Hello, everyone. I'm Sten Sörensen, the CEO of Cereno Scientific. We are a biotech based in Sweden. We are pioneering efforts into diseases with high unmet need, where we believe our research can do a very good value and deliver value to the patients. So I'd like to extend a warm welcome to you here, in the location, and also to you, on the internet, on the web, following us today. So it's been a year, a little more, since we had the Capital Markets Day, and we've been looking forward to this a lot. And I think we have a very exciting setup, of speakers, both, our internal experts, as well as others that have joined us today. So first, some house rules for you that are here. In case of emergency, there's one exit.
We have a very tight agenda. There is one break in our three hours that we'll spend together. You can decide whether you want to drink coffee or do something else, powder your nose. But you're gonna go upstairs, and I suggest you bring the coffee down, so you know, have a chance to not miss anything that we are saying here. There's gonna be a Q&A, so questions that you can ask at the end, about 20 minutes, if I remember it correctly. There's also been sent in questions from over email to us. We'll try to answer that in a panel up here. After the scientific and business session, we'll gather together in the Orangeriet and chat a little about what we have experienced here today together. Let's get started.
So the setup here is, we have Dr. Raymond Benza, our Principal Investigator, based in, at, in New York, at Mount Sinai. We have Dr. Jason Guichard in from South Carolina. He is the doctor that has recruited most patients in our PH trial. He will also be joining us here for a few minutes, and of course, many of you know Professor Michael Holinstat from University of Michigan. He's sitting in the front row here. He will present one piece of the agenda for you that we believe is very exciting, too. And you've seen the recent communication that we have done a partnership agreement with FLUIDDA.
So the CEO and one of the founders of FLUIDDA will also join us here today and talk about that technology and how that can be helpful for our efforts to develop valuable drugs. So this is the agenda. I won't go through it now, and I think you probably have it with you. We'll return to this agenda as we go forward. First, I'll start with an introduction about what we're trying to do at Cereno. It's about this. So this is a person, healthy, midlife, no diagnosis. Suddenly, this happens. She's diagnosed with pulmonary arterial hypertension, and this is actually what's going on. She has a progressive development of remodeling of her pulmonary arteries, resulting in very narrow artery, very stiff artery, and a high pressure. Eventually, the right heart fails, and she dies. Current treatment don't address this. Life expectancy is seven years.
Midlife, this person has probably a family, children. So the question you'd ask yourself if you are in the business of innovation is: what if? What if we could develop a drug that's disease-modifying? Here's another example. Healthy couple, one of them suddenly is diagnosed with IPF, another rare disease, even shorter life expectancy, fibrosis of the lung. No drugs address the underlying disease on the market. What if somebody could develop a drug that could halt or maybe even reverse this progression, enhance life, enhance quality of life? A third example, the most common cause of death on this planet is thrombosis, resulting in the most dangerous things like a thrombosis of the brain, called stroke or myocardial infarction. 20 million people a year die of this.
Issue, you'd like to have more effective drugs, but you can't because all the drugs out there cause very dangerous bleedings. Three out of 100 die. 25 out of 100 get bleedings like you see in this picture. You have to go to the hospital in many cases. So what if you could develop a drug that doesn't cause bleeding, could be added to the other drugs? That would result in higher efficacy without increased risk. So what we are trying to do at Cereno is develop drugs that answers the question or meets the demand of these needs, enhance life and prolong life, root cause of the disease, disease-modifying agents. Now, we believe we are pioneering the effort with HDAC inhibition, so epigenetic modulation through HDAC inhibition, and we're bringing that into cardiovascular disease and now also lung disease.
The reason is the multitude of publications and studies done, more than 500 articles are published, and a hundred of those were published in the Lancet by our scientific advisory board in 2021. The recent Nobel Prize is also related to epigenetics, by the way, okay? So our portfolio, we have two HDAC inhibitor drug development programs, and one of those, we just finished the phase II program in the rare disease, pulmonary arterial hypertension. And we'll revert to all of these three programs throughout the day. The second program, today, we announced that the target indication of CS014, our novel HDAC inhibitor, is gonna be IPF, idiopathic pulmonary fibrosis. It's currently in phase I, and we'll complete phase I by the summer next year, then we'll move it into phase II. So it's pretty close, right?
So two programs are today in rare disease. The third program, CS585, which have been documented to prevent thrombosis without increasing bleeding risk, we'll discuss today, and Mike Holinstat will entice you with some new information. Now, why do we do this? We do it for the patients. We'd like to develop these drugs to help the patients. Higher quality of life, longer life. But of course, the way to the market, to the patient, can go different ways. About 70% of all new drugs are developed by biotechs, but pharma bring them to the market, the industry, the big players. So that's why you have all these deals between pharmaceutical companies and biotechs. So we are developing this to be valuable for patients, but of course, also to be attractive for such deals.
If you look at our portfolio, you can see the rare disease, pulmonary arterial hypertension, CS1, IPF program now identified for CS014. We have an attractive HDAC portfolio. We have a thrombosis portfolio, both CS1, actually, CS014 and CS585, can prevent thrombosis without increasing bleeding risk, as documented in very translatable models in mice by Mike Holinstat here. Very translatable to man, I should say. We are based in Gothenburg. We were founded two thousand and twelve, on the stock market two thousand and sixteen, and we have grown the company. I'll revert to that a little later today. But you are part of the almost 10,000 shareholders that Cereno has, as shareholders today, supporting our effort, and we're very thankful for that.
We just moved out of Astra's BioVentureHub into GoCo, a very vibrant research hub next to AstraZeneca in Gothenburg, in Mölndal, where the little more grown-up companies from startups are moving. So we moved there in July, and it's a good place to be. That's where the management of what we do have offices. But look here, these are all the various companies, consultants, et c., that we work with, collaborators worldwide. And the recent addition here is FLUIDDA. You can see that on the top, that you will hear more about today. We have an ongoing collaboration with Abbott, major. We have three- or four-year or plus four years collaboration with University of Michigan. So many, many collaborations and continuous work with these parties. So we're not doing it alone.
We also have a very, very strong scientific advisory board supporting our efforts, and you will hear from one of them today, Dr. Raymond Benza, and I'd like to introduce him now, actually. I hope the technology works. Hello, Dr. Benza.
Good morning.
How are you?
I'm very well.
You have an empty office?
I'm in transit.
Okay. All right. All right, very welcome. So, you know, as you know, we have an audience here, about 60 people, mostly shareholders in the company, and then we're also sending live over the internet. So that's your audience.
Fantastic.
I know you're gonna speak about Pulmonary Arterial Hypertension. Thank you.
It's my pleasure. And I'm curious if the videographer could focus on the screen at this point, because that way I can see how my slides are being advanced.... Perfect, and if we can move to my first slide. It's a real pleasure to be here this morning, and to speak for Cereno regarding therapeutics in pulmonary hypertension. And the focus of our small conversation today really will be to discuss what I feel are the missing links in contemporary drug therapy. So as Sten mentioned, I am a professor of medicine and the System Director for Pulmonary Vascular Diseases at the Mount Sinai Heart Institute at the Icahn School of Medicine here in New York City, in the United States. If you move the next slide.
So today, we'll talk a little bit about the missing links in contemporary drug therapy. As most of you know in the audience, pulmonary hypertension is a deadly disease without cure that affects primarily middle-aged women in the prime of their lives. Now, we've done a lot to improve mortality with this disease, but our seven-year mortality rate is still very excessive, and our patients continue to have a lot of morbid events. And we think that many of this is related to a variety of reasons that are outlined here. But one of the most important reasons is the last one, that many of the drugs that we have to treat pulmonary arterial hypertension do not target the disease itself.
And we're going to go into a little bit of that throughout this talk, but this will be the main focus of what we'll discuss today. You can advance the slide. So the way we predict prognosis in pulmonary hypertension is by using multidimensional strategies. And this is important because we know that no one singular variable, like NYHA class or natriuretic peptide levels, really give us the full description of how a patient progresses with this disease. Advance, please. And our current treatment strategy, our goal is to achieve a low-risk status. If you could advance one slide, please. Is the achievement of a low-risk status, defined as less than 5% mortality at one year. So we use these multidimensional strategies to try to push patients in this direction.
Next slide. Now, the reason this is important, as I mentioned earlier, is if you hang your hat on a singular feature like NYHA class or the six-minute walk distance or even hemodynamics, you can see that if you use these variables in and of themselves, their likelihood of telling you the wrong information is very high. And that's why we use multimodality prognostic equations like the REVEAL score, because it gives us a very much greater enhancement in our predictability to predict who or who will not have an event and what the effect of our therapies are on a patient's time course and progression through this disease. Next slide, please. So the systems that we use currently, if you can just advance the animation one, so we can see the scoring systems.
The systems that we use now from this multidimensional strategy is called the REVEAL Score, and this is a score that I helped develop a number of years ago. It uses a variety of different demographic factors, as well as factors from diagnostic studies, to paint the entire picture of how a patient will progress with this disease. And these scoring systems, which are used as continuing scores, allow us to get multiple lines of risk, if you can, advance the slide, so that we can depict a patient's prognosis in a very linear and very granular function. So improvements of score mean, improvements in outcome, and detriments of score mean worsening outcome. If you advance one slide, please. So the advantages of using scoring systems that have this continuous risk is that you can follow the integer of change very, very granularly.
If you could move the next slide. So if you're using the REVEAL score, the REVEAL Lite score, this is very important to understand that if you have a one-point decrease in score at 12 weeks, that patient is predicted to have a 62% decrease in the relative risk of clinical worsening. And no matter which trial that we've profiled this in, we see the results from the REVEAL, excuse me, from the FREEDOM EV trial, from the GRIPHON trial, and from the PATENT trial. This very, granular change in score always reflects an improvement in outcome. So this is very, very important.
This is one of the reasons why we use this scoring system in the phase II trial, because it gives us this very good estimation of how patients will improve if they can improve their score in this manner. Next slide. So, let's talk a little bit more about what we have and what we don't have in terms of contemporary drug therapy. And we'll talk a little bit about how survival and morbidity in this disease is still too high. How our current disease targeted therapy really focus on vasodilation as opposed to really remodeling the blood vessels.
How our current drugs lack specific tissue targeting, what the side effects of our current profiles are, and why there's this persistent need for parenteral therapy to really move our patients in the forward direction, and why we need new drug development in this area. Next slide. So our event-free survival and quality of life in pulmonary hypertension, is this really where we want to be with our current contemporary therapy? Next slide. As I mentioned earlier, pulmonary hypertension remains a very deadly disease, despite all the drugs we have in our current armamentarium. Our seven-year survival rate, although improved from what it was in the past, in fact, we've tripled life expectancy, but a seven-year mortality in a disease that affects primarily middle-aged people is really not acceptable. Next animation.
And so there's still too much death and suffering, even with contemporary drugs that we have to treat this disease. Next slide. In addition to having still an unacceptable mortality, despite our improvement in survival, our patients are still having morbid events that have not changed over the last two decades of drug development. Our patients are still being hospitalized for worsening pulmonary hypertension and right heart failure, and our patients are still requiring escalation to triple therapy, including parenteral prostacyclins, in order to maintain stability. Next slide. In fact, as you can see on this slide, if we don't throw the kitchen sink at our patients and use triple combination therapy upfront, greater than 50% of our patients will still stay at high risk, and this is very, very significant because we want to drive people to this low risk.
We want them to have the lowest REVEAL score possible 'cause that's how we know that they're gonna have an improved survival. Next slide. So our mortality still remains very acceptable, even on the best and most aggressive contemporary therapy, and this slide shows you that our upfront mortality, even with triple combination therapy at three years, is very significant and unchanged from even using other additional therapies. So we really need more and different therapeutics other than what we have to really drive this mortality to be much lower. Next slide. So if you look at our current medications for the treatment of pulmonary arterial hypertension, and you look at this from a meta-analysis perspective, and you look at mortality and clinical worsening hospitalizations, you see some very interesting things, if you can advance the animation.
You can see that really all of these hit the unity line. Next animation, and then the subsequent animation. So as you can see here, all of our contemporary therapies really hit the unity line in terms of mortality, clinical worsening, hospitalizations, and this is why we really need the advent of new therapies that focus on the disease and the remodeling of the pulmonary vessels other than vasodilation. Next slide. So obviously, what's very important to our patients, as opposed to living longer and staying out of the hospital, is, do they really have an improvement in the quality of life? Advance, please. And you can see that despite what I've shown you, that the quality of life on our current therapeutics still remains very poor.
Again, if you look at the hazard ratios and the forest plots of these, you again see some of the similar things that we saw for hospitalizations and mortality and morbidity: that our quality of life with current medications has really not improved very much. Next slide. If you look further on this meta-analysis, you see a lot of brown and orange and yellow on this slide. In this meta-analysis, those colors represent non-improvements in our major endpoints that we want, including functional outcomes, hemodynamic improvements, safety outcomes, and efficacy outcomes. We have a lot more work to do, despite what we have in our contemporary armamentarium, to really push these functional and hemodynamic and outcome measures forward. Next slide. What do our current drugs do? How do they... Do they really change the pathology of the disease? Next slide.
