Hi, and welcome to Cereno Scientific's Capital Markets Day. My name is Tove Bergholt, and I am the Director of IR and Communication here at Cereno. We're very happy to have you all here, and for you joining us online. We have an exciting program that we will kick off today. We will hear about the need around the management of cardiovascular disease. We will hear about Cereno's portfolio, what do we see as the solutions to some of these management needs at least. We will also hear more about some of the remarkable data that we've reported over the last few weeks, and in our Phase II study of CS1. We'll also hear more about how this helps us in our vision to move forward. We will have a Q&A at the end of the program, so please hold questions until then. We will also, of course, for you joining us online, have the opportunity to submit your questions just, I think, under the live stream platform there. Our esteemed faculty for today, we have both from the Cereno management as well as the delegation from the U.S., I suppose. We have Raymond Benza, Phil Adamson, and Mike Holinstat to join us. Yeah, without further ado, I would like to welcome Sten Sörensen to the stage. Thank you. Thank you, Tove. So, happy that you're here and, also you online. We've been looking forward for a year to the Capital Markets Day because then we can talk more directly to you about what we're doing and our vision, and how excited we are to develop solutions for people in need, both orphan and, common cardiovascular diseases. And, I have a few introductory slides, but the real focus here is actually our guests, and our partners, Dr. Benza, who's Principal Investigator, Phil Adamson, who is, Head of, Technology at, Abbott, and in charge of CardioMEMS, and also Mike Holinstat, who is running our pre-clinical programs at University of Michigan. So, listen carefully, you will be interested in what they have to say. Well, I'm also excited every year to join the Cardiovascular Congress, European Society of Cardiology. It's the biggest gathering of the brightest minds from all over the world that are meeting up and discussing how to provide better care for people in need with cardiovascular diseases. And actually, last week, all of us arrived here directly from European Society of Cardiology Congress in Amsterdam. And, as was the theme this year, joining forces to provide solutions, and that's actually a theme that we do at Cereno. So we have joined forces with Abbott, we've joined forces with University of Michigan, and we've joined forces with top leaders in the diseases that we are pursuing solutions for, including Dr. Benza in pulmonary arterial hypertension. At this meeting, there were 40,000 cardiologists, and in this room here, you can see almost 2,000 people. Two of our people and thought leaders in our Scientific Advisory Board actually received lifetime awards. Dr. Bertram Pitt, for 40 years plus helping patients and driving new innovations, and the gold medal of this association, and it's live sent worldwide. Dr. Gunnar Olsson, who's previously was Head of all clinical research at AstraZeneca globally, who also is on our Scientific Advisory Board, got the President's Award by the ESC Governance Committee. So we have connected with the best in the world to drive our solutions. Why are so many people focusing on cardiovascular disease? Well, it's the primary cause of death on the globe if you exclude communicable diseases. In our case, we focus on thrombosis as one of our aims, because it's 80% of the death in cardiovascular disease, often resulting then in stroke and infarction in the brain or in the heart, vital organs. We want all of us to provide better solutions. If we look at thrombosis, this major risk, getting an infarct in major vessels, the drugs that are on the market today to help patients and the tools for the doctors, they actually have a great risk of serious bleedings to the patients who get them. Actually, about 3%, 3% out of 100%, who are getting these drugs, antiplatelets and anticoagulants, die of the drug itself, due to severe bleedings, and up to 25% get any kind of bleed, bleedings that you see here. So the physicians really need effective therapy that can be provided with much less risk of bleeding or no bleeding risk, and that's what Cereno is aiming for, to provide effective and safer drug. If we move to another disease area, and the one that's the, the number one in our portfolio, the first one,... the orphan disease, pulmonary arterial hypertension, it's a very short life expectancy with all tools available up to 7.5 years from diagnosis. These patients really need something that can address the disease, the underlying cause of the disease, and the progression of the disease. So they need something better than what's out there. They're very affected in the quality of life, beyond also the effect on survival. So we really think that we have something that could be very good for these patients, in our CS1 program. We are addressing that with a completely new mode of action, epigenetic modulation, for cardiovascular disease and specifically first program for these, these patients. And we believe that we have a possibility to address the underlying cause of the disease and actually reverse it, for these patients. You will hear more about this. So Cereno is indeed a global effort. We are based in Gothenburg, but we also have offices in Boston, in the US, and our major programs are run in the US. So the lead program for CS1 is now in a Phase 2 trial, together with Abbott, our study partner, and together with 9 investigator centers. You will hear more about that later. We aim to conclude this trial by Q1 next year. We got some really interesting data this summer, and we've initiated some things to take care of that data, and you will hear more about that today. We are also driving our preclinical programs at University of Michigan since 2.5 years back. So we have both evaluated these new programs, CS585 and CS014, and then we're documenting them to prepare for an IND submission to the regulatory authorities and then go into man. And CS014, our new HDAC inhibitor, we are aiming to bring to man in the spring. CS585 is really exciting as a program, too, because it's based on an endogenic, an inner lipid, if you will. And it's Mike Holinstat here, that is the inventor of this at University of Michigan, together with a partner, and Cereno signed an exclusive rights to CS585 this spring, and we're continuing to develop this with the skillful work of Mike Holinstat. So I mentioned our scientific advisory board, and you see them here, and two of these smart people got awards at the ESC this year, and I, I'm sure more of these will get awards later on. I think if we do what we do and succeed at pulmonary arterial hypertension, for instance, Dr. Benza would up there on the stage. So three programs in our portfolio. CS1, epigenetic modulation through HDAC inhibition for the orphan disease, pulmonary arterial hypertension. Target to complete the trial and top-line data in Q1. CS014, novel, HDAC inhibitor. Actually, a variant of the first one, that looks very interesting. We are aiming to go into man, as I said, in the spring. So we're completing the IND, the file that you send to FDA or regulatory authorities where you want to do the trial. And then CS585, a novel IP receptor agonist. These, this class is on the market already, but not this kind. This is very novel, and you will hear more about it. That's a little later in the program, a year and a half behind CS014. So we are seen all over the world now, and you might have noticed that we, Mike Holinstat and co-authors, got accepted and published in Blood, the top-tier journal for blood diseases, last week, Mike, right? But also Mike and Dr. Benza are presenting around the world our, what we aim to do and also our findings. And it's being noticed, I'm sure. By that, I will conclude at the end of the program, but by that, I'll leave the word over to you, Bill. Thank you. There you go. Well, it's a pleasure to be here today, and I think my job for this first part of this interaction is to review a little bit about the disease state that we are treating with CS1, because I'd like to leave you with some lasting impressions about this disease. As we know, pulmonary arterial hypertension is an intimate relationship between the pulmonary vessels and the right heart. And this is a really important relationship, not only in that it accounts for some of the delayed recognition of this disease, but also the type of death that our patients experience is heart failure.... And many of you have read diseases about left heart failure and how patients suffer and act with this disease. Right heart failure is no different. Now, the interesting thing about pulmonary hypertension, as you know, is that your lungs have millions of miles of pulmonary arteries, and this accounts for some of the delayed presentation that we see in this disease, because a lot of those vessels have to really become abnormal before they impact the right heart. And so many of our patients who have this disease have it brewing in them, and they never know it, and therefore never get treated for the disease. So this is a very serious disease, and many of the patients that we see come to us with late stages of right heart failure. Well, as Sten alluded to before, this is a very deadly disease. Without therapy, the mean life expectancy for these patients is only 2.5 years. This is like the worst malignancy that you, that you've ever seen. In fact, many of the cellular processes by which pulmonary hypertension propagates itself is very, very similar to what we see in oncology, with unchecked growth of cells within the pulmonary vessels. Well, we have done a good job with some of our medications, and we have tripled the life expectancy of our patients with the disease to 7 years. But I really want you to put this in perspective. The mean age of diagnosis of this disease is 55. Also remember, this is a disease that unfortunately has a predilection for women with a 5-to-1 ratio. So just imagine a 55-year-old woman, could be someone's wife in this room, who develops this disease in the prime of her life, at the peak of her career, at a time when she is starting to enjoy their grandchildren and only has a 7-year life expectancy. That's not a lot to add to this woman's life. And again, we see many young women with this disease in their twenties. These are women in the prime of their lives. They're just starting their careers. They're thinking about getting married and having children. So although seven years to me as a physician is a great achievement, for these patients, seven years is not enough. And so we're limited by the current pharmacotherapy that we have for this disease state, which is shown here in this slide. And this has been a wonderful evolution of drugs over the last two decades. When I first started treating this disease in the 1980s, we had no treatment, and lung transplantation was the only option for these women. But we've now evolved over the years with a number of different drugs. But the thing with these medications are, is they focus on only three pathways. They focus on inhibiting the endothelin pathway, and as you know, endothelin is probably the most important vasoconstrictor known to mankind. So our drugs block the effect of this drug. Our other drugs enhance the production of cyclic AMP or cyclic GMP through the prostacyclin or through the nitric oxide pathway. Again, these molecules are some of the most important vasodilating drugs known to mankind. But as you can tell, sorry about the animation. Vasodilation is not enough for this disease state. So you can see as this disease evolves, as the vessel becomes more and more architecturally different, the beginning phase of this disease is where vasoconstriction really comes into play. And so this is where our drugs now are really focused on, is reversing this vasoconstriction. But that's not the end of this disease. This disease continues to propagate beyond that, to a point where the vessel itself becomes architecturally abnormal. The inner lining of the vessel expands, the middle lining of the vessel expands, the outer core of the vessel expands. And this is architectural remodeling that our drugs currently have very little effect on. That's why this is a disease of constant progression, because we don't have drugs yet effective to affect this