Good afternoon and a warm welcome to all of you who have gathered here in Stockholm, Grev Turegatan 30, as well as participants on the web. I hope all of you are excited as I am to be here with Cereno Scientific on its inaugural Capital Markets Day. My name is Lars Frick. I work as a financial journalist at the Börsveckan magazine, and I cover life science in particular in that magazine. From my own experience, I know that companies within this sector usually requires a little bit more thought than perhaps most other sectors to truly understand, and that's why a Capital Markets Day like this is extra valuable. In particular, since today we have the great pleasure to introduce not only management from the company but also members of scientific boards and partners who will provide further clinical and research insights to truly dig into the CVD therapeutic area. We hope that today's presentations will give you insights into the area in general and PAH in particular. We have an agenda. First off, we'll start sort of top down with an overview of the market, and then we'll delve into each part of the pipeline and the challenges and opportunities ahead. The day will be concluded with a panel discussion, and after that, a Q&A session. Today's participants, we have two representatives from Cereno Scientific. Its CEO, Sten R. Sörensen, and Dr. Björn Dahlöf, who is CMO. In addition, a very well-renowned and highly respected team of researchers and a partner, Dr. Phil Adamson from Abbott, who will explain the partnership with Cereno, which is very interesting. Dr. Michael Holinstat, who runs a very well-renowned lab. Dr. Raymond Benza will join us on the web. Last but definitely not least, Dr. Gunnar Olsson, with a very, very wide range of experiences, not least from top-level positions in AstraZeneca. Now, there are a few practical notes. If you're participating on the web, if you look down below the window where the film is streaming, you will see a box. There you can write your question, press Send, and time permitting, I will reiterate the question during the Q&A session. So just write the questions in there online and save your questions from the... For the Q&A at the end, with one exception. If there is time, we will take maybe one or two questions directed at Dr. Benza's presentation since he's participating on the web. With that in mind, and no further ado, I would like to introduce CEO Sten R. Sörensen. Welcome. Cereno Scientific is a pioneering clinical-stage biotech company driven by strong scientific leadership and innovative drug development, uniquely positioned to make an impact on rare and common cardiovascular disease. Cereno grew out of Professor Sverker Jern's discovery of the potential of the HDAC inhibitor valproic acid for treating cardiovascular disease. Working at the forefront of new drug development, Cereno is looking to transform the treatment of cardiovascular disease, including through HDAC inhibition, enabling reverse remodeling of diseased heart tissue and blood vessels. Cereno's current focus is on developing a disease-modifying treatment for the fatal rare disease pulmonary arterial hypertension, PAH. PAH is a disease characterized by vascular remodeling, which increases pulmonary pressure and ultimately compromises the right heart ventricle. Cereno's lead drug, the HDAC inhibitor CS1, is currently being evaluated in an innovative phase II trial in collaboration with leading healthcare company Abbott, conducted across 10 sites in the United States. This trial utilizes Abbott's leading-edge CardioMEMS technology to frequently monitor pulmonary pressure in a drive towards defining the optimal dose range for subsequent clinical trials and clinical use. The primary endpoints are measures of safety and tolerability. Running alongside are a range of efficacy markers for cardiovascular function, quality of life, and disease prognosis. Epigenetic modulation unlocks DNA and impacts gene expression without changing the DNA structure. HDAC inhibition by CS1 allows DNA unfolding to confer beneficial disease-modifying effects, encompassing restoration of endogenous fibrinolysis and a unique multiple mode of action, pressure reducing, reverse remodeling, anti-fibrotic, anti-inflammatory, and anti-thrombotic. CS1's unique efficacy profile forms an excellent match for PAH's disease mechanisms. Strong clinical and preclinical drug development programs are pursuing multiple cardiovascular disease indications, supported by leading clinical and scientific experts dedicated to improving the health of patients with conditions that have high unmet needs. Cereno Scientific has a novel HDAC inhibitor in the pipeline, along with a novel prostacyclin receptor agonist. The potential for patients and clinicians is significant. Cereno Scientific's commitment to developing this exciting portfolio for the treatment of rare and common cardiovascular diseases heralds a future where patients with these conditions will be able to live longer with better quality lives. Cereno Scientific. Welcome to the future. There you go. That was the premiere of our corporate video. I hope you liked it. It's not an easy effort to undertake to make this when you are involved in science in the cardiology arena. Do I need that? Yes? Okay. We've made some efforts during the spring here, and we'll also work together with Phil to make sure that we don't overstate anything about CardioMEMS. I'm very pleased to be here and with this team. As the moderator said, Lars here, that we have Phil Adamson from Abbott here, normally residing in the U.S., working around the globe, and Mike Holinstat, our Director of Translational Research, but also leading our programs at University of Michigan, the preclinical programs. You're welcome. I'm sure you'll be excited to hear what they're saying. We, of course, also have the other presenters, and Gunnar Olsson here from our scientific advisory board, and Dr. Benza as mentioned, sending directly from or participating from Ohio. Of course, our CMO, Björn Dahlöf, who will have an extensive session here for you, so you can understand maybe better, even better what we're doing. Why are we in cardiovascular disease? Well, it's a major health problem around the world, and it's the most costly and deadly disease sector in the world. There's such a high unmet need that somebody's gonna be involved here and make a real difference. The people in this room that are involved in Cereno are. Have made a difference for these patients through their lifelong careers, and Cereno aims to do the same with our drug development. We are a passionate people, and we're also very skilled in what we do. I think it's good for you as investors to know this. Cereno Scientific was founded in 2012, based on Professor Sverker Jern's vision and discoveries. It was basically to uncouple the epigenetic modulation capacities for cardiovascular disease. Early focus was on thrombosis, and we'll get into thrombosis later in the program. Our current lead focus is in the rare disease pulmonary arterial hypertension, and you will hear more about that today. We have a drug in phase II in the clinical trial in the U.S., and we'll get into that. That's our lead program. We have two preclinical programs going on at University of Michigan, and there we aim to submit an IND during the next year. I know you're curious about those programs because we haven't disclosed a lot about them. Just keep your ears open. Now, this is our scientific advisory board. I just came back from the second-largest gathering of scientific minds in cardiology in Barcelona, European Society of Cardiology. There, all the major companies that are producing tremendous value for this sector gather every year to present new data, but also discuss business and also plan what we're gonna do with the results that we have today and move forward. Cereno was there, of course, and we had two gatherings of our scientific advisory board, one on thrombosis and one on pulmonary arterial hypertension. We were actually more outside the conference hall than in the conference halls because that's if you're in pharma business or biotech, you do a lot of valuable work at these conferences because everybody that you want to work with or is working with is there. Now, these are the three programs. As I mentioned, CS1, our lead project, is in phase II, 30 patients in the rare disease, pulmonary arterial hypertension. Top line target data, Q1 2023. As you've seen, we have our first patient dosed. We're very happy about that. Then the other two programs, we haven't decided on the target indication yet. We are evaluating what to go for first. They are applicable for multiple diseases, I can say now. We are going to select which target indication to go for further on. You will hear some very interesting data of the current documentation that Dr. Michael Holinstat has produced and been able to see at his work in University of Michigan today. Well, if you're expanding in a couple of years from having one phase I drug, CS1, to have that drug into phase II in the United States, collaborating with a CRO and with Abbott and pursuing this very important indication in a major effort, and at the same time, you secure rights to two preclinical programs that are very interesting and have highly significant potential in this field and define to pursue two major development programs for these preclinical programs, then you need to expand your team with experience and knowledge. This is part of our team, the more senior people maybe here. And I'm very pleased that you will be able to see or meet Fredrik Frick, who is Head of Clinical Operations. He's here in the audience. From a couple of decades at AstraZeneca working globally in many areas. He's heading up our clinical operations and with main responsibility for the phase II trial. We also have recruited Nick Oakes as head of preclinical operations. He couldn't be here today, but we're very happy with that recruitment too. Of course, Mike Holinstat is responsible for his own research lab at University of Michigan, but you also engaged as Director of Translational Research for us. We have strengthened the team significantly over this year. Now, just as an indication of this sector being very interesting from a commercial point too. If there's value to deliver to the patients, there's also a commercial potential for pharmaceutical industry. This deal that was made in November by Merck acquiring Acceleron Pharma for $11.5 billion is a benchmark for the value of compounds that have some disease modifying potential in this orphan disease indication. The main reason Merck bought this company was the phase II program, which is now in phase III with sotatercept. You will hear more about how we view our compound in relation to sotatercept later by Björn, our CMO. Cereno is making some waves in this industry, and this year we have presented three at three major congresses, the PVRI, which clinical design presentation by our principal investigator, Dr. Raymond Benza. At the two other conferences here, EHA and ESC, just a few days ago, Michael Holinstat presented some very interesting data in thrombosis. With that, I conclude this lead-in and hope you're excited for the following to come. Thank you very much, Sten. We're moving forward with the program of course, and I'm very pleased to introduce Dr. Björn Dahlöf, CMO at Cereno Scientific. Welcome, Björn. Thank you. Stage is yours. Thank you. I need to have it this mic as well. No. No? It was only Sten. CEO's privilege. My voice is enough. Okay. Thank you. Yes, it's a pleasure to be here. Exciting days for us, and this is the first time we have this Capital Markets Day, and I hope you will be enlightened. To paint the background, we thought it would be appropriate to just have a bird's view of cardiovascular disease and Cereno's focus areas. Do you think that it all started with the Big Bang some 13.8 billion years ago. A man appeared about 200,000 years ago. Cardiovascular disease of epidemic proportions appeared a couple of 100 years ago, and now it's the number one killer in the world. It goes fast. We talk about COVID epidemic and so on, but this is more serious, actually kills more people, and it's really a problem. As we stand here, 200 million people in the world are at high risk of having a cardiovascular event. Why? Previously, we used to work ourselves to death. Today, we rest ourselves to death while eating easily available food. Just to give one indication of how dangerous inactivity is, that is just equal to smoking. Sten showed this slide, and I show it again because I think it's worth thinking about. 20 million people die from cardiovascular disease, and 80% of those deaths are stroke and MI, and majority of those are thrombotic complications. Cardiovascular disease and thrombosis, that's really something big here in the world. As Sten said, there is a lot of disease, of course there is a lot of opportunity for treating that disease. There are numerous drugs available, but we still have a huge unmet need in this area. Just to give you a hint on some numbers, the cost for cardiovascular disease in the world is enormous. This is $210 billion U.S. dollars or euros in Europe, and around $550 billion in the U.S. I guess these are not accurate numbers exactly, but the size of it you can imagine. That means also that the market for treatments are huge. The global antithrombotic drug market has been estimated to be around $43 billion-$44 billion 2025. The global market for PAH around $12 billion. It's really a large numbers. We are excited about this, and Sten explained what we have, and I will explain a little bit about epigenetics because I think that is really a key to what we are doing. Genetics play a role in disease, definitely, but epigenetics may be the missing link between the environment and the transcriptional responses. To unfold the genetic code that certain genes that have been hidden and in relation to disease is really a worthwhile enterprise. What happens with HDAC inhibition is that you can unfold the DNA for transcription. The discovery that Sverker Jern and his team did back in 2012 was that the epigenetic regulation of tPA in the body was really a link to improve on the endogenous fibrinolytic capacity and that we started out to develop a thrombosis treatment. This has evolved enormously. Looking into this field of epigenetic modulation, HDAC inhibition have kind of unfolded multiple effects that could lead to treatments in a variety of cardiovascular diseases, and you see some of them here. That's not the limit. It's actually just some examples. We are focusing on both rare and common cardiovascular diseases, and our two focus areas for the moment are PAH and thrombosis. PAH, that's a rare disease. It's a disease which is fatal, a disease that have a very poor prognosis. Untreated, 2.5 years survival. Treated, you can gain a few years, but it's not possible to cure it. The only cure, if that can be called a cure, is transplantation. Most people don't get there. Today, there is a need for disease-modifying therapy, and the ultimate effect is reverse remodeling of the vascular defect, vascular proliferation that takes place in the pulmonary vessels. We think that HDAC inhibition with its epigenetic modulation can disrupt that and be a disease-modifying therapy. We are thinking about five different effects which all fits very