Most of our therapeutic agents work on both the endothelial cells and the inherent smooth muscle cells, and their major activity is really to stimulate the smooth muscle cells to relax and to have the blood vessel dilate, but we know that this vasodilation method is really not pushing our patients where we are, as I mentioned further, if you could advance the animation, and this is where the explosion in new research, looking at a variety of different pathways that really can do something to change the integrity of the blood vessel as opposed to just vasodilating the blood vessel. Next slide, and again, just to push the point home, if you look at are we really remodeling the pulmonary vascular bed with current therapeutics, you can see something very interesting here.
So if you look at mean pulmonary artery pressure, pulmonary vascular resistance, you can see that using singular or even double therapy really doesn't change these hemodynamic parameters, which define this disease. Animation, please. It really depends on using our full armamentarium, including parenteral prostacyclins, where we really see the dramatic reduction in pressures and resistance that we want, which we know that mitigates this disease. Next slide. So our current drugs obviously are not tissue-targeted, and that's what we want. Next slide. We can also see that we continue to have terrible side effects with our contemporary medicines that's compounded by multiple drug use, if you can advance the slide. 47% of our patients experience significant adverse events from their medications. Advance the slide. And these adverse events occur with significant, and lead to significant medical non-adherence.
If you could advance the slide. So despite having these medications, the side effects really prohibit us from using them to their fullest extent, and this is significant. So we have drugs both that don't remodel the blood vessels and because of side effects, are very difficult to use and to maintain good adherence to. Next slide. And this is where, again, new medicines are needed involving all these pathways, including mitigating dysregulated angiogenesis, working on the extracellular matrix, working on calcineurin signaling and enhancing BMP2 signaling, mediating and mitigating other growth factors, vasoactive mediators, in order to really drive this disease and to make these blood vessels move in a direction where they're not only vasodilated, but where the intima and media of the blood vessel have regressed and the vessel becomes a larger lumen size because of remodeling, not just vasodilation.
We have clinical trials currently that are targeting metabolic syndromes, glycolysis and fatty acid oxidation, next animation. We have new drugs that are targeting inflammation in pulmonary arterial hypertension for modulating cytokines and inflammation. Next animation. We have new drugs that are modulating the estrogen pathway, the PGDF pathway, that are augmenting BMPR2 signaling and working on oxygenation. Next slide. Even with these new trials, we can see that many of them have failed to meet their clinical endpoints or have remained neutral, including some very recent trials using inhaled imatinib and modulating the serotonin pathway did not meet their primary endpoints. Next slide. The conclusions from what I just told you is that despite our contemporary therapy, mortality has improved but remains suboptimal. Our morbidity remains substantial.
We have really suboptimal improvements in patients' well-being and functional capacity, and the traditional pathways now only affect a small subset of the available pathways to develop downstream therapeutics. The side effects are prominent, leading to suboptimal drug compliance, and tissue targeting is limiting. And this is what really needs us to enable new targeting paradigms to really mitigate this disease. Next slide. And this is where we feel CS1 comes in. Because of its unique properties, it's antifibrotic, its remodeling activity related to this, its anti-inflammatory activities, which I showed you is a prominent mechanism driving this disease, its known reduction in pulmonary pressure in preclinical models, and very specifically, its antithrombotic activity. One of the main pathophysiologic mechanisms that drive this disease is microthrombosis.
So this antithrombotic activity through HDAC inhibition is really a very important mechanism which drives this process in the right direction. Next slide. You'll hear a lot about the phase II trial that we just conducted by Sten and some of the other speakers. Nonetheless, I think to highlight what we did in this particular study. Next slide. We really wanted to take advantage of this novel compound with its novel action, particularly its HDAC inhibition. We used novel innovative endpoints in this trial, including the REVEAL score, which I mentioned to you earlier. Change in score reflects an improvement in morbidity and mortality. We used cardiac MRI to really carefully evaluate changes in the right ventricle.
We used a CardioMEMS device instead of standard hemodynamics because of the enhanced ability to detect changes, over periods of time. As many of you know, in standard hemodynamics, these hemodynamics can change throughout the day, and these, hemodynamics that you classically see are really only small snapshots in time. So being able to understand the area under the curve and the change in these pressures is ultimately very, very important, and changes in the total time, that we see a patient experiences with reduced pressure really translates into improved outcomes. We're looking at novel biomarkers in this study, as well as the traditional endpoints of six-minute walk test, standard hemodynamics, echo, and biomarkers.
So with this, I hope I have properly informed you to let you know that we need new pathways to explore, that our current medicines are really not doing what we want for this deadly disease, and new compounds with novel actions like CS1 will hopefully drive us in this direction. And with that, I thank you for your attention.
Thank you, Dr. Benza, for an excellent presentation and informative. So, I know that we might have space for a couple of questions from the audience, if anybody is brave enough to ask. Any questions? Here's one here.
Hi. Thank you.
Maybe say your name.
Joe Hedden, Rx Securities. Just in terms of the adverse event profile of the current combination therapy approaches, I mean, how do you see that evolving as hopefully disease-modifying therapies like CS1 come in? I mean, these drugs are being added on top of presumably combination therapies. So is there any way that is gonna alleviate the current side effect profile of the drugs, or is it just that so many patients don't go on to parenteral prostacyclin?
That's an excellent question, and what we're hoping with these new drugs that have very potent reverse remodeling characteristics, that we'll be able to wean back some of their standard vasodilators. So the way I see that management will evolve in this disease state is that we will stabilize patient using our contemporary medications. We will start our reverse remodeling agents, and when these agents start remodeling the blood vessel, we'll be able to peel back some of these vasodilators, so patients will have far less side effects from them because we have the advantage of remodeling that we're doing with these newer therapeutics.
Any other question? All right. Thanks a lot, Ray, and, you know, I know you need to get back to the clinic, I guess. So, talk to you soon.
My pleasure. Thank you so much.
Yeah.
And if anyone has any further questions for me, please email me. I'd be happy to answer them.
Excellent. Thank you. Okay, so we are on time. I hope you found that useful, and good. And, now I'd like to invite our Head of R&D and Chief Medical Officer, Dr. Rahul Agrawal.
Thank you very much, Sten.
Welcome.
It's a delight to be here, and I welcome you also to this day. As you could hear already from Ray, there are several unmet medical needs. Even though there are many, many medications on the market, but there's still a high unmet medical need. You also heard from him that there are certain areas that need to be touched upon when we look at certain endpoints. He mentioned the REVEAL risk score. He mentioned the functional class. I'll go into more detail there and try to elaborate why, what we did, what we saw, and then maybe share those results with you. This is me. You see a much younger picture of mine than now, the original, but please don't be surprised there. Photoshopping does it all. I think you had briefly seen the slide from Sten.
These are the three compounds that we have. They're progressing well. We're going to talk about our lead compound and the phase IIa trial that we performed. CS1, as you heard, is already in phase I, and CS585, you're gonna hear some more very exciting news from Professor Holinstat and Björn, from our Chief Scientific Officer, as well. So allow me to just briefly go into a little bit of introduction, and maybe it's a repetition of what Raymond Benza was showing you, but I would like to hone on, that means focus on, the reverse remodeling. What does that really mean? If you look at the vessels, on the left-hand side, you see a healthy vessel, a very dilated vessel with a good blood flow.
Over time, reverse remodeling, though it may have a positive connotation, actually something very deleterious, very dangerous, because the vessels get, they have vasoconstriction, and they get tighter and tighter. That means the blood flow, but with that also the oxygenation of the tissues behind that, is not as optimal. So this is something which one definitely would like to reverse. There are several factors which have been identified over the years that lead to this reverse remodeling, like endothelial dysfunction, inflammation, that means there is, these, fibrosis, fibrotic changes in the vessel walls, plexiform lesions. We're going to show you also what kind of effects we have with some very new data that has just come out. And of course, all in all, you see a vasoconstriction.
That means tightening of the vessels, and naturally, that means there's an increased strain for the heart, especially the right side of the heart. This is what people often die of, shortness of breath and right heart failure. So these are the things that one has to really address. So far, the current therapies are more vasodilators. That means for a short time, they dilate the drugs, but they do not address, if you would like, the underlying cause. So there are key unmet medical needs. You heard that also from Dr. Benza. There are unmet medical needs, that the disease-modifying aspect is missing. And of course, very important also for patients, they should be safe and well-tolerated, because if a drug is not well tolerated, it will not be taken.
As you also saw, nearly 50% don't take their drugs because they don't tolerate them, so something one should keep in mind, so what we believe and we are addressing is, we're tackling, if you'd like, the root cause of this reverse remodeling and what we want to show is that we can hopefully come from sort of the late stage of pulmonary arterial hypertension and reverse it to some extent. Why? Because as you saw in one of the previous slides from Sten, we have properties where we show antifibrotic properties, anti-inflammatory properties, where we have seen, and I'll show you some, pulmonary pressure reduction, and so on, so there is a big promise, and that's one of the reasons why also we performed this trial. This promise stems actually also and has been shown in preclinical trials.
I just want to show you two of those, which were performed with VPA in some standard animal models, in rat models, with so-called monocrotaline rat models, hypoxia model, and also on the other side, other further models. And what you see there is that if you give VPA, there is a reduction of the wall thickness on the left-hand side, those bars that you see, and we have highlighted that with the blue arrows. And on the right-hand side, what you see is there is a certain reduction of the pressure, but also of the so-called muscularization of the vessels. That means vessel thickness. So if you give VPA, there is an improvement. These preclinical trials are, of course, very promising, but so far, there were no clinical trials in this direction dedicated to PAH patients. So this is what we have done.
Basically, the goal is, ideal sense would be to, of course, reverse pathological remodeling. But you also heard from Dr. Benza that this is a deleterious, continuously sort of, you know, worsening disease with no spontaneous improvement. So of course, we would love to see reverse remodeling, but even if we could stop the progression, that is a big win in itself. Please keep that in mind. Not only stopping reverse remodeling, but if we can stop the progression, that is very good. That means if the patients are either stable or improve, that is the best we can hope for, a medication or a treatment in this case. So I would just briefly like to go into what were the results of our phase IIa trial.
You may have heard it at the webinar, but we'll go a little more into details here. Again, it's a phase IIa prospective, randomized, multicenter trial, and very important, primary endpoint was safety and tolerability, and we explored efficacy parameters. Keep that in mind. All right. I'd just like to briefly highlight, and I'll go into all the aspects one by one in more detail. The primary endpoint, and this is a big success, primary endpoint of safety and tolerability was reached. Keeping in mind what Dr. Benza said for other drugs, many are not tolerable, so we have a good and safe drug. Very important prerequisite. We also looked at exploratory efficacy parameters, and I'm going to go into detail regarding the REVEAL Risk Score. We'll tell you why we chose that.
The functional class, I'll tell you exactly what the importance of that is, and also some results of the CardioMEMS, the continuous mean pulmonary artery pressure measurements. Okay? Then all in all, the nice thing is, we'd like to show you how that is consistent and how we think this is sufficient to take the next steps for another larger trial. You may recall how the study design looked like. All in all, the primary endpoint, as I was saying, was safety and tolerability. We had used CardioMEMS from Abbott in close collaboration with them. They were also excited to collaborate with us in this patient group. We had a treatment period of 12 weeks. We had three dosages, 480, 960, and 1,920. In the end, we pooled the data together. Why?
We'll show that to you later, but what we saw is that all of them, if you look at the blood levels, they were practically, one could, put them together and group them together. This you will also see when we show the results, it will be a grouped result of all the patients. All in all, we had 25 patients in the safety analyses. Of those, 21 in the efficacy analyses, and I'll go into one by one the details there. 12-week treatment, and all in all, this was the thing. So after 25 patients, our clinical steering committee advised us to sort of stop the trial because they had, they said we have gained enough sufficient insights, so there's no need to continue. Keeping in mind, primary endpoint was safety and efficacy. All in all, we had screened 38 patients.
Of those, 25 were randomized. Initially, a very nice distribution over the three dosages of 9, 8, and 8. As you can see, four were, three were early terminated, one because of withdrawal of consent, one had sepsis, drug-independent, one sort of had adverse events, but we don't know exactly what the reason was because they are multimorbid patients taking many medications, and it was not specified it was CS1 or something else. A fourth one we had to exclude because of protocol deviation, because that patient was taking drugs which were not allowed in the trial. So out of the 25, we have 21 patients in the efficacy analyses. All in all, it was, as you know, three-fourth of the patients were females. Unfortunately, there's a predominantly female-affecting disease.