end-stage remodeling of these vessels. So our women will continue to progress despite the advances we've made in current vasodilator therapy. And this is where all the research is going now, is how to reverse this remodeling to really get a more potent effect and lasting effect that can probably reverse this process and make these people live longer. Well, here is the problem that I just mentioned again. You can see here the effect of our current pharmacotherapy on the hemodynamics of this disease. Now, remember, this is a hemodynamic disease. These vessels, when they become atretic, raise the pressure in the pulmonary arteries, and it's this pressure that kills the right side of the heart. You can see very clearly on this slide that even with the maximum therapies that we have, we're getting only very modest reductions in pressure. If you see here on the blue parts of the slide, this is our common upfront therapy for this disease, two oral agents. Yet we only get a 10% reduction in pressure with that combination of medications. It's not till we get to the very high potency and even more toxic therapeutics with high levels of intravenous prostacyclins, that you can see where we get modest and more large reductions in pressure and resistance. This is important, because looks, look at what it takes to actually make the right heart better. You need almost a 50%-60% reduction in the resistance of the lung to actually make the right heart better. That's incredibly important. I just told you that most of our drugs only give us a 10%-15% reduction in pressure, not this 50%-60% that we need to make the right heart better. And as I mentioned earlier, the right heart is really the crux of this disease. This is where, this is what's killing our patients. So if we don't design drugs that affect that vascular remodeling that I showed you and work beyond just pure vasodilation, we'll never get to this pressure reduction that we need to make the right heart better, to make these patients live longer. And that's where the role of these new therapeutics that are coming out are going to be very, very important because they make use of a variety of pathways that we know will remodel that vessel. They're not just going to dilate it, they're going to remodel it. They're going to push it back to the normal architecture to get that massive reduction in pressure and resistance to keep the right heart going. And this is where CS1 lies, in this new era of remodeling therapeutics. Now, unfortunately, many of the drugs that we've tested in this have really not worked yet, and that's why it's so exciting to have a potential new medication with a novel mechanism of action that really may push this remodeling backwards the way we want to, to achieve that pressure reduction that we need to make these patients live longer. Now, CS1, as I mentioned, is a very novel therapeutic, and I was very excited about the way this drug works because epigenetic regulation is really a new era of therapy in cardiovascular disease. We have many new examples of these type of drugs being very effective, particularly when you're looking at vascular diseases. Applying a drug like this to a pulmonary vascular disease, to me, as a scientist and a physician, was incredibly, incredibly exciting. This drug has anti-inflammatory activity, antifibrotic remodeling activity, and antithrombotic activity. As you noticed on that first slide, these are all the mechanisms that allows the vessel to retain and to reform itself into a normal architecture. One of the major issues that we see in pulmonary vascular disease is as those vessels become atretic, they become clogged with microthrombi. And remember, thrombi are just not clots, they're actually generators of molecules, of cytokines, of growth factors that make the propagation and remodeling of that vessel work. So getting rid of those bioreactors using a drug that has antithrombotic activity makes a lot of sense. And as I mentioned, and showed you in that slide of growth factors, the anti-inflammatory pathways and the antifibrotic pathways are essential to remodel this, disease. One, because you remember, the outer lining of the vessel is all made of fibroblasts, and counteracting the growth of those cells allows the vessel to expand properly. So we have potential with this therapeutic to affect each layer of the vascular wall, to really push that remodeling back the way we want it. And, I think that's where a lot of our excitement is, 'cause this is our goal. Our goal is to try to normalize pressures now, to allow that right heart to recuperate, to restructure these vessels so they look more normal, so that the right heart can go from this large, dilated form back to normal form, and that's where we're going to save our patients. That's the important piece. So this drug can have a role in a variety of different mechanisms in this disease state. It can be used to force further remodeling on top of our vasodilators, which we typically would now use to stabilize the patient, and then we would use this drug to remodel the vessels, to push them more towards normal. It can be used even in upfront therapy with traditional vasodilators. So you start vasodilators to stabilize, and you start our structural regrowth modification to get the vessel towards normal along the whole line of therapy. We can even use these drugs potentially in primary prevention. We know the genetic causes of pulmonary hypertension now. We also know that certain disease states, like scleroderma, 70% will develop this disease. Well, why not start a medication to prevent the disease from starting in the first place in these patients? It might be a very good application of that. Chronic thromboembolic pulmonary hypertension, as you know, is a growing entity in the civilized world, and unfortunately, many people don't realize they have this. 40% of people who have large pulmonary emboli in each lung will develop pulmonary hypertension. So having a drug that actually works on thrombosis would be key in mitigating this form of pulmonary hypertension, but also key to treating it after a successful endarterectomy. Because you remember what I told you, these clots are not inert, they're bioreactors. So the clotted vessels in chronic thromboembolic pulmonary hypertension not only cause the disease, but the cytokines and growth factors that they elaborate damage the distal vessels that are not clotted and make them remodel abnormally. So having a drug that can then take care of that secondary vascular remodeling is very important... Group three disease by interstitial lung disease is a huge disease that we see now, particularly coming off COVID, where interstitial lung disease has become a prominent late manifestation of the disease. And having a drug that can work in these instances and not prevent VQ mismatch can be very, very important. And then lastly, in group two disease, which is the largest group of patients that we have with pulmonary hypertension, that type of pulmonary hypertension attributed to left heart disease or left heart failure, which is an epidemic in Westernized civilizations, having a drug that can reverse the pulmonary hypertension in that instance, that acts on both arteries and potentially veins, could be a very useful area for this compound. I hope I gave you a good idea about this disease state, who it affects, what the problem with our current therapeutics are, and where this drug likely fits in the treatment of this really deadly disease. I thank you for your attention. Well, thank you, Ray. And so I welcome you here, and thank you very much for coming. Some of your faces I recognize from our adventure last year, and so it's good to see you again. I don't wanna repeat things we talked about, but I would like for you to understand essentially why Abbott and Cereno have collaborated in this clinical trial called to evaluate CS1. I'm Phil Adamson. I'm a heart failure cardiologist. I've practiced over 30 years developing remote monitoring for people with left heart failure, as Ray mentioned, the epidemic of left heart failure. Really focusing on the ability to understand the lesion of that disease and decrease the progression of it, and not only to keep people out of the hospital, but to decrease the chances of them dying. In that process, we developed a pulmonary artery pressure sensor that can be fully implanted. I want to spend some time with you discussing that technology and how it has been validated in left heart failure, what we found there, and then how important it is for us to develop a new paradigm of drug development, drug pipeline development, with efficacious abilities to dose, to titrate, to effect, and to really treat the underlying disease process. So the CardioMEMS Heart Failure System consists really of three components. The three components include an implantable sensor, a small sensor, which I'll show you during our time, I think, of questions- and- answers. The patient's system, the electronics in which the patient from home then is able to interrogate that sensor and send information to providers through the third component, which is a web-based informatics system that provides the information on a daily basis to practitioners who review that periodically and make medical changes to maintain the patient's stability. So this is all done remotely after implantation. The device itself is considered a microelectromechanical system, so it took me a long time to be able to say that. That's why I said it. Microelectromechanical systems essentially are passive sensors that are only activated during interrogation. So this device is implanted in the pulmonary artery, as shown in the circle on the side there, through either the vein in the neck, called the internal jugular vein, or the vein in the groin, called the femoral vein. An over-the-wire delivery system finds essentially the proper place in the pulmonary artery to implant this device, and then it is dropped into the bloodstream and it lodges and safely sits in the pulmonary artery. Patients then interrogate that from home. And the way they are able to do that is here. And the physics behind this, I won't spend a lot of time on, but essentially, radiofrequency energy is taken up by the sensor. The pressure on the capacitor, which is the black strip that's in the middle of this silicon housing, moves under pressure in nanometer deflections. And those nanometer deflections change the resonance frequency that's sent back to the antenna, so in a linear way. And once calibrated, then this device is able to remotely measure local pulmonary artery pressures and a variety of other calculations that we need to understand in order to personalize medical therapies for patients with heart failure and with pulmonary hypertension. So you can think of this as a blood pressure cuff that we use for body high blood pressure. This is a blood pressure cuff for the pulmonary artery. We have, Ray demonstrated to you, we have two separate circulations, one to the body, one to the lungs. We've never been able to measure regularly the blood pressure in the lungs, even though this is a deadly disease once you develop high blood pressure of the, of the lungs. So patients then lie back on this pad from home. They upload... They, they interrogate the device. The information is in, is, encrypted and then sent either over a, an embedded cellular transmitter that's inside this device, or a local area network. That information then is sent to the, to the web and displayed graphically to provide trends of pressures assessed on a regular basis. Now, I show you this, it seems like a cute little picture, but I want you to remember that to get this information prior to this device, the patient would have to be in the intensive care unit in a hospital in a very extreme situation. That's where we have traditionally been able to understand hemodynamics, is in the context of a hospital. To be able to get this information anytime you want it, was a major breakthrough in technology. Now, we examined this process of uploading pressures, making changes in medical therapy in patients first with heart failure. And here you see the pivotal trial, called the CHAMPION trial, and here, and this is what we thought. We thought if we could get these pressures on a regular basis, if we could make medication changes personalized to the patient's own pathophysiology, guided by the pressures that we had, we would reduce those