rheumatoid arthritis. You get new cells in. You get inflammation, neutrophils, and you have proliferation of other cells that we potentially do not want to have in there. The neutrophils, they are recruited. They become very pro-inflammatory. They induce a whole cascade of inflammatory events that we would like to avoid. The macrophages, the lining is disrupted. They go from, you could say, a protective phenotype to a pro-inflammatory phenotype. They, again, stimulate this cascade of immunological responses that gives the disease. These are the two target cells of our compound. We know that we can reduce the activity of the neutrophils.
We know that we can reduce the influx of neutrophils into a tissue. We never induce neutropenia as many other compounds would do. The macrophages, what I showed you on the previous slide, they will be less pro-inflammatory and a subset of them will go to this pro-resolving pathway that we are looking for. From that perspective, it makes a lot of sense to go into rheumatoid arthritis. Basically, what I just said. We had the animal studies that supported that. We have tested that in collagen-induced arthritis. We tested that in a KBNX model of arthritis. We tested that in combination with methotrexate and saw some, to the right, some surprising findings that it seems to have a super additive effect that is helping us.
That's one of the reasons why we got the combination patent that Thomas is going to talk about later today, issued this year. We started off in a small study called BEGIN. What we saw there, we looked at the disease activity and showed in these patients, the vast majority of them were newly diagnosed. The majority of them had signs of systemic inflammation. There we saw a significant reduction in disease activity already after four weeks. The same when we looked at the ACR scoring system, which is typically what you apply to development in Phase 3, where you have large cohorts of patients that you treat.
If we only look at those patients of interest, as I said, in the expand study where we got this unfortunately negative study, when we then dipped into the data, identified the patients that we were looking for, those who were newly diagnosed, those who had signs of high disease activity with systemic inflammation, we saw very, very nice treatment effects. We saw more than 80% of these patients responded to ACR20. We saw that the reduction in disease activity was much higher on active versus placebo. We saw that both with DAS28 and with CDAI. In all these patients, we gave this as a, you could say, in combination with methotrexate, meaning that we gave it completely according to how you should do if you follow the guideline.
When you then look at the patients, approximately more than half of the patients newly diagnosed do have high disease activity when they are diagnosed. These patients and the vast majority of those patients do have signs of systemic inflammation. That's not to say that you cannot find increased CRP as indication of systemic inflammation in patients with moderate disease activity. I think that right now we are focusing on those with high disease activity where we had this scoring system, the DAS28 and the CDAI. That is how we are recruiting our patients together with a CRP outside normal range. If you look at the market for these patients, it's approximately half of what you see there. You can make the calculations down and say, how big is the market?
Market penetration of half the patient, 25% of that. You can discuss the price of a compound like this. If you take a third, like for example, the JAK inhibitors, you still would, from a business perspective, have a very, very attractive business case. Just to put it into the current guidelines, you fit very, very well in as first-line treatment when we start with methotrexate. We would also fit into a setting where you have started to treat with methotrexate for a few months that you still have high disease activity, non-responders, CRPs that are still outside normal range. You could potentially also find these patients. We have decided to go for first-line because that's logic that you could avoid a lot of the later patients. That's where we are right now.
The study that we are running, the ADVANCE study, it's a 240-patient Phase 2B study. It's run under the U.S.- IND. We opened an IND back in 2022, meaning that we have discussed the development program with the FDA and report to FDA and can get the scientific advice from them on an ongoing basis. What we are doing here is that we have set this study up as a classical dose range study on sites in the U.S. as well as in Europe, including sites in Denmark, and that we give the compound in combination with standard methotrexate treatment with uptitrating of methotrexate to 20 mg over three months.
When we come to glucocorticoids, they are only allowed as rescue medicine, meaning that after the first four weeks' dosing, if you can't control the disease, the physicians are allowed to do that, to give glucocorticoids to potential disease control. From the previous study we have done, we know that when you do that, the use of glucocorticoids is very limited. This would really look very, very much forward. We are using DAS28 as the primary readout because, again, U.S. FDA recommends to use this, not the ACR score for dose response studies, simply because if you should use a yes/no response as the ACR scoring, you would need extremely big groups in order to find relevant difference between different dose groups. It makes a lot of sense then to follow the guidelines to use the DAS28. That's what we are doing.
That is, by the way, also what the European authority, EMA, would like to see in phase three. We initiated the study last year. We filed with CTA. We had the first patient in November. We are now recruiting according to plan and collaborating with our CRO. According to plan, we would have the last patient dosed by the end of the year. As we have short follow-up, we could have the key results very soon after that. When we then have the results, and we strongly believe that it would be positive, we will know not only whether or not it is active versus placebo, but we will also know which doses to potentially be brought further into Phase 3 development.
This is important to say that we intend to go to EMA and FDA and discuss Phase 3 plans with them on the back of this study because it's so important to have this progress in the development in order to move forward. It's the same one more time. I would like to say just a little about rheumatoid arthritis, comment on future opportunities. Today, 90% of the market in rheumatoid arthritis is in more advanced cases, you could say, patients who do not respond to methotrexate, who have been too long without diagnosis, without adequate treatment. If you look at the history of rheumatoid arthritis, many of these patients, especially those who are, you could say, what's called seropositive, they have markers in the blood. Many of them develop pain. They can go with pain for months and years without any adequate treatment.