Most of the patients had idiopathic pulmonary arterial hypertension. Please keep in mind that in this trial, every single patient was already on standard of care for at least three months, stable standard of care. What does that mean? They were getting between two and three drugs, which are approved and seen as first line, either endothelin receptor antagonist and/or PDE5 inhibitor, and/or prostacyclin. And our drug was given on top of that. Yeah? And the class, functional class, were II and III. 40% were in functional class II, 60% in functional class III. So I think you have heard it. I love to repeat it. So we reached the primary endpoint of safety and efficacy. All in all, there were no serious treatment drug-related events. Very important to know, because this would mean that because of that, they had to sort of stop the trial.
Of course, there were adverse events, which is obvious. There are nausea and the usual ones, which are well known, but there were no serious drug-related adverse events, and we have highlighted that in gray. So all in all, good safety and tolerability. And we also, of course, looked at the liver values, because as you know, there are reported liver enzyme increases. We did not see any CS1-related liver enzyme increases, and also no clinically relevant platelet decrease or bleedings. So again, a very good sign all in all. And of course, with that, CS1 was well tolerated in these 25 patients. So this was the primary endpoint of safety and efficacy. Then, of course, we wanted to, of course, also look at the efficacy parameters, but these are exploratory. Why are we really pointing out to that? Very simple.
It's a small 25-patient trial. Efficacy parameters, as you also heard from Dr. Benza, show a huge variability, and of course, you need much larger trials, but our aim was to harvest signals to see if our drug is doing any good already in the first 12 weeks or not, so that's why these are exploratory efficacy parameters. Despite that fact, we see compelling positive signs there regarding the REVEAL Risk Score, and I'll go into all three of them in detail now. REVEAL Risk Score, functional class, and the CardioMEMS data, I'll call it. That means a continuous measurement of pulmonary mPAP, so mean pulmonary artery pressure. All right? Okay, so let me start with the REVEAL score. You have seen that, Dr. Benza just showed that.
What it shows is that the higher the score, the higher the mortality is, and this score is made of several components, nearly a dozen. It's like a composite endpoint, if you would like. It includes WHO class, it includes gender, it includes age, it includes functional class, it includes six-minute walk test, it includes a lot of hemodynamics, it includes echo data. So a lot of things which are put together, and the REVEAL Risk Score has been identified as these prognostic, most powerful risk score of the various risk scores that there are. And very important, if you can reduce the risk score by one within twelve weeks, that translates, and you heard that also from Dr. Benza, it translates into a 23% reduction in mortality within one year. That's remarkable. Just imagine, twelve weeks you treat, you reduce the risk score by one point.
That means a 23% reduction in mortality within one year. Taking in mind that patients only survive for seven years, mean survival. They're in the middle of their ages. They're around 50. Ladies in the middle of their lives with a family, in the jobs, and you can just improve mortality considerably if you improve the REVEAL Risk Score. Keep that in mind. How was our result? We showed in 43% of the patients, so nine out of 21, we showed an improvement of one point. Already after 12 weeks in this trial, we showed in 43%, so nine out of 21, that they improved by one point, and if you recall what I've shown you in the other slide, that the goal has to be either, of course, reversal is the ideal thing, but and/or stabilization, so we looked at that.
All in all, 15 out of 21, that is 70%, had either improved or stabilized their REVEAL Risk Score. That is remarkable. This already within 12 weeks. Keep in mind, and I would like to repeat that, one point reduction within 12 weeks translates into a 23% reduction in mortality within 12 months. Just think about that. Twelve months is one year, October 2025. If you can reduce the mortality by 23%, if you improve risk score, that is something remarkable. I just want to put some life to the numbers. Numbers are numbers, but if you think of it, this is something impressive. This is REVEAL Risk Score, the composite endpoint. This is one that we looked at because we think for a small trial, for initial exploratory, this is something good to look at. But we looked at further things.
The physician doesn't have all these tools. It doesn't have a right heart catheter, you know, to push every time. It's an invasive thing. So what they usually rely on is, of course, their impressions, and that is functional class. You may know what functional class is all about. Function class, very simple, divided into four classes. Four is sort of already in bed at rest. They have complaints. Function Class I, at rest, no complaints. Two and three are in the middle. Two is mild complaints when at rest, and three is marked complaints at rest. Why is that important to know? Because this is something which the physician, she or he, takes as a decision point to change, alter, improve, extend the therapy if need be, for a patient.
Function class in everyday, and I'm saying that myself as a cardiologist, is very important because you base your decisions usually on how you perceive the patient, and that's why we, of course, wanted to see how that looks like. As you can see here, we had in one-third of the patients, 7 out of 21, an improvement in function class already within 12 weeks, and 18 out of 21 either improved or were stable. To give you more details, most of the patients were in Function Class III, that improved to Function Class II, and there were some which improved from Function Class II into I. Keeping in mind what I said before, what that means, at rest, no complaints if you're in Function Class I. Mild complaints in Class II .
Every improvement is a big deal, actually, and stabilization or improvement is in itself something very remarkable. So all in all, 86% were either stable or improved within these 12 weeks. Let's have a look at another parameter, hemodynamic. As you know, right heart catheter is an invasive tool. You cannot do it every day. I did a few thousand in my career, when I was in the clinic, but you don't do that every day. So for a trial, you do it usually one in the beginning and one in the end. So you just have two time points. That's it. And you try to derive your conclusions from these two values, if the patient improved or didn't improve or whatever. So what we tried to do is to get a better feel for it and used CardioMEMS.
CardioMEMS is a continuous, it allows a continuous measurement of the mean pulmonary arterial pressure, and then it is taken, the means are taken out. Explain that. But, so what happens is, at the first right heart catheter, you implant a tiny device into the pulmonary arteries, and then what happens is it is fixed there, and what the patient has to do is they get a mat at home. They just have to lie down there, and for 20 seconds, those 20 beats or whatever the heart rate is, are averaged, measured, and then that is done over the extent of the trial. And in our case, it was twelve weeks. So all in all, it was around 85 days. So what was the result?
The result was that most of the patients had a reduction in their mPAP, that means mean pulmonary artery pressure, in CardioMEMS. As you can see on the y-axis, this is mPAP area under the curve, AUC, and we gave also the units of one to 85 days. And as you can see, by the way, we have highlighted this special patient that you know, the patient case is in green, a bright green color. And the others, there were some that even had a larger improvement in their area under the curve. If you want to translate this to right heart catheters, because you say, "Well, I just know values of two, three, five. Suddenly, I see 400 mmHg . What does that mean?" Rule of thumb, very simple.
If you just look at it, these values between two hundred and four hundred, if you just divide them by 85, you get values around 2.5-5 mmHg . That is approximately equivalent to a right heart catheter. But please keep in mind, a right heart catheter and a CardioMEMS are two different devices giving two different informations. You cannot just put them one-on-one together. The information that one derives is additive, symbiotic, if you like, but it gives a good hint on where the pulmonary artery pressures are going in which direction. So all in all, a very good improvement, and as I was saying, it's around between two hundred to around four hundred and fifty. To compare it to a right heart catheter, you can, you know, divide it by 85. Who's good at math?
No, I won't do the test here, but it's around 3-5 mmHg . If you look at it, what has been published in the literature, a reduction of 3-5 mmHg , and this is not exactly mean pulmonary artery pressure. This is a diastolic pressure, very similar, though. You see that there's a marked reduction in mortality. Again, this does not mean that our patients had a reduced mortality, too small a trial, but it is an indicator that it improves in that direction between 19% and 30% if you reduce the pressure between 3 and 5 mmHg . Again, what is important is that all these three, REVEAL Risk Score, functional class, and CardioMEMS data, are pointing in the right or in the same direction, in this case, the right direction. What I had said, I'd like to just repeat.
43% of the patients in the REVEAL Risk Score showed an improvement. Functional class, one-third showed an improvement, 86% either improved or were stable, and the CardioMEMS data, again, showing promising results with the measurements. With that, I'd like to briefly hand over to my dear colleague, who is Head of Preclinical Development, Nick. Please, Nick.
Thank you very much, Rahul.
Thank you very much.
Yes. It's a great pleasure to be here and share some of the results with you today, in this wonderful building and this, very nice city, so I'm going to just show you some results. I'm gonna take a little detour here now and move into some preclinical results with a very closely related compound to CS014. This one's called CS014, and, you know, we've been sort of looking up until now at a bit of a cartoon world, where we depict vessels as being very straight-sided structures, and they're highly simplified. The reality is, however, quite different, and if we look, first of all, at a healthy vessel, so we look down a microscope, these are tiny vessels, much less than 1 mm in diameter.
What we see is the image to the left here, and in the center, you'll see an oval-shaped object, and what you're looking at is a vessel that's been cut side on, and it's the cross-section of that vessel. Surrounding it are the tiny air sacs that make up the lung. Now, on the right-hand side, what you see is a very different and very nasty picture of pulmonary arterial hypertension. This is from an animal model, but a very similar picture emerges in human beings with PAH. That central open lumen has been filled in by all of these proliferating cells here in the middle, and it's been. A single lumen has been replaced by multiple, very tiny lumen, and this makes it extremely difficult for blood to flow through that vessel.
Now, the reason, you know, we've been talking a lot about our hypothesis, but here's the reason that we believe that this principle, CS1, and this very closely related molecule, CS014, can do the job of remodeling these vessels. And it's shown, first of all, if we look on the far left of the figure that you see on the left-hand side there, you can see the occurrence of these kinds of plexiform lesions in the lung. They don't exist. When you look in this animal model of pulmonary artery hypertension and don't treat them, you see the incidence is around 20%, meaning 20% of the vessels that you look at under the microscope are blocked and filled in with these plexiform lesions.
And then, what we've done is treated the animals for just three weeks with these different increasing doses of CS014, and we can see that we dose-dependently reduce the occurrence of those vessels. So now, if we switch back again to the clinical study, we can't actually image those vessels in that detail, so we're forced to use indirect methods to assess the degree to which the vasculature is blocked. And that, the parameter that best reflects that is the pulmonary vascular resistance, or PVR. And, you know, what you see on the left-hand side of this slide is the pre-treatment levels. So as Rahul pointed out, we measure with this methodology at the beginning and at the end.
So at the beginning of the trial is plotted on the x-axis, and by the end of the trial is plotted on the right axis. And if there was no effect at all, all of these points for all the individual patients in the study would lie along this diagonal line, and you see that some have fallen below the line and some are a little bit above. But overall, there's a general tendency for the entire group to fall below. And what I wanna draw your attention to are the ones that are encompassed in this rectangle, which are really extraordinary.
So five individuals we saw with marked reductions in PVR, and if we look in the literature at reference information from large studies, placebo-controlled trials, so these subjects on standard of care treatment, we would say that having reductions of this magnitude are very, very unlikely. So we're really interested in understanding more about those individuals who had these very large reductions in PVR, consistent with our hypothesis. And so when we looked at the data a little bit more, what we could see, this figure on the left-hand side shows the relationship between the change in pulmonary vascular resistance on the x-axis and the change in stroke volume, so how much blood the heart pumps in a single stroke, in a single beat from the right side of the heart.
What we could see is that in those individuals, which are shown in purple, the ones that had the very large reductions in pulmonary vascular resistance, we could see that they also showed a very large increase in stroke volume. So we had evidence then of our main hypothesis, reversing the vascular remodeling, and also an improvement in right ventricular function. Now, so we have evidence that we've fixed the plumbing in this group of patients, but what about the clinical status? This slide really shows, I think, in a nice way, how we have not only fixed the plumbing, but it's also fixed the prognosis of the patient.
So in those individuals where we saw these very large reductions in PVR and in the increases in stroke volume, we also see that they have improvements in REVEAL Risk Score and also functional class. Which gives this really gives a sort of central verification, if you like, of our hypothesis. So just bringing together then the clinical and preclinical data, and as Rahul mentioned at the beginning here, we don't see any clear dose dependence of efficacy in our trial. But you know we have to acknowledge we have a small trial, but we think we understand why that is. And the reason we think that we don't see any dose dependency is that we are already at supratherapeutic levels of drug.
That's shown here in this slide, in this figure to the left, where we compare actually the exposures of drug from the preclinical work with the exposures which we achieved in the clinical study. You can see that all of the doses, even the low dose, are above the levels of maximum efficacy that we saw in the preclinical studies. We think that this indicates that we are already at a very good level of exposure at the lowest dose. Yeah, if I take this one, just to summarize then. I've shown you some data, preclinical data, showing this very beautiful and robust reversal of the remodeling. This is what we're really talking about. Also, specifically, this very hallmark feature of pulmonary arterial hypertension, which are these plexiform lesions.
I forgot to mention that we see in those studies a reduction of fibrosis, and that the maximum efficacy is occurring at equivalent exposures to the CS1 trial already at the low dose, which is why we don't see this dose dependency in that study. And that, you know, 24% of the patients responded with these remarkably large reductions in PVR and associated improvements in prognosis, and that, these, I mean, they were very substantial reductions and that, these changes in hemodynamics are kind of consistent with our hypothesis that we are improving clinical outcomes. So with that, I hand back to you, Rahul. Thank you very much.
Thank you very much. Thank you.
Yeah.