pressures, and that reduction in pressure would reduce the need for hospitalizations in this population and improve quality of life, and that's what we found. In the first pivotal trial, all of these hypotheses, both primary and secondary endpoints, were met. That led to FDA approval of this system for people with congestive heart failure, left heart failure, regardless of what kind of heart failure they had. The indication that came from this study is shown at the bottom, which is important in the, in as we go. Where are we today? Well, that was, that was some time ago. Where are we today in our investigation? What is the evidence base to prove that in heart failure, as Dr. Benza mentioned, the second group of pulmonary hypertension patients, we've now studied nearly 10,000 patients in a variety of different study designs, including three prospective randomized clinical trials, all demonstrating very consistent results with significant reductions in the need for hospitalizations and consistent long-term improvement in quality of life. So the paradigm of understanding what the pressures are, guiding medical therapy, personalizing it to the individual, has been tested in all of these studies. Remarkably consistent data over many years and many trial designs. I wanna just go into the MONITOR-HF trial. You may have seen that trial. It was reported at the ESC HFA meeting in May and published in The Lancet simultaneously. If you wanna find these data, all of them, it turns out, have been published in The Lancet from GUIDE-HF, which is a large trial in the United States, CHAMPION trial, and MONITOR-HF, which we'll talk about, which was a Dutch trial performed throughout the Netherlands and funded by the Dutch government. The MONITOR-HF trial included about 370 patients that were randomly assigned to either Dutch medical delivery through a variety of different clinical clinics throughout the country, or receiving the CardioMEMS device for heart failure management. The primary endpoint was the improvement in disease status and quality of life, which is measured by this instrument called the Kansas City Cardiomyopathy Questionnaire, or KCCQ. By the way, this was the patient committee's choice to have this as the primary endpoint. Patients, when asked: "What do you think we should be doing for you?" This is the number one thing they would like to have, is a better quality of life with this disease, as well as with pulmonary hypertension. A significant, remarkably, robust improvement in the disease state and quality of life. There are five domains. You can. I'm not gonna go into those, but each very consistently improved over time, with a 44% reduction in the need for hospitalizations. And the Dutch medical delivery process is very sophisticated and very unique, and so this was superior even to that delivery system. I wanted to show you this because we'll talk about this later in our question and answering. But when we think about what are we trying to do here, in right, in left heart disease, left heart failure, 85% of patients who have symptoms have secondary pulmonary hypertension. That means that their blood pressure in their lungs is high. So when we lower that blood pressure, which is the blue line that says mean AUC, which stands for area under the curve, that mean area under the curve was reduced as a result of personalized medical therapies in the Dutch trial. That resulted in a significant reduction also in other biomarkers, which could not be achieved in the control group without hemodynamic-guided care. So this reduction in PA pressures is what is associated consistently across all those trials I showed you, and the outcomes of better quality of life and the reduced need for heart failure hospitalizations. Now we see, at about 16 months, an improved survival. How did they do it? This is how they did it. In left heart disease was personalization of diuretics, which is the most important medication we give over time, but titrated to effect. We have no other titration scheme, but CardioMEMS, and we found both up and down titration was performed more in the monitored patients than in the clinically managed patients. This then lowered the pressures. The lower the pressures, better outcomes, better survival, and at a very low risk. So this is now an amalgamation of over 3,000 patients studied in adjudicated trials, in which we looked to see, well, does it hurt people to put this sensor into their pulmonary artery? And the answer is the device or system-related complication rate is very low. So how are we collaborating with the U.S. FDA, with Cereno and Abbott? This is one of the first, I think, corporate-to-corporate collaborative efforts to improve a disease state. Cereno's technology together to understand how this disease can be treated better. And not only the corporate collaboration was remarkably unique, but the regulatory collaboration I've never seen before. So the Center for Devices and Radiological Health, CDRH, the device side of the U.S. FDA, the drug side of U.S. FDA, got together and agreed to co-regulate CardioMEMS and CS1, and be able to allow a new indication to come out of this investigation. Remarkable collaborative efforts, both from a corporate to corporate, but even in the regulatory environment as well. So I'll stop there, and, I'm looking forward to your questions here in a little bit. Thank you. Thanks, Phil. That was a really good overview of the technology that we're using in the phase two trial, which I'll elaborate on now. But I also think Phil brought up some very good themes to remember, that pressure reduction in a disease of the pulmonary vasculature is key to success in terms of improving mortality, improving morbidity, reduction in hospitalizations, and most importantly, making the patients feel better by improving their quality of life. And this same theme holds true of primary diseases of the pulmonary vasculature. Lowering the pressure improves the right heart, improvement in the right heart reduces hospitalizations, reduces mortality, improves people's quality of life. So our trial is very unique in two aspects. One, we're testing a compound that has unique vasoremodeling properties, as I mentioned earlier, and we're testing this drug in an environment of very novel technology. So the things that I'm very excited about in this phase two trial is that the amount of data that we're acquiring on these patients will allow us to fully phenotype them clinically. We're really gonna understand how this drug remodels the pulmonary vessels by monitoring the pressure real-time with the CardioMEMS, but also how it affects the restoration of right ventricular function by using a variety of highly advanced imaging techniques. So this is a really, really nicely designed trial that's including not only our traditional endpoints, which are six-minute walk test, echoes and biomarkers, but these very novel and innovative endpoints, which I'm gonna review a little bit in a second, including risk scores, cardiac MRI, and the CardioMEMS device. Let's talk a little bit about the risk scoring that we do now. Modern therapy or contemporary therapy for pulmonary hypertension really revolves around lowering a patient's risk for both morbidity and mortality events. The only way that we had to do this in the past was by looking at singular variables. Are they improving their functional class? Are they improving their 6-minute walk test? When you look at these individual tests by themselves, they only account for 6%-12% of the risk imparted by this disease on those patients. That's not a very comprehensive picture. We've developed now multi-parameter calculators based on demographics, hemodynamic properties, imaging properties, biomarkers, and some of the traditional variables to be used together as a conglomerate, which gives us a beautiful depiction of how these patients survive with this disease state. These are the two calculators that we use currently in the U.S., which are the REVEAL 2.0 calculator and the REVEAL Lite calculator. You can see on the REVEAL Lite calculator, you'll go and you will find where these variables are, and they get a certain score, and then you develop a score, which you can then see on the bottom, gives you whether this patient's at low, intermediate, or high risk. This is very important because these scores very highly depict how a patient will thrive with this disease, both from a mortality perspective and a morbidity perspective. Now, we're using these scoring systems in this trial in two different ways. One, we're enriching the population. We wanna know which patients are gonna have events. We don't wanna really thrive on the low-risk patients now, who have low-risk events. We want to enrich this trial with people who are really gonna have events, the intermediate risk and the low/high risk. And these systems allow us to do this with great levels of discrimination. So we're getting the right population of patients for this study. It's not like many of the other contemporary trials that have really filled their trials with low-risk patients and have required lots of patients to show the efficacy of a therapeutic. Here, we're using this to enrich it, to find the right population, to really prove CS1's effective, remodeling effect on, on the architecture. But we're also looking at this to determine CS1's efficacy, because we now know, by using, these, scoring systems, that changes in these scores correlate very highly with future events. So if you can reduce the score on these multi-parameter calculators by one point-... You will be guaranteed a 20% reduction in mortality or morbidity from this disease. And we've proven this in several contemporary trials. So this is a really powerful tool to give us an early indication of efficacy. This is very, very important, and we're using this tool in this trial to look at this. As Phil mentioned earlier, hemodynamics are really the basis in the heart of this disease, no pun intended. And the only way we were able to get hemodynamics in the past is by taking people to an artificial environment in the cath lab, having them lie down, stick a catheter in their neck or groin to measure the pressures in their lungs. And this was very effective, but really, when you're looking at a disease state that is constantly progressive and where pressures are so important, having singular snapshots at the beginning of therapy and some time during therapy doesn't give us all the information that we need to make sure that we have our patients on the correct trajectory of this disease state. And so the solution to this was the CardioMEMS device that allows us to monitor these pressures in an almost real-time environment with daily assessments of pressure so that we can tell the overall effect of this therapeutic with a high degree of certainty. And that's very important because hemodynamics are the first thing that changes in this disease state. All the other things that I told you that we monitor are really late manifestations of the disease. We have changes in hemodynamics very early in the disease, and then here are the biomarkers and scores that we look at. These are late manifestations of the disease right before the patient's about to have symptoms and be hospitalized. Be able to push back that monitoring to the very early manifestations of the disease allows us to really be proactive in treating these patients and knowing, in this case, what the early effects of this drug can do. Because remember, changes in pressure are what we needed to fix the right heart, and fixing the right heart is what allows our patients to live longer. This is one of the important things I learned as a clinician that we published that made this information so much more valuable. If you bring a patient to the cardiac catheterization lab, you will define for us patients who do or do not have pulmonary hypertension, okay? Single snapshot in time. Now, when you look at these same patients after they have a CardioMEMS implanted, you can see that some of these patients who we thought were normal were not really normal when you start looking at the area under the curve of their pressures. So 19% of these patients really have pulmonary hypertension. So think of this at the end of a clinical trial, when you get one snapshot of a pulmonary, pulmonary pressure, are you gonna bang, are you gonna put all your bucks on that one determinant of pressure? To me, when I see this