nicely with the pathogenic genesis of PAH. That's pressure reduction. It's the remodeling of the vessels, the reverse remodeling of the vessels and the heart, the anti-fibrotic, anti-inflammatory, and anti-thrombotic effect. All of these are important aspects of the disease. As said, thrombosis is also an area where we are interested and have interesting data in and could be an indication in the future. We have, as said, as Sten said, not decided yet exactly how to move forward. There are multiple opportunities in thrombosis. You can see here all the different areas where you have opportunity to treat thrombosis all the way from the carotid stenosis with risk of stroke and a coronary syndrome with the risk of an MI to peripheral arterial disease. Some of them are more mature than others. Some have treatments. Some are not really a good treatment available. All of the existing treatments for thrombotic complications, and here are just a few names, is that you have a systemic inhibition of coagulation or platelets twenty-four/seven with an increased risk of bleeding twenty-four/seven. There is a huge need for something that could have the same or better antithrombotic effect but not have the problem of bleeding. This is the way it looks. We have the classical warfarin, where you also have a problem with that you need to titrate it a lot to find the right dose. We have the NOACs and the antiplatelets, but they have increased bleeding. We have, as it looks in our data, opportunity for coming forward with something that can cause the same or better antithrombotic efficacy but not cause the same risk of bleeding. I stop there, and that's just our focus today, PAH and thrombosis. Thank you very much, Dr. Dahlöf. Now hopefully we have Dr. Raymond Benza with us, who's Professor and Director at The Ohio State University at the Wexner Medical Center. For those of you here in the audience, when Dr. Raymond Benza comes on, his presentation will be viewed there. Dr. Benza, can you hear me? [audio distortion], I can't hear. Are you with us? All good things come to those who wait. Dr. Benza, are you with us here today? Can you hear us? I can hear you. I'm here. Right. Dr. Benza, if you can hear me, perhaps you could unmute your Zoom app. I am unmuted. Well, here's how it is with technology, but it's a small hurdle. We'll get through it. Dr. Raymond Benza, I think your Zoom app is on mute. I am not on mute. Uh- [audio distortion]. All right. Could you please perhaps adjust the system here? Right. Dr. Raymond Benza is here, and hopefully we'll be able to hear his presentation shortly. Do we have sound? Can you guys hear me? Yes. Finally. Okay. Welcome. Here we go. Thank you. I'm sorry about that. I I don't know what happened. Can you still hear me? Yes. Can you still hear me? Yes, Dr. Benza. We hear you loud and clear. Please go ahead. Okay. All right. Now will you be advancing my slides for me? Yes. Just, say when, and I will be advancing them. All right. 'Cause I cannot see the slide screen, so I'm just gonna assume that you're on my first slide. Yes which is pulmonary hypertension focused on pulmonary arterial hypertension. Great. All right. Well, good afternoon, everyone. It's really a pleasure to be here. What I'm gonna try to do is give you a whirlwind tour through the disease state of pulmonary hypertension so that you might understand a little bit more how CS1 fits into the new drug paradigms of disease-modifying agents that are making their way through the clinical arena. If you could advance my slide, please. Check. Really, in order to understand pulmonary hypertension, you really have to understand how the normal circulation works. This is a slide just showing the heart, which is the center of your circulation. As you know, your heart is divided into two sides, a right and a left side. Now the right side here depicted as the RV receives blood back from the body after the body's utilized it, and it comes back to the right heart very low in oxygen. The right heart then pumps those blood through a series of pipes, and if you could advance the animation for me. Yep. Through a series of pipes called the pulmonary arteries, these brown little pipes that you see here now. Now the pulmonary arteries then take that blood that is low in oxygen and transfer that to the lungs so that lungs could put oxygen back into the bloodstream. Then the blood returns through another series of pipes at the left side of the heart, and the left side of the heart pumps that blood that's rich in oxygen out the aorta so that the body has all the oxygen you need to do your daily activities of living. Well, pulmonary hypertension is a disease of the pulmonary arteries, and if you could advance my slide once. A normal pulmonary artery is a very thick vessel, but with a very wide lumen, and so the blood can traverse these pipes very, very easily. Now, pulmonary hypertension is when an abnormal pressure develops in these pipes, and that's where the name pulmonary hypertension comes back. It's very important to understand how the circulation works, because anywhere there is a break in this circuit afterwards or including those pulmonary arteries can cause pulmonary hypertension. I will explain that a little bit later. Pulmonary hypertension again is an elevated pressure in the pulmonary arteries. If you could advance the slide. The definition of pulmonary hypertension is really a pressure definition. The normal pressure in the pulmonary artery is a mean pulmonary artery pressure of 20 millimeters of mercury. Excuse me. Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 20 millimeters of mercury. Usually, the normal pressure in the pulmonary artery is anywhere from 10- 15 millimeters of mercury. As you can see, this is a very, very low pressure circuit as compared to the systemic circulation. For example, when you take your blood pressure, your mean arterial pressure is usually 90. The degrees of pulmonary hypertension are defined by how elevated those pressures can get. Very severe pulmonary hypertension is when we have a mean pulmonary artery pressure greater than 55 millimeters of mercury. If you think about this in the systemic circulation, this would be equivalent to a blood pressure of around 360 over 240 in your systemic circulation. This is a very, very high pressure in that artery. Go ahead and advance the slide. As I mentioned, pulmonary hypertension is a disease of the pulmonary arteries. As you remember, the normal vessel that I showed you earlier, a vessel that has pulmonary hypertension becomes a very narrowed vessel so that the lumen is become incredibly encroached by a muscularization of the rest of the artery. The consequences of this, if you could advance the slide. Is that the right heart becomes very dysfunctional. As you remember, the right heart is connected to the pulmonary arteries so when the vessels become diseased and narrowed, that pressure is turned back onto the right side of the heart and the right side of the heart, as you remember, is not built like a left side of the heart. It is a very non-muscular side of the heart and when the RV sees this abnormal pressure coming back from it from these atretic and narrowed pulmonary arteries, the right heart becomes very big and eventually will fail, and that’s how our patients die with pulmonary hypertension. They die from right heart failure, and it is a very, very miserable form of death. If you could advance the slide. Now, there are several forms of pulmonary hypertension I think it's important for you to know about, and if you remember how I described a normal circulation, anywhere there’s a break in the circulation afterwards and including the pulmonary arteries can cause this disease. For example, if you had a problem with the left side of the heart in that it didn't contract well or didn’t relax well or if there are broken valves on that side, instead of oxygen-rich blood going out to the aorta to the body, it will back up into the lungs, and from the lungs, it will back up into the pulmonary arteries and raise the pressure there, kinda like a clogged sink. Indeed, diseases of the left heart are probably the most common form of pulmonary hypertension that we see in the clinical arena with seven out of ten patients having that form of pulmonary hypertension. If we go back in the circuit even more, now we’re in the lungs, diseases of the lung air spaces or interstitial spaces that prevent the lungs from taking oxygen out of the air and putting it into the circulation can cause those pulmonary arteries to go from a very large caliber to a very small caliber, and you can imagine the pressure that the right heart would have to do pushing blood through a smaller caliber pipe than a large caliber pipe. Diseases of the lung parenchyma like COPD or interstitial lung disease or bad sleep apnea is another very common form of pulmonary hypertension that we see with two out of ten patients having that form. Now if we go back in the circuit again and now we’re in the pulmonary arteries themselves, there are diseases that directly attack these arteries and make them atretic, and these can be diseases like connective tissue diseases like lupus or rheumatoid arthritis or scleroderma. Viruses can do this like HIV or hepatitis C. There are genetic abnormalities that can cause this. There are also drugs that can cause this. Very commonly were the old anorexigens that we used to lose weight, and more commonly now are chemotherapeutic drugs that are used to treat bone marrow malignancies and renal cell carcinoma that can really cause abnormalities in these arteries, and that’s a very special form of pulmonary hypertension called pulmonary arterial hypertension. About a half a person we see in the clinic will have this. We'll talk a little bit about this more. This pulmonary arterial hypertension is the most deadly of all forms of pulmonary hypertension. The last common form of pulmonary hypertension are when blood clots form in the legs, break off, travel through the right heart, and clog up all the pulmonary arteries. If you can go to the next slide, please. The four main causes of pulmonary hypertension are seen here. Pulmonary hypertension due to left heart disease, due to lung diseases and hypoxemia, due to pulmonary artery obstructions from blood clots, and then pulmonary arterial hypertension, which is gonna be the main focus of today. Now pulmonary hypertension was once thought to be a rare disease, and if you can advance the slide. In actuality, pulmonary hypertension is a very common disease, and in fact, one out of 1% of our population globally suffers from this disease, and when our population ages to 65 or over, it actually increases to 10%. 10% of the global population greater than 65 will have pulmonary hypertension. This is a real pandemic in and of itself, and that’s demonstrated very nicely here on this little chart in which you can see in a community in the United States in Minnesota that when we screen patients with echocardiography, that 50% of the population we screened had an abnormal pulmonary artery pressure, with 25% having already a pulmonary artery pressure greater than 30 millimeters of mercury. Pulmonary hypertension really is a global burden. If you can advance the slide. Pulmonary arterial hypertension, as I mentioned, is the most serious of these forms of pulmonary hypertension, and it is a progressive chronic disease primarily affecting women with a 5-to-1 ratio, and with a mean age of around 50 years of age. The life expectancy, as Björn Dahlöf told us earlier, is about two and a half years without therapy, that we’ve now extended to seven and a half years with modern therapeutics. If you think a bit about this, in a disease of middle-aged women, extending life only seven and a half years is really not where we want it to be. We need to do much better. That’s where the need for new therapeutics that work differently than the ones that we have now are really, really important. As Björn also told you, there is no cure for pulmonary hypertension except lung transplantation, and because of the shortage of donors for lung transplants, this is not an option for all of our patients. Unfortunately, unlike left heart failure, there’s no long-term acceptable mechanical options to treat right heart failure. That puts us in a real quandary, and I think you can appreciate very much when you see the next slide, if you could advance, and actually look at the faces of my patients with pulmonary hypertension. These are lovely women in the prime of their lives, and only extending this for seven and a half years is just not doing these women justice. Therapeutics that can advance their lifespan even longer than this is what we really need to do. If you could advance the slide again. One more slide, please. To really understand the pathology of pulmonary hypertension, you have to understand what are the mediators of this process. What I'm showing you now is really a cut through the pulmonary artery. The inside of the pulmonary artery is lined by a series of cells called the endothelial cells, and these are really the generals of the vasculature. They're the ones that command how a vessel grows and remodels in response to certain stimuli. They do that by secreting certain effector molecules, which then go in and affect the smooth muscle cells, which are the cells that actually cause the elasticity to the artery. The smooth muscle cells, you can imagine, are the infantry who receive information from the endothelial cells about how to grow and how to dilate or constrict the blood vessel. If you can go to the next slide. When you look at the pathology of this disease, going from a normal pulmonary artery with a very big lumen and a very narrow media, which is where the smooth muscle cells live, what happens in this disease is that the endothelial cells no longer produce the commands that keep the blood vessel wide open and with a large lumen. What happens is the smooth muscle cells begin working by themselves, and they start proliferating, and they don't die anymore. As you remember, every cell in the body undergoes preprogrammed cell death as it ages. Well, these cells become ageless, in other words, and they don't die. That media becomes very, very thickened, and the vessel starts to constrict naturally because it no longer has the mediators to allow it to dilate. As that media becomes progressively thicker because of unchecked proliferation of these smooth muscle cells, the lumen becomes more narrow and becomes infiltrated by inflammatory cells because they feel that a process is going on that they need to respond to, kinda like a viral infection, and the inflammatory cells just make this problem worse. Now, as these lumens become more narrow, blood starts to clot within these lumens, so microthrombosis becomes a very important problem in the later stages of these diseases. Remember, blood clots are not inert substances. They are chock-full of growth factors and mediators that are elaborated by trapped inflammatory cells within the clot, and these mediators make the blood vessel even more abnormal. Eventually, when the lumen closes, the body's response to this is to try to redevelop new lumens, and you get these very small lesions called plexiform lesions, which is the body's response to try to recannulate these blood vessels. Unfortunately, this recannulation doesn't work, and these blood