So the remarkable thing is, as Nick was mentioning, the reversal of plexiform lesions, even in the preclinical model, is something very unique, and this is something we're really excited about seeing. I mean, we're also excited, of course, about the results, but also the explanations, and we're seeing this in the preclinical thing. We have shared with you the results, we have shared with you some preclinical data that we're excited about, but we thought what would be equally interesting, and even more maybe for you, would be to hear from an investigator how he saw the patients. He treated several of the patients in our CS1 trial, and maybe I could request Julia to make sure that Dr. Guichard is now tuned in, and I'll just briefly introduce him. Dr. Guichard is a professor at the University of South Carolina. He's a Principal Investigator.
He's Chief of H eart Failure PH Clinic in South Carolina, belonging to Prisma Health, which is a $7 billion hospital chain, the largest in South Carolina, with several thousands of beds. So he sees a lot of patients, and we had requested Dr. Guichard to share his thoughts on, A, what excited him to join the trial, but what he saw while he was treating several patients with CS1 and what his impressions were. So, Jason, I hope you can hear us, and thank you so much for joining.
Yep. No problem. Thank you, Rahul.... so thank you everyone for coming. Can you hear me okay?
Very nice. Yes.
Okay, perfect. So yes, nice to meet everyone here virtually. And, why we decided to collaborate with Cereno for, CS1-003 was really kind of threefold. Number one, you have a novel pathway in this rare disease, which you guys have heard about already this morning. So that's number one. Number two, being an oral medicine, I don't know if you guys have touched on kind of the therapy for PAH there. It's kind of a phased out different medicines all the way from oral to IV. Of course, you might imagine in any disease process, oral, is always, better, you know, advantageous from a, from a patient standpoint. CS1 is an oral medicine. And then number three, was the CardioMEMS component of this trial. So we are very, active CardioMEMS program.
So it was combining two things that we loved, PAH and CardioMEMS. So this was a trial we were very interested in. Our experience with the trial, the patient's done very well. Across the board, the patients had a symptomatic benefit very early on, even at that one month, you know, a couple weeks to one-month mark. And I think one of the most important things of all is the side effect profile was minimal. You touched on it earlier today, the side effect profile of a lot of these PAH medicines is very high. So lots of headaches, lots of GI side effects, pain in some cases with some of the, the ways we administer the medicines. There was very little side effects to CS1, very few patient complaints, which is actually quite unique, in the PAH world.
And the feedback that we received, you know, like I said, patients felt better. And when we were invited to do the expanded access program, the patients resoundingly wanted to participate. There wasn't a single patient that we had, that wasn't interested in getting back on the medicine. I mean, in fact, a few of them, you know, almost kind of pleaded to go back on medicine because they definitely felt worse off the medicine. And anecdotally, I know that you've seen the evidence from the trial already, but anecdotally, we had a patient, you know, who came off the medicine, you know, after that last right heart cath when the trial was finished, and began to kind of backslide a little bit in the months after getting out of the-- or after the trial completion.
We repeated his right heart cath, you know, to see if he needed additional medicines, and his hemodynamic numbers were, you know, right back, you know, terrible, right back to where they were before the medicine. So he definitely had a regression in his disease process coming off the medicine. And we had to get him started on additional therapies to help improve those numbers. So lots of positive experience, both from the, you know, physician side and from the patient side for this medicine that's novel, that's oral, and then, of course, you know, had positive results with CardioMEMS. So we're very excited for CS1, and as well as utilizing FLUIDDA. I think this will be a very interesting and fascinating way of kind of looking at the disease process and reversibility.
I'll go ahead and pause there and see if anyone has any questions.
Thank you so much, Jason, for sharing your thoughts and input. Are there any questions maybe you would have directly to him? Because he has experience with patients. He has included nine patients in our trial. Any questions to Dr. Guichard? This is a one-time opportunity that you can ask one-on-one, unfiltered to one of our most active investigators.
There's one.
Yeah. Where? Oh, sorry. Yes, please. Microphone here, please. If you could just kindly say your name for him.
Hi, Joe Hedden, Rx Securities. Just wondering if you could perhaps give a little color on, when you're talking about improvements that you see in terms of patients walking into the clinic, like, how stark has this been in perhaps some of the, I don't know, most positive cases? I mean, what-- how can you kind of like, lay that out for us in what... How does it appear visually? Not the human dynamics, et cetera, but in terms of how they appear and what they're able to do, like, is that obvious?
Yeah, good question. And yes, it's obvious to the patients, and it's obvious to us. So probably the biggest improvement is daily activities, right? So they are able to dress themselves a little bit easier, you know, vacuum their house a little bit easier, you know, play with their kids or grandkids a little bit easier. It's kind of your daily activities or activities of daily living, where really that improvement is seen. As far as the degree, I think that was kind of another one of your questions. So the PAH, you know, when you first get diagnosed, you know, kind of standard of care, at least on the front end for most patients, what we call combination therapy, so a PDE5 inhibitor or NO pathway, as well as an ERA.
Generally speaking, when you get patients, you know, started on that combination therapy up front, patients will, you know, feel better, have that incremental benefit, symptomatic-wise. But the patients that get started on CS1, you know, I would say that that same benefit was again, kind of twofold, right? So patients, you know, get better with that first step of medicines. And then when they get started on CS1, you know, that same kind of incremental additive benefit, you know, after those two medicines. So you can definitely see, you know, kind of that improvement in just that short period of time with getting started on additional medicine, you know, which is exciting to see. And of course, we didn't know at the time, you know, the results of the study or the hemodynamics, you know, behind the scenes.
You know, we just kind of saw the patients. But to see that the hemodynamics internally improved, as well as externally seeing those symptom improvements, seen as just an exciting win for the medicine.
Perhaps just another one. On the patients who have a really remarkable PVR response, and I'm not, again, I'm not sure how many of those patients were yours or whether you've seen data from all the other centers, too. But is there kind of any commonality that's strikingly obvious from those patients and perhaps, you know, any insight into how you might enrich future trials, or is it too early to say at this stage?
Yeah, so that's a good question, and I don't have the individual patient data, you know, matching up which ones, you know, their PVR, you know, matched up to their symptoms or, or which patients they were. However, I will say, you know, the PVR is a great measure of kind of improvement and kind of, combines two important measures, right? Your PA pressures as well as your cardiac output. So it's a very good kind of surrogate for kind of good things, if you will. And we do see that as the PVR comes down, you know, the patients do feel better. But as far as specifically, you know, which patients, you know, had the best benefit and if we were taking care of them, I don't know that.
But I will say that, you know, those are all kind of very, you know, exciting outcomes for this medicine. And, you know, every patient's gonna be a little bit different, and patient selection is gonna be tricky. You know, as Dr. Benza would say, or, you know, would attest, you know, some patients do very well on these medicines, and some patients don't. And just like with any disease process, whether it's high blood pressure or high lipids or what have you in cardiology, you're gonna have your, you know, non-responders, you know, you're gonna have your average responders, and you're gonna have your super responders. And it's the same thing with the PH world.
You know, sometimes people can have, you know, life-threatening, you know, high pressures, and you just get started on one or two medicines, and it completely gets better, whereas some people need three or four, so there's you know, the human body is way more complex than just kind of a simple pressure, and sometimes it takes, you know, one medicine or more, you know, to get these patients managed, and it's, you know. If we ever figure out which patients are gonna respond, and when, you know, that'll be kind of the holy grail in all of medicine, not just pulmonary hypertension, but definitely something I'm sure people are working on.
Great. Thank you very much.
Okay. Thank you so much for taking your time out of your busy schedule and I know it's early morning where you are, but thanks a lot for sharing your thoughts.
No problem. Happy to do it. Thank you.
Thank you. Take care. Bye-bye.
Bye-bye.
So that was, I think, very interesting to hear from him, who has looked at several patients and his impressions. Allow me to maybe just continue. Briefly, we have heard from Jason, and now it's my turn again. I hope you're not getting too bored with me, but let us continue maybe the path forward, and that is something exciting. This is based on what our experiences, what our thoughts are, and where we want to go. We think we have an exciting plan to really create value, create a difference for patients, and really make a difference also in this whole arena of PH. You had just briefly heard from Dr. Guichard regarding the expanded access, that he's of course very interested. We already have one patient in.
I think we had shared that in a press release, and we are working to get the others in as well. Expanded access, if you ask, why is it taking so long? We are working on the paperwork, and paperwork is unfortunately something which takes longer and longer, so... We're working, and we're gonna get the patients. We are, there are many patients who are interested, as you heard also from Dr. Guichard. Many of his patients are interested in participating in that. I'll also briefly maybe regarding the analysis of the trial. The analysis of the trial is ongoing, and of course, we'll share it with you, but right now, we're still awaiting the tables, listings, and figures, and all of this will be coming over the next few weeks.
We'll be publishing it over, hopefully, the next few weeks and months, and as it comes, we'll be, of course, sharing those things with you. Regulatory path, I'll just go briefly into that as well, and the FLUIDDA story, and for that, we also have a guest, but I'll go into that more detail just briefly. You heard from Dr. Benza this morning, before, that yes, there are really many benefits for CS1 that are seen, and that's why actually the compassionate use was instigated by an investigator who wanted to continue after the 12 weeks. So we, of course, applied for it. We got the designation that we are allowed to use it, which is also a good sign that the FDA feels confident that this is a safe drug to for patients to be used in.
So the first patient, as you know, was dosed in August of this year, and we're of course continuing our efforts to include more and more patients. The expanded access for compassionate use is ongoing here, and the activities are ongoing. As I was saying, regarding the analysis, I've just talked about that. They are, as we speak, they are being done, they are being completed, and as they come in over the next few weeks, and as we publish them, of course, we'll then share them with you as well. We are going to engage with the regulatory bodies. Absolutely. We're going to go through the FDA, we're going to go through the EMA, we're going to present the data, but we will also talk about a phase IIb trial, and if they want phase IIb/III trial.
We have a path forward in our minds. Naturally, the FDA has to approve it and the EMA, but we think based on the data we have, based on the experience we have inside the company, but also with our clinical steering committee, we have clear path forward on how we want to progress to gather harder evidence that CS1 is really making a difference in this patient group. And what I would further like to briefly share with you is the FLUIDDA partnership.
FLUIDDA, what this is all about, and what it is actually, and here, what it is, it's a new method, and we'll just hear from the CEO of FLUIDDA, who will just dial in, in a second, where you can show and visualize through CT tomography, computed tomography, you can visualize the vessels, but different also aspects of the alveoli and so on and so forth, in a color-coded fashion. So it's very visible. It's not, of course, invasive, and you know that, Nick was sharing the plexiform lesions, but that you can only do with a biopsy. That is pretty dangerous in these patients. So we were looking for innovative methods which could really maybe illustrate it and, show it, and we have found this method with FLUIDDA that can show it.
Let us try maybe now to have the CEO of FLUIDDA dial in here, and that is Jan De Backer. He has a very interesting background. We got to know him some months back at a conference. Jan is actually an aeronautical engineer, but then he and you can maybe share that briefly, how you pivoted into this very exciting world of FLUIDDA. So, Jan, welcome, and thank you very much for taking your time.
Thank you, Rahul. Do you hear me well?
Yes, very clearly.
Perfect. Excellent. No, it's great to be here, and it's, it's great to, to give you a little bit of a flavor of what, functional respiratory imaging is, and since you mentioned the background, I'll very briefly, mention that. So indeed, I'm an Aerospace Engineer by training. I went to, to Delft University of Technology, so not too far from, I think, where you are. My father is a respiratory physician, so he's a professor of Respiratory Medicine in Antwerp, in Belgium, and about almost 20 years ago, he said, "Oh, it's kind of cool, you can simulate flows," 'cause I was using computers to simulate flows around wings, engines, and so on.
Can you also simulate the flow in the lungs?" The reason he was asking that at the time, he was a reviewer for the EMA, and he said, "It's very difficult just using the conventional endpoints to really understand what these interventions are doing." Pretty much across lung diseases, whether it was COPD or asthma, ILD, or pulmonary hypertension. The idea was to see if we could combine methods from aerospace engineering with medical imaging to do two things: enhance our understanding of lung diseases in general, but maybe even more importantly, understand the effect of interventions. What do these drugs do in terms of changing airways or blood vessels, et c.?
And can we maybe use it to speed up drug development, and to the point earlier, can we maybe redefine some of the diseases around responder phenotypes to make sure these drugs are as effective as possible? Functional respiratory imaging, as you see here on the slide, is a quite new technology, so it starts from the conventional CT scans. So we don't need to have additional hardware. We can work with pretty much any site that has a fairly modern CT scanner. And maybe you know that today, still, the vast majority of these CT scans are only visually assessed by a radiologist, and we believe that that way, you probably extract maybe five to 10% of the information that's actually embedded in those CT scans.