data, I say, "I need lots of estimates to really tell if this drug is really working, not just this point time that we had." And this is where the value of adding the CardioMEMS to this trial is, that we will tell you with a high degree of certainty what this drug is doing to this patient's pulmonary pressures. So that's a really unique aspect to this. And I just want to show you the power of this device in managing patients and setting their trajectory. This is actually one of my patients with pulmonary hypertension and whom I'm treating. Their top panel shows the changes in the morphology of their right heart as I am lowering their pressure. And this is a nice example of what I mentioned earlier. This is a 33-year-old woman who's a schoolteacher and actually has one child of her own, and she came to me with very severe symptoms, was a REVEAL high risk to intermediate to high risk, but she didn't want to be put on a parenteral prostacyclin because she's a teacher. She needed to move around with her children. So we had to treat her with what we had, which was upfront dual combination therapy with tadalafil and ambrisentan. And you can see with this therapy that we did have an improvement in pressures. And again, to reorient you to these slides, this red line is the pulmonary artery systolic pressure, the blue is the mean pulmonary artery pressure, and the green is the diastolic pressure. You can see we have a very nice change in pressures that remain very stable over a long period of time. Now, this person markedly improved, both by their REVEAL risk score, they became low risk, and by other functional parameters. But her right heart wasn't normal yet. So here is the quandary: do you leave a person who's feeling better but still has an abnormal heart? And we know now, now that that answer is no. We need further remodeling of that vessel in order for us to really normalize that right heart and extend this 32-year-old's life way beyond the 7-year limit that we have. And so by knowing that, we add an experimental medication in this instance that markedly lowers her pressure and normalizes her right heart. This is the same concept that we want to do in this trial. These are some of the other interesting parameters that you can get with the CardioMEMS device that Phil may be telling us about a little bit later in the question- and- answer session. But there are new novel technologies using the device where we can manage and actually detect stroke volume. So understanding the output of the heart, as well as the pressures, really gives us information about the resistance in the lungs, which is really the golden chalice for us in managing this disease state. But this is the power that this device is going to give us to really test this molecule to make sure it's doing exactly what we want for our patients with this disease. ... Okay. So I'm Björn Dahlöf, I'm CMO of the company. I just want to give you a little snapshot on where we are with the study, because that's, of course, important. Is this the one that you go forward? Yes. So as have been told, we have a multimodal mode of action for CS1, which we think will give a remodeling effect and affect the disease in a way that is the, quote, unquote, "disease modifying," which is what everyone seeks for in this, and with epigenetic modulation and with HDAC inhibition. So this is the basis for the whole study. And as Ray said, we have a multitude of different ways of trying to figure out the mode of action. What Ray didn't mention, I want just to emphasize that we have three doses, and these three doses in the study are chosen. The first dose, the lowest dose, is the dose that in our Phase I study could affect PAI- 1, 50% reduction. So that has an effect in man. The middle dose is the lowest dose that has been, if you translate animal work to man, been effective in PAH models, and the higher dose is twice that dose to see if we can achieve even more. We started the study, activated, already in March 2022. We had some bad luck, so to say. This was during the pandemic, and we had a slow start of activation of centers. So we had not the full power initially. We had all centers activated in January 2023, and during the spring, we have had a nice uptake of recruitment. But during the summer, and July, August, it has been a slowdown, so we are actively recruiting a couple of more centers. I'll tell you a bit more about that. So what we have today is that we have 25 patients that have consented to participate in the study. 16 patients have an implanted CardioMEMS now, 16 have been randomized to active treatment, and five patients have completed the study. We have nine centers going, and you can see from this distribution, I'm not going into detail, but there is a huge variety in performance between the centers. And that is not that they are not putting a lot of effort to find the patients, but they have been more successful in some centers than others. I told you that we have 16 randomized to 25 that have consented. Some have failed in the screening process, so. But we have 24 potential patients still under evaluation, and some of them have already been put on a new visit to start the study. But maybe, and we think, just to secure the recruitment, that the existing centers maybe cannot find all the patients we need. So we are actively starting two new centers, which have a good track record of being, performing very well in other studies, and we believe that they will do that in this study as well. So otherwise, you can see that the existing centers are well spread out over the U.S. So we are starting these two new centers, which we think will be up and running in the coming month, hopefully. Maybe they can, in time, provide 4-5 patients, and that, with the existing centers, we think will get us to a top-line result in Q1 next year. We have a lot of other mitigation efforts, and I think this will be a successful recruitment to give you top line next year, Q1. Okay. So now I think it's Ray again. Yes, to talking about patient case. Hopefully, you're not all getting tired of me coming up to the podium repetitively. What I wanted to show you is just an interesting case that we had the opportunity to look a little bit more in detail with regarding the use of this therapeutic during the clinical trial. So, the patient I'm gonna describe to you is again a 51-year-old woman who had symptomatic pulmonary arterial hypertension for 3 years. So remember three years now on the 7-year timeline. She's a functional Class II, her walk distance is about 444.6, so someone who is made better with current vasodilator therapy, but not perfect. This person's on three medications for this disease to get this effect: two oral medications and a very appropriately dosed parenteral prostacyclin. With this, she's had some improvement in her pressures, but is still left with a mean pulmonary artery pressure of 33. Again, this is 13 millimeters of mercury above normal and cardiac output of 4.7 L. And she agreed to participate in this trial. She had her CardioMEMS sensor implanted without issue, and she was randomized to the highest dose of CS1. And you can see with treatment of CS1 after 12 weeks, that we normalized this woman's pulmonary arterial pressure. This is fairly remarkable, again, in the context of a disease that has been prevalent in this patient for a number of years, and also on maximum contemporary medication, we were able to push this person's pressure even further down to normal, resulting in an improved cardiac output and almost a 50% reduction in total pulmonary resistance. Now, remember from my first slide, that's the area that we want in order to normalize the right heart, a 50%-60% reduction in resistance, which we achieved in this patient. And this was achieved with no changes to her contemporary medications, which were fully maximized. This lady improved to functional Class I, had an improvement in her REVEAL risk score even further, and had no adverse events related to the PA sensor or the device itself. And these are kind of the measurements that we made on her using the CardioMEMS device. And again, this tells you intuitively a lot of how this drug is gonna work. Not only the magnitude of effect, but when the effect occurs and the duration of this effect after the drug is discontinued at the end of the study. So just to reorientate you to your-- to this slide, the red is the pulmonary artery systolic pressure, the blue is the mean pulmonary artery pressure, the green is the diastolic pressure, and on the bottom of this curve is another interesting analysis that we can do that gives you the area under the curve of the pressures. So how much time this person's pressure has remained below their baseline pressures. So it gives you a very nice, much more clean depiction of what's going on in the pressures. And you can see here's where we started CS1, and you can see this very undulation of the pressure. This is very typical in a patient with pulmonary hypertension who is not well medically regulated, because when we see that, the pressures are very uniform. And so that you can see as CS1 is started, something starts happening right around this instance. You can see the undulations in these pressures becomes distinctly different, and then you can start seeing the drop in the mean pulmonary artery pressure being much more consistent. This is where we think the onset of action of CS1 may be based on this data, anywhere from 4-6 weeks after starting therapy. This is distinctly different than what we see in all other medications that we use to treat pulmonary hypertension, which typically take 8-12 weeks to really kick in to see an effect. So we're seeing an effect of this drug, at least in this one instance, a lot earlier than we're seeing with traditional medications. When you look at the area under the curve analysis, you can see this nice, steady reduction in pressure over time. So again, this is remarkable because this is a patient who is on three therapies for pulmonary hypertension. Everything that we know to treat this disease with, this patient is on, and we were able to get this additional change using this medication, likely through this remodeling effect that we discussed earlier. It looks like we're gonna be able to define the onset of the action of CS1. We think it will be around this week, if this is a typical example. So we're very excited about this information. Again, shows you how we can use these therapeutics to look at what we want. So just from looking at this one case example, and others, we're pretty sure that the sensor is gonna be a really great way to monitor these patients. They're really gonna tell us a lot about how we use this drug, in addition to magnitude and duration and onset of effect. CS1 appeared to lower the mean pulmonary artery pressure in this patient to normal. And remember, that's what we're looking for. We're looking for these dramatic changes in pressure to really restore right heart function to improve outcome. The lowering of this pressure resulted from improved cardiac output and resistance. Remember, pressure is the relationship between flow and resistance in the vessel, and we had an improvement in flow with an increase in cardiac output, but our effect on resistance was much more than we would be expected just with a change in cardiac output. That means that this vessel is actually remodeling, and the resistance is coming down, but through a change in architecture of the vessel. That's really exciting to me. The onset of effect is possibly early, 4-6 weeks. Again, very novel, and very exciting for me to have a medication that works this quick, and it really sets the tone for the completion of our studies. So, I just wanted to give you that brief introduction to one of the patients that we've treated so far. ... I guess it's me again. As Ray said, this is, I think, a remarkable patient case, and it gives us high hopes for this medication. It has also triggered an initiative that we are having to look at what we achieve, what we collect from the CardioMEMS at an earlier stage than at the end of the study only, and I will tell you a little about that. But just before—just to remind you about the, the, so to say, the power of this technology, I mean, there are many benefits for a study like this to use this technology. We can have unique efficacy data points over the full study period, enable a smaller size population to find an effect, and