vessels disappear. If you can advance the slide. This again shows you the blood vessel, the endothelial cells, and the smooth muscle cells and show you three of the common chemical pathways that the blood vessels use to try to maintain its patency. The most important of these pathways is the prostacyclin pathway and the nitric oxide pathway. These pathways work by increasing certain chemicals, cyclic AMP on the prostacyclin pathway and cyclic GMP on the nitric oxide pathway. These are the mediators that are responsible for keeping smooth muscle cells in check and to make them vasodilate instead of vasoconstrict. The endothelin pathway is a pathway that is usually very lowly expressed in these blood vessels because its main function is to constrict the blood vessels in response to certain stressors. If you can advance the slide again. We make use of these various pathways by developing drugs that can counter or enhance these pathways. For example, in the endothelin pathway, we really want that turned off, so we've developed endothelin receptor antagonist. If you could advance the slide again. In order to accelerate the nitric oxide pathways, we have developed phosphodiesterase inhibitors, which inhibit the enzyme that break down cyclic GMP that allows the blood vessel again to respond normally to stressors. If you could advance the slide again. We've also developed soluble guanylate cyclase stimulators that directly activate cyclic GMP to get an abundance of this chemical. Lastly, if you could advance the slide again, we've developed prostacyclin derivatives that will directly increase cyclic AMP, which is one of the good molecules we want. Now, unfortunately, the major focus of these drugs, if you could advance one more time, is to cause vasodilation of the blood vessel. These agents aren't really recreating the lumen, in other words. They're just trying to vasodilate the blood vessel as much as possible. This type of therapy indeed has a number of limitations in why newer molecules that actually enhance vascular remodeling are really needed. If you could advance the slide. Now we'll talk a little bit about managing pulmonary arterial hypertension, if you could advance the slide again. This is a slide again showing the survival rate for patients with this disease. The red line is the original survival curve without therapies, and then the green line is the most modern line that we have with therapeutics. As I mentioned, we have increased in median survival, but still the seven-year survival rate is unacceptable. Now the disease has been fraught with morbidity events in addition to mortality events. If you could advance the slide. Weirdly, to make it a big improvement in the disease now, I think further changes in the survival are going to be dependent upon either changes in management style, which is risk-based management, and new therapies that are disease-modifying, such as CS1. If you could advance the slide. Now, risk stratification is ultimately important in taking care of patients with this disease, because frankly, we don't know when the disease is progressing fast or slow. We don't know how fast the right ventricle will adapt or not adapt to the high pressures. Having a risk prediction system that takes into consideration a number of variables that could predict how fast the disease is progressing is intimately very important in how we treat the disease and how we align our armamentarium of existing drugs. If you could advance the slide. Advance the slide one more. This is our current risk stratification system in pulmonary hypertension. As you can just see, we assess risk of progression at multiple times during this disease course. Based on the level of risk, this determines how we use our medications, whether we start with a single, a double combination, or a triple combination, or in very severe disease states with very high risk, starting with parenteral compounds. If you can advance the slide. In risk stratification, again, we try to use a combination of a number of factors because using one, two, or even three variables, really doesn't depict how a patient will progress. If you advance the slide. We think we all believe that there's a collective need for a measurement tool to predict survival in pulmonary hypertension, that supplements clinical gestalt and experienced providers, but also serves as a key decision tool for less experienced providers. This is very important because in the United States, many of these patients are no longer seen in the centers of excellence, but are being seen by community physicians who are a lot less versed in how this disease is managed. If you could advance the slide again. This tool here is the REVEAL risk score calculator. As you can see, it has a number of variables that are depicted from demographics, comorbidities, hospitalizations, and then certain tests that we use, and will summate and depict a patient's progression based on a total score. We have the REVEAL risk score here. If you advance the slide one, we also have a smaller version called the REVEAL Lite 2 calculator, which makes use of just modifiable factors. These calculators allow us with a very, very high level of discrimination to depict which patients are going to be the high progressors and which patients are going to be the slow progressors. Again, this is very important because this allows us to use our medications in a more intelligent way. We'll be using these type of tools in the phase II Cereno trial, as we'll mention later. If you could advance the slide. As I mentioned, we have a lot of drugs now to treat this disease. We have about 17 FDA-approved molecules. Again, the majority of these molecules mainly act by vasodilating the blood vessel. They don't actually reverse the remodeling that we see in these vessels, which is really what we need. If you can advance the slide. That brings us to the new era of pulmonary hypertension therapeutics, which makes use of a variety of different pathways shown here that not only vasodilate the blood vessel, but also rearrange those chemical signals to try to remodel the blood vessel back to its normal state. We do this by making use of these various pathways now. As we mentioned, one of the new directions that we're going in is with epigenetic modulation, and CS1 is really the novel drug in this pathway. Well then, making use of these various proliferative and vascular dysfunction and metabolic disorder pathways, there have been a number of drugs that have come to market and are being tested in this pathway if you could advance. This just shows some of the names of these drugs that have engaged in clinical trials, trying to remodel these blood vessels. As Björn and Sten mentioned earlier, sotatercept is one of the key molecules in this pathway. Go ahead and advance the slide. We haven't had all success in doing this with these vascular remodeling drugs, and many of these drugs shown here which had a lot of promise never really made it to market because they didn't do what we wanted to do. If you could advance the slide one more. The contenders now in this area of therapeutics that remodel the blood vessels that are currently in clinical trials are shown here. Manipulating the BMPR2 pathway is where sotatercept lies, and BMPR2 is a particular molecule that is underexpressed in patients with pulmonary arterial hypertension. Sotatercept actually works by increasing the levels of this and in doing so, remodels the blood vessel. We have other drugs like seralutinib and imatinib that are being delivered through aerosol. Then we also have drugs that elevate serotonin, which is another vascular remodeling chemical. If you could advance the slide again. This is where CS1 really falls into the play by being one of these key new molecules that regulate this proliferative process within the blood vessel. It does this through a variety of different mechanisms, and you can see that many of these mechanisms reflect the pathways that I showed you on that slide where we want to focus on pathways that actually remodel the blood vessel. So it has very potent antithrombotic activity, which is important because of the micro thrombosis that we mentioned. It has anti-inflammatory activity, anti-fibrotic activity, and all these actions allow us to reduce the pressure in the pulmonary artery. If you could hit the animation. That leads to our phase II trial using CS1, which we hope will be effective in subjects with pulmonary arterial hypertension. I hope that was helpful in kind of giving you the underpinnings of this disease. I'd be happy to answer any questions, if you have any at this moment. Thank you very much, Dr. Benza. Do we have time for maybe a question from the audience if there's anyone who wants to ask something. Well, I have one question. It might be a bit basic, but when you talk about reverse remodeling, and given that it's an epigenetic basis for this medicine, do you foresee a chronic treatment, or in best case, that remodeling would go so far as to allowing patients to go off the drug after a certain treatment period? You know, I think that this is a continuous disease. If we have medications that modulate this growth factor milieu and push the vessels back to a normal state, I think there will always need to be a chronic maintenance phase. I think what might be even more important is that we know a lot of the risk factors that develop this disease and using molecules like CS1 as perhaps a preventative molecule that could prevent the remodeling from occurring at all might be another avenue we might want to explore. The important thing to remember is that this remodeling occurs not only in pulmonary arterial hypertension. We just use this initial subset because it's the cleanest of all the subsets that we have with pulmonary hypertension. All forms of pulmonary hypertension, the blood vessels remodel in these ways. Extending drugs like this to other populations with pulmonary hypertension, I think, is also gonna be a very important avenue of exploration. Thank you, Dr. Benza. I'm afraid that's all the time we have. Thanks once again. Sorry, yes, it's the second presentation. Go ahead, Dr. Benza. No. Should we go directly into this part? I think this was scheduled for a little bit later, to going over the clinical trial itself, or are we doing that at this point? Well, according to the schedule, I think it's been moved to now. Please, Dr. Benza. Okay. Very good. If you will. Okay. Very good. Let me just throw my slide back on. Okay. So what I'd like to do now is talk to you a little bit about the design of our phase II trial that's utilizing CS1. If you can, advance the slide. This shows really the algorithm for which we are testing CS1 in this phase II trial. Now remember, our primary endpoint, as is the phase II trial, is really to look at safety and tolerability. We all will be looking at other variables that give us indications of efficacy, including the standard six-minute walk test, one of the risk scores that we mentioned earlier, the REVEAL risk score, as well as defining pharmacokinetics and dose finding based on changes in mean pulmonary artery pressure. This is a really neat part of the trial because we'll be utilizing the CardioMEMS device. The CardioMEMS device is an implantable hemodynamic monitor that I can place in the pulmonary artery that gives us real-time pressures in the artery so that we can see the direct response of CS1 to the changes in pulmonary pressures that it might create. By allowing us to do so, we can really find the optimal doses of CS1 that can remodel the blood vessels. We're gonna be enrolling 30 patients at 10 different U.S. clinical sites, and we hope our first results are in Q1 2023. As you can see on the bottom of the slide is the paradigm for study. In the screening phase, patients will undergo the CardioMEMS implantation, and this is a very simple implantation that we do through a right heart catheterization procedure that adds about 10-15 minutes of the study in which we release the hemodynamic monitor into the pulmonary circulation, and it remains there indefinitely. The sensor is activated by radio frequency waves that allows us to develop pressure signals from an external antenna that we can read very easily. We allow the CardioMEMS device to sit in place for up to six weeks. We go to our randomization portion in which we randomize to 1 - 3 doses of CS1, either 480 milligrams, 960 milligrams, or 1,920 milligrams. Our follow-up period is around 12 weeks, at which we will be taking constant measurements with the CardioMEMS device as well as assessing other clinical variables. If you can advance the slide. We presented this very innovative study design at the PVRI Congress, and it was very well-received. We had abundance of questions and a number of people around this presentation. One, because we're using a very novel drug, CS1, but also because of the very innovative endpoints that we're using, including risk scores, Cardiac MRI, as well as the CardioMEMS device. If you could advance the slide. We've enrolled our first patient, and they've entered the study's treatment period. This gives you just an update on the study itself. Our first site was activated in March. We screened our first patient in July. We randomized our first patient in August, and then we'll continue to activate clinical sites throughout the remainder of the fall. As I mentioned earlier, our top-line results are expected in quarter one of 2023. If you could advance the slide. Now, the really, again, innovative thing about this study is not only the compound, but also, the novel and innovative endpoints that we're using, including the REVEAL risk score, which I outlined to you before. Cardiac MRI, which is the single best marker for looking how the right ventricle adapts, to pulmonary pressure. The implantable CardioMEMS device, which allows us to look at pulmonary pressures every day without the need for another right heart catheterization, as well as some very novel biomarkers, that tell us, a little bit more about the mechanism of CS1's activity. We'll also be marrying these with traditional endpoints that we commonly use in pulmonary hypertension studies, including six-minute walk test, echocardiogram, and standard biomarkers. If you could advance the slide. What I wanted to show you was kind of the interesting thing about using the CardioMEMS device. In this slide, you see really the progression of disease in patients with pulmonary arterial hypertension. You can see where the various things that we measure to look at disease progression or regression along the top part of this triangle. You can see things like NYHA symptoms. I'm sorry, if you can go back, just stay on this slide. You could see that symptoms and physical exam changes in weight, so very late manifestations of disease progression right before someone is hospitalized, whereas risk scores allow you a little bit more forward window into determining progression. What really gives you a key insight and a very early warning of progression is looking at changes in hemodynamics, which occurs really at the apex of this triangle. Looking at hemodynamics using the CardioMEMS gives us a huge gain in time of how this disease progresses. Now you could advance. This slide shows how we usually measure pressures, and it's using right heart catheterization, which is this yellow tube that's inserted into the