What functional respiratory imaging does is we convert these 2D CT slices into 3D reconstructions of anatomical structures. We can look at airways, blood vessels, lung volumes in 3D, but we can also measure them, and we can convert them into structured data. In this day and age of artificial intelligence, structured data becomes quite important, becomes quite powerful. By taking an inspiratory and expiratory CT scans, and these scans are very low dose, so there's not a lot of radiation involved. By taking an inspiratory/expiratory scan, we can make these static images come to life, and we can look at regional ventilation, airway resistances, and we can also look at the deposition of inhaled particles.
So just by using the CT scans, if somebody uses their inhaled drugs, we can see on a patient-specific basis, where do these particles end up, and are we sending the right drugs to the right parts of the lungs? So just by taking these two low-dose CT scans, you have a very comprehensive set of parameters that help us to understand what's going on in those lungs. So we have endpoints and structures that look at lungs and airways that we can visualize and quantify. We can look at the parenchymal structure, including things like air trapping, emphysema, fibrosis as well, so it's being used in diseases such as IPF. Very importantly, especially for this compound, is looking at the blood vessel structures, and I'll show you a little bit more of that in a second, but we can look at the blood volume distribution.
We can separate the arteries from the veins, so specifically for pulmonary arterial hypertension. Zooming in on the arteries is quite interesting. We can look at the blood vessel wall thickness and see how it compares with healthies or within a disease group, and vessel tortuosity are other parameters that we can specifically focus on. And then the last categories is more the functional parameters, as I said before, ventilation perfusion, et cetera. 'Cause it's quite important to, we believe, to see if we can get a good handle on the core function of the lung, and as you know, the core function of the lung is to make sure that the oxygen is transported from the environment into the bloodstream, and things like ventilation, perfusion, et cetera, are obviously quite important for that.
So the visuals is also one element which is quite useful here. So instead of having to rely on somewhat black box parameters, like even symptoms or right heart catheterization, that is pretty much a sum total of everything that happens in the lungs. With these images, you can visualize on a regional level what's going on. And so here on the left-hand side, you typically see a healthy subject and then a matched PAH subject, and these are the blood vessels. And so what you see immediately is that there's quite a big reduction in these red zones, and the red zones are the smaller vessels. So you see typically in pulmonary arterial hypertension that the small blood vessel volume reduces, and then the larger vessels dilate. So the blue zones here, which are the larger vessels, they are significantly larger than in a healthy subject.
So you do see a redistribution of the blood from the smaller blood vessels into the larger ones. You can visually see that, and you can also quantify that. Here are some of the numbers where you see, compared to a healthy subject or a healthy group, you see a reduction in small blood vessel volumes. Here, the BV5, which is the volume of the blood with a cross-sectional area below 5 mm² . That's a kind of technical term, the BV5. And then you see that blood is being pushed in the larger vessels, in this case, the BV10, which is significantly larger than a matched healthy control population. We see correlations between these parameters and hemodynamics.
Typically, if you look at the pressures, you see that if the pressures go up, if the disease becomes more severe, you see a reduction in the small blood vessel volume and an increase in the larger blood vessel volume. We also see that when we compare it with the pulmonary vascular resistance, so higher resistances are associated with lower small blood volumes and higher large blood volumes. It's not just PAH where we can use this. We use it pretty much across all lung diseases, but indications like COPD, COPD- PH, as you see an example here, are quite interesting indications because in general, in lung diseases, the vasculature for many, many decades has been overlooked.
We typically, especially in, on an asthma COPD sites, we look at spirometry and how the airways are doing, the lung volumes, but we never really look at the vasculature because it's hard to do if you wanna do it in a non-invasive way. But now with these quantitative and functional imaging approaches, we can get much better insights there, and it opens up a whole pathway. As I said before, we can, especially using these advanced AI algorithms, separate the arteries from the veins, and that allows us to really focus in on these two sides, whether it's pre or post-capillary, to get a better handle on what these drugs are doing and potentially also look for phenotypes that respond quite favorable to some of these interventions. We can look at the blood vessel wall thickness.
So if we use contrast, we can measure the thickness of the blood vessel wall from the arterial and the venous side. So here in a PAH subject, you see that the red colors indicate thickening of the wall versus a healthy subject. And then the green colors on the venous side show that the venous side typically is more normal compared to or is matched with a healthy subject. So again, more quantification, visualization also of these blood vessel wall characteristics. So we started the company almost 20 years ago, so we've been around for quite a while, and we see over those last two decades that imaging is really moving from, let's say, a nice to have, more towards a need to have.
So also because the standard of care is improving, and luckily for the patients, we see more and more drugs coming to market across all lung diseases. So there is a bigger need now to differentiate the different drugs or to look for better phenotypes in these patients. So we are working with quite a number of companies in the PH space and beyond that. And we're also quite experienced in training clinical sites. So we also are an imaging CRO. So we go to the sites, we train them, we make sure the image quality is optimal, such that the quality of the scans and the quality of the study can be optimized. So we train more than 550 clinical sites worldwide.
And we're very much looking forward to working with Cereno to assess their new compound and maybe several compounds in the future. So if you have any questions, please feel free to ask. Here are my contact information if you wanna know more afterwards, send me an email or we can connect over LinkedIn. Happy to do that, so. But please, if you have any questions, let me know.
Thank you very much, Jan, for sharing those insights. Do we have any time for questions? Yeah. Okay, any questions? As you can see, this is really top-notch AI-used technology, which will can really visualize the vessels' non-invasive methods. So this is what we are also aiming to use, as you heard from Jan and from Dr. Guichard. We are going to engage at least one center for this, and we're going to use this technology. We want to visualize, we want to show, because we believe in CS1, that it makes a difference in the patients, in their vessels, so that we are not just theoretical, whatever. We're talking not theoretical, but also really showing it. Nick showed it beautifully in the preclinical scenario. We cannot biopsy patients out of obvious reasons, but if we can show that here, lovely.
Any questions to Jan? ... Okay, we have, we have one master question. Yes, thank you.
Hello?
Yes.
Yeah, Joe Hedden from Rx Securities again.
Speak up a bit, please.
Sorry. On the previous slide, you showed some of the trials where you've been using this across PAH and other lung diseases. Just interested in, like, what did you see? I mean, did you see some strong effects in some of these trials that suggests any kind of disease-modifying activity or effects that suggests just a normal symptomatic. Are you able to tell the difference with the technology at this stage? Yeah, just any color on that.
Yeah, absolutely. So a few of them already showed results, like the Merck compounds, the MK-5475, is a vasodilator. And there we did a study at different dosing levels, and that the drug works very well. So it vasodilates, you see dilation of the vessels, which was correlated with changes in the right heart catheterization data. Maybe interesting as well is the Gossamer data, so the seralutinib. The TORREY study readout where we did see significant improvement, specifically in the BV5 to BV10 arterial ratio compared to placebo. So what we saw in that group is that the treated group increased in their BV5 volume, so the small blood vessel volume, and reduced in the larger vessel volume.
A redistribution of the blood vessels that we would think is associated with an improvement in these patients, and that also correlated with stroke volume, improved physical exercise, et cetera. So, there's quite a lot of evidence that the CT is a very sensitive endpoint to detect these changes, and that the changes that we see tend to correlate with other clinical endpoints that either show stabilization, improvement, or deterioration, often the placebo group. So it's quite hopeful. And then we'll see a lot of the data coming out, especially in PH-ILD, a very tricky disease, as you probably know, where there's a lot of things that are going on from the parenchymal side, airway side, but also from the vascular side.
And there we also see quite interesting results, and those will come out pretty soon. So yeah, we're, as I said before, we've been doing this for quite a while, so it's not a, let's say, novel technology anymore. I think there's good evidence that this is quite a valid way of looking at lung function and structure. And we're looking forward to seeing more drugs coming through so that we can start to kinda see where all of these individual drugs can be positioned in the market.
Thanks.
Okay. Thank you very much. One more? Okay, one more, one short question, and then... Yes?
I wonder, can you see the difference between the blood vessels and the alveoli themselves? Can you follow the relaxation of the muscular tissue in alveoli and so on?
So no, unfortunately, the resolution of the CT scan does not allow us to directly visualize the alveoli, so we can go to a resolution of about 1 mm . But the nice thing, of course, with fluid dynamics in general, that everything is connected. So you kinda see where if a signal happens more upstream, you can infer what's happened further downstream. So that's why these looking at a redistribution of the blood volume from the larger vessels to the smaller vessels or vice versa, is kind of a good surrogate to understand what's happening even more downstream in the microvasculature. So it's probably the way, the most sensitive way in an in vivo setting to get to what is happening on a fairly small level in terms of the vasculature.
Okay. Thank you very much. Thanks a lot, Jan, for taking your time and sharing your thoughts. That was lovely. Thank you. I just want-
Thanks.
I just get a signal right now. I mean, again, don't get me wrong, but if there are more questions, the pause will be shorter, again. It's. But as you can see, we're working on several fronts to be innovative, to really elucidate as much as we can from CS1, as much information we can get in, of course, a thing that patients can well tolerate. And hopefully, we move in the right, fast direction to really create value for us all, for patients, but also for us all. Okay, with that, I'd like to hand over briefly to Sten.
Thank you, Rahul.
Thank you very much.
Good job. So now you have about. Well, it's seven minutes past, not five minutes past, so now you have eight minutes to take the pause. Kidding. So about ten minutes, come down here again. Bring the coffee, as a suggestion, or tea, or water, and then we're gonna look at CS014, IPF. It's gonna be cool. All right, the countdown is done, so we're live again. So it seems, in the male audience, there's not a lot of guys with the age of prostate problems. You got back in ten minutes. So anyway, joke, joking aside, so I hope you enjoyed the session about CS1, and now we have two sessions still left. So CS1, CS014.
Mm.
So that's the analog of VPA, actually. Very similar compound, but better profile. And Björn, Chief Scientific Officer, joined the company already when it was inaugurated, 2012. And actually, he's been part of developing another drug that's in development for IPF. So has a long history, of course, Björn-
Yeah.
And we don't have time to go through that.
No, no, you don't have to.
Please, the field is yours.
Okay. Thank you. Can you hear me?
Yeah.
Okay, good. Good to see you. I recognize a lot of faces here. Must have been in contact with us before, some of you. So it's good to see you, and it's a pleasure for me to go into the, you can call it new indication, the CS014 going forward. And can I have the first slide, please? Oh, it's me to do it. Okay, sorry. So the first slide sometime. So this is CS014. You know, it has been developed in relation to VPA to improve on the molecule. It's a new chemical entity with a patent protection. I will come back to more details about that. So we are going to talk about a disease called idiopathic pulmonary fibrosis, and that's a devastating disease. Patients suffer severely. They have dry cough, almost constant dry cough, dyspnea, fatigue.
The lung structure is destroyed with fibrosis, and the lung loses its compliance, and it loses its ability to exchange the gas. The oxygen coming in and the gases going out, that is impaired. So these patients usually progress into respiratory failure, and the lifespan for these patients is in the range of three to five years. And this is a disease that comes in middle age to elderly in most cases. And I just made a comparison here with cancer diseases, and you can see that the survival for these patients, around 45%, five-year survival, that it's below the average cancer form. It's more severe than many cancer forms. So this is really hitting the patient with both the survival and a very poor quality of life.
This is some more detail just to show you that in the upper, to the left, in the upper panel, you see a normal lung with nice alveoli and vessels in between. In the lower panel on the left, you see the destroyed pulmonary parenchyma, so to say. Not many alveoli left, lots of other tissue, and the blood vessels are far from the alveoli. The fibrous tissue, if you go to the right here, you can see it, it kind of gets in between the bloodstream and the, where the air is coming in, in the alveoli. That kind of gets worse and worse and worse. It has been compared to constantly breathe through a straw. Try to do that sometime. You put a straw in your mouth, breathe for a minute or something, and do something strenuous.
It's really a poor quality of life. This disease affects mainly men, predominantly men. Some have smoked, so smoking has been discussed as, but it's not every smoker that gets it. It's a rare disease still. But it is idiopathic, so we don't really know what really causes it. It's kind of a scarring. It's misdirected scarring in the lung, you can say, the progression of the disease is, for many patients, kind of slow but constant. Some are rapid progressers, but the majority goes on a slope that ends in three to five years. But some have these exacerbations, meaning that you have a certain drop in your lung function, and you have to be hospitalized, and that could be deadly, and we don't really know what happens when these exacerbations come, but it's a very severe development of the disease.
There are some patients in the world, quite a few. If you take Europe and U.S. together, it's around three hundred thousand patients. But it's still, in both U.S. and in the European area, a disease that fulfills the criteria of being a rare disease, and you can have orphan drug designation for your drug. So it fulfills that, those criteria. The diagnosis, you have heard from Jan De Backer from FLUIDDA, that CT is a good measure, and you can see lots of things in the lung. Actually, high-resolution CT is something that you can also diagnose IPF with. In some cases, you have very, very particular and characteristic changes, and you can. The diagnosis is done by only CT, but in some cases, you need to go further to differentiate it from other interstitial lung diseases.