it supports the definition of an optimal dose for the patient. So I think that this technology will help us enormously to try to figure out, in addition to all the other endpoints we have, the profile and efficacy of CS1. So this is what we get. I mean, this is just repetition, just to give you the snapshot of that the power is that you can do it in the patient's home, you can do it on a daily basis, you have a monitoring over the whole duration of the study, and that gives us a lot of good data. And as Ray said, this is so powerful that you see the effect in one patient. You actually do a study with n equals 1 in a way, with this kind of technology. So, I wanted you to keep in mind when we talk about also what we see in this patient case that triggered our monitoring quality control initiative. I mean, we calculated at the beginning of the study, very conservatively, I would say, that we need 30 patients to show an effect with CardioMEMS. Now, we can see, since it looks like the efficacy is higher than expected of the intervention, that we can see it in single patients. So together with all the other, and Ray has already alluded to that, we actually phenotype these patients very, very thoroughly, and we will have not only pressure, but we will have lots of hemodynamic data, and we will also have all the other perks that a study of this kind have. So I think that together, but many of these endpoints require a fair number of patients to be able to show because they are snapshots. But when it comes to the CardioMEMS, we were triggered by the patient case that we should really safeguard both this new technology in a new patient category, that we really collected the quality data needed, that we could look at this and see if we had all the transfer quality and everything needed to see the power of the full technology. So we think that the outcome of this quality control is that we can have a look at the pulmonary pressure collection of all the randomized patients so far. And you remember, we had 16 patients, five completed, and many have been quite advanced into the study. So it is a good database to look at what we collect in terms of of not only quality, but we will also have a potential to have an early readout of the efficacy of this drug. So this initiative was taken in June. We communicated it just recently, that we are going to do this. And in Q4, after having done this analysis in September, we will see both the quality and the signal of efficacy, and that could help us also in making the data really conclusive at the end of the study, but also to have an early discussion with regulatory authorities of how will the next study look like earlier than we thought before. So that is this initiative we have taken, and I'm really excited about that. So it's me again, but this is to introduce what Mike Holinstat is doing, but put a kind of perspective on that. And as Sten said, thrombosis is what most people die from in the world. That we have to remind ourselves sometimes about that. Thrombosis, occlusion of vessels, is really the modern epidemic. So, and if you look at it from a perspective of a company developing new therapy in the area, I think you can realize that this is a huge market. It's a huge cost for society. Look at the cost for U.S., $700+ billion. I mean, it's almost difficult to understand figures like that. So this is. And the but the PH, which we have talked about a lot, is also a fair market and worthwhile for a company to develop something for. But now I talk market and money. I mean, for me, as a physician, having worked 40 years in hospital, of course, the excitement is that we can bring novel therapy to patients and help them to live healthier and longer. All drugs that have been developed for thrombosis have one problem, as Sten mentioned, and that with no exception, bleeding. That leads to undertreatment and underdosing of the therapy. Many patients fear the bleeding, or the doctors fear the bleeding so much that they either give a too lower dose or they don't treat at all, which of course leads to that we have still a lot of thrombotic events. So what we need is new therapy with less risk of bleeding. And of course, if you can also achieve higher efficacy, that's also a... But the ratio, the kind of ratio between efficacy and bleeding have to improve. And these are just some more figures showing that really, the traumatic complications occur in a fair number of patients, in maybe 2%-4%. The figures are different in different surveys, but it's mainly hemorrhagic stroke and massive gastrointestinal bleedings that are the most feared complications, and that goes for any of the therapies available today. But we think that with epigenetic modulation, we have a chance to bring antithrombotic therapy with less risk of bleeding. But also, and Mike will tell you more about that, that a drug with a prostacyclin, with a IP receptor agonist, with high selectivity, potency, and less risk of bleeding, is actually a very important contribution. So we just to put the Cereno portfolio in a perspective, I mean, you know that classically it was rat poison that started antithrombotic therapy, that's warfarin. Then came very novel therapies, NOACs and antiplatelets of different kinds, but they all had the risk of bleeding. We think both with CS585 and our HDAC inhibitors, that we have a lower risk of bleeding. And Mike will show you data from both CS585 and CS014, and we have previously data with CS1 as well, that provides evidence for antithrombotic effect without bleeding. So I'm very proud of our portfolio, and now Mike will tell you about CS014 and CS585 preclinical data that you have so elegantly provided from your lab. Please, Mike. Well, great. Well, welcome, everybody. You've heard a lot about thrombosis today, but I just want to put it in perspective to begin with. So as higher vertebrates, we have a closed flow system, which means we need the flow to occur in order to have oxygen go to our all the organs of our body, to provide nutrients, to get rid of waste. So it's an essential component of life for humans. That said, any injury you have, and you have hundreds of injuries a day that you don't even notice, it's the platelet whose primary job is to form a plug, stop blood from leaving the vessel, and to maintain hemodynamics and allow one to, to function. So platelet activation is normal. I just wanna-... Start with that because we don't think of this like we might approach cancer, where you see it, you have to stop it. We think of, we think of the blood flow, and we think of platelets more as a pendulum. We want to maintain hemostasis, that's blood in the vessel, but we don't want to go into a thrombotic range where you're actually occluding the vessel. Right. So this is where we are today. Right? This is the... Don't forget the pointer. Yes. Okay. The tiny little pointer. Yeah. So when we think about antiplatelet drugs, and most of us think they've been around a really long time. Well, you might be surprised to know that COX-1 inhibition, the first antiplatelet clinical trials with aspirin, started in the late 1980s. So we've only had antiplatelet therapies since the early 1990s. And with that said, we've only targeted very few targets successfully with lots of drugs. Right. So we targeted Plavix, most of you know of, P2Y12 inhibitor, and there's lots of drugs for that target. COX-1, we have aspirin, we have all the other NSAIDs. We have the alpha IIb/beta 3, the integrin receptor, and then most recently was PAR-1 with Vorapaxar. And as was alluded to by Björn, bleeding is the major concern. In fact, Vorapaxar's Phase III study resulted in significant intracranial hemorrhage because it was conducted as a triple antiplatelet therapy. So a better therapy where you need fewer drugs on board is going to be our best bet going forward. And I do want to point out, antiplatelet therapy has decreased morbidity and mortality significantly, by more than 25%. That said, it's still the number one cause of death globally. So the new drugs that are gonna come are going to further decrease platelet activation, but not at the risk of bleeding. A very tall ask, and I'm gonna show you how Cereno is approaching this. And it is not through hitting the same targets with new drugs, but it's identifying new targets with new drugs. Right. So our portfolio for targeting thrombosis involves CS014 and CS585. CS014 is an HDAC inhibitor. It's a new way of thinking about targeting targeting thrombosis without actually inhibiting a receptor on the platelet. So we're doing this through altering the environment of the blood and the environment of the platelet through increasing the ability to break down a clot and decrease the ability to form a clot. And that has—I'll show you data supporting its role. CS585 is an IP receptor agonist. You may have heard other IP receptor agonists or prostacyclin receptor agonists been discussed today. Their challenge is multifold. One, they don't do well in the blood. So the prototypical prostacyclin receptor agonist, iloprost, the FDA recommendation is to give it 6-9 times a day aerosolized. Now, that's a, that's a tall order to ask a patient to take anything 9 times a day. So I'm gonna show you data that's suggesting sustainability. Another issue with the prostacyclin receptor agonist is selectivity. It's well established that most of the prostacyclin, if not all of the prostacyclin receptor agonists, have off-target effects. They hit other receptors in other parts of the body, and this is where a lot of your, what we call side effects, come from. So CS585 was developed with that in mind, and it was developed through discovery we had made earlier on, showing that an endogenous, a natural product made in the blood, could selectively and potently target specifically the prostacyclin receptor. Okay. So one of the first assets I'll show you is a, is what we call the, a cremaster arterial thrombosis assay. So the cremaster is just a, it's a muscle head. It's a small artery assay. It's an in vivo assay in an animal, where we induce a small injury with a pinpoint laser. In real-time, in vivo, we can monitor the amount of platelets that occur in the plug, as well as the fibrin that forms the underlying formation. And you're looking at still shots of a movie just for time's sake. And what you can see is if we give a vehicle of CS014, if we give saline, within one minute of an injury, the green, which are the platelets, form a significant clot at the point of injury. And the red, which is the fibrin, significantly forms underneath. However, in animals that are dosed with CS014, you have a very large reduction in the amount of clot that forms. It's an 80%-90% reduction in the clot, and the fibrin is almost absent. So in an in vivo setting, if we have an HDAC inhibitor, such as CS014 on board, we can prevent clot formation in small vessels. We've also shown this in large vessels. We've done carotid arteries, and we can delay the amount of time in a carotid artery that it takes to occlude the vessel. This is time saved in small animals. We talk about time to occlusion, but in humans, that's time to save their life. We've also shown in the venous system, so a saphenous vein, we do what's called a puncture wound. We pinpoint puncture the vessel and identify the platelet accumulation. So what you see as the saline is this, when we puncture the vessel, a platelet plug immediately forms. We wait, and we re-puncture the vessel a second and then a third time. And you can see each time a new platelet plug forms, and each time you get on the other, on the right, you see more fibrin forming. However, animals dosed with CS014 do not form a platelet plug in a venous system when they have a injury or a puncture wound that occurs. This is tantamount to a major injury, and you do not get fibrin that forms. So in a large vessel and small vessel on the arterial side, as well as the venous side, so you might be thinking DVT, we can prevent these occlusive thrombi from forming. Now, I want to switch to CS585, our other drug program. CS585, and we'll come back to the bleeding momentarily, because I know that's what you're thinking. Well, if there's no clot, then there must be bleeding." But we'll get to that. But so we turn to CS585. So what is a prostacyclin receptor? So the prostacyclin receptor, its primary role is to form a compound known as cyclic AMP in the cell. CS585 directly binds to the prostacyclin