I strongly believe that the future is in those patients more to the left. One reason to say that is that last year in Lancet in 2000, I think it was in October, it was published this study here, the APRIPA trial with BMS's T-cell inhibitor, where the concept was that if you were seropositive for rheumatoid arthritis but did not have any arthritis but joint pain, you were set on 12 months' treatment with a compound. Look at that. That is the blue line. The red line is patients who were just being followed by placebo. You avoid a lot of patients who develop rheumatoid arthritis by doing so. In the future, not only that, you also avoid a lot of use of glucocorticoids in these patients.
I think that in the future, when we know more about this disease, when we are in a few years' time, you need something who is safe, well-tolerated. The T-blocker is not first-line. The T-cell blocker is not first-line treatment due to the side effect profile. You need something that is safe and well-tolerated and can be given in the right patient at an early time point. I would think that it's something to look for in the future in rheumatoid arthritis. Polymyalgia rheumatica. Through our interaction with our rheumatologist and advisors, we have been actually invited to go into a collaboration where we will have the full ownership of all data and run that in an investigator-driven study.
I'm not going to give you the exact design today because when we planned this meeting here, it was a question of doing that and initiate and sign the contracts and all. What you should do is pending that we got financing. We have the financing now. And we will execute on this as we have done on many other programs. Polymyalgia rheumatica, and I--sorry, there is an L missing out in this slide here--is a disease that typically is seen in the Western world. It's typically affecting middle-aged women, more often than men, that is giving specific, especially in the morning, pain and decreased functionality in the shoulder, more than anything else in the shoulder area. There's a lot of--and you could say there's a lot of similarity in the pathophysiology to giant cell arteritis, temporalis.
Just to say that this is not only another indication with a rheumatic disease where you have an unmet medical need, but it's also, you could say, a model for a more severe giant cell arteritis disease where there also is quite a need for new treatments. Because we got the question here, is it not a very heterogeneous group? Yes, it is, unless you make your diagnosis based on EMA. Our study, we will work with rheumatologists on very specific definitions of the indication, including EMA evaluating to set the diagnosis. When the diagnosis has been set, standard treatment in these patients are glucocorticoids, typically 15-25 mg per day for a minimum of four weeks. You gradually start to reduce the glucocorticoids. As I highlight here, there is a high, high risk of relapses in the disease.
Many patients end up in more chronic glucocorticoid treatment. One of the physicians we are working with said that I have dedicated my life to find a way where we can secure that our patients are not ending up in chronic glucocorticoid treatment. Methotrexate works in some patients. Again, it's the neutrophils. It's the macrophages who play a major role here. That's exactly the cell that we are treating. It makes a lot of sense to try to test our compound in this indication. Glucocorticoids, you start typically with up to 25 mg of prednisone. You treat for a minimum of four weeks. Then you could consider methotrexate as second-line treatment. That's not what you do. You typically try to get out of the glucocorticoids. You, in many, many, many cases, end up with glucocorticoid treatment again.
There have recently been reported studies on IL-6 blockers as well as on JAK inhibitor. Could be used as second-line treatment, third-line treatment, as it does in rheumatoid arthritis. First-line treatment will never, ever make for these compounds. The tampering strategy is to try to get down in doses and try to get out of it. You end up in the short, even if you go for a 12-week study, as we intend to do, you will see that a significant fraction of the patients that you have tried to take out of glucocorticoids will develop symptoms. You simply have to give the glucocorticoids again. If we can combine our treatment with glucocorticoids and significantly reduce that, we could go directly in as a new first-line treatment option in these patients. That is the whole idea of running the program.
Basically, this is all what a drug should be able to do in polymyalgia. I think we fit into all of those. I think it's logic what we are going to do here. We will, as soon as we file the clinical trial application, update you on the exact design of the study and also on timelines. The clear intention is to have the study up running with active recruitment this year. Again, as for rheumatoid arthritis, we fit very, very well into the treatment guideline as first-line treatment, as well as, you could say, semi-second-line treatment after initial glucocorticoids treatment. Good. Then actually I would give the word to Mauro Teixeira, who has been--you will do that. That's good.
There are some questions first, I believe, for you. Thank you very much, Thomas, for the presentation. I think I'll sort of begin with asking you about the parallel tracks that you're currently taking. From a scientific point of view, since you're the Chief Scientific Officer of the company, what sort of challenges are you facing with running parallels? What sort of rewards are you expecting?
I think the challenge is that we would always like to do more than we have money to do and manpower to do. Besides that, I think that with the collaborators we have and also with the limited staff we have in-house and the CROs we are working with, we are in good hands. I think they fit very well into each other. Of course, you can discuss the development potential in them. I think it's high in both of them.
In the treatment of RA, you mentioned that it was a highly competitive market where you have an USP in sort of attacking it early. I'm curious today, with the current sort of treatments towards that that are available today, when are patients usually starting to get treated and diagnosed? What would their ideal be?
Yeah. In rheumatoid arthritis, if you follow the guideline, it's very, very clear saying that you should, as soon as you have symptoms of rheumatoid arthritis, you should be sent and get the diagnosis. When you get the diagnosis, if you have moderate or high disease activity, you should start first-line treatment. First-line treatment is, unless it's not tolerated, methotrexate. The guideline opens for the possibility to, you could say, use glucocorticoids for a short period to get fast symptom relief. Because methotrexate typically has to be given for at least, depend a little, but at least some weeks before you have effect, efficacy. The guideline said that after three months, you should have a measurable effect. Alternatively, after six months, you should have disease control, meaning that you should have low disease activity or remission.