pulmonary artery, which is a fluid-filled catheter. It allows us to measure pressures. Unfortunately, this is the gold standard for doing this, but it is an invasive procedure. It only gives us a single snapshot in time as to what the pressures are. It only can be done in a supine at-rest condition. If you could advance the slide. That's where this implanted sensor, the CardioMEMS really comes into play. This is just a picture of that sensor shown here. That sensor is about the size of a dime that can be inserted very easy into the pulmonary artery. If you can advance the slide to the last one. This is the kind of measurements you will see from the CardioMEMS sensor. That upper panel, which has the red, blue, and green line, are actually the depictions of the pressures in the blood vessel. The red is the pulmonary artery systolic, the blue is the mean pressure, and the green is the pulmonary artery diastolic pressure. You can see how these pressures change in time as I add therapeutic agents to that depicted by the thick blue vertical lines. You can see how with the addition of three medications that this person's pulmonary pressure really came down and responded to that. The bottom panel also gives you an idea how the right ventricle is responding to this disease process by allowing us to look at the stroke volume, which is shown in black, the peripheral resistance, and also the cardiac efficiency. This indwelling hemodynamic monitor really gives us a lot of information of how CS1 will actually work in these patients, and really gives us an adequate timeframe of how the drug will work over time. That's the end of this particular presentation. Thank you again for your listening. Well, thank you again, Dr. Benza. Right. So do we have a question from the audience regarding the phase II trial design? I'll check if we have any questions to Dr. Benza from the web. Well, I think we have a couple of questions here, but we can take them during the final Q&A. With that, thank you, Dr. Benza. Just a sec. Is Dr. Benza available at the final Q&A? Otherwise, it's now. Right. Well, we don't have any questions from the audience. Okay. All right. Well, we have one, please. No problem. Given the tissue changes with these patients, is really, 12 weeks a sufficient long treatment period to, conclusively see effect of this treatment? I believe so. When you look at the majority of the clinical trials that we've done in this disease state, including with some of the newer vascular remodeling drugs, we begin to see effects in the vasculature at around eight weeks. 12 weeks gives us an additional four weeks to notice these changes. Remember, we will have the CardioMEMS device in permanently in these patients, so we will even be able to see changes and response to this drug up to 52 weeks, if we need to. We should be able to start seeing these remodeling effects by 8-12 weeks. Is that, does that answer your question? Right. Very well. Since we don't have any further questions, thank you, Dr. Benza, for an excellent presentation and. Thank you. Lots of insights. It's time to move on in the schedule. Dr. Benza mentioned the MEMS, and now I have the pleasure to welcome Dr. Phil Adamson from Abbott, who'll talk more in depth about your new device. Thank you. Thank you very much. Can you hear me okay with this microphone? Good. Well, thank you for the opportunity to be here. I'm very excited to share about CardioMEMS and the general collaborative efforts that we have at Abbott with Cereno. I am the Chief Medical Officer of the Heart Failure Division at Abbott, and I'm very proud to be here to talk about the CardioMEMS heart failure system. First, let me start with just describing in detail what Ray mentioned in his talk. First, the system itself is comprised of three specific pieces. One is the implantable sensor, which is a micro electromechanical system. That sensor then is interrogated by what we call a patient electronic system, which is essentially a radio frequency antenna on which patients lie every day to upload the local information in the pulmonary artery pressure information in the pulmonary artery to a website, which is the third piece of this system. The website then graphically illustrates those pressure values, and I'll get into some details about that acquisition in just a moment. But the graphic representation of those details are what the practitioners look at as they are managing patients currently with left heart failure. What you see here is essentially the three components and what we do first is implant as Ray mentioned, the sensor in the pulmonary artery. This is a very simple transvenous approach, right heart catheterization, either from the right internal jugular or the femoral vein. That approach then allows a transcatheter delivery over the wire of this device. The target vessel for the device is an important vessel to evaluate, so an evaluation with a limited angiogram is performed, and a wire is advanced into the target, and then the device itself, the sensor is released off the end of a catheter and over the wire catheter. The vessel size is important. The device is implanted in a blood vessel greater than 7 millimeters, because over or under sizing the vessel can affect the longer term reliability of the device. We have now implanted over 30,000 PA sensors in patients around the world, primarily as I'll show you with the current indication in just a moment, in patients with heart failure. This device is remarkable, but it does upload digital pressure waveforms. This interrogation sequence generally is about 18 seconds long and daily performed by the patient from their home, and that 18-second acquisition is sufficient to obtain pressures over at least two cardiac or respiratory cycles. That's important because respiration changes the pressures inside the thorax, and if we aren't able to sample at least two of those, we may get the wrong impression as to what the daily pressures are. The patients upload daily primarily to develop a trend over time, and that's the trend analysis that's displayed on the website is what is used for medical decision-making. That medical decision-making is, are those pressures higher or lower than what the target vessel or target pressure would be and what the ranges of those pressures would be. A high fidelity digital acquisition of pressures from the patient's home at any time the provider or the patient wants to upload those. Typically, that's once a day. Medication adjustments then are used to control those pressures. In left heart failure, that typically controls congestion, which is responsible for 91% of the hospitalizations for that disease. Now remember, we've talked about the global impact of cardiovascular disease. The end stages of heart disease, heart failure, are when the most expense occurs. Typically, patients with heart failure are hospitalized multiple times for recurrent congestion events that makes it very difficult for them to breathe. It's an emergency. It requires intravenous rescue therapies, and those intravenous rescue therapies must be delivered almost always in the context of a hospitalization. In the United States, the most common reason for Medicare beneficiaries to be hospitalized is congestive heart failure. You can see that one major cost center associated with this disease is hospitalizations, and that's where we started with the development of the CardioMEMS heart failure system was to understand how these pressures could help us understand when patients are changing because as Ray mentioned, pressures change long before patients understand that they're having a problem, and this becomes a very important cue for us to guide the therapies for heart failure. Let's look at this sensor because every time I look at this is really remarkable. The physics of the sensor are described as a micro electromechanical system. These sensors are ubiquitous. They're in your automobile, your cell phone. The consumer use of MEMS-based systems is far outweighs the medical application currently. It was developed, the hypothesis was developed that if we could make this miniaturized and could make it safe to implant, we would be able to utilize this in medicine, and that's what we did with the CardioMEMS heart failure system some years ago. I'll briefly tell you how this works and not pretend to be a physics expert, but essentially, the radio frequency energy is taken up by the gold rings you see in this sensor, and those gold rings serve as an antenna. The radio frequency enters that antenna and is passed through the capacitor, the dark part in the middle of that sensor, and as it passes through, it re-emits that radio frequency. Now that radio frequency is changed in a linear fashion based on the pressures that are on the capacitor. You see that relationship illustrated by this graph, and if you wish to use the formula, there's the formula. I won't go into that. Essentially, that gives us the local pressures. In a very high frequency-initiated interrogation, one can now create a pressure waveform by drawing essentially the pressures at given time. Each point on these waveforms is a pressure. The mean pressure obtained by the CardioMEMS system is actually an average of all the measurements in that waveform. Again, we do that for 18 seconds, all those measurements are then averaged and that's what patients upload. As Ray mentioned, previous work, we have traditionally developed an algorithm clinically to manage patients based on changes in weight since development of symptoms and have thought that if we could frequently assess the patients, we might be able to capture changes that might lead to an avoidance of hospitalization. Now, that has never worked. In multiple clinical trials, evaluation of early detection of symptoms and weight changes simply is a clinical oddity. It's done all the time, but it simply does not work. The reason is that most of the things that predictably change as patients progress from hemodynamically stable to hospitalization with left heart failure occur when patients don't have symptoms, and their weights don't change. When we have continuously monitored patients, we have seen over time, again, predictable events occur both from an autonomic control of the heart as well as in intrathoracic impedance changes. The first lesion that causes this disorder and progression is hemodynamic embarrassment. We have now evaluated that in about, over 8,000, nearly 10,000 patients studied in clinical trials and with remarkably consistent results regardless of the trial design, including two prospective randomized clinical trials, the last of which was reported this last year, GUIDE-HF, as another consistent, significant impact on reducing hospitalizations. That's where we started with this sensor. What we discovered as we went along was that here is our indication, and certainly this is what we've proven effective is using the CardioMEMS heart failure system in the United States is indicated for patients with heart failure, certain symptoms, either previous hospitalization or biomarker evidence of congestion. In Europe and CE mark countries, it's still Class 3 patient, our initial and original indication, Class 3 patients in a previous hospitalization. You can see that this was focused on trying to prevent hospitalizations. The most exciting part about our collaboration with Cereno is not only the collaboration between two companies, which sometimes is difficult to do, but also the collaboration we see with the United States Food and Drug Administration. What we have seen is that the drug side of the U.S. FDA, or the Center for Drug Evaluation and Research, have collaborated with the device side such that they can now, they have agreed to regulate CardioMEMS in the context of the IND, or the drug evaluation on the drug side. The device side of the FDA will evaluate the safety of CardioMEMS in this population, using the IND that's established with Cereno. What do we all get out of this? It's a win-win situation obviously because the novel evaluation of this drug is now, for Abbott, an opportunity to evaluate safety in the population. Our hopes at the end of the day will be for us to have a new indication for this population for CardioMEMS. The way we'll use this in the clinical trial is shown in this slide. You've seen the upload and download of information. All centers that we've chosen are centers that have used CardioMEMS and have active pulmonary arterial hypertension clinics and expertise in that area. Both sides of that story are covered with expertise. Patients will upload daily from their home, and then while the drug is being titrated, data will be continuously measured and recorded, but investigators will review that twice a week, and then effectiveness will be described as a secondary endpoint by its effect, the drug's effect on the targeted lesion, which is the pulmonary artery pressure. What we have discovered since we have focused on reducing hospitalizations is that the patients that we study to reduce hospitalizations have a very high prevalence and a high pretest probability for the presence of significant secondary pulmonary hypertension. That's World Health Organization Group 2, as Dr. Benza mentioned, very prevalent, most common cause of pulmonary hypertension, and you can see in most of our clinical trials we see a very high prevalence. In the latest trial, These are all patients with Class 3 symptoms. We thought in our latest trial it would be great opportunity to see that less symptomatic patients certainly would have different profiles of their pressures. What we found in fact was that regardless of symptoms, Class 2, 3, and 4 the pressure profiles for those patients were very similar. In fact, 82% of the patients who had Class 2 symptoms, so these are symptoms that come into play with moderate exertion, already had secondary pulmonary hypertension, 80%, 82%. The novelty of these findings is that this very widely prevalent disease called secondary pulmonary hypertension is in need also of new drug therapies because as the pressure on the right ventricle in this disease causes right ventricular dysfunction, what you see is that the presence of secondary pulmonary hypertension with right ventricular dysfunction is a death sentence. Mortality increases exponentially. This is a very significant need and certainly one we've discovered is much more prevalent than maybe we've thought in the past based on intermittent right heart catheterizations. How do we look to the future? We look to see that possibly we're unifying the impact, the understanding the impact of pulmonary hypertension moving from a heart failure diagnosis or any diagnosis that leads to pulmonary hypertension. We know that in heart failure, pulmonary hypertension worsens and progresses without producing symptoms. It only produces symptoms, not only, but most of the time produces symptoms when the right ventricle starts to fail. Our next adventure is starting now with the Sorrento collaboration because what we want to understand is when does right ventricular uncoupling from the circulation, when does right ventricular dysfunction occur, can we now identify patients at risk for that to happen before that happens and prevent their progression on to right ventricular failure? This is a very exciting time for us to collaborate on this adventure, and we're very pleased certainly to be involved in