Thank you, and good afternoon, everyone. So welcome to this research and development update hosted by Guard Therapeutics. My name is Tobias Agervald. I'm the CEO of Guard. And this, R&D update is really triggered by recent, and I think, exciting advancements in the clinical development program of our lead candidate drug, RMC-035, but also by important regulatory feedback that we recently had by the US FDA on the path forward. These are our disclaimers, which can be found in full within the presentation materials. So going into the meeting objectives for today. So in the first part, we would like to review really the current status and, you know, just look, where were we before we had the results of the phase II AKITA study? Where are we now, and really, where are we going?
And also linked to that, review the strategy for the further clinical development, RMC-035. In the second part, we aim to provide more of an external perspective, actually, clinicians' perspective on the indication itself, the unmet medical need, and also link those perspectives to the AKITA results. And finally, in the third part, we will be more forward-looking, and introduce the planned phase II-B study, designated the POINTER study, and also showcase some of the new opportunities and some of the research work we've done, on our preclinical discovery platform.
So to reach these goals and objectives, I'm happy to introduce two additional speakers today. First of all, we have Dr. Michael Reusch, our Chief Medical Officer at Guard Therapeutics. So welcome, Dr. Reusch. It is also my honor and pleasure to introduce our distinguished guest speaker, Professor David Goldsmith, who's an Adjunct Professor of Nephrology at King's College in London. So appreciate to have you here, Dr. Goldsmith.
Thank you.
Just a few, I think, extra words on Professor Goldsmith, because I really think we're honored to have a truly global key opinion leader in the space of nephrology. He's been clinical practice for more than 30 years in nephrology space, served as multiple, or as an investigator or co-investigator in multiple large-scale clinical trials in this space. He's an author of more than 300 scientific chapters, articles and book chapters. So again, it's really, really valuable to have you on the call. So here's the agenda today, to meet those objectives that I already listed. So following my brief introduction, we will go into the path forward, discussing some of the AKITA results and the recent FDA interaction.
But this is not only to tell you about what's going to happen, but also provide a little bit more insights into the reasoning, and I think the insights, the intelligent strategic decisions that underlie the plan forward. This also includes a corporate-level perspective, including some, some aspects of business development. After that, Dr. Goldsmith will review again the indication, loss of kidney function after cardiac surgery, and provide that in the context of AKITA results. This will be followed by Dr. Reusch, who will speak briefly on the overall design of the next planned phase II-B study from the POINTER study, and I will round off with him discussing some of the new findings we have in our preclinical discovery platform from the GTX platform. At the end, we will end off with a Q&A.
So to set the scene for those who are really not familiar with Guard Therapeutics, we're a clinical-stage biotech company. We recently had a readout of the study I already mentioned, being termed AKITA study, which is a phase II-A proof-of-concept study. This was a large-scale global study with 177 patients in total, where we ended up having a clinically significant effect on important regulatory endpoints and clinical endpoints, which provides the basis for continuing the development. We have a U.S. FDA Fast Track designation for RMC-035 in the lead indication, which is reducing the risk for either death, dialysis, or a permanent loss of kidney function in high-risk patients undergoing open chest cardiac surgery.
We now also, which we will speak to today, have mapped out the next steps in the clinical development journey, which is fully supported by the FDA, and also, we see some opportunity for breaking new grounds in phase III. So there's overall an attractive risk-reward, we think now in the program. Michael will also speak to some of the operational preparations for the upcoming phase II-B POINTER study, and they progress well. As I said, we will also discuss elements of the GTX platform. Again, for those of you who are not familiar with Guard Therapeutics, this is our company pipeline. We have the lead candidate drug, RMC-035, the lead program in open-heart surgery, where we're now past phase II-A, going into phase II-B.
We also have a second program with RMC-035 in kidney transplantation, having conducted a phase I-B PK safety study in this patient population. Overall market potential is $1 billion+ in open surgery, about a third of that in kidney transplantation. Patent protection goes up to 2037 for the composition of matter, RMC-035. For the GTX program, we're looking at multiple indications in chronic kidney disease, but also in the non-kidney space. These indications are yet to be determined, but we will show a flavor of those results. We have patent protection, or anticipated patent protection, up to 2044.
Also, to review the current competitor status in the lead indication, open-heart surgery, and I think the key point here is that Guard is actually the only now company with a proven proof of concept or having proof of concept data in this particular indication. And I'll explain why. So Novartis is currently in phase IIa, but that's a clinical program which have not yet shown any efficacy. But we know that study will actually read out by the end of 2024. We have a compound by AstraZeneca, Alexion, with a different mechanism. It's a C5 inhibitor, but this is an already marketed product for a couple of orphan indications. So essentially, they're looking for a label expansion and opportunity in cardiac surgery.
But that also means they haven't provided any clinical data as of yet in this particular indication. We have the AM- Pharma, who's had a compound which they've tried multiple times in sepsis, and that failed in sepsis, but they announced the intent to now switch into open heart, heart surgery. But again, there's no available clinical data. Finally, we have Renibus Therapeutics that made a relatively small phase II study and announced the intent to go into phase III with a slightly different sort of approach, and not really focusing on the kidneys. In that sense, they are not, you know, a real competitor to Guard Therapeutics.
So before going into sort of the strategy and the tactics and the feedback by the, by the FDA, I think it's important to, to really look at, you know, the basic sort of steps in drug development, and this is a highly simplified view, of course, of that. You can call it the school book of, on clinical development, if you wanna do that. So in essentially in phase I, the key objective is to evaluate safety, of course, of the compound, and something called pharmacokinetics, which is essentially what the body does to the drug. Once you pass that point, you wanna go into phase II-A, which is really about detecting a relevant effect signal or efficacy signal.
That is a really big hurdle, and you can see that illustrated by the high brick wall, because this is more than when the 50% of drugs typically fail, often because simply preclinical work and all the animal results that you've accrued over time, they simply do not translate into the same effects in humans. This is, again, a real significant hurdle. Once you clear that hurdle, you go into something termed phase II-B, which is really about optimization and optimizing the efficacy signal. It's really because you wanna make sure you're absolutely ready, you're completely lined up on every level, and make sure all ducks are in a row. This is not only in terms of phase III design, but on every level and every aspect of the project, including your commercial launch strategy, drug manufacturing, bioanalytics, just to give a few examples.
Because