And then you do either a biopsy from the bronchus, from the airways into the lung, or you can do what I call BAL, which is you kind of inhale liquid, and you exhale the liquid, and you get some fragments from the lung, and you can do some histology on that. So that's the way you diagnose it. The therapy is very poor, you could say. There are two available drugs, and that's it, and that has not been coming in new for many, many years. The patients have several comorbidities. They develop pulmonary hypertension. There is an association with lung cancer, with venous thromboembolism. And the therapy, if you look at that a little bit closer, you can say that it prolongs modestly the life of the patients.
There is a modest effect on progression, but there's very poor tolerability. Many patients don't want to take the medication, and many stop the medication because you can't promise any cure for the patients, and what is really disturbing, I think, is that the therapy doesn't have any real good effect on symptoms either, so the patients have their cough and their dyspnea and their other symptoms... and they don't have any real effect on mortality either, so it's really a poor prognosis, so you can summarize it that neither of the drugs is associated with any consistent improvement in patient-centered outcomes, symptoms, physical capacity, or mortality, so that's really a unmet need to fulfill, so I've said that there are several comorbidities, which are important. IPF is associated with venous thromboembolism, and that's where we have kind of a stronghold with HDAC inhibition.
It is associated with lung cancer, where HDAC inhibition have shown to have effects on some cancerous diseases. So I think we have a very strong position from that perspective. But also, and you know, we have good data in pulmonary hypertension, in the PAH. These patients develop a similar vascular remodeling as the PAH patients, but that comes from a little different direction from . It starts with the IPF disease, and then they develop the remodeling successively, and more than 50% go into pulmonary hypertension. And if they do that, they have a worse prognosis than if they don't. So that's also a very important aspect. So before I go into the rationale for why we believe CS014 is a good choice in this, is that IPF is a devastating disease with poor quality of life and no cure. Survival rate is on par with worse cancers.
There is a poor tolerability of therapy, no effects on symptoms. You have a very modest effect on disease progression and no effect on mortality. So there is definitely a need for new therapy, disease-modifying therapy. And then we come to HDAC inhibition, and you have heard about it. You have seen this slide several times before. 2019, I did a deep dive into the literature, found around 600 articles about HDAC inhibition in various diseases. Mainly, it was documentation for VPA, and you have seen these effects. You can have a reverse remodeling of the vasculature. You can have an anti-fibrotic, anti-inflammatory effect. You can reduce pressure and have an antithrombotic effect. We think with this profile, an HDAC inhibitor could be a very well match with the disease.
Already in two thousand and nineteen, we did this schematic, where we tried to identify different indications. You can see there is a whole list. We have PAH. We went forward with CS1, and we have IPF now for CS014. We are on that path, HDAC inhibition. Does HDAC inhibition fit with the disease? Yes. We don't have to go into detail, and we don't have time for that, but there are several publications showing that there are changes in the HDACs just fitting the Class I, which is where VPA and CS014 is. We had good data with PAI-1, with VPA, and there is a good association between PAI-1 level and collagen formation in this kind of of inflammatory lung injury. There are good data to show that IPF patients have about two times higher thromboembolic risk.
And CS014, as said, had many properties similar to CS1, and it was developed to retain the benefits of VPA but improve on metabolism. So this is the patent-protected new chemical entity. It has very similar pharmacology, and it's basically the same doses that are needed. So it's a very good follow-up to VPA. Well, there are several studies, I don't have time to go into detail, that shows that giving VPA in models of IPF, mainly bleomycin models, have an effect on the fibrosis that is relevant for this disease. And you have heard about the data on CS014 in the PAH model, showing both a reduced incidence of fibrosis, but also a dose-dependent reduction of occlusion of lung arterioles, endothelial proliferation, and of plexiform lesions. And on top of that, Mike's work here in thrombosis is also relevant.
We have three different models which have shown very clearly that CS014 is an antithrombotic without the risk of bleeding. So before I sum up, I just want to say there is a close relation between pulmonary fibrosis, thrombosis, and pulmonary hypertension. So IPF patients have an increased risk of venous thromboembolism. Pulmonary hypertension affects up to 50% of the patients with IPF, and the pathogenic mechanisms are very similar. So what I've told you is that this is a devastating disease with a poor prognosis, limited therapeutic options, huge unmet need, of course. And the rationale for having CS1 in IPF is that HDAC inhibition, in particular VPA, have very good data in fibrosis, venous thromboembolism, and in proliferation, like in cancerous diseases.
That CS014 have shown in preclinical very good data on both fibrosis and vascular remodeling, and that these patients have pulmonary hypertension and VTE. So that said, I think we can see in the future a very important aspect of this disease being addressed with CS014. And I just want to finish off with this slide, which was a slide shown by Jan De Backer, that we can look at the vasculature in a very profound way. I think we can also have a very good view on the fibrosis with this technique. So with that said, I think I stop there. Okay. So now it's my pleasure to introduce Mike Holinstat. And you are professor at the University of Michigan. You're in clinical pharmacology, and you have a very keen interest in the hematology and in particular, the platelets function.
So we are looking very much forward to hear your view on CS585, with these aspects in mind.
Great.
Please.
Yes. Well, thank you. And it's really a pleasure to be here to talk to you a little bit about CS585 and the new preclinical program that we have, because it really takes us in a different direction. We have lots of patent protection on CS585. I'm gonna talk to you on where the holes and gaps are in current therapy, and where this will actually drive us forward in the future. Those are platelets you're seeing. That's what happens when the platelets in the vessel sees a site of injury.
Since the nineteen eighties, we've recognized that platelets are the key in the blood for regulating thrombosis and that every 34 seconds, somebody dies of a cardiovascular disease, and 50% of that cardiovascular disease death is due to clotting, and so the platelets play a key role, and they're. That's why they're viewed as first in class, right? The challenge is that we've actually focused on several targets, and we have lots of drugs for four targets, and that's been beneficial. It's decreased morbidity and mortality by 26%, but still, as I mentioned, every 34 seconds, somebody dies of a cardiovascular disease, so we need to do better, but what we need are new targets, not new drugs for the same target.
The other challenge is, we need to decrease thrombotic risk, but we can't do that at the risk of bleeding. Bleeding can be more deleterious than the clot, so it's a tall task, but I think I can convince you here that we are onto something. Cyclic AMP in the platelet inhibits activation. There are some drugs on the market that try to do this. PDE3 inhibitors are used in very special cases, but they're not well-tolerated, so it's only very specific circumstances when one can use that. We know that cyclic AMP is a viable target. The challenge is targeting the activation and formation has not been successful to date. I will talk about where I think CS585 has overcome some of these barriers.
So we developed CS585 to target the prostacyclin receptor. I'll just refer to today as the IP receptor. We demonstrated that CS585, potently in the low nanomolar range, can form cyclic AMP in the platelet, that formation results in the activation of molecular targets, in this case, the activation of VASP phosphorylation. And you can see again, at very low nanomolar concentrations, you get that molecular activation. That molecular activation translates to activation of the pathway and inhibition of platelets. We've shown, and this is all human data, that in human platelets, we can inhibit the activation or aggregation of platelets through multiple pathways. I'm showing here collagen, but we've demonstrated thrombin, ADP. All the endogenous pathways to activate the platelet can be attenuated or inhibited through activation of the prostacyclin receptor.
Does this actually translate to an inhibition of a clot, which is a real problem in the man? So if we turn to animal models, we can see that CS585 in the mouse potently inhibits injury-induced activation. We'll get into that a little bit later, and how that is different than the other prostacyclin receptors that currently exist. So now that we have a pathway and we have validated its utility, there are a couple of questions that come up. There are other IP receptor agonists that exist. However, they are challenged. They're challenged with selectivity, they're challenged with having very short half-lives, and they're challenged with their utility in the blood. So this is why the IP receptor agonists are limited in their clinical utility to pulmonary arterial hypertension and not to blood diseases themselves, such as thrombosis.
So there are a couple of areas we wanted to determine. We wanted to determine first, is CS585 able to have, be more selective than the other IP agonists that exist? And does it have sustainability? Can you give it to a patient or an animal in the blood, does it have a long-lasting effect, and is that effect reversible? So first, I'm gonna show you a little bit of data, again, this is all human data. If we look at human platelets, and we want to know, does CS585 show selectivity? We can see that the molecular target, VASP, that I mentioned before, it's dose dependently causes activation or phosphorylation of that protein.
If we inhibit different receptors on the platelet that go through similar pathways, that also are known to regulate cyclic AMP, such as the prostaglandin receptor pathways, the EP2 and the EP4, if we block those, you can see in the green line that has no effect on the ability of CS585 to phosphorylate VASP. If we block DP1, the prostaglandin D pathway, it also has no effect. However, if we pharmacologically block the IP receptor, prostaglandin receptor itself, we have no ability to phosphorylate or activate those proteins. So we can interpret that to usually mean that we are specifically going through that receptor. And what you see on the right is the dose dependency. And I want to point out that at the molecular level, we are inducing activation in as low as 100 pM of drug.
And that with the IP receptor inhibitor, all of that is gone. We then. Does that translate to actual platelet activation? So we repeated these dose-dependent experiments, and we looked at human platelet aggregation. And again, you can see blocking the EP2, the EP4, the DP, none of that affects the ability of CS585 to inhibit platelet aggregation. Neither do they inhibit it or do they shift the curves. However, pharmacologically blocking the IP receptor completely reverses the ability of CS585 to inhibit platelet aggregation, suggesting, again, selectivity towards that receptor. We now turn to whole blood. So there was an assay we conduct, where we take whole human blood, and we flow it at arterial shear, what one would see in the carotid arteries.
And we look at the ability of those platelets as they fly through, to adhere to a strip of collagen. Collagen is what underlies the endothelium. So when there's an injury, it is the collagen that the platelets would see, and that's what causes the clot. And what you can see on the left, in a vehicle control condition, is that you get a lot of platelet adhesion to that collagen at arterial shear, which ends up with a thrombotic event. On the right, the same human blood treated with CS585, you severely attenuated the ability of those platelets to adhere under arterial shear. Now, if we look at the third row here, that's CS585 in still shots, but if you look at the bottom row, we've now taken that whole blood, and we've inhibited the IP receptor.
If we inhibit the IP receptor, we completely reverse the ability to adhere to the underlying collagen and form those clots. Again, supporting the selectivity. Selectivity is really important because this is the cause of most of the off-target effects, the nausea, the GI issues that we see with the IP receptor agonists that currently exist. We finally moved. That was all human data. We finally moved to animal to say, "Well, what in a very complex in vivo environment would happen with CS585?" We take anesthetized animals, we expose their arteries, we take a laser to pinpoint, to cause a pinpoint induction of a vascular insult, and we use antibodies in the bloodstream to visualize the platelets as they enter and form a clot.
Now, to know whether in this condition, which is as close as one can get to human, before you get an IND approval and can put something into man, we use an animal that doesn't have an IP receptor. So this is, again, the in vivo experiment. And what you can see on the left is the, it's a real-time experiment as it's occurring, and you can see in wild type animals on the top row, you induce an injury, you get a clot within minutes, the platelets accumulate. Wild type animal treated with a single administration of CS585, you completely block that clot from forming. If we take an animal that doesn't have an IP receptor, you can see that you get an even larger clot without drug, but with CS585, it has no effect on that clot from forming.
Each one of these assays was done or repeated 40, in 40 different vessels. So we have an n of 40 injuries for each condition, highly reproducible. We then wanted to turn to sustainability, and we wanted to actually compare this to two drugs that are on the market. So we looked at iloprost first. We gave a single administration of iloprost to the mouse, and we looked at different time points. How long would we have protection? And what you can see with iloprost, you are fully protected for 10 minutes. Well, that's not surprising since the FDA guideline is for iloprost is to give it six to nine times a day, and it does not have, and it's not reported to have any utility in regulation of thrombosis.
Then we turn to our, one of the newer drugs, selexipag. Selexipag is better. We can block platelet activation for up to four hours, but again, post four hours, you have full activation that occurs. And that is really in line with the half-life of selexipag. We then compared that to CS585. And what you can see with CS585 is that through the entire IV 18-hour time window following a single administration, we have full inhibition of injury-induced VASP activation. We then wanted to know, because really, we would think about this as an oral administration. We wanted to see, well, if we gave a single oral administration to the animal, do we get protection? And what we found is we protect from injury for over 24 hours, but importantly, at 48 hours, we get a full reversal.
So what we have is a molecule that has sustainability in the blood, works for over 24 hours, but is reversible. This is really important. Where could we use this? Right? So I just mentioned at the very beginning that thrombosis is a major problem, and 50% of cardiovascular death is due to clotting. But one of the really important issues is that there's a number of rare thrombotic diseases for which there is no treatment or not good treatment. And so here are a couple of those. We have ITP, which is immune-mediated thrombocytopenia. It's a rare autoimmune disease where the immune system mistakes your platelets and destroys them.