You measure that by this scoring system that I mentioned, which is tendons, swollen joints, and the patients and investigators and so on, evaluation of the level of disease activity. The thing is that in many cases, the patients do not come in very fast. The second thing is that in many cases, they are treated with methotrexate in an insufficient way, either because you give glucocorticoids on top of that and continue to do that. Alternatively, you do not do that at all. You do not try to treat your methotrexate. You have to go to second-line treatment, which, again, is very expensive. For many, one is many can't afford to pay that. The setting is fight the patient early, treat them early. In that case, give them our best opinion.
What we are going to prove is give the methotrexate and resomelagon. And forget about, yeah. And then the hope is reduce glucocorticoids and postpone the second, third-line treatments.
There's a question in the chat here that asks regarding PMR. Do you have an expectation of what the value of the market is there?
I would think that we have made these measurements. I think that it's approximately one-tenth of the first-line RA treatment. Thomas is saying yes because he's made the calculations and the evaluations.
Great. We will open up the floor for any questions. We have one here.
Coming back to RA, since this is a resolution therapy, if you get effect of your treatment, is the idea to phase out the treatment after six months, eight months, and then only start anew when symptoms come back? Or is it a continuous treatment?
That's a very, very good question. The way I would answer that is that for a Phase 3 program where you need to give compounds in order to reach market for up to one year, I think it would be with continuous treatment for one year. It might be so that you would have one initial dose for the active disease and then go down in dose. That's one possibility. Another possibility is, of course, to try to get out of there, actually to stop treatment, and then see whether you have a rebound or whether that is something that could be given at a later time point. I think in many of these questions, we can't answer on this side of potential market launch. It is very, very, very valid questions.
Do we have more? Yes?
Could you say a few words about why glucocorticoids are so bad?
Yeah. Because glucocorticoids are good if you give them acutely. Glucocorticoids are associated with a lot of side effects. First of all, you have an androgen, you could say, suppression of the androgen glucocorticoid axis up from the hypothalamus down to the adrenal gland, which secretes glucocorticoids. That can be inhibited in a way so it does not work. You need glucocorticoids in order to have normal functionality. Glucocorticoids also, when you give them in pharmacological doses, induce a lot of side effects. It induces bone loss. It induces water salt retention, so you can get edemas. It reduces changes in the collagen gene, so you get irreversible changes in your skin. It is associated with a higher risk of cardiovascular disease. It is associated with development of type 2 diabetes. All in all, it is not something you would wish to have your patient on chronic glucocorticoid treatment.
That is why it is so important to stay for as short a treatment as possible and avoid them if you can.
Yes, we have two more questions.
This question is a bit premature. But this study is limited to 140 patients. How big do you think a Phase 3 needs to be? And will you succeed in having only one Phase 3? Or will you have to do two Phase 3s?
I think when it comes to sizing, we have 240 in this study. That is based on what we think should be sufficient to see significant treatment effects and potentially discriminate between different doses by using the DAS28 differentiators as primary there. It is also a feasible size from a safety perspective. When it comes to Phase 3, I think the best way of answering that question, number one, is what have other companies done? For the JAK inhibitors who have been developed for first-line or Phase 3 have been conducted for first-line treatment, it is 350-400 patients per group. A question, of course, is how many groups you would have. In an ideal world, it would be one dose of active, one dose of placebo, 800 patients.
Next question, whether we should go for one or two studies would probably be a question that we could answer when we have had the next interaction with FDA and EMA. Most likely two. Also to build up sufficient safety database.
We had one more question in the back.
Yeah. Since women are more prone to RA, is the disease more severe for them? Did you look at any effects, the difference between women and men during EXPAND?
No. During EXPAND, we did not look into difference. I mean, the sample size was simply too little. We know that clinical trials are typically a little screwed in the way that we know that there are more women than men who develop rheumatoid arthritis. But women are also easier to convince to participate in a clinical study than men. What you see is from most studies that you have an overrepresentation of women. It is difficult to say whether there is this gender difference. We have not seen anything that indicates that. Of course, I looked at it. The numbers are simply too small.
Thank you very much, Thomas. We will now hand it over to the professor who is waiting here over at LINC. It's Mauro Teixeira, who will walk us through the host-directed therapy in viral infections. Welcome.
Hi, everyone. And good afternoon for you guys. My apologies. Can you hear me well? Just to confirm, yes? OK. Apologies for not being able to be there. I just had a surgery a few weeks ago, and I am not allowed to travel these days. It's a pleasure to be with you anyway. Can I have the first slide? Yes, it's there already. Next one, please. The previous one. OK. I think life is about interactions. When we talk about infection, we are really talking about what we call host pathogen or host microbial interactions. This is when we look at trees, or we could look at anywhere in the world. If we look at a human, next slide, please. We are obviously surrounded by microbes.