receptor, results in the platelet and formation of cyclic AMP or any cell that has an IP receptor, activation of proteins that end up inhibiting the platelet. And we've shown that, very eloquently in a paper just published in Blood this week. We start with human blood, and so what we... On the right, what you're looking at is a human assay where we take whole human blood, and we dose it either with CS585 or without CS585, and we flow it over at arterial shear, at coronary artery, carotid artery, high shear rates over collagen, which is an injury. That's what the blood would see if there was an injury in the vessel, and we monitor how many platelets bind. So what you can see in the real-time experiment is, on the left, the control, on the right, the CS585. Two things: one, I hope you'll agree that there is less green. There are less platelets binding. But two, there aren't no platelets binding. There are some. That's really key. If there were no platelets binding, we would assess that this drug causes bleeding. We have just enough that we think we have overcome the bleeding risk while preventing an occlusive clot from forming at a major injury site. We then went, and we dosed. We said, and we did in vivo dosing and say, "Well, how low can we go?" And you see, we can go all the way down to down to 0.5 mg per kg before you before you recover what we call a normal clot. At 6 mg per kg, you have no clot. We don't think we want to go into the 6 mg range because we don't need to. We can down, be down at the 0.5-1 mg per kg, and we don't affect fibrin formation. This is what differs from CS014. So CS014 is going to prevent fibrin formation and prevent clotting. CS585 is gonna prevent clotting and spare fibrin formation. So we can... These two drugs in our pipeline do different things in order to give us the protection. We also have shown that we can give this either by IV or orally, and here you can see by IV, we can go up to 18 hours, single IV dose and have protection. And then if we give orally, we show that we get reversal at 48 hours. This is really important. Most antiplatelet or anticoagulant drugs, the biggest challenge is reversibility. So we have a major inhibition. It's in the animal, 24 hours, full inhibition, 48 hours, reverse. So sometime, some point between 24-48 hours in the animal, we get reversal. This gives us the benefit of getting the drug off when we need it off, if the patient needs other therapy. Then finally, I told you I would get at the last point to bleeding. So we do a tail vein bleeding assay. It's crude. It's actually state-of-the-art for pharma. We cut the end of the tail, and we monitor how long it takes for the animal to stop bleeding. And what you can see is within less than 200 seconds, a normal animal will stop bleeding. And CS014 has no increase in bleeding. Now, remember back in the previous slides, fully blocked clot, fully blocked fibrin, no bleeding. So it's the mechanics of the flow that allow that we believe is allowing enough hemostasis to occur at a point of injury where you don't get that bleeding. If we move to CS585, on the top, you can see the same thing. At low and high doses of CS585, we don't get any bleeding. Additionally, with 585, we've looked at coagulation components with the idea that one might want to give a antithrombotic in a condition that a patient's already on a required anticoagulant. So we look at it using an assay called thromboelastography. This is a clinical test that is commonly used to look at bleeding risk in patients. It's point of care, and we can see that CS585 shows no difference from vehicle. However, if we give a factor Xa inhibitor, rivaroxaban, it's an anticoagulant, you significantly delay the time to clot. That's exactly what one would expect. Very importantly, if we give our drug on top of a factor Xa inhibitor, we have no further additional delay in clotting, suggesting and supporting in this early study that, in fact, at least one, if not both of our approaches, may be able to be used with anticoagulants, so dual inhibition. And this will allow us to think about applying this to patients who are, for a number of reasons, on an anticoagulant or need to be on an anticoagulant. We don't have to get them off and then wait and put them on our drug. So with that, in conclusion, I hope I've shown you that the HDAC inhibitor CS014 inhibits both small and large arterial, as well as venous clotting and fibrin formation and doesn't cause bleeding. CS585 is a novel IP agonist that survives and is sustainable in the blood, prevents clotting, doesn't alter fibrin formation, and is reversible, and effective up through between 24-48 hours and fully reversible. The bleeding risk is non-observable. We've used multiple assessments, every assessment one would use in any drug program and have not seen a bleeding signature to date. And so CS014 and CS585 has significant potential as new approaches in treating this disease. And then finally, this is the what's in development slide. And so what you can see, IP receptor CS585 is gonna be the only game in town. The other prostacyclin receptor agonists just don't work in the blood. None of them that are FDA approved or in development have shown efficacy for having utility for thrombosis in the bloodstream. CS014 with HDAC, not targeting the platelet itself, being able to target the genes regulating the blood and blood clotting environment is a completely novel approach for treating thrombosis. And so with those two new targets and new drugs, I think we have a great opportunity to really treat this this fatal disease that as everybody so far has stated today is puts patients at major risk. Thank you. So, isn't this exciting? A few words, I think this slide has been up before. So Cereno is trying and aiming to revolutionize treatment for the orphan disease, pulmonary arterial hypertension, as measured with CardioMEMS point-of-care measurement, and eventually, hopefully, being able to titrate these patients to normalcy and remodel back patients from severe symptoms back to a normal life. So that's the real aim, and we believe that in our first glimpse at this in the patient case, with a lot of data points, it looks very promising. That's one aim. The other aim, the biggest killer on the planet for man, thrombosis, was discovered and new treatments in the nineties for therapies, they all cause bleed. Intracranial bleeds in your brain or other bleeds that are very dangerous for the patients, of course. And we believe that we will revolutionize, and we have a good chance to revolutionize therapy for the biggest killer in the world with effective therapy that can be used alone or in combination with what's out there to improve efficacy without causing additional risk of bleed. So this is our journey. And as Björn mentioned, if you look at the orphan disease, it's not a small aim as a business case. So we're talking about improving patients' life and their life expectancy. But of course, Cereno is in the business of developing drugs that will be commercially successful. And if you are in a market that there's a very large medical need, you have something that you can get done. And if you're successful, of course, it will be a commercial success. This market is soon $12 billion, and we will have a new, very important therapy if we are successful. So it will be a great business case for Cereno. Now, those of you who have followed us for a while, you know that we started early with a vision in thrombosis. But in a company like this, working with the best leaders in the world, thought leaders in our scientific advisory board, working together with Abbott in the PAH trial, we work way ahead of what we tell the market. So we have worked on strategies for a long time, and that's why you see some of the fruits of that today, that we have a portfolio of interesting development drugs. We own, we're not a one-trick pony, so to speak. The strategies are to improve life and prognosis, and we are developing several therapies to do this, alone or in together, in the portfolio or with other therapies. So as you can see, we have a PAH portfolio aim, we have a thrombosis prevention aim, both to improve quality of life and prognosis in both therapies with completely new approaches. We are pioneering HDAC inhibition, epigenetic modulation in cardiovascular disease, and we are entering into PH as the first in man, but soon we'll be in man with thrombosis prevention. So we're aiming to get into man next year. Now, a biotech such as Cereno, what is, you know, what's the commercial end here? Well, we want to be successful for the patient, that all our work is gonna provide improved health and improved prognosis. We can do and aim to do that alone. Most biotechs do partnership on the way, and some biotechs sell their assets completely. Potentially, eventually, Cereno will be bought by a company. We are opportunistic here, if you will. We are driving this to push these drugs to the patients as fast and as good as we can. If we see a deal that will do this faster, we'll do that. It will, of course, be beneficial to the shareholders if it's an exit to a major pharma for one of the portfolio drugs here, or if the company is bought like Acceleron was bought by Merck for $11.5 billion. We are in the same field. You know, you've seen our press releases, and you've heard today very exciting things. Of course, the patient case is very exciting, but also, Mike here is one of the leaders in the world in blood science. And Blood, the top-tier journal, just accepted and published your work, Mike, and that is a major achievement. So what's coming up for us now? Well, Björn here mentioned our initiative to look at the data, and the quality control of the data to maybe optimize that as we go along, and that we will be able to come back internally and externally of how that looks like. That would also give us an insight into possible efficacy in the same line direction as we see with our patient case. And of course, as Björn also mentioned, that information will give us an insight into how to define our next trials, and we can get an early discussion with FDA about how, how that should be done best for the patients. CS014 is nearing completion in preclinical. We are aiming to start first in man in the spring, so we're quite soon gonna be able to submit, if we succeed here, and looks very good, an IND to the regulatory authorities, so we, we can get it approved and then go into man. Then we'll have two HDAC inhibitors in clinical programs. Of course, top-line data for the PH study is targeted and expected at Q1. I mentioned that. So to conclude, we are part of, of this, people who try to develop better health, and you've seen the joined forces here today. I hope you share my excitement. Thank you very much, Sten, and all of our faculty. We're heading over to questions. I'm sure you have several of them. And just as a reminder, you who are watching online, please do submit your questions, if you have any. And for you in the audience, we have a microphone, so we'll go around. I'll just be asking everyone, if you wanna get up on our stage here. You can probably... Yes. Do you wanna just stand over there, please? All of you online. I think I just wanna kick us off before handing over to the audience here, but especially to our kind of esteemed faculty. So what makes you so excited about working with Cereno? Some might say that we are a, you know, small biotech from the little country, Sweden, but obviously, we've..., and Sten and Björn's done a great job of kind of raising the word. But, Phil, if you wanna start, just give a few words. Well, sure. I alluded to some of my excitement earlier, but I can't emphasize enough from our perspective how the new paradigm of drug development, drug pipeline, titration to an effect rather than a forced titration to an effect to a dose that has been tested in a population. Personalized medicine that can be achieved with remote monitoring is nirvana almost for the development of new pipelines, especially vasoactive compounds. So we see a tremendous interest in the community to collaborate further, and this is a proof case set, proof set for us to really open up an entire new developmental market, as well as bringing drug development much more efficient, much more powerful, and much more focused on the patient's outcome. So I tell you, that changes a lot of things that have been done for many, many years, and I'm very excited