We have HIT, heparin-induced thrombocytopenia and thrombosis, where patients who receive heparin for procedures will then form an antibody complex, and those patients bleed and clot at the same time and have about 25%-30% mortality. VITT, vaccine-induced thrombocytopenia and thrombosis, you're all familiar with that, due to COVID-19, and we have APS, antiphospholipid syndrome, so APS is when antiphospholipid antibodies are formed in the body, and they cause the immune cell to form NETosis. That's neutrophil extracellular traps, where the immune cells literally explode. They release all their DNA into the blood and form a net, and that net, combined with platelets that are active, form a thrombus.
That's now appreciated, that NETosis through the immune cell and activation of the platelets are the two key aspects of thrombo-occlusive thrombosis in the microvasculature. Where would CS585 actually have the best utility? With ITP, it's complicated, right? It's a platelets are a key aspect of the disease, but there are a lot of challenges in the disease due to the acute nature of onset and resolution, and the fact that we really don't fully understand how ITP progresses. HIT, heparin-induced thrombocytopenia and thrombosis, is most prevalently seen with unfractionated heparin. But with the shift from unfractionated heparin to low molecular weight heparins, that incidence has decreased, and with the increased use of anticoagulants, such as factor Xa inhibitors, that population has continued to decrease.
Vaccine-induced thrombosis and thrombocytopenia, that is, we've seen that throughout history, that patients who get vaccines, some will sometimes clot. And we also know that during COVID-19, if you didn't get the mRNA vaccine, there was a high incidence of clotting. In fact, I believe it was one in 10,000 patients in the hospital during COVID-19 had a clot related to the vaccine that they received, and that was typically the AstraZeneca and the Johnson & Johnson. And so, that's going to be challenging going forward because now mRNA-produced vaccines are becoming more prevalent. Therefore, VITT is going to decrease in its prevalence in society. APS. So let's think about APS for a second. So the hallmark is a decrease in cyclic AMP. We know that our drug increases cyclic AMP, so you start to address that. It causes NETosis.
That NETosis is directly related to the decrease in cyclic AMP. That's known. So by increasing cyclic AMP, we can begin to address that. Neutrophils have an IP receptor, so we can target them. And the other aspect of APS is platelet activation. So the platelet activation and NETosis result in microvascular thrombosis. The only treatment for APS currently are vitamin K antagonists, anticoagulants. They work in about 80% of the patients, but only in the large vessel. So large vessel arterial thrombosis can be blocked in 80%. So one in five, the anticoagulants will have no effect, and the anticoagulants have zero no ability to inhibit microvascular thrombosis, which is the major pathology of APS, whereby the microvasculature that feeds the organs of the body cause dysfunction and eventual multi-organ failure. So what are we showing?
Our drug that we've developed can increase cyclic AMP in the neutrophil, prevent NETosis, can increase cyclic AMP in the platelet, prevent platelet activation, and those two together can prevent thrombotic event in the microvasculature and begin to address and treat these patients. When we think about the patient, like, why would we need to treat APS versus any other patient? Here are some facts about these patients. One in 2000 people exhibit some form of APS. It is defined as a rare disease. It falls under the orphan drug designation, both in the U.S. and Europe. It is thought to be responsible for up to 1% of thrombosis worldwide.
20% of people younger than 50 who have a stroke are thought to have an APS as part of that sequelae, and it's reported to be 10 x more prevalent in women than men. The unmet need? Well, the only treatment is the vitamin K antagonist, and the vitamin K antagonist don't work. They don't work for where the real pathology is, which is the microvasculature that feeds the organs. So these patients are in an environment where they really have no alternative or opportunities. And catastrophic APS results in microvascular blood clots, leading to organ dysfunction and failure. So CS585 has the significant potential as a novel therapeutic for limiting clotting based on the neutrophil and platelet, being able to target both.
Based on the characteristics of CS585, where it increases cyclic AMP, it's highly selective, and it has long-sustaining activity in the blood. This might be one potential target for CS585 as we move forward. With that, I thank you. I'd like to invite Sten to come back.
Thank you. Thank you, Mike.
Yeah.
It's almost like you want to make applause when he speak. Yeah, so, you know, before I continue, you've heard scientists and experts in the field here, and I think you get a feel for how we work at Cereno, right? So deep science, medical need, and target, where we can do the best value for the patients. So, you know, we're moving fast in our agenda. I have a few minutes here to talk about strategic priorities and future outlook, and then we have, I think, 20 minutes, depending on how I do, to have questions and answers. I think also for those of you who have time to stay, that might be an even better session for Q&A because you can approach individually and grab Mike or Nick or Rahul or Björn and talk. Okay?
Strategic focus of Cereno and what about the future? Well, you've heard today, and you know about CS1 and the focus in the rare disease as the initial target indication. We've got good safety and tolerance data in our phase II, and it looks exciting that we can improve risk score in 43%, 44% of the patients. That improvement is 23% reduction of mortality risk within 12 months. So that's what the physicians would like to do. What they also like to do, maybe even more, is to improve the function of these patients, the functional class, actually, the physical capacity, because they're living quite short lives. They want to live good lives, as good as possible. So that's the functional class, the physical capacity. And of course, you want to address the hemodynamics and protect the heart.
So PVR, increased stroke volume, and stop the pathological remodeling that's occurring in both the vessels and the heart, and the heart failing eventually. So that's our target. We're moving towards the final analysis and then into the next program to confirm what we have said and maybe more. And of course, with FLUIDDA and compassionate use program, that's gonna be long-term therapy with CardioMEMS as a tool, with FLUIDDA as a tool, and all the other measurements. So our drug can also, in that compassionate use program, be titrated to the dose the physician like to use of the three we have. CS014, now, today, we communicated that we are moving that into also a rare disease, also deadly disease, even shorter timelines that you heard from life expectancy than PH.
So the mean is around three to five years, like severe cancer. And that's also attacking the lungs, if you will, but on the lung side, not the pulmonary artery side. And with the characteristics and the documentation that exists already, and there's information about HDACs involved in this development, and we have documentation on VPA, the mother molecule, if you will, that it actually works in IPF. So that's super exciting. We're doing the clinical trial, phase I now, so that's in healthy volunteers. That's gonna be done by summer, and then we're gonna move towards FDA or Europe, we'll see, and pursue an IPF study, right? In phase II. So that's not too far from now. And of course, now you just heard about CS585, and you can hear, right?
We're looking at rare disease also for that compound. We haven't selected it, but you saw Mike's recommendation here in his analysis, is APS looks really good, right? So we'll see where, when, and what indication we'll pick. It might be APS. Now, that program is ongoing under the lead of Nick, Nicholas Oakes, our Head of Preclinical, who's been with Astra for ages, and we're thankful to have you with us. That program, we hope, will conclude by 2025 and then move into the clinic. So that's our target, so that means tox studies, et cetera, et cetera, next year, so increased focus on rare diseases. Why? Well, we're working with patient need as the, you know, driver for us. We want to help patients.
But it's you know, our drug needs to fit for those, and there is a significant unmet medical needs in the indications we talked about today, and our drug seems to have a high potential to deliver value, our drugs in these patients. The more severe disease, if you have an effective drug, you can impact the better, right? You have a high potential. Now, orphan drug status is attractive from a business perspective. You there are incentives, of course, but you get exclusivity also upon market introduction in Europe and U.S., 7-10 years. And of course, it has a shorter development timeline and less capital intense to develop. So that's a really good fit for a biotech, right? So a major common thrombotic indications is 10,000, 25,000 patients to get it to prove.
So it's big, big. That's for big pharma. These things we can pursue longer ourselves. Yeah, so a quote. So how does our portfolio look now? Well, if you look to the right here, IPF is suddenly on our portfolio as a target. So we, we are, as I said, up front, we are developing this to be attractive for physicians and for patients. But often, and in 75%, maybe 80% of the new drugs are developed by biotechs, but snapped up by pharma before they go to the market. And pharma is super good at the marketing, the last clinical trials, and then marketing, serve the doctor, serve the patients. They do that best, but biotech actually is more innovative, global biotech than pharma is.
So the more attractive the portfolio, the more likely that a biotech will do a good deal for the company and for the shareholders, and not least for the drugs development. Just a quick look, you know, as how do you build a biotech? The company started 2012. Vision was prevent thrombosis, endogenous strengthening of the defense mechanism through HDAC inhibition, epigenetic modulation. We moved into orphan disease in 2019, so that we moved to that focus because we had done the evaluation of the characteristics of HDAC inhibition, super fit with PH. We also decided around that time, 2019, and I've had communication with some of you about, "Oh, there's something new coming." We started several years ago, but you didn't know.
The strategic focus is always way ahead of the communication to the market when it comes to the details or the secrets that we are pursuing. But we decided to broaden the portfolio, so we acquired CS014 from a group at Astra, a biotech group that's been with Astra before. But we also made a deal eventually with University of Michigan after working for some time with Mike, and it's actually Mike's innovation. He's the innovator behind CS585. And that, all that work was published in Blood recently, the most prestigious journal in the blood diseases. We also decided several years back to pursue a new chemical entity strategy. The first program is a repurposed compound that's been on the market for 60 years in epilepsy prevention.
But you know, if you want to build a company, you could build on repurposing, but we thought and we think that HDAC inhibition deserves more molecules, and we have improved VPA into CS014, and we're pursuing that now for IPF. So all those strategies were decided in 2019 to 2023, and we moved on those. So now we have, in 2024 , what has happened? Well, we have multiple clinical assets. We have two in the clinic now, one in phase I, one just completed the first phase of phase II. And we have increased our orphan disease focus. That's happening now. And maybe not a strategic move, but we have completed the phase IIa trial, and that has provided some very valuable information.
As this goes on, we become more strategically interesting for pharma, but what has happened also, and you're part of this, we have grown in a number of shareholders that are investing in the company, and that's very good for us and the vision and mission we have. So you can look at this different ways, and I've shown an earlier slide of this before, but when you go from a generic compound and an idea, you don't have a lot of value. You can't do a business on that. But if you pursue a target where it has a value and a benefit and formulate that into CS1, you can... You increase your value.
As you then build the company and build more assets, your new chemical entity, and move into the clinic, and then into the rare disease space, the value of the company goes up, the risk goes down, and the interest from partners goes up. Now, in 2025 , there are new things that will happen. What will happen? We will pursue discussions with the regulatory authorities for the next program. It can be a phase IIb, it can be a phase IIb/III trial, a pivotal trial. We'll see. But that we expect to get done, and we have an approval for that. It's probably both going to be FDA and Europe because of the size of trial. CS014 completion, phase I, moving toward a regulatory process to get phase II approved.
I didn't write it there because I don't know exactly the timeline. Might happen next year already. And then, of course, long-term, extended, expanded access program and usage of CS1 in PH patients with CardioMEMS and the FLUIDDA technology that you heard De Backer speak about. And of course, then in 2026, that's gonna be a really exciting year. We're gonna start the pivotal trial, perhaps, and also start the phase II for CS014 and IPF. And we're gonna start phase I, so we're gonna have three drugs in the clinic in little more than a year from now. Yeah. Back to the patient. What if this could be the remarkable patient case, right? 50 years, four years left to live. What can you do? What if you can do disease modification and help this patient?
We did it with a remarkable patient case, as long as she could use the therapy. She was on triple therapy. We added our drug as a physician to her. Within three months, she moved functional class I from functional class II barely feeling her disease. So maybe we can offer this to many patients, and you saw from our trial, 25% of the patients are super responders. 44%, we decreased the risk of one point and improved the prognosis. Disease-modifying therapy with CS1 HDAC inhibition. Now, even shorter lifespan, if you're unlucky to get IPF, the current drugs don't do disease modification. We know that this works in animals for this disease and that HDAC is one of the drivers here involved.
What if we can provide CS014 to these patients with a disease-modifying drug for fibrosis development and prevent that? CS585, this is the most common cause of death, thrombosis. The drugs cause bleed and difficult to use. You can't add them together. What if you can add a drug here that doesn't cause bleed and especially you heard today about rare diseases and potentially we can start that drug into a rare disease. APS might be it. So that's what we are about at Cereno. That's what your money is going to, those of you who invest. So good. All good. So thank you for listening today and just opening up for questions. Maybe I need some help here. I don't know if I need help, Julia. So who has questions? I know Rahul should actually. Am I moving?
Here, you go ahead. You're supposed to do this, not I.
I know.
We have tables to stand by.
All right, perfect. So I'm surrounded now by green tables. Don't be in any way intimidated, but I think this was very exciting. This was, of course, with Cereno, my first Capital Markets Day, but you saw, you heard about portfolio strategy, commercial, innovations and new ideas, but also scientific innovations on all three compounds: CS1, CS014, and CS585. So maybe there are some questions that you have. I would just like to warn you, there are already many questions coming from our guests who are on the internet. So please feel free to ask questions. And yes. Oh, there are persons already here. Please, and just kindly mention your name and then thank you.