Indeed, there are about 10 to the 12, 1 trillion microbes on Earth, the vast majority of which we do not even interact with at all. The most relevant interactions we have—next slide, please—have to do with our own microbiota. These microbes, they are in our gut mostly. It is estimated about 500 different species of bacteria in the gut alone, plus virus, archaea, and fungi. This is quite relevant to our immune system. Next slide. Not only to the immune system, but also to our metabolic capacity. Indeed, next slide, as we eat and interact with others, our diet will change this microbiome. It does change a lot our capacity to—it enhances our metabolic capacity. It does change our immune system maturation and function. There is a lot being said and studied about this.
It creates a superorganism, which is us and our microbes, which is really necessary. This is what we call the physiology of the immune system. We are ourselves and our microbes. Next slide. In contrast, when we talk about infections and human diseases caused by pathogens, we are actually infected by only about 10 to the 3 pathogens. It is actually 10 to the 3 pathogens over 10 to the 12 microbial species on Earth. We are really quite good at actually dealing with infection. Next slide. As I said, physiology of the immune system has to do mostly with our resident microbiota, the microbiota that is in our gut, that changes our immune system, matures the immune system, changes T- cells, B- cells. Next slide, we are interested here in the 10 to the 3 pathogens that actually cause infection and eventually disease and death.
I think COVID got everyone scared about that. Everybody thinks of the relevance. It's all part of a continuum of interacting with the microbiota and then interacting with the pathogen. It's not something that infection is separate from this overall interaction. That's why I wanted to mention that. As we get infected, next slide, you will see on the left-hand side, when we have a productive interaction with a pathogen, there may be infection. Our immune system responds to infection. It's the production of mediators of the inflammatory response that will lead to the acute inflammatory response that will contain infection, prevent it from spreading. It will also instruct adaptive immunity. It will also instruct adaptive immunity. The combined action of containing infection, adaptive immunity. Next slide.
There will be a control of infection, eventually decrease of parasite replication, death of the parasite, of the microorganism. Next. We tend to return to baseline. Next slide. If we do not have a properly working immune system, as we see in HIV, for example, or in cancer treatment, we are not able to mount an acute inflammatory response. We die of infection. These are frequent causes of severe infections, unopportunistic infections. Next slide. OK. This is the good side of inflammation. Indeed, the good side. That is what we think the immune system was created in first coma for. It does contain infection. It does instruct the adaptive immune system. However, that same acute inflammatory response to infection will actually cause disease.
Fundamentally, next slide, we have a situation here that the immune response that is generated to control infection actually causes disease. Our hypothesis is that disease results when these mediators of the inflammatory response are inadequate, which could be in a lot of things. Insufficient, as we see in HIV, excessive or misplaced, as we see in sepsis, outright different mediators, as we see in different diseases. There has been a lot of work. Next slide. To suggest that, can we find out which are the good mediators or where they should be produced to control infection and separate from the inadequate response so that we may be able to block this inadequate immune response and favor the good immune response? Obviously, this is easy to say.
If you look at single mediators, this is quite challenging, especially because it's not easy to mimic human infection in animals. The idea is that we want to find molecules from the host that are relevant for the disease. We want to block those, but still allow protective immunity to occur. Next slide. This is something that we have worked a lot with in the last two decades. The concept of generating these anti-inflammatory response, anti-inflammatory drugs to infectious disease has gained not only experimental evidence, as already revealed in 2010, but more recently. Next slide. Shown by COVID. Clearly, COVID has actually presented the best evidence so far that blocking aspects of the inflammatory response, such as steroids, anti-IL-6, not 16, or kinase inhibitors, does decrease your risk of severity after an infection.
We call these anti-inflammatory drugs that we use during infection host-directed therapies. The idea would be I will block the non-beneficial part, but the disease-causing part of infection. That would allow me to deal with infection, but have less disease. Next slide. Changing gears to what Thomas said and using the two concepts together. Now, as I mentioned, it's very hard to find individual molecules which go wrong in different infections. Can we actually use a different concept, which is the concept of resolution of inflammation going wrong during infectious disease and trying to make it go better? Can we give pro-resolving molecules during infection in such a way that we tend to normalize the immune response, not prevent it completely, but make it in a better way? Immunologists tend to say modulate the immune response.
I think it's a good word because it doesn't mean that much. The idea being that I do not want the part of the immune response that causes tissue damage. I want the part of the immune response that deals with the infection. What is the place there is for resolution pharmacology in that space? Next slide. I will obviously talk about resomelagon or AP1189. I will use these two names interchangeably. Next. Pretty much, we start looking at that during COVID. This is a model of beta coronavirus infection in mice. As you can see, for example, in the left-hand side bottom, if you infect mice with this beta coronavirus that resembles human SARS-CoV-2, there will be disease. There will be cytokines. There is viral replication.
If you give compounds such as if you give AP1189, if you treat animals and I want to make sure that we always show that every time that we do these experiments in mice, we are doing it as a post-treatment. Because this is what real life is. You do not think you will get infected. You take a drug. You are infected. Then you are treated for the infection with an antiviral, antibiotic. What we are suggesting is an anti-inflammatory drug. OK. Treating with AP1189 clearly decreases the histopathological score. It decreases the cytokine score. Next slide. If we go to a model of SARS-CoV-2 infection in mice, it is not ideal because you are expressing a human protein. It is not really COVID. It is only pneumonia in mice.