about that possibility. Benza, would you like to add to that? Yeah. I, you know, in being in this field for now 30 years, I've worked with many, different companies and, and different products. And what I found unique and what's really attracted me to working with this team is the synergistic energy, that this team has in terms of both its scientific advisory board and the company leaders itself. This has generated fantastic ideas, like the incorporation of new technology, the ability to really phenotype our patients, so we really know how the drugs work. To me, as a physician-scientist and, someone who treats patients with this disease, that's very endearing to me. You know, this is a company that really wants to understand fully how its therapeutics work. And, and to me, that shows that the heart's in the right place, and, and that's why I, align myself here. Mm-hmm. Mike, yeah. I think, the willingness to go outside the box, to understand that the great discoveries and the great advances in filling these gaps are gonna be by not targeting the same thing over and over again. And I think the passion that Cereno brings, the team working with the team, it's really been amazing to see their willingness to look in new directions and take the chance, because that's how great discoveries and great advances in medicine are made. Thank you. And, we've talked a lot about the... our portfolio and, what we are aiming to do. I'm thinking more of the competitive landscape. We haven't touched so much upon that so far. What are we seeing in both the, I suppose, yeah, other drugs out there or what's in the pipeline development, especially for, say, PAH? As I showed you, there, there is a direction towards developing molecules that push the remodeling of these blood vessels towards normalcy. I've seen a lot of these molecules come, tested, and not work out the way we want to. It's nice when we see early efficacy in, in this type of therapeutic like we're seeing here. Mm-hmm. It will fall into the portfolio of others, of other therapeutics that are coming through to just pass their phase II and phase III studies, like, sotatercept or seralutinib. Now, the interesting thing is that these therapeutics, although work on the remodeling of the vessel, their delivery systems can be somewhat complex, to use, for our patients, injections or multiple inhalations, as opposed to an oral preparation, which is- Mm ... what CS1 will be. And so I think from a patient perspective, familiarity with the dosing is gonna set aside how patients accept this, but also the knowledge that they can potentially achieve near normalcy in their pressures is gonna be something that's really going to align them with this type of development. Anything to add about thrombosis? Yeah, well, absolutely. So I put a slide up at the end talking about the new potential targets, but with that said, I think where most development has really missed the boat is they've not gone to human fast enough. So with the prostacyclin receptor agonists, a lot of the data we showed, the data in the blood paper, we started with human blood. It works in human blood, and we'll move forward. With the CS014, that's the first potential target that doesn't actually directly hit the platelet as a drug, which means it will limit the bleeding risk, right? And so both targets and the thrombosis side, I think, are revolutionary. And I think that that's going to put it above what's out there right now. So, I think most of the interest lies with the CS1, of course, since we're in phase II, and just talked about the patient case study and like the also the monitoring initiative. So I suppose starting at the end of it, how do you see our future would look like with CardioMEMS and CS1 approved in PAH? So the benefit to patients, to physicians, and society. I think you see the benefit of CardioMEMS. I think we've demonstrated that now in multiple disease states. And I think, one of the things that's very important to remember is that CardioMEMS is in the patient for the rest of their lives. This, this device does not have moving parts, essentially, and so there's nothing to break, and the patient has that opportunity to monitor those pressures. So we are now able to really take a systemic blood pressure paradigm. No one, I think, in at least that takes care of patients, and no patient would want us to throw pills at systemic blood pressure without measuring the blood pressure to see if the pills worked. But that's what we have done essentially over time with the pulmonary circulation, and now we don't have to do it. So I think that there's this opportunity to take an entirely new look at the reason why people have high blood pressure in their lung circulation. The vast epidemic of what we call WHO Group II, which are people with heart failure. Like, like I mentioned, we've discovered this surprising thing that 85% of patients with heart failure already have secondary pulmonary hypertension. Targeting that disease is gonna be incredibly important because those patients die because their right ventricle gets damaged from that high blood pressure over time. Now we can target it. Now we can use novel agents to understand how we can bring those pressures down safely and prolong life. It's really remarkable how you change your perspective of a disease when you're able to monitor it regularly. It really gets at the idea of personalized medicine. Mm-hmm. Mm. You know, you are targeting a disease, but you're monitoring the essence of that disease, and then changing the trajectory of that disease with a therapeutic that pushes the way we want the vessel to reform, I think, is very unique. Mm. Mm. The patient case study that we presented, that goes obviously... We showed real remarkable initial results and what triggered the Data Quality Monitoring Initiative also that will be reported in Q4. Perhaps, Björn, do you wanna just add some more to what this will actually mean for the study and the outcome of the report? Yeah, I mean, I mean, I've been in clinical trials for, for 40, 45 years or something, and usually, you measure something in the beginning and at the end, and, and, and you need a lot of patients to, to, to see a result. I mean, and that's what goes for clinic as well, I mean, when you treat a patient. Now we have a novel technology in a, in a new application, new indication. We can actually monitoring day by day what defines the disease. That is the pressure. That is how you have the diagnosis. That is the, the pressure increase, and now we can define that. And we have a study of 30 patients. We have now randomized 16, and I think it's a great opportunity to both look at the quality of the data, to be able to, if there is anything we can improve, to get a really conclusive result at the end. As a clinical trialist, that, of course, is to the benefit of everyone, even also the patients, because that will help them- help, help us to give them a therapy earlier. It will also give us an opportunity to look at efficacy, because if we can see efficacy and maybe define some of the properties of how CS1 works at that time, that gives us the opportunity to discuss the next study much earlier than we thought. That also gives us the opportunity to go to the authorities and discuss that next project, and that means that we can have a faster development, and that will bring it to the patients at an earlier stage. So I think this gives us a lot of opportunities with this initiative. Yeah, that's critically important because you remember, the timeline starts when that patient's diagnosed, and that 7-year timeline is gonna continue to progress- Yes ... unless we have something to intervene quickly. Mm. And so bringing these drugs to market that are efficacious at an earlier time point, to me, provides my patient with the protection and what they want, to live a longer life. Mm-hmm. Mm-hmm. Yep. I think, I think it's very important to mention that the reason we looked at that patient is they petitioned to stay on drug. They were rotating off drug per, per protocol, and, and they felt so good. I think it's a one patient, and we have to look at safety, we have to look at a bunch of stuff, but I think, you know, to have that happen early, is what spurred us to say, "Okay, let's see, you know, in a blinded way, can we understand how this drug is working in this population to inform how we move forward? Mm. I think that's the- The patient knew something was different. Knew something was different. And I think, if I may add, so, you know, this technology that you've seen, you can measure continuously. And, of course, the dream potentially would be to, for every patient to have this, with this diagnosis, and then you could tailor-make, as mentioned here, for normalcy or the best outcome. And that is when approved. However, we're gonna continue our development, so this way of measuring will have impact on how we define future trials, and it will possibly require much less patients than if you would do it the traditional way. And that's a very good thing for the patients, for the regulatory authorities, and of course, also for us as developers. So being able to measure this way in the next study will provide us to do faster and more complete work, in these patients with less patients involved. ... That's at least if you look at what we've seen so far, and we are already working on the next phase, of course, and that's part of this qualitative data monitoring initiative. So in Amsterdam and yesterday, we're talking about the next step already. But I also want to add, it sounds like less patients is less information. I would say less patients and more information than with traditional. Mm-hmm. Mm-hmm. That is, I think, the real advantage. Great. Thank you. I think we'll open up to the audience. Okay. Thank you. Maybe say your name, sir. Yes. Gustav Wallner. Thank you for taking my question. So, I have a couple of questions for Dr. Benza, if I may. You discussed the risk classification, so I was just wondering: how are the patients divided between those different risk groups, and where do you see that you would use CS1, if it gets approved, in all or just a couple of those? And a follow-up question, also based on your experience as a clinician with 30+ years in the clinic. So, this case study, how often do you see patients on stable medication spontaneously regressing their disease? Yeah, two very good questions. The majority of the patients that we see in the clinical environment are at intermediate risk. That's where at least 70% of our patients live. And so a therapeutic such as this will certainly be used in those higher-risk patients to push them back off the cliff. The one thing that we didn't mention about the right ventricle and pressure is that this is not a linear reduction in function of the right ventricle. When a certain pressure is achieved, the right ventricle just fails. And so bringing those people back from the cliff, so to speak, is a really essential part of what our therapeutics are designed to do. And so for certain, these remodeling therapeutics will be used on top of the classic vasodilators, which are typically used now to stabilize patients, but these new novel drugs, like CS1, will be used on top of that to remodel the vessel, to push the pressure towards normal. But as I mentioned earlier, you can foresee many other uses for these drugs. We typically can bring up to 25%-30% of our patients to the low-risk category, so low risk of mortality and morbidity, but we haven't normalized their right ventricle. As a clinician, when I see that, I am perplexed on what to do next because my training has taught me that I want that right ventricle normal in order for this patient to achieve a normal life expectancy, not adding another three or four years to that seven-year timeline, but to normalize that life expectancy. So I would foresee that remodeling agents are gonna be used even in low-risk patients, to push that artery modeling as much as we can to achieve normalcy in pressure and normalcy of the right heart. Now, the second question was- Spontaneous uh- ...... Spontaneous improvements like that, I usually jump for joy when I see that. It's not very often that I see remarkable pressures, and as I showed you on those slides with upfront combination therapy, we're hoping for a 10% reduction in mean pulmonary artery pressure. Here, we saw a 30% reduction with one drug- Twenty on top of three therapeutics