this clinical trial. Thank you for your attention, and we'll have some discussions when we're done. Thank you. Thank you very much. It's time to yet again welcome, Dr. Björn Dahlöf, who will talk about CS1. Welcome, Björn. Yeah. We have heard a little. Maybe that one will work now. Oh, yes. You gave it to me. Okay. Now, you heard a little about CS1. CS1 is a development, a formulation that we have worked quite a lot on. The basic active substance is actually quite well known since before. It's valproic acid. That has been in man for example, epilepsy for more than 50 years. It was quite late discovered that it was an HDAC inhibitor, and that could have other very beneficial effects. The effects are listed on the right. You've heard about some of them, but there are more. This is one of the most widely researched HDAC inhibitors, especially in cardiovascular, and it has a profile that makes it possible to give for these kind of diseases. It have, for example, no QT prolongation, which many other HDAC inhibitors have. It's a whole host of epidemiological studies that indicate that patients with this treatment can have beneficial effects on MI and stroke compared to both other treatments of epilepsy and populations of similar characteristics. We reformulated this into a very innovative delayed immediate release formulation, which is now protected by three different patent families and has orphan designation for PAH. As Ray says, there are several established drugs in pulmonary arterial hypertension. You have the different classes here. Basically, what they do is vasodilate. They don't really affect the real progression of the disease. There is, of course, some remodeling from reverse remodeling from the pressure reduction. The real core is the so to say almost cancerous-like proliferation in the vessels that comes from the cause of the disease. That is what we think with this kind of therapy that CS1 represents. HDAC inhibition with epigenetic modulation could be a disease-modifying therapy. This epigenetic modulation, you have seen this before. Raymond Benza used it also to give the example of that epigenetic modulation is in the forefront of the new drug developments. The unfolding of the DNA to be able to transcribe the right factors to get your effect is very important. The rediscovery, which we alluded to from the beginning, was that Sverker Jern and his group discovered that VPA could, through epigenetic modulation, increase the tPA production and storage in the vessel wall, meaning that you could improve on the endogenous fibrinolytic capacity, which in itself is an antithrombotic way of a way to create an antithrombotic effect. If we look at, for example, the VPA in the epigenetic context, it has been researched, and I just show one type of review here showing that VPA goes into several of the very important pathogenetic steps in the development of the disease, both on the vessel level and the right ventricular level. What we have are two different HDAC inhibitors. CS1 we now have in phase II in the study that you have heard from Ray described. We have a runner-up, which we will hear more about later from Professor Mike Holinstat. I think this is very exciting times for us. As Sten mentioned, this is a busy slide, and it's not for reading in detail in this projection. It's just to make a comparison with sotatercept, which has been seen as a benchmark in terms of an innovative drug for PAH. We have compared preclinical data for VPA and for sotatercept, and we find that for most actions, they all have very similar data, both reduction of pressure, reverse remodeling, anti-fibrosis, anti-inflammation. There is one difference, that is no antithrombotic activity documented with sotatercept. To make it simple for you, I just made this simple schematic, and you can see that the antithrombotic is a real difference, and also that this drug is given subcutaneous every three weeks, and it has dose-limiting problems. They cannot use the same high dose as they've done in the animal research, and that could probably have some impact on the future development. To put CS1 and sotatercept in a context, I'm not going to go through this for obvious reasons, but I want to make two points. One is that all the therapy you see above CS1 here is the established therapy, and that established therapy has basically no effect on reverse remodeling or fibrosis or inflammation. While the new developments like CS1, the sotatercept, and some other drugs all claim from animal research this capacity of reverse remodeling, but none of the developments have this antithrombotic activity. You heard Raymond Benza say very clearly that the thrombotic component, especially later in development of PAH, is very important because it clogs the vessels. This is what we have, and we believe that we have, with CS1, an epigenetic modulator, an HDAC inhibitor with potential of reverse remodeling and disease-modifying capacity through these different modalities that really fits like five fingers in a glove. As Ray said, this has to be tested, and you have heard how we're going to do the first test. There's more to it. If you remember, I showed that VPA and HDAC inhibition have many more potential effects. There is a very interesting article published last year in The Lancet, showing the broad-spectrum therapeutic potential approaches with HDAC inhibition in cardiovascular disease. I did a literature review some years ago and found that if you listed the potential indications, as you can see here, it's really a whole host. Of course, for a small company like us, we cannot have development in all of that. It gives us very good feeling that this is something, an approach that makes a difference in the cardiovascular field. Just two examples before I finish off is that this is the study which is the proof of concept in mice showing that we have an antithrombotic effect that is very clear without bleeding. Another very important aspect for the treatment, one of the biggest indications for NOACs and antithrombotics is atrial fibrillation. This is a model of transgenic mice showing these are prone to atrial fibrillation and thrombosis of the atrium. With VPA, it was shown that you could reduce the fibrosis, you could reduce the size of the atrium, you could prevent development of atrial fibrillation and reduce the thrombus formation in the atria. Really what you would like to see for the treatment of or prevention of stroke in atrial fibrillation. Of course, for us as a company, this is a very wide range. You have heard that we are in PAH in phase II. Of course, some other lower hanging fruit is if development of something for thrombosis, venous thromboembolism, or for prevention of stroke in atrial fibrillation or secondary prevention in AMI or stroke. We cannot do everything. We have not decided exactly what we are going to do with our preclinical assets. When you have seen the data that Mike Hollenstadt will present, I think you will also start to think about what are we going to use this for. I can tell you this is very nice days for Cereno because the results, I think, are spectacular. Thank you. I actually can introduce myself for the next, because I'm just going to introduce Mike with three slides. That is, I think in the interest of time. Mike is our director for translational research. He's a well-renowned researcher at University of Michigan. He has a facility that is fantastic with. He can do almost everything in his lab, it seems. He will tell you about some things he have done so far. Linked to the lab or linked to the university is a huge preclinical facility for all kinds of experiments where, for example, his friend Andy White is situated, a molecular wizard, you could say. He has been with Pfizer before, has been part of or behind Lipitor, which is probably one of the most sold drugs in the world. I think that this creates for us a huge opportunity to be linked to this fantastic facility. CSO 14 we acquired from Emeriti Bio. Again, very skilled molecular chemist. They have been part of development of Nexium, for example, which is the follow-up to Losec, also one of the most sold drugs in the world. Been part of evaluating this and then starting a full preclinical program. We have nominated the drug candidate out of those data, and we hope we can be ready for start of phase I in 2023 or at least have an approved IND at that time. CS585 is really novel also because that's an innovation from Mike. He will tell you more about that. But we as a company have acquired the rights to license this if we after 24 months of development and documentation like it or think it's worthwhile to continue, we have a right to license it in with worldwide rights. That we think also will happen in 2023, and then we can go into man. Mike is going to tell us about those data and a little more, I think. Thank you. Now it's. I think you should. Yeah. Properly introduce Mike. Well, it's the Cereno way to do it by the book, right? Yes. We're moving forward, progressing here in our schedule. We are very pleased to welcome Dr. Michael Holinstat, who will talk about the preclinical pipeline. Please, Michael, come up. Great. Thank you for the introduction, and thank you Björn for the very nice words. We're very excited about the preclinical program that we're working with Cereno. First I'd like to talk to you about CS585. Then we'll follow that with a advancement of CS014. CS585 we view as a first-in-class target for IP receptor prevention and thrombosis and without the risk of bleeding. We view it as a first-in-class because while many have tried, no one has yet succeeded in utilizing IP receptor agonism as an antithrombotic agent in the clinic, and there are a number of reasons for that we can go into. This is the facility we work in with a lot of resources, as Björn mentioned, to enable us to develop from early preclinical all the way through man. These are my COI. When we think about thrombotics, we need to think, where is the space we're working in? This is the vessel, and what you can see in the vessel, you have hundreds of times a day, you'll have microvascular insults. When those insults occur, blood will leak out of the vessel. Very quickly following leakage, platelets will form a plug along with fibrin, allowing the blood to stay in the vessel, minimizing bleeding and maximizing delivery of oxygen to tissues downstream. This is essential in order to maintain a healthy heart and a healthy brain. When, however, we have pathophysiological conditions, here I'm showing a pathophysiological condition such as atherosclerosis, when you get an injury, you'll get that same initial hemostasis, but very quickly, the clot will continue to expand until the point in which you get occlusion of the vessel. At that point, there's no more blood flowing downstream, no more oxygen, and in the heart, we call this a myocardial infarction, in the brain, we call this stroke. Recognizing that the platelet is a first-line therapy in cardiovascular disease, the pharmaceutical industry has spent a number of years developing interventions directly targeting the platelet. What you see here are some of those targets. The alpha IIb/beta 3, the integrin receptor, activation has been targeted with oral, with IV drugs, such as ReoPro and Tirofiban. If we think about the COX-1 by using aspirin to block COX-1, you're gonna prevent thromboxane formation, which was gonna activate platelets through the thromboxane receptor on the surface. P2Y12 is another target. P2Y12, clopidogrel you might be familiar with, has for many years been the second leading selling drug in the world, peaking out in its last patent year at about $14 billion a year. Then more recently, the triple antiplatelet therapy target of PAR-1, one of the thrombin receptors. All these have resulted in a significant decrease in morbidity and mortality of about 26%, but that's come at the risk of bleeding. We know that even with these interventions, the rate of morbidity and mortality is about one in three people will die of a thrombotic or cardiovascular event. We need to do better, but we need to do better in a very focused way. New therapeutics need to continue to decrease the risk of having an occlusive thrombotic event, but they need to do this not at the expense of bleeding. This is where we think CS585 has a superior advantage, and I hope to show you some of this. Where did CS585 come from? We initially had conducted a screen to look at and take advantage of the lipids in the platelet. We know that the lipids in the platelet membrane, when they're oxidized, form bioactive lipids or oxylipins. These oxylipins can feed back onto the platelet and towards new platelets to regulate their ability to become activated. We did an initial screen and looked at these fatty acids and their oxylipins, and we were able to identify a single oxidized lipid, 12-HETE, which comes from one of the fatty acids. 12-HETE, when given to human blood, shown here, inhibits its ability to activate the platelet to form an aggregation. We then turned to mouse, and we injected 12-HETE into the mouse vessel and used an in vivo intravital microscopy, fancy way of saying that we're looking at the vessels in real time and looking at a clot that forms. You'll see platelets forming in green at the site of injury and fibrin in red. When we use a laser injury to induce an injury in the vessel, you can see that in control mice in the top, you get a nice platelet clot that forms with fibrin underneath. In the bottom, in the vessels that have been treated with 12-HETE, you have very little clot that forms. However, you still get a fibrin. This tells us that we were maintaining a coagulation pathway and not getting into the high bleeding risk area, but we were preventing the platelets from forming what could be an occlusive clot. In the animal model, to prove this was an IP receptor, we used animals that did not have an IP receptor, IP knockout animals. What you can see in the bar graphs, when IP receptor knockout animals were treated with the 12-HETE, you completely lost any ability to inhibit. This told us that it was highly selective. Then in the bottom, VASP, this is just a biomarker in the cell that told us we were actually activating this pathway. We've then went and needed to show selectivity. If you look at the graph here, what we're really looking at are all the receptors on the platelet that signal through a similar mechanism. We wanted to know, are we really just looking at a nonspecific effect or something that really targets the IP receptor? What we showed, and this is published in Blood Advances, we showed that in fact only the IP receptor was regulated through this, through that 12-HETE. We then knew we have an endogenous metabolite that selectively signals the IP receptor in the platelet and regulates thrombosis and hemostasis. We were then able to take advantage of that and move into the therapeutic stage. Working with my colleague, Andy White, who Björn mentioned previously, we developed a therapeutic that mimicked CS585, that mimicked 12-HETE. We call that CS585. We're starting with human blood, so I will try to really keep you informed when we're moving back and forth between human and animal. It was really important to know that this really works in the human blood, as that really sets us up in a developmental aspect. At much more advanced stage than starting with cells in