Even then, you treat after disease onset, you clearly have a very marked inhibition of tissue inflammation and damage without a major effect on viral host. I think there are two major messages here. We are not interfering with the ability of the host to deal with infection. We are decreasing inflammatory damage to the lungs in the case of these animal models. Based on these experiments and based on a lot of evidence we had before with the role of inflammation in infection, we conducted a small trial. Next slide. In humans with COVID. This was the resolver one study. It was a randomized double-blind placebo-controlled trial in a hospital. We asked patients that were severe enough to be taken to the hospital, how long would it take me to remove oxygen from them?
These were patients needing oxygen to keep a saturation of oxygen above 93%. They would receive AP1189 or placebo. We would follow them for 28 days and see what would happen to the micropaths to remove oxygen from them. They would be at saturation of above 93% at room air. Next slide. These are patients clearly needing quite a lot of oxygen at this time, and it was a phase two study, a small study. We were not really looking at those already in ventilation, but those individuals severe enough to be needing oxygen, but not that severe that they would need intubation. Next slide. Clearly, in these individuals, if you compare blue with red on the right-hand side, they tend to remove oxygen much earlier, the blue compared to the red. Because you remove oxygen earlier, they tend to go home earlier.
In fact, patients on placebo took about six days to have their oxygen removed, whereas AP1189, I could remove oxygen on a median of four days. As far as hospitalization, there was a two-day difference in hospitalization, which means a lot when you have all your hospital beds filled up with patients. Next slide. If we try to understand what AP1189 was doing, it clearly decreased D-dimer levels. All of these patients were already in steroid use. There was no change in cytokine levels systemically. If you look at the cells, PBMC cells infected with SARS-CoV-2, AP1189 or resomelagon could actually decrease quite significantly the production of cytokines ex vivo from human PBMC. Next slide. This result is actually the first one ever to show the ability of a pro-resolving molecule to significantly have a positive effect in a human infection.
In the case of resomelagon in COVID, there was a significant reduction in time to respiratory recovery without any major treatment-associated adverse event that limited the efficacy. Next slide. What I want to try to convey to you in the next few slides is that the beneficial effects of resomelagon on viral infection extend much beyond COVID-19. I will show you briefly some results on Influenza. It is also an infection of the respiratory tract. It has received a lot of spotlight recently because of the risk of H5N1, which is still in birds, but it has the very large potential of spilling over to humans and causing a major epidemic. Next slide. We have conducted experiments in animals. If you are infected with Influenza, it all depends on the dose. I am not actually entering any detail. There is weight loss. Some animals die.
The knock-on was such that was very severe. About 50% of the animals died. And this was associated with a marked infiltration of leukocytes in the lung. If you treat with AP1189 from day two of infection, you clearly see a marked inhibition of the inflammatory infiltrate. There is no prevention. The inflammatory infiltrate is there. It's just modified. And weight loss is decreased. And the severity is decreased. And fewer animals die. Changing gears a little bit. Next slide. Moving away from the lung, as I mentioned, is the lung. We've done quite a few studies with arboviral infection. The term arbovirus comes from arthropod-borne virus, so virus transmitted by arthropods by insects. The two major ones are dengue and chikungunya. Next slide. I'll try to show you a little bit about dengue and chikungunya.
Dengue has been increasing a lot in the last 70 years, but mostly in the last 20 years. There are now over 3 billion-4 billion people, or half of the world population, that's at risk. About 10% of the population is infected every year. And about 100 million cases are actually clinical cases of some significance. The problem is the infections occur in two-three months. That actually causes so much havoc to the health system that pretty much prevents any health system from working when there is an epidemic. It does not mean that there is a high death rate. When you calculate death rate over 400 million cases, you can actually see the impact of the disease is very, very large. Next slide.
Not only is there dengue, but there are two other major mosquito arthropod-borne viral, arboviral infections transmitted by the same mosquito, which is the Aedes aegypti mosquito or Aedes genus of mosquito. There is Zika, which generated a lot of interest a few years ago because it does cause microcephaly and kills kids. More recently, or concomitantly, there are a lot of cases of chikungunya, which has a little bit of the acute case, but the most important problem is it causes arthritis, arthralgia. It resembles a little bit rheumatoid arthritis and sometimes ankylosing spondylitis. The point I want to make is these three diseases are increasing worldwide. Zika has disappeared for the moment. Chikungunya and dengue are on the increase. The reason being, next slide, that as the global mean temperature elevates, you actually switch the capacity of these mosquitoes to live up north.
Next slide. Pretty much because they live longer, they bite more, and the incubation period is much decreased. The probability of transmission increases a lot as the temperature rises, as mean temperature rises, and you move north. Indeed, next slide, you'll see these are just some extracts from newspapers. There is already a risk in Southern Europe of these diseases actually spreading to Southern Europe and Southern United States as well. Next slide. The DNDi, Drugs for Neglected Diseases initiative, has initiated a dengue alliance of which we are part. I mentioned this because as we were discussing before on rheumatoid arthritis, there's a lot of doubt on how to develop drugs for dengue, how to do the clinical studies, which are the patients, how do you do a phase two, how do you do a phase three.