I am [Rutger Smith]. I have two questions. I'll take one at a time. First of all, I have a problem accepting that already in 12 weeks you have a remodeling of the arteries in the lungs. Have you shown that in animal models that this has already occurred? I would readily accept no new fibrosis, but reversal.
Yeah. No, so your point is absolutely, I think, spot on. It's a very short time period to see this. However, we know that in animal models, we can achieve the effects that I showed in just three weeks.
Mm-hmm.
You know, we don't know what the relationship is in terms of the duration between the effects in animal models and in human beings, but remember that we're talking about three months treatment. So, you know, I mean, we do believe that those effects are... You know, we compare the pre-treatment situation with the end of the three months, and the data shows a remarkable change, which would not be expected based on, you know, published data on patients on standard of care, placebo, treated patients on standard of care. We would not expect that magnitude of change. So yes, I think it is surprising that we see evidence that this is occurring, and all I can say is that, you know, if we run the study out for a longer period of time, we're expecting a lot more.
... you know, this is the data as it is. We compare beginning with end of three months, and these are the numbers that we see, and they are consistent with what we see preclinically.
Allow me to add, sorry, if I may, just briefly. In oncology, there are two VPA, as you know, compounds. They have shown remarkable results already within three months. Is it the same compound? No, but it's a VPA derivative, and they are showing. They have not been biopsied, but they show in oncology patients.
Yeah
... differences already within three months. So that is maybe also a good indication.
Yeah, and maybe just to add, maybe you remember, Björn, the studies with VPA, the animal studies that you actually showed up here.
Yeah, yeah.
So what's the length of those?
Oh, it's about three weeks treatment-
Yeah
... in those.
All right.
And so dramatic-
Do you see impact-
Yeah
... on vascular wall thickness, et cetera? And there's also data on...
But-
... cardiac hypertrophy.
So maybe we can talk about that. The ones we have seen in this shorter time are very responsive, and others take longer time. So I mean-
Yeah
... the time span is, could be different for different patients also.
Allow me to just add-
Question.
Yes, please have a next question. We'll have short questions, short answers, so there are many more questions.
Yeah, mind the short.
Yes.
My second question relates to the patent situation. If I were a clinician knowing that valproate or valproic acid is off patent since a long time ago, why... How can you convince me, sending my patient to buy a drug from Cereno for probably thousands of dollars, rather than to any pharmacy for a few dollars?
That's a very good question. Would anyone like to jump in?
Do you want to?
Otherwise, I'll be very happy to do so. Number one, of course, we have a different formulation. As you know, immediate, delayed release. Number two, as you know, also historically, there are many examples that if you have in certain dosages, the proof, you will not be able to actually just take a drug in a different combination, different dosage, and hope for the same effect. I'll give you one example, sildenafil Revatio, also in PAH. It is a drug which is approved and makes a turnover of over $350 million a year with 40 mg. They have 20, 40, and 80 mg. So it always depends, of course, on the approval. The FDA is very adamant on it, and so is the EMA, as you know. Off-label, there's no control.
But we know that once it's approved, physicians, hospitals, and especially specialized centers are very interested in only taking the approved dosages. So we are confident, and this is just one example, there are several others, that this would definitely make sense.
In addition, it's illegal, so.
That's a different thing.
Yeah. I'm just saying that you, as a physician-
Yeah
... you take a legal risk, so if something happens to your patient that you didn't expect, so that's a legal aspect, but thank you.
Yeah.
All right. Good questions.
Further questions. Further questions? Yes, please. There's a microphone coming. Yeah.
Hi. Joe Hedden, Rx Securities. Just two on CS014. Now that you've announced the shift to IPF for the development focus, can you just give us some commentary on commercial expectations and how that might have changed? And the second one, in the phase I trial, were there any biomarkers included that might be useful to kind of give an early, not efficacy indication, but, you know, some kind of activity relevant to the new indication?
I can take second one.
Yeah, and I think commercial you can take, Sten.
I mean, the market for IPF is smaller than the, you know, total thrombosis prevention market, but we hadn't selected a thrombosis indication yet for that. So that could have very well been an orphan thrombotic disease of similar magnitude to what we have here with IPF. So I think that from that perspective, the market is attractive. I don't have the number in my head at the moment, but the market is very attractive.
Mm
... for us due to the need for new disease-modifying agents. As you heard before, they're not really there. And in addition, as a rare disease, you have the ability to both protect it seven, 10 years if you get orphan drug designation, which we assume we would get, and then the pricing of rare disease drugs is favorable. And the reason for that is, specifically in the U.S., the reason for that is that the government health authorities want you to want biotech or pharma to develop for these diseases, otherwise there will be no new development. So it's attractive for us, but I don't have the exact numbers with me now.
But there is a huge market growth, as Sten is saying, only two drugs. But second part of the question, yes.
Yes. So in relation to biomarkers for CS014, so of course, we're very keen to build in biomarkers into that study, but we also are very aware that we would like to keep those simple and robust. So we've actually taken in biomarkers from our experience from Mike's team.
Yeah.
To look at thrombosis, but also to look at bleeding risk as well. We are assessing thrombosis and bleeding risk, and in addition, we're, I can't say exactly what it is at the moment, but we're also looking at a specific biomarker of HDAC inhibition in that study as well. Yes, we are.
And maybe if I may also request Björn to give an answer, and there are two other questions related to CS014, and maybe you can answer those at the same time as well. Will CS014 target all patients or only those with pulmonary hypertension and IPF?
Mm-hmm.
And the second one, which was coming, is, what are the next steps for CS014? Would you like to elaborate on that?
Okay. I think what I wanted to say for the first question, the one about biomarker, I think for IPF, of course, it's nice with biomarkers, but there is a very well-established primary endpoint for these kind of studies. That's the forced vital capacity, which have been accepted by the authorities, and it's easy to follow, and it has a very high acceptance. And nowadays, there is also a possibility to measure that on a daily basis at home. So that will be even easier to follow, so to say, in these patients. Because if you look at the historical data, there is a trajectory for these patients, which is in, on a population level, very, very well defined, how fast they progress in this.
Mm-hmm.
I think that. The second question, just remind me what the second was.
What next steps we are planning?
No, there was one before that.
Oh, that was the first one then. Are we targeting all patients or only those with PH?
Yes, I definitely think we target all patients because I think the fibrotic component and the data supporting the anti-fibrotic effect are very strong. But what I think is also that we have, with HDAC inhibition, both prevention and reversal of vascular remodeling, and that fits very nicely with the development that comes successively with PH, PH in these patients. You can hopefully prevent the remodeling going into pulmonary hypertension, so that's the idea. So with this, so definitely, yes, all the patients, it's one. The next step in this kind of a development is that you do a phase II trial where you...
But the design of that, we cannot reveal, and we have no, no, nothing to say about the exact design, but it definitely a well-defined study that you can do with this-
Yeah
... primary endpoint that is, available.
Thank you for this very short answer. Yes.
Very brief-
Nick, yeah
... clarification. So what I was referring to as biomarkers were in the phase I trial-
Yeah
... which are healthy volunteers, and what obviously Björn-
Yes
... was referring to is-
Yeah, for the patients.
IPF, yes.
But that's okay.
Okay, further questions. I have two still more on the page, so if... Yeah, perfect. Please, just briefly mention your name, please.
Yes, so my name is Carl Gustafsson. I have a question regarding the phase II trial for CS1 was delayed quite a few times. Is this something to be worried about for future studies?
Why don't you-
So, yeah, I'll take that. So thank you so much for that question. Keep in mind that, of course, we are a small biotech. We had a learning curve, and what we will do, of course, now we are much better informed. We're much better prepared. The CS1 compound is also better known. So with a focused approach, no, we will be definitely much more streamlined here. We have a clear path forward, as I shared with the regulatory pathways, FDA, EMA. We know how that goes. We have all been there several times. We know approximately how the studies will and should be looking like. We will make sure that we have the right partners with the right expertise to go ahead and take the next steps.
Yeah.
If I can add there, too.
Yeah.
So, thank you, Rahul. So, you know, this was when we initiated. This was post-COVID. If you've ever listened to a head of a hospital in the U.S., I've done several times, they were crawling on their knees. They didn't have staff. Doctors were leaving, staff were leaving during COVID.
Mm
... and they didn't get them back, but the patients' numbers increased. So the regulatory or administrative process to get the study done or approved, contracted, et cetera, was much more difficult. Post-COVID has been much more difficult, and it's not only Cereno has experienced that.
Yes.
So that process took a lot for us. In addition, we had both CardioMEMS implantation and PH centers, so that, there are, like, two different that you need to have this cumbersome process with. So the actual contract and ethical approval process, which suffer from the same, you know, understaffed scenario, took much longer than we anticipated in all the centers. So that was the part of this delay. Of course, we have a learning curve.
Mm.
And looking forward to a trial in IIb slash maybe III, there will... We haven't-
... defined that protocol yet. It's unlikely that the majority of patients will have CardioMEMS. It's very unlikely. Maybe a segment of those will have it, and you don't need it in all the patients. So, but that procedure is too cumbersome to have in a high number of patients. Okay.
Thank you. So any further questions here in the room? Yes, please. Just a second. Christina? Yeah. Just kindly mention your name. Thank you so much.
Hello, my name is Moi Brajanovic, and I have a question maybe to you, Doctor-
Sure.
Maybe to you, Nick.
Yeah.
I've written them down, so the first one, I want to congratulate on the promising data. And so-
Thank you
... related to that, I have a question regarding the dosing strategy. So the top-line data indicated that the patients in the low group, low dose group, responded particularly well, especially with significant reductions in PVR. So do you think this might be to possibly a saturation at the highest dose? Or and will you optimize the dosing strategy for the upcoming pivotal trial-
Mm-hmm
... based on these findings? And then secondly, in the interim results, you sort of also present the data showing an early onset of cAMP production as early as three weeks and the sustained reduction two weeks after the actual study. Do these sort of top-line results sort of confirm the early and prolonged effect? And do you have additional data to support these findings related to top-line data?
Mm-hmm.
Thank you.
Thank you, first of all, for the good wishes.
Need, need-
Exactly. You'll start with the dosages, if I may say, and then-
Yeah
... we can continue. Yeah.
It's a really good question on the doses, right? So, you know, we started with equal numbers of patients in each of the dose groups, but by the end of the study, we ended up with almost double the number in the low dose. So we don't actually think that we have a dose relationship there. We think that once you have, you know, that 480 on board, that's all you need. Moreover, I think what's really important to say is that, you know, we would like our patients to stay on the dose that we give, and we know that the mid and the higher doses, we had to lower a bit in four patients.
Yeah.
Once we lowered them, those doses were well tolerated, so that's not a problem. Of course, when you do this, you would like to have a dose that is giving efficacy and is well tolerated, and that's what, at least initially, we think we see here. It's you know, it's not a huge amount of data. Yeah.
Yeah.
That's fine.
And maybe the second part that you had regarding the hemodynamics, and again, I'll maybe start where Nick ended. That is, this is... We're looking for signs, and these are 21 patients where we looked at efficacy. Some of them really showed nice results. Is it sort of generalizable? No. That's why we need to do a larger trial. That's what the plan is. And there we, I think, with much more confidence-
Mm
... we'll also tell you, "This is the effect, this is how soon it's coming in, this is the characteristic." So now I think, yes, we're very happy that we're seeing those signs, but it is, of course, mixed with a slight speculative aspect as well.
Yeah.
Okay? Thank you so much.
Running out of oxygen, maybe.
I have one more, I have one more question here, and then if there's no one in the room. Any questions in the room? It's not like an auction, but you can still
Yes.
All right, then I have one more here, and that's to you, I guess, Sten. Do you have ongoing discussions with potential partners for licensing either CS1 and/or CS014?
I'll give you a rhetorical answer. Define discussions.
Yeah.
All right. Now, of course, we are meeting with potential partners, that's ongoing. But, you know, you'll see somewhere if there's a deal that's happening, right? So, and before that, nobody's talking. So I think, you know, we are getting attention, and, you know, pharma is contacting us, I would say, but that doesn't mean that the deal is imminent. It just means that the attention is going up, and if a deal was imminent, I couldn't tell you, right? So just keep your shares.
Buy more!
I never give investment advice, by the way. You know, it's just a joke. All right. Thank you so much.
Mm-hmm.
I have a few-
You have some closing-
... few-
-remarks
closing remarks.
Yeah, perfect.
I won't be long.
Thank you very much for the questions.
Thank you.
Thank you, guys. What should one say here at the very end? I don't think there's more to say, actually.
Can you see the slides, by the way? Sorry, we'll just move the tables.
Yeah, I think you can do.
Here we go.
Yeah. So I think I said it before. So I think this, this environment, this time, gives us more opportunity to show you what we are about and who we work with and what's driving us, and how deep the science is. So, and that's the foundation, of, of any good biotech or pharma. So, this has been a great opportunity to do that with you. Very happy that you are here, and, and, I think there's a few online too. So thank you very much, and, you know, meet you up at the coffee. You can ask more questions and more privately, maybe. Okay? Thank you.