animals and then eventually hoping that it works in human systems. What you can see in human blood, we've looked at VASP phosphorylation. Again, that biomarker that tells us that we're hitting the receptor, and we wanted to know potency. How potent is CS585? If you look at the graph, you see that we start to see VASP phosphorylation in as little as 10 picomolar of drug. Really potent. In comparison, if we were to look at iloprost, one of the leading FDA-approved IP agonists, you only hit the IP receptor at about a nanomolar. We're about 1,000-fold more potent. We then went to flow cytometry to look at the platelet surface. We said, "Are we modifying the integrins? Are we regulating granule secretion?" Granule secretion is what's going to recruit those other platelets in. It releases all the small molecules, and it puts P-selectin on the surface of the platelet to make them sticky. What we show here is that PAC-1 is an antibody for integrins. We completely block integrin activation. Imagine those αIIbβ3 inhibitors that I mentioned at the very beginning that were state-of-the-art about 15-20 years ago. CD62 is an alpha granule marker. It's for P-selectin. P-selectin is what is going to make the platelets sticky and activate to bind to immune cells and endothelium. CD63 is a marker for dense granule secretion. That's what releases into the blood ADP, ATP, serotonin, all the small molecules that are going to recruit more and more platelets to that site of injury. We showed CS585 attenuates all three of those aspects. Then we looked at dose response. Does it really work? This is all again in human. We looked at collagen. What I don't show here is we've also looked at thrombin. We see at nanomolar levels, you completely block platelet activation and aggregation through both of the major pathways in the blood. We then wanted to go back and look at selectivity. Did we lose selectivity when we went from an endogenous metabolite to a drug? Which can happen. What we show here is pharmacologically, still in the human, that if we block the IP receptor, if you look at the top left, you block all ability to inhibit platelet aggregation. However, if we look at the other receptors in the human platelet that would move through the same pathway, the other prostaglandin receptors, the DP1, the EP2, the EP4, none of those had any effect on the ability of CS585 to inhibit platelet aggregation. This, again, is a differing point from CS585 and the prostacyclin receptor agonists that are currently on the market, many of which are known to target receptors other than the IP receptor. Finally, we wanted to look at potency in vivo, so we go back to the in vivo system. What you're looking at here on the left is an animal not dosed with vehicle, and on the middle and right, animals dosed with two different doses of CS585, 3 mg per kg and 6 mg per kg. What you can see on the bottom are reproducibility curves. Each one of these conditions was repeated in at least 40 different vessels. What you can see is that even at one mg per kg, you significantly inhibit the clot formation. What's really key, we don't affect fibrin. Here we are differentiating. We are affecting platelet accumulation without affecting fibrin. We then move to large vessels, carotid artery. In the carotid artery, we denude. That means we remove the endothelium of the carotid artery, using iron chloride, and we look at animals dosed with or without CS585 to determine how long does it take for that vessel to occlude. This mimics a major injury. What you can see in control conditions, in about 12-15 minutes, you get full occlusion of the vessel. If we look at dose dependence, we went from 6 mg per kg down to 0.1 mg per kg. You see a significant delay in the ability to form an occlusive thrombus. Not only small vessels, but large vessels also show a propensity to be spared from occlusive thrombosis following injury. Finally, we went to bleeding. Bleeding matters. As I mentioned at the very beginning, we can have the best antithrombotic in the world. If it causes bleeding, it's not gonna move forward in development because of risk. We looked here at thromboelastography. This is an assay where we look at whether the intervention is gonna alter coagulation. You see that in our control conditions, versus CS585, the time to clotting does not change. It's not affecting coagulation. However, if we treat the blood with rivaroxaban, a well-known factor Xa inhibitor, you significantly delay the ability of a clot to form. This holds true to what is observed in patients as well as the clinical data, and very importantly, if we give CS585 on top of rivaroxaban, there's no additional defect in coagulation. We shouldn't expect any additional risk to bleeding to give a compound such as CS585 to a patient who would be on a factor Xa inhibitor such as rivaroxaban. What's not shown here is we've also done tail bleeding in the mice, and tail bleeding assay where you resect the end of the tail and you measure the amount of time it takes for the bleeding to cease. We see no difference in tail bleeding time between CS585 at low or even high doses compared to control conditions. I would say that selexipag is a potent and selective inhibitor of platelet activation through activation of the IP receptor. CS585 is also selective, potent inhibitor, and it is stable in the human blood. It's stable in the mouse blood and stable in the human blood. That its potency is between 1,000-100,000 more potent than the endogenous ligand that it was designed as a mimic to, and it doesn't result in bleeding. I would purport that this is our new model, that CS585 through activation of the IP receptor will be an extremely effective and potent mechanism by which to limit platelet aggregation, maintain hemostasis, so we don't bleed, but prevent thrombosis clotting. With that first part, this is the group that really helped develop this. This is our team, and the original work was done in collaboration with Andy White and Cereno Scientific and University of Gothenburg for the development of CS585 as we moved forward. Should I move right on to the second? Okay. All right. Our second compound, and again, we're really excited about these two different approaches because they give us different aspects of regulation in the blood. CS014, we engaged with Cereno to identify if it could be utilized as a novel HDAC inhibitor that would regulate platelet activity, fibrinolysis, and clot stability. First thing we did was we looked in vivo at the ability of CS014 to regulate clotting in the blood. Now, that's a different approach. Because this is an HDAC inhibitor, we're not just acutely dosing it. We dose this for five days, and the animal will allow the genetic program reprogramming to take place and then conduct the injury. What you can see is CS014 at 100 mg per kg was able to regulate clot formation as well as fibrin. This is where it again differentiates from CS585. You have a significant decrease in fibrin formation, as you can see on the right. It's important to note, while we show 100 mg per kg here, we've done multiple dosing regimens of CS014, and it is effective at many doses below 100 mg per kg. We went to carotid artery occlusion, and in carotid artery you see a significant increase. We moved from 15 minutes average clotting time to 25 minutes average clotting time. But what we really need to note here is the 30-minute. 30 minutes is a time point by which we ethically need to stop the experiment due to pain and suffering of an animal bleeding out. All those green dots on the CS014 that say 30 minutes are 30+ because that's the point at which we stopped the experiment. It's likely much more than one star if we were to allow the experiment to go to fruition, but due to ethical considerations, one would stop. The point is made, you get a significant delay in occlusion. We then went to what's called a saphenous vein rebleeding assay. This serves several purposes. One, it allows us to look at bleeding beyond the vessel in an animal. It's a low shear, low flow system. It's a vein. We can start to think about disease intervention treatment in not only the arterial side but the venous side, DVT and VTE and such. What we see, what you're looking at on the left are the black lines are platelet accumulation when we puncture the vessel. We're using a laser to puncture the vessel. We've all always done this with a needle. We're puncturing a hole in the vessel, and you can see immediately platelet accumulation occurs. We wait five minutes, and we puncture the hole in the same place again. We wait another five minutes, we do it again. This is because often during in the biology in the vessel, that clot that's starting to form can be ripped off by the flow. That's what we call it a rebleeding assay. You can see on the right in the black, you can see at every point in time when we punch that hole in the vessel. Along with platelet activation, you're getting fibrin formation. Now, if we look at the animals that were treated with CS014 in the green, you see that you get no platelet activation in the flow system. In the venous flow system, when we punch a hole all the way into the vessel, platelets aren't forming. When we look at the fibrin side, there's no fibrin being formed. Again, this is, these are highly significant data and highly reproducible. We then went and looked at tail bleeding time, and we see no tail bleeding, increased risk of diathesis or increased risk of bleeding when the animals were dosed with CS014. We think a lot of this has to do with the increase in tPA and the decrease in PAI-1. You're changing the genetic program in these animals. We went and did thromboelastography. Unlike the CS585, which was TEG in human, this is TEG in mouse blood. Again, it's whole blood for animals that have been treated for five days with the drug, and we take the blood out and we assess its ability to alter coagulation. You can see that CS014 doesn't significantly alter coagulation, whereas rivaroxaban again does. Rivaroxaban plus CS014 had no increased risk of altering coagulation over rivaroxaban alone. We were able to conclude from these studies that CS014 is a novel HDAC inhibitor. It's effective in both small and large vessels for inhibiting not only the clotting but fibrin formation. It does not seem to increase the risk of bleeding, and we were able to show that by no difference in bleeding time, no difference in thromboelastography, and no additive effect of CS014 in the presence of a known bleeding agent, factor Xa inhibitor rivaroxaban. We can start to think about CS014 as a new class of inhibitors for prevention of platelet activation. There has never been an HDAC inhibitor to date that has really gone through a clinical program for thrombosis. We can start to think about this for myocardial infarction, for stroke, and then we can also think on the venous side, possibly for DVT and VTE. These are just some of the potential pipeline targets one could think about for a novel HDAC inhibitor in addition to, obviously, PAH, which thrombosis plays a major role in regulating. CS014 represents a potential new drug class for prevention of thrombosis without increased bleeding. With that, are we taking questions now, or do you wanna... Thank you very much. Thank you. Perhaps you could stay here, and I would like to welcome Björn Dahlöf and Phil Adamson up here, as well as Dr. Gunnar Olsson. All standing around me. Perhaps you could, Also we have- Jätterum and kätterum in Swedish. If you could stand around this table, please. Okay. I will stand there. Okay. Should we start singing? All right. Yeah, sure. Well, we have a very distinguished group of researchers and professionals here. I would like to start off with a simple question. We're here at Cereno's Capital Markets Day. What's making you excited about Cereno? How come you decided to join this venture? Perhaps Gunnar? What makes me excited, that is really the three projects. Of course, in the PAH, we know the medical needs. Having a molecule with so many different effects in this complicated disease pathophysiology seems very exciting when we see that present drugs, both in development and those that are marketed, are mainly focused on one of these effects at the time. Having a molecule that does most of it will be very exciting to see the clinical results when they come. The two preclinical molecules, I think that they are really exciting. I've been in the development of antithrombotics since early 1990s, and it's very evident that we have very effective antithrombotics in the NOACs and in the antiplatelets. However, almost all patients will at some time have bleeding problems. Having new, better antithrombotic drugs that really have the same or even better efficacy and at the same time reduce the bleeding risk, that is a very, very important step on the journey to further improve medicines in the area of antithrombotics. I think that is really exciting. All right. How about you, Michael? Would you agree with Gunnar that, sort of multiple mode of action is what truly sets Cereno apart or and the pipeline? Oh, absolutely. It's been very challenging in the thrombosis world to develop new targets without that increased risk of bleeding. I think identifying two targets and really being able to show that neither one causes bleeding and that they might be used in complementary fashion, either with each other or with NOACs or other avenues, really opens the door for Cereno as being unique. Right. That's very interesting because, from a layman's perspective, it seemed like there was a bit of a paucity in new drugs within the cardiovascular field, and all of a sudden there is lots. I mean, we saw a slide earlier where there were several current new drug in phase II, even phase III. Has there happened anything in the market? Maybe a better understanding of the disease panorama that has sort of led to a better platform and then leading to new drug in the pipeline? Gunnar, do you have any- I'll try to give you your response. I think that looking back the time I've been in pharmaceutical world, and that is since the late 1980s, the interest in different disease areas is a bit cyclic. I think that over the last 10 years, we've seen the shift over to more oncology. I sense now that the oncology interest is or has peaked. Maybe new discoveries like the one we're discussing here, as well as other things happening in the cardiovascular arena. I'm thinking about the SGLT2 inhibitors, the Factor XI inhibitors will shift back. So I'm not so surprised. But of course, what we need to see that is that all the very fascinating effects that they can translate into the clinic. Now, in my working life, I've been developing drugs all from antithrombotics to antihypertensives to antidiabetics to lipid-lowering. Looking at all these type of areas, I think that one of the areas with best translatability from animal to man is actually the thrombosis area. I think it's very exciting, even if we only have animal data at this point in time. Right. Lars, sorry. Sten. We have also Raymond Benza for the Q&A. He's on the TV now, so. All right. Okay. Yeah. Great. I will definitely come back to you, Dr. Benza. I think Björn wanted to add something here. Well, I just want to say, I mean, I've been in cardiovascular drugs for 40 years. I mean, in parallel with Gunnar. He's in the company. I've been out in the clinic. I've made a lot of research in