The whole dengue alliance has been doing that for the last two, three years. We have been very involved in trying to dissect the best way to move forward with finding out how to do these dengue trials. Next slide. The concept for dengue, chikungunya, and even Zika is very similar to that of COVID, in which there is an initial febrile phase in which you probably will treat with antiviral drugs, followed by an inflammatory phase that actually causes the severe disease, that actually causes death, that will be manageable to anti-inflammatory drugs or these host-directed therapies that would allow patients not to be hospitalized and not to suffer the severe consequences of the disease. Next. Experimentally, we have shown that AP1189 shows efficacy in animal models of dengue. It is better in the next slide, please.
For example, if you look on the platelet levels, it's a very important marker of disease. Dengue will cause thrombocytopenia. That's associated with vascular permeability changes. If you treat with AP1189, you will see there is a reversal of that thrombocytopenia as compared to control animals. You also see that inhibition of cytokines by human PBMC infected with dengue. It's quite interesting that in dengue, you tend to see an inhibition of dengue replication, probably because the virus needs an inflammatory stimulus to replicate better. Next slide. You also see beneficial effects in chikungunya. Chikungunya is all about pain. It's all about arthritis that lasts about two years. You can mimic some of that in animals. If you infect animals with chikungunya on your left bottom, you will see in the black dots that they will have chronic pain.
If you treat with resomelagon, 10 mg per kilogram in green, you will have a reversal or inhibition, a complete inhibition of that pain associated with chikungunya. Next slide. Not only do you decrease pain, you do that without changing the ability of the host to deal with a viral infection. This is a very important thing. Pro-resolving molecules such as resomelagon are not immunosuppressive for viral infections. They are not. This is very different from what you've discussed with anti-TNF and some of the kinase inhibitors. Next slide. Again, in chikungunya, treatment with resomelagon will decrease infiltration. In the middle, you see very clearly associated with chikungunya infection. It decreases the cytokine response without changing the viral load. This is clearly associated with a clinical benefit, at least in animals. Next slide.
I think the major message I would like to convey to you is that treatment of resomelagon has clearly clinical benefits in the context of COVID. This is actually beyond the effects provided, the benefits provided by glucocorticoids. It is not only about COVID. Protective effects, at least in animal models, are shown for Influenza, dengue, and chikungunya. This is what we are trying to study now in dengue patients, as Thomas mentioned earlier on. I think the next slide is the final one. Thank you for the attention. I'm happy to take any questions. Yeah.
Thank you very much, Mauro. I'll open the floor directly to any questions from our audience. Yes.
Now, there is a difference between the pulmonary infections with hypoxia. That seems to be very obvious that you should start with resomelagon at an earlier stage if you can to avoid hypoxia.
Also in these other viral infections, it seems, if I get you correctly, that you should start, if resomelagon is shown to be effective, then you should start treatment almost as soon as the diagnosis is put. Is that correct?
Yeah. Overall, there is always a safety worry with anyone. For COVID and all of the animal data, it is absolutely safe to start earlier. Right? Obviously, you do not want to start concomitantly because that does not exist. What we are trying to see is to mimic the real situation. Someone comes with fever, usually two, three days after infection. How do you model that? And would it be safe to give the compound at that early stage? I think it is safe, but we need to show that.
All of these studies have within them the design to actually follow viral load or viremia or viral quantities in the lung during treatment to make sure that you are not preventing the capacity of the human host to deal with infection. I think the experimental data is incredibly strong. Obviously, as a safety issue, we always do that. For example, that is one of the reasons we do not give steroids too early because you do actually have an increase in viral numbers in patients.
Do we have any other questions from our audience? No. All right. We will simply hand over the word. Thank you very much, Mauro, for giving us the presentation and answering our questions. Next up is Thomas Boesen, who will be talking to us a little bit about some patents, but also the TXP program. Welcome, Thomas.
Hi. Thank you. Before I start to talk about the TXP program, I just want to spend a little time on resomelagon and also a little time on why our patents are important. The reason I'm doing that is that this spring has actually been a very important year for SynAct Pharma because we had had some patent issues. I just want to, it's not easy to maybe understand when a press release gets out what does it mean to the company and so on. If I look at what is important here is that we do have two sets of compounds. We have the resomelagon patent series, where we have about nine public patent families. Then we have the TXP peptides, where we also have three patent families. I believe that we have a very strong patent position in TXP, sorry, in SynAct Pharma.
What is important here is to understand that the patents, it is what gives us exclusivity on the market. Thomas talked about how big the market is. That means how much value will be in the future when and if this compound gets launched on the market as a drug. This is a very generic curve here where you see there will be a market entry. There will be some competition when people find out what that is. At the end, there will be generics coming in. Then you'll lose some of your market potential as well. What you see down here is that we have patent protection here up until the end of this. That will define when the competition and generics comes into the market.
What we can do here is that we can extend this period. This is what is important, what we can see from what we have done now. I just show you here. This is just to show that the revenue is getting bigger. What we have seen here in March is that we have gotten, what we, I'll talk more about that, a patent on our crystals. We have another patent, which is in Europe from our formulation. We have a patent that is the use patent where we have use of resomelagon in combination with methotrexate, which is important in the eye, as we have seen. A press release here in May on that we got extended time, which means that we have actually moved the brown bar that you see at the right there. It's actually got quite extended a lot.
It's a lot of value that we are adding to our programs by doing that. What it is, our strategy is that we have our asset, AP1189, here in the middle. It could be a peptide or so. Then we have some layers of protection. We have what we call the composition of matter patents. Those are the most important because they are specific to the compound or the salts and so on that we have. Then you have other layers on top, which is the use patent, such as the combination of methotrexate and RA. You could have also later on a process patent and so on.