already. That's, that's really remarkable. Thank you. Maybe we should move over for the camera. Okay. Rutger Smith. I start with one question on PAH. I believe no one knows why the disease sets in, but obviously, there is a fibrosis part in the vessels. And then it's surprising that this study is only 12 weeks, with 2 weeks follow-up, because one should think that removing this fibrosis should take a much longer time. So that's one comment. Then, on this specific patient, on your slide, it ended in April this year. Now we're 4 months on. Is the MEMS still in place? Do you have new data on her pressure? Has it continued to stay on that level or even perhaps diminished, or what has happened? Yeah, that's another really great and very astute question. So, certainly, we would think that a drug with remodeling effect might take longer. However, fibrosis is not the only issue that causes the vessel to remodel. The fibrosis on the arterial part of the vessel, but then we have vascular smooth muscle hypertrophy and smooth muscle proliferation and also expansion of the intima, which is the inner lining. Now, some of these processes can be reversed relatively quickly in a period of three months. Three months is usually what we consider the optimal time for remodeling just based on our experience with other therapeutics. So, seeing an effect on remodeling in six weeks, I think, shows the po- ... potency of this particular therapeutic in that area, and this is, again, one of the things that I find very exciting and interesting about this, is that we do see this remodeling effect very early. We do have the CardioMEMS implanted for life in these patients. And so we will have data on what happens to these pressures once the drug is removed. Now, we haven't looked at that in this particular patient, but we will have that data at the end of the trial to know how long this remodeling effect is lasting for. And this is really important for regulators because for these remodeling drugs, they're asking us more and more often to have withdrawal studies to see what the long-standing effect of this is. We will have that information automatically with this study because we have the device in place, and we'll be looking at that data. So that's going to be really exciting. Mm-hmm. Yeah, yeah. And then a question on the clotting. Dr. Holinstat, you showed some pictures, but that showed animal experiments with clotting and fibrin formation. And there seemed to be cases where there was a small clot and a small fibrin blanket that was sufficient to stop bleeding. Mm-hmm. Now, my question is, did the great creator get it wrong with humans? Do we all create two big clots, too much fibrin blankets, unnecessarily large? Do this or this tendency between... I mean, people are different. Do I have a tendency to create two big clots? Mm-hmm. You may not have that tendency. How, how do you see, look upon this? So that's a great question. And so if we go back in history, and we think about early man and the life expectancy wasn't what it is today. People didn't have heart attacks. They didn't live long enough to have a heart attack. In fact, the largest danger to life was injury and bleeding. Mm-hmm. In fact, still today, on the combat field, the largest injury to life is an injury that causes bleeding. I think that he didn't get it wrong. I believe that, when in doubt, clot, stop the blood from leaving the vessel, because if the blood leaves the vessel, you have no oxygen going to any organs in the body. Your heart gets deprived of oxygen, your brain is deprived of oxygen, so you need blood flowing. As a by-product of that, I think it's too good. It's too sensitive, often, and that's where we get occlusive thrombosis. So I think that that's how the system was designed. Remember, closed vascular system is only upper vertebrates. Nobody else has them. And so it's a unique problem for higher-level vertebrates, like humans. And so I don't think that it's by accident. I think that if one had to choose, you'd choose not to lose your blood, right? But we are lucky enough; we get to make better choices. We live longer, and we live generally in an environment where we're not as worried about bleeding to death. And so now we have the luxury of treating the opposite, which is the occlusive thrombosis. So if our drugs eventually prove to be work and with no serious side effects, once you turn 60, 70, you might want to have this drug to prevent clots from forming. It's good primary prevention. Yeah. So we used to think about aspirin like that, and the reason we got away from aspirin is because its target, unlike our target, actually causes negative vascular effects in smooth muscle and endothelium, where our target, we don't believe, will. So yeah, so could think of it as a over-40 prevention, as we used to think about aspirin. Hmm. Yeah. All right, next person. Yes, Alexander Kramer from ABG. I have a question to Dr. Benza as well. First of all, thank you for taking my question, and very nice talk. The question relates to the cardiac output. So you presented very nicely that it's a cardiac failure that patients die from. And I guess the cardiac failure stems from that you have a gradually increasing diminishment of the cardiac output. And if I remember well, correct me if I'm wrong, in your case study, there is data that actually the cardiac output in your case study, in this woman, it increased by 20%. Mm-hmm. What I wanted to hear about, the cardiac output from you is, like, how does this 20% improvement in cardiac output relate to, for example, sotatercept, or like the standard of care or like the best available therapy at the moment? Like, how does it improve? So that's the first part of my question, and the second part of my question is, like, the cardiac output increase? Like, how does it relate to, like, the life expectancy or, like, the life quality of the, of a patient? Yeah, I'll answer the first, the last question first. So the stroke volume of patients with right ventricular failure is probably one of the number one prognostic factors that determines life expectancy. And as I also mentioned, the right ventricle is different than the left ventricle, in that it has a threshold effect on the right heart. It's not a linear effect that you see with left heart failure. So small improvements in stroke volume and right heart failure lead to large increments in improvement in survival. Because of that step-off effect, you drive it back. And so the improvement in stroke volume and a remodeling drug is a little unusual because we're expecting really the major effect of that drug to be from a drop in resistance. But having a drug that drops resistance and also improves cardiac output is a real benefit to patients. So you're not only remodeling, but you're affecting coupling of the right heart, which is really important. So when you couple the vessel with the right heart, that results in improved perfusion. And so in this one example, a 20% increase is substantial. That's really going to improve this patient's quality of life. And you know, some of the other therapeutics that we have, for example, sotatercept, it did have a an improvement in resistance and a more limited change in cardiac output. So again, we don't know the effects of CS1 on the ventricular myocardium. There may be some additional benefits that we're seeing on the myocardium itself that are separate than its afterload reduction properties. That makes this a very attractive compound for treating a disease state where the right heart and in a relationship with the vessel is so important. Thank you. Right. So, a few questions from the people online. Phil, the collaboration between Cereno and Abbott seems to be a win-win. How concerned are Abbott to complete bringing CardioMEMS to market also in PAH? And, is there an opportunity to continue collaborations in a pivotal study? We're very concerned and excited about bringing CardioMEMS to pulmonary arterial hypertension patients. I mean, that's the disease you're treating, so, I mean, having a measurement technique is really astounding. The pathway for approval, in the United States at least, is really focusing on a regulatory evaluation of safety. The regulatory agency does not feel we have to ask questions of: Does this measure pressures appropriately? You know, are pressures important? Should we focus on... It's just, is it safe to put this device in this population? Mm-hmm. And the indication will likely be granted when that's sufficiently proven. So I think this is a remarkable opportunity for us to gain a new indication for a very needy population, and it's a straightforward pathway. Mm-hmm. In terms of further collaboration, obviously, the next step, in my mind at least, is: Can we now set a precedent of how you do this? Mm-hmm. How do we develop drugs? Are we gonna develop drugs with intermittent right heart catheterizations, which may mislead us? Are we gonna and takes a lot of patients in order to understand that kind of variability. Are we gonna titrate to effect, get the pressures under control, monitor it closely, and have a much more precise way, with a much more efficient trial design to look at both onset, effect, and withdrawal? And so I think that this is a remarkable opportunity. So our next step would be to prove that that process is in- Mm-hmm ... is effective and can impact the efficiency of these trials. Mm-hmm. Yes, we're very interested in continued collaboration. Nice. I guess I could have said that at the first, so. That's the short answer, but we like the long one, too. Okay, good. And I think, just Sten, if you wanna continue maybe on that point, because obviously people are interested as well about the interest from kind of the external world. We have already presented some interesting indicative data for CS1. So has there been, you know, some sort of additional interest from potential partners or big pharma or Yeah, it's a good question, and you know, we've had interest a long time ago, I should say. And so we've received many calls to during the pandemic before we actually got the sites approved. And so people are looking at, and we've had discussions, and... But it's really. You know, so people are, like, very excited about the design. And they are, of course, curious about this new mode of action. We have animal work that shows that it's very good in animal work. It reverses right heart hypertrophy, vessel hypertrophy, it lowers the pressure, so, and it prevents disease progression. It actually reverses it in animals, in rat models, and similarly to sotatercept, actually. So we have that kind of data, but in man, we don't, right? We didn't until a few weeks ago. So you have the patient case now, so that's really a breakthrough in getting a glimpse of what we can do. So in one patient, I think it's 1,800 data points or something, 90-12 weeks and measuring 8 points a day or something. So, so it's area under the curve, quite impactful, and volume of data. So this patient who is reported back from functional class two, very affected by the disease, back to functional class one. So we have, in this patient, improved her life during the study over 12 weeks, seen already after 4-6 weeks. But with the parameters that we have seen there and with cardiac output, the extrapolation of that is probably prolonged survival, right? So and we got that glimpse just very recently. So I expect, to answer the question, that we will be in several talks over the next six months, but actually before the end of the year, when we have qualitative data from the Q4 reporting back, little more information, that people are gonna want to talk to us: What's our next step? Would you be interested in collaboration, et cetera, from the pharma business side? I would expect that, and we, of course, will also drive that process. I think that very nicely concludes and sets the next steps forward for Cereno. So, I think we're ready to conclude the event. Thank you very much for coming here, and thank you for joining online. Great to have you! Yeah. Let me just extend my thank you to you guys. You've been really busy at European Society of Cardiology Congress, and for the second time now, you have taken time to come here and talk about our collaboration. And of course, our investors in Sweden and abroad are our base for continuing our work. So thank you to you, and thank you to the investor base that we have. I hope you feel our excitement. Thank you.