this, but it has mainly been in the areas of risk factors and trying to manage risk factors like lowering blood pressure, lowering blood sugar, lowering lipids, and so on. But I think what we are seeing now is that we have a much more fundamental approach to the pathophysiological process with anti-inflammation, anti-fibrosis, antithrombosis, which goes to the heart of a whole spectrum of cardiovascular diseases. I think that sparks new interest in the area as well. Yeah, like truly disease modifying. Yeah. Did you want to add something too, Michael? Yeah. I just wanted to point out that one of the other aspects that makes these developments unique is that we're starting many of the assays in man. We're starting with ex vivo human blood. We're not trying to establish that we can block thrombosis in a mouse and hope that maybe there's something similar in a human, which is where many of the programs have failed as they translate. I think that's really important to bring out that our programs started with human ex vivo, moved to mouse for in vivo, and will move back to human in vivo. Right. I want to add, I’d forgotten that when I said it, that actually what Phil represents, that we can monitor the cardiovascular system in a much more profound way also is part of a new interest into developing drugs. I would like to hear your view on that. That's why I'm excited to be here, honestly. Imagine, if you will, trying to develop an antihypertensive drug and never measuring or very seldom measuring the blood pressure, measuring it maybe every six months. That's what we've done with high blood pressure in the lung circulation. The development of drugs have been imputed essentially to two points in time, temporally diverse, with impossible control over what happened in between those two points in time. What we see now is a direct measurement of a direct effect. I think to me, that's the most exciting piece of validating the ability to monitor the lung circulation in a way that we would do the systemic circulation. Again, no doctor in the world would try to treat hypertension without a sphygmomanometer, but we've done that. Now look at what we found. We found pulmonary hypertension exists in other states that we didn't think it did, and in a prevalence that is astounding and explains so many things, such as right heart failure developing into advanced heart failure, limiting advanced heart failure interventions. It's really an exciting time. I can only imagine all of the observations that we will be able to identify as we develop drugs monitoring their effect directly. That makes me very excited to be here. That's why I'm here. That's a great point. I think in addition to yours and Cereno's collaboration, which is kind of unique, it also shows an interconnectedness between not only a device, but the ability to measure things, get more data, reliable and time-sensitive data, which in turn helps to develop drugs. Are there any other factors? Like we're talking about the future of PAH treatment here. Are there regulatory issues as well? Like let's say CS1 reaches the market, do you need to educate doctors on how to use it? Or, will there be hurdles in treatment until the, let's say, insurers or FDA catches up and sort of incorporates that, these sort of disease-modifying treatments in their standards? Fortunately, I believe that we've paved a lot of those roads. Obviously there has to be uptake education, when results are found. Again, the opportunity is remarkable. I think in pulmonary arterial hypertension, and Raymond, I'd like to hear your voice on this, but you know, that typically that disease is cared for by a very discrete group of folks, physicians that have very significant specialty expertise. United Kingdom, I think there's only three PAH programs in the country. So all of the patients are treated there and, whereas in heart failure, they're treated by just about everyone. The opportunity to directly interact with those who care for those patients is a big advantage, I think, for this particular disease. Raymond, do you disagree, agree? Sorry to. Well, in Europe it is very much like you described. These people are taken care of by specialists. In the United States, it used to be like that. However, a lot of these people are now moving out to the community and being treated by community physicians, which makes it even more important to have the ability for these community physicians to follow the disease in a more intelligent way. That's where devices like CardioMEMS comes in because they can do this from the luxury of their office space, and the patients don't have to come to see them. You know, adding these virtual touch points to a patient, I really think is gonna improve management and eventually outcome with disease states like pulmonary arterial hypertension. Lars, if I could make one more statement. Sure Because there's a second thing that's very important here. I think you asked me about the regulatory implications, and I'm gonna speculate and predict the future, which I've never been successful at. Frankly, when one looks at drugs that are developed to treat systemic hypertension, no longer do we have to have 100,000 patient trials to understand if we lower blood pressure that we reduce the risk of stroke or heart attack or heart failure or kidney failure. We know that happens. The regulatory milieu for antihypertensives is, can I safely lower systemic pressure? And that's the endpoint. We hope that the same evolution will happen such that drugs that are vasoactive treating pulmonary hypertension will be regulated based on their safe ability to lower pulmonary artery pressures. The only way you can do that is to measure the pressures. Right That was my second point. Sorry. Björn, would you like to- No, I just wanted to take up another aspect of this drug and monitoring that makes it possible to continue the movement into the home of the patient. That means that we also have more reliable data because coming to hospitals for many patients is a very, so to say, stirring thing and they get not representative values for what you measure. I think can also improve on adherence for medication because people understand. Look at what happens with diabetics and glucose monitoring and then the insulin pump. It might be for cardiovascular, you can do a similar thing. You monitor, you have an intelligent pump that gives the medication in the way that the body medicates, so to say, with different substances. I think that this is just the beginning of this linking therapy with sophisticated monitoring, and I think that also sparks interest in the area. Thank you. I have a question for you, Raymond. Obviously, for obvious reasons, we focused on pulmonary arterial hypertension today. What do you see going forward? Is there a possibility to moving into a sort of broader spectrum of pulmonary hypertension? I mean, you described it's a rather heterogeneous illness with different genesis. Do you see a future for CS1 in regular pulmonary hypertension as well? Yes, I do. I think that is really one of the courses of action that we should proactively take. The vascular remodeling is very similar in these more common forms of pulmonary hypertension and particularly in forms like chronic thromboembolic pulmonary hypertension. This is a perfect compound for that disease state. I definitely feel that there is the ability to transcend this molecule from this novel starting point with pulmonary arterial hypertension to these other more common forms. It was also very interesting to hear you start talking a bit about possibly even moving into a prophylactic use. However, as I come to understand, you have hemodynamic instability before you have any symptoms. I guess that would mean you would have to catch patients early asymptomatic. I guess the Abbott device, your MEMS, is maybe one way to show. How would you go about to finding the proper patients? Screening, or would you look for risk factors to identify maybe a subset of the market or any one of you could perhaps- Well, maybe I can start with that. Sure We can get some other. In essence, what we have discovered is that patients who are perceived by their physicians as having less severe illness based on an assessment of their symptoms actually don't. The problem is that we rely on symptoms to define the disease, when in fact, the disease is much worse than what the symptoms would portray. Our most recent alteration in the United States for indication is that we move back earlier in the symptoms cascade because we found that those patients are equally sick. It's just they have less symptoms. That's the way I think we can start, and then as we evolve further, we can discover how to get to patients before they even develop a pulmonary hypertension. Right. I mean, if you talk about the larger indications, I think it will be difficult with this invasive device to implant an invasive device. Maybe. Maybe not in the future. Maybe it can be done in a more peripheral or something like that to monitor. I think in high-risk patients for developing certain manifestations, you can identify those patients more and more efficiently. It could even be worthwhile to have some of these devices implanted to really be proactively preventing their disease progression. Right. Gunnar? Just to add on to Björn's comment, I put a question to you that I know you have the answer, but it's good that more than we talk about it in private. For how long time will the device be working in a patient that get it implanted? The remarkable thing about this technology is that it has very little in terms of moving parts. There's a nanometer deflection of the capacitor. We've seen this device function perfectly for 14 years, is the longest in a patient with congestive heart failure. This is, I think, a dramatic technology. So, so it is really- Essentially the life. Working so that you can use it for very prolonged chronic period. Likely the life of the patient. Yep. Because it was the patient that gave up, or was it the device where at 14? The patient is still alive, but as Okay. It was the device. The device still is working, but the last time we measured from the device. Oh, okay. It's been 14 years since implantation. Okay, okay. It's still working, and we still measure from it. Okay. So. Right. There are a lot of other- Dr. Raymond Benza, would you like to add some flavor to this discussion? There are a lot of other patient subsets that you can use a drug such as this in a preventative manner. For example, patients with scleroderma, 60% of them will develop pulmonary hypertension. This is a unique group that you can use a preventative drug on, before they even develop the disease. Same thing with those who have genetic mutations that develop pulmonary hypertension. These are families with six or seven people who carry mutations that a preventative approach may be excellent in preventing disease. Similarly, in HIV, they have a six times risk of developing pulmonary hypertension than a normal person does. Again, there are lots of patient subsets where the disease is so penetrant that preventative therapies like this could be very, very helpful. Yeah, I would like to add all the patients with fibrotic lung disease and that also develop a lot of pulmonary hypertension. Right. There seems to be lots of. And I've, uh- Yeah, please. I'd just like to add, in the thrombotic area, age is a risk factor. 65% of post-menopausal women with diabetes will die of thrombosis. You already have a huge population for which age becomes the point at which you start to intervene. If you have interventions, if you have drugs that have a good safety profile, you immediately have an advantage over what's out there. Which leads us back to the preclinical pipeline here and Cereno. Raymond, I know you're very optimistic about CS1. You've called it a potential game changer. Now with data on CS014, perhaps you could share your thoughts on that data that has been released with regards to CS014. I'm very encouraged by the preclinical data, particularly since in knowing the pathogenesis of the disease and the mechanisms that propagate the disease, and this molecule touches so many of those. I really feel that this is an agent that we will need to watch. That's why I'm so excited about participating in this particular program. I've seen lots of drugs come down the pipeline, and I've not participated in all of these because they are very similar to what we've had. This is the uniqueness of this compound and why I've engaged myself with Cereno because of the plausibility that this drug will be able to positively affect the patients that I treat. Right. I have a question which sort of borders business and science, so perhaps you could give the science side to this. It's common practice among analysts to assign a zero value to preclinical projects due to the high uncertainty. Now, not talking about valuation, but given the preclinical data, seeing it as it is, do you think it's strong enough to sort of motivate a perhaps slightly more optimistic view than zero value on the preclinical portfolio? I mean, for instance, you mentioned that a lot of your data comes from actual human tissue, not animal studies. Perhaps that's one difference. I've tested pretty much every antithrombotic at the platelet and anticoagulant side. I would say that the safety profile of these preclinical drugs are significantly better than most of what we've seen out there. Most anticoagulants in an ex vivo system will result in some bleed, which so bleeding was predicted in the anticoagulants. It had to be an accepted risk where we have yet to see a bleeding signature. Thrombosis wasn't as potently altered, so you couldn't maintain hemostasis and while preventing secondary hemostasis. The variety of tests we do as well as the fact that we start with human tissue, I think gives this a better than zero starting point. Thanks. Phil, did you have anything to add there? Oh, I'm probably not the best person to ask about that. Time for the formal panel discussion is over, so I suggest perhaps we could just move into questions and answers. Mm-hmm. Are there any questions from the audience at this time? Please go ahead and then. Yes. Thank you very much for the presentation. I have a question on the preclinical asset CS585. It's really interesting that from arachidonic acid, the metabolism of 12-lipoxygenase, this by-product comes. My question is, you have described very well how the antithrombotic effect is mediated. Do you still have any vasodilatory effect by activation of the IP receptor? Yeah. No, that's a great question. That is something that's currently in process. If I were to predict, I would predict a vasodilatory benefit. That is something we would want to test before making a statement on that. Thank you. Is it on? Yes. Maybe a question for Dr. Adamson and Dr. Benza. How well does a pressure reduction in the CardioMEMS correlate with clinically meaningful benefits, for instance, in a six-minute walk test? I'll start, then Ray can answer from a PAH perspective. Every clinical trial we've done has demonstrated a direct association with a reduction in pressures and a reduction in hospitalization events and improvement of quality of life. Now we see the signal that a reduced pressure influences survival in a positive way. Thus far, in several thousand patients studied, it has been remarkably consistent