The point is that it's not allowed for our competitors to infringe any of these patents during the period where we have exclusivity, which means that the more patent layers we have, the more difficult it is for the competition to get into the market. That is the strategy. This is what we are pursuing. Just to show an example here with the crystal form patent and why we believe that is very, we call it a pivotal patent family. We had this first patent issued in the U.S. You can actually do kind of a fingerprinting of the compound here that is unique to that specific crystal form we have and we use in our patent. Almost no matter, you can actually, but in almost all cases, whenever you mix, you can find that fingerprint.
If people are using that same crystal, they would be infringing our patent. That is a very, very strong patent to have because no matter the use, you are not allowed to use that crystal because we have the exclusivity on the market. That actually, as we have written in our patent, in our press release, is extending our exclusivity until 2042. That is going to be quite important when Jeppe and others are going to discuss with potential partners because they will look at that market potential there at the end. This is just to update you on the patent before I go on to the TXP. I do not know if this was quite a surprise, but maybe there are some questions to that. I do not know.
Yes, because we are on also the topic on resomelagon before we head into TXP.
First of all, how did you decide on this patent strategy and has it been validated?
Yeah. Yeah. That's important because patent is obviously good to have exclusivity on the market, but it also means that you give out information that you only possess. It's kind of a trade-off between society and the inventor that you give something and then you get something back. Sometimes it's not good to go out and get a lot of patents early on because you want to have extended time on the market. Therefore, it's a delicate way to do a strategy there. We're not doing that alone. We are working together with a company in Denmark called Højberg, our patent attorneys. They also have an office here in Stockholm.
They have a strong network of agents around the world, including the U.S., where we have Baker Botts that are representing in the U.S. We do have a discussion in that network about the specific strategy that makes sense on each country, each market, and region, and so on. We have also had it validated by when we do due diligence, people go in and look at our patents. We have also done it ourselves, gone to some of the biggest law firms in the world, actually, and had them evaluate and give us a second opinion on our patent strategy. They are very much aligned with what we are doing.
On the topic of resomelagon, there has also been a question from a viewer that I will address now.
In Expand, you concluded that CRP levels above three is needed for resomelagon to work optimally. You're saying resomelagon would decrease CRP levels, right? If so, what happens to the effect if CRP drops below three?
That is, I guess, Thomas, to help on that, I think.
Okay. Yes. We use CRP as an indication of active inflammation. It's a good question. I think it falls back to what we discussed half an hour ago about the long-term strategy for the compound. In this study, and what we also know from what we already have done, is that it's important when we start that we have signs of systemic inflammation. There's nothing that indicates that if we go, you could say, down into normal range, that a potential treatment effect disappears. From these 12-week studies we have conducted.
Thank you very much, Thomas.
I'll turn to Thomas then to talk a little bit about TXP.
Can I just.
Just a question on the patents.
Sure.
If I may. This may not be relevant, but on blockbusters with a crystal form, there are some specialized companies that create amorphous substances with the aim to round the patents. What's the situation if that were to happen here?
Yeah. That's a very relevant question. The thing is that we have done a lot of investigations into this. We have characterized a lot of crystal forms, crystals at different salts of the patent of resomelagon and included that in our patent application. What we have done now with this specific patent is that we have carved out the most important to get the strong protection around that.
Then we have the rest that we are still processing in our patent execution or processing with the authorities. For the acetate salt that we are working on, we have seen three forms. The one that we are using is the most stable form. We have also, I can say, looked into long-term stability and so on. We think we are in a very good position.
Now, Thomas.
Yeah. Can I just ask how much time I've got? If I'm very short, I have only five or seven slides. It is not a long presentation now, just so you know. I like to start here saying that now we are kind of changing track. We have, as you know, brought in TXP peptides as a different technology, but it is complementary to resomelagon. This slide indicates the difference between the two.
We have small molecules versus peptides. We have also a different pharmacological profile of the compounds. We have different ways that it actually binds to the receptors and different ways that it will activate. The opportunities are different in the two. That is what I want to illustrate here. The peptides, to focus on that. The endogenous hormones in the body, the one that activates the natural receptors, is a peptide. What we have got with the TXP peptides is analogs of the natural hormones. The important thing is that we have modified these peptides with a technology that we call Branched Amino Acid Probes, BAP. Those, as I will show in the next two slides, modifications actually are improving the pharmacological effect and stability of these peptides.
The TXP peptides, the aim for this is to use them first of all in intensive care, as Thomas was referring to, to have what we call an IV, intravenous injection. You could also do subcutaneous SC injections. It is a different way to administer the peptides as opposed to the small molecules where we have an oral. Peptides is difficult to administer as an oral compound because our stomach is actually built for degrading peptides and proteins and so on. Good. To move on, just to save time, I just want to show that we have data showing that we get increased affinity to the receptor when we modify the peptides with BAP and also better potency. This is measured in vitro here. You can see the different subtypes. We have melanocortin receptor 1, 3, 4, and 5 here.
You can actually see that, for instance, our compound TXP-11 has a better binding affinity here, lower number than the natural endogenous peptide. Oh, sorry. Also better than a modified compound here that is actually marketed as a drug at the moment. On top of that, also the pharmacological effect of the peptide is getting better because you get higher activity actually of the compound when you do the modification. What you can see here also is that there is actually difference across the receptors. That is quite important. I'll get back to that later on. Here, you can see that we have also tested that the peptide compared to the natural endogenous peptide is actually more stable in human serum when we do the BAP modification.
That is actually what gave us the very good patent protection, is that we have higher efficacy and we have better stability. What can we use this for and why is it important? Activating the MC1 receptor or MC3 receptor as we do with resomelagon, even if it's the other pathway, the orthogonal pathway, will give some of the effects of the melanocortins and be helping resolving inflammation as we see with resomelagon. It's basically the same biological or pharmacological area we're working in. Thomas and Jeppe have worked before with a compound in Action Pharma called AP214 that was taken into phase 2 clinical trials with cardiac surgery. We know quite a lot about this type of biology and also clinical data from similar compounds.
What's important here is that when you do big surgeries such as a cardiac surgery, it could be other big surgeries, it's very often associated with an organ failure or maybe even death after that. You can have this dysfunction as well. You see that in the kidneys where you can have acute kidney injury after surgery. That is in up to 50% of the cases here. You can have atrial fibrillation in a wide range. Also the acute respiratory distress syndrome as we see with COVID and stroke. These are very serious effects that a lot of people experience after a big surgery. The point is here that you can go in, treat at least data has indicated that you would go in, treat with a melanocortin agonist and then prevent some of these effects.
You do that in intensive care. That fits extremely well to the administration route that we have. You can actually go in with an injection while people are on the operation table or just after or just before. That is very good. You treat with the peptides for a short time in intensive care. This is the kind of market we are aiming at. You can say we have talked about that before. We have selected TXP-11 as our lead compound because it's the one that has been mostly characterized and where we have actually moved it into our preclinical tox studies that will enable to go into man. We got a very good, you could say, safety profile. This looks like it's way beyond what we need for pharmacological effect in man.
What we have also done is that we have done the full development in CMC. We actually have formulations. We know a lot about the compound, the stability of the compounds. We know that the formulation we use is stable for several years. We do not have a lot of manufacturing issues with this compound. What's needed and outstanding before we can go into the first in man study or first in human study, I would say, in Phase I is we need to have some more pharmacological data in some animal studies where we can say more about a relevant dosing in a later phase in the clinic. That's a requirement from the authorities. We need to demonstrate that without any doubt with positive controls and so on in some animal studies.
This is what we are working on to get a sound data set. It takes time because some of the models are complicated. Some of the models have a long duration. Sometimes when you go out and work with people, they have difficulties in actually demonstrating the control compounds are working. If it does not work that way, then we cannot use the data on our own compound because we need to have sound data. We have reached out to a lot of people. We are working with the collaborators with our Mauro Perretti in London and his team around that. Also with Mauro Teixeira that you have just seen. He is also working in models where we are testing the peptides. We have been working with commercial CROs and setting up models with those.
This will eventually lead us to a first in man study. That study is going to be a study where we go in with healthy volunteers. We need a single ascending dose. Then we need multiple ascending doses for a longer period to cover. It is not a long period, but you have to cover the time in the ICU unit so you actually can demonstrate that this compound will be safe for the patients. Of course, you need to know something about if you could change doses during the time depending on how the surgery affects the immune system and so on. That will be my last slide. I will say that, as Thomas and Jeppe has alluded to, we are well on our way. We have good collaborators.
We are pretty sure that we can generate all this data that we need to have in place in order to file a clinical trial application as we have indicated.
Thank you very much, Thomas. As we're a little short on time, I will simply say thank you. We do not really have time with the Q&A. Instead, I will hand over to Jeppe here, who will give us some closing remarks in regards to today's Capital Markets Day.
Thank you very much for your patience and for listening in. I think I should have a slide here showing a short of a wrap-up. It's not coming. All right. I can do that anyway. I think what we have sort of tried to address today is a status on exactly where we are. With the RA study, we are on track.
We will get data at the end of the year, hopefully good ones. The main aim is to do a deal. We have launched the PMR, as we have discussed today. I think it complements really well the RA setting. It definitely complements the deal structure that we would like to make because it fits in with the potential partners. As we have said and explained, we have raised additional funds so that we are fully funded for the whole 2026, probably a bit into 2027 as well. Thanks to supporting investors. We still have developed further on the investor base. We are now in a situation where we have more than 15,000 shareholders in the company. We are very happy about that. We can also say that we have worked hard. The team has worked hard on getting a new homepage up and running.
Use that one. We will fuel in a lot more information. I know you have gotten a lot of information already today. We will try to communicate more as we have more programs advancing towards the clinic. By that, I would like to say thank you very much for your attention. If you have any burning questions here at the end, I will be happy to take those.
Do we have any questions from the audience? Yes.
Regarding the last presentation by Thomas, I will expose my ignorance. Are there already today melanocortin agonists on the market in order to prevent post-operational damages? So SynAct can be the first one with such a compound.
Yes. Yes. Any more?
Can I say for the audience?
Yes. We can say that. There's no other compounds in that field tagging the same.
Is there more questions from the audience? No.
All right. Thank you. Okay. Jeppe, thank you very much. And your whole team for being here today and giving us your Capital Markets Day.
Great. Thank you very much for taking the time. Appreciate it. Thank you.