that lowering pressures in heart failure patients is associated with improved outcomes, including survival. I think with pulmonary arterial hypertension, Ray has demonstrated in a smaller cohort of patients that indeed we can get a remarkable idea of how well the drugs are working, how well combinations of drugs are working, and I'll set him up to answer his portion if you'd like by saying that. Ray. Yeah. The really important point here is that the reductions of pressure allow the right ventricle to recouple itself with the pulmonary vasculature. This is really, really key in most events in which heart failure is a primary player, because when this coupling occurs, you're able to augment the output of the heart, which is stroke volume. Stroke volume is what is directly correlates with the increase in six-minute walk distance. By lowering pressure, you recouple the right ventricle with the pulmonary arteries, increase stroke volume, and hence improve six-minute walk distance. We've been able to show those direct correlations in this study that Phil had mentioned earlier that we did in PAH patients. Thank you. Thanks. So Raymond, we have a question from the audience, which I think you could answer. The question is from Tim, who wonders, what compounds will the patients in the current phase II study be medicated with outside of CS1, for instance, sildenafil or- Yeah. Oh. Yes, because, you know, the way we do clinical trials in pulmonary hypertension now is usually on background therapy. Patients in this trial will likely be on combinations of two or three medications for treatment of pulmonary hypertension. We will see the effect of CS1 on top of stable therapy, with several compounds. Thank you very much. Phil, we have another question from the audience, which is right up your alley. Samir says, "CardioMEMS is a truly remarkable technology." He wants to know if the combination of using MEMS as well as CS1 will help to shorten the phase II trial and make it more effective. Well, that's a great question, and certainly that's our hope. As I mentioned, what we envision by coupling a monitoring system in this disease with a drug intervention is shortening the process of early evaluation to approval, again, with the same concepts and an idea of using antihypertensives in the systemic hypertension world. If you lower the pressure, that's the effect you wanna see. Now, the CardioMEMS system is being designed to look also at stroke volume and other outputs, so there is this comprehensive package that will be available. But there is a real hope here that this will change the landscape of regulation to make these drugs much easier to develop and quicker to the patients, in a more effective way. Thanks. Björn? I just wanted to mention that when we talk about pressure, I think we have to distinguish between an earlier vasodilatory effect, which has an immediate effect on resistance and pressure. If we believe in, which we do, and hope for reverse remodeling of the arteries, which is more so to say to the core of the disease. That will take longer time. That will take for the remodeling to have an impact. You have to remember that in a vessel, the lumen, the radius of the lumen is linked to the fourth power of resistance according to Poiseuille's law. That means that just a small change in the thickness of the wall have huge impact on the resistance. On that and if that, then the reverse remodeling comes in and in addition to the pressure, helps the vessel to open up with the smaller and smaller wall thickness. That is a huge additional benefit. Gunnar, I think you have an addition here. Just in addition to the question, if you think about the traditional way where you have catheterization and you have sampling of blood pressure measurements for a very short period, you will see a huge variability. By using the CardioMEMS, you have longer periods where you sample, and you have more frequent periods when you sample, meaning that the variability of the pressure measurement will go down. It's really the variability in your measurement that drives sample size. We definitely believe that this is a way of dramatically reduce the sample size in the pivotal trials. Well, let me just build on that because Raymond Benza has demonstrated earlier in our CardioMEMS world that if you compare what we get in the cath lab measuring with a right heart catheterization, it seems in at least 25%-30% of the patients to be different than what we get with an ambulatory monitoring system. The artificial world of the cath lab may actually miss the diagnosis about 30% of the time when we're trying to find patients with pulmonary hypertension. This seems, at least in my mind, to be a superior way, as Gunnar mentions, to not only decrease the variability, but increase the accuracy of the diagnosis. Mm. You concur, Björn? Yeah. I just want to emphasize the difference between the reverse remodeling and the vasodilation. The reverse remodeling, if it works the way we think and have predicted, then if you discontinue therapy, it has been shown in animals, the pressure stays down. But if you have a vasodilator and you discontinue that, it goes up again. That goes to much more profound effect. Right. A fundamental question. I mean, we're dealing with a rather novel technology here, epigenetics. There are some drugs on the market within this field, but it's still new. Do you think this presents an extra additional challenges? I mean, maybe it's harder to interpret data or predict the future since there are very few precedents. I mean, perhaps one of you can. I can say that I don't think it will be more difficult to interpret data because the readouts are not epigenetic. The readouts are hard facts. Right. I think if you see the effects that we believe. Gunnar? Yeah. I would say to me, it's more about understanding how a molecule can have multiple different effect. That is because they have an effect on switches on the DNA so that you have more or less expression of certain type of proteins. Yeah. As to understand exactly the mechanism can be more complicated, but to see the effects or interpret the study result will not be more difficult. Results are what matter, right? Yeah. Michael? I mean, I've always said that the patient is more interested in that drug works than how it works. Mm-hmm. Did you want to say something, Michael? Yeah. No, based on my experience, in drug development, when you have a new target, a first-in-target, you actually can speed up the regulatory pathway. You can get fast track, you can get ODD. It's first in class, gives a new set of tools to the physician in the clinic, that are not currently available. While one might initially think that the rigors are higher, the benefits are even higher, and the regulatory agencies tend to recognize that. Right. I mean, with Cereno's pipeline, it's not only first in class, but it's also an orphan indication. Yeah. Makes maybe for an even speedier. We have another question here. Just a second. Thank you. Yeah, as you were saying, I mean, the mechanism can be a little bit more difficult to understand, let's say, in terms of molecular pathways. Regarding CS1, are all the mechanisms that are associated to the molecule is everything epigenetics or there is like some kind of mechanisms that are like not epigenetic? We cannot say that, like, everything is epigenetic. For example, the IP effect, we don't really know if it's epigenetic or not. We know that the tPA effect, we know that the anti-inflammatory and antifibrotic, and so on, they are based on HDAC inhibition. The IP effect, we are not 100% sure about. That was almost by serendipity, we discovered it. It's, we cannot say that we know it entirely. I wonder with this study, hopefully we will see a lowering of the pressure, but the follow-up period is only two weeks. Isn't there any possibility of following up this for a longer period so as to see whether this is a, an effect that will stay for at least a longer period? I mean, it should be, no harm to the patients, really. No, this is not seen as the definitive study of course. This is a dose-finding safety, tolerability and dose-finding study where we have lots of readouts to be able to decide on the dose and then do the definitive study. Of course, it can be that some patients that still have the CardioMEMS can be continued for various reasons with therapy, but the formal evaluation will be after 12 weeks to see the effect. I think the great opportunity here is that the patients will have this device for the rest of their lives. The opportunity to understand the length of effectiveness and then allowing their providers to use CardioMEMS for the other drugs for this disease is a real nice opportunity, I think, as well. I have a question for you, Phil. Does Abbott access to the daily data generated and collected by CardioMEMS, or is this data only seen by the DSMB until top-line results? You mean access in terms of analysis or? Yeah. Oh. In terms of if you can see the data? No. We will follow good clinical practice and clinical trial practice here. All of the data is stored in the Merlin system, but we won't have access to for analysis. We will have access. Blinded people will have access to troubleshooting, and that's always been the case with CardioMEMS. If there's a problem, we'll be able to look at the pressures to understand what the problem is. For an analysis per perspective, we won't be doing any kind of interim analyses or following that. Time flies. Unfortunately, this is all we've got. I think we should give a big hand of applause to this excellent panel. Thank you. Thank you. Many thanks for enlightening us. I read a quote once, "I'm still confused, but at a higher level. I want to read that. It's been very enlightening. I think we have some concluding remarks here from Sten. Please, Sten. Yes, me. me. Yes. Given that your mic didn't work before, perhaps. I think it might do now. Right. Wasn't that a great discussion and Q&A session? I loved it. Now, some concluding remarks. Those of you who are investors in Cereno and follow us for other reasons, you've seen our progress the last 1.5-2 years, and I've just shown a little list of the progress this year. We have nominated two candidate drugs earlier this year, and we have presented remarkable data on both the candidate drugs, a novel HDAC inhibitor, which you've heard Mike presented, so in thrombosis. Prevention of thrombosis without bleed, which is so much sought after in the care of these patients. None of the drugs available have that capacity. The same goes for the CS585, actually, but in a different way. That's an antiplatelet drug. CS014, the novel HDAC inhibitor, has both antiplatelet and fibrin or anticoagulant capacity. Cereno, through the great research by Mike and through the discoveries of these two agents, have been able to present this year new drug modalities that could be effective and could be safe, safer in these patients, addressing the highest risk for these patients and for physicians treating these patients. We will see. We have to develop them further and to bring them into clinic. We have been able to finally get our first patient into the PH study. It's been post-pandemic hurdles, less patients in the fairly large hospitals, and less employees to handle the bureaucratic process and the contracting process, so to speak. Important processes to make a study start, but they've taken longer time for us. We are very happy that we have our first patient not only included, but also randomized to dose. You will see we'll be able to communicate to you about the progress of this study and the target that we have now moved to the first quarter next year, we hope we can keep. It demands a lot of effort from us, but that's our target. Now, through this year, we've also solidified our patient position in the various families for CS1. We have a stronger even stronger protection than we had from the beginning, in addition to the Orphan Drug Designation that we have achieved, which gives us seven years exclusivity in the U.S. market upon market authorization. I mentioned to you that we have strengthened our team, and you can see the results of having Mike as a collaborator in University of Michigan, but also having Abbott as one of our collaborative partners. Of course, now our internal team are working very hard together with these partners to pursue our portfolio. These are our a little longer term objectives. Top-line data next year for CS1 in PAH, and then IND submission for both of the preclinical drugs. That's also a tough target for us, and we have a target to start phase II-B/III in PAH during 2024. After this study readout and analysis, there comes a process where you define the next trial and you negotiate with the FDA and others how you want to pursue, and then get approval to start the next trial. That's a big effort and takes some time to get done, approved, and then initiate. That's gonna be 2024. For the two preclinical assets, we aim for early 2024 for the phase I studies. There are various milestones in the development programs, but there are also financial milestones for biotech. They are very important for us. You might already have realized why we have this Capital Markets Day today. We are in a pricing period of a warrant package, and it's gonna continue. It started the twenty-ninth of August, continue until the twelfth of September, then we're gonna have a subscription period of two weeks also. If fully prescribed, that will provide SEK 114 million maximum to the company before cost. At current price levels, it will be less than that, but we'll see. Perhaps somebody will be more transparently available of the data we have and will buy both stock and warrants. We'll see. But we're confident that we will be able to capitalize the company moving forward with this kind of program and this kind of data that you've seen today. We have a global presence. We are based in Gothenburg. We have an office in Boston, and we're pursuing both a phase II trial in the U.S., and we have a major collaboration with, under the leadership of Mike Holinstat, with University of Michigan. We are in a market that has a large need for new drugs, and specifically PAH, as you've heard, but also thrombosis. We are nicely positioned with two new, three programs and two new modalities in that area, those areas. As you've also heard, there are many different indications that you can pursue. This is hopefully just the beginning for these, drugs and modalities to be developed. You've seen from the scientific advisory board, but you heard today the people we're working with. This is not a small biotech. We have great minds surrounded by with Cereno working that have been in the field for decades and are top of the line. I think we are very thankful for that, and we also have a very productive scientific and business discussion and creation. By that, I thank you everyone that have listened to this, and I thank you to those who have been part of the program and specifically to Phil and Mike who are here from abroad. Thanks a lot. Thank you very much, Sten. Thank you very much to all of you who attended here at GT30. Thank you to the web audience. Remember, this will be available at later stage if you couldn't catch all of it. With that, I think it's time to conclude Cereno Scientific's first Capital Markets Day 2022. Thank you very much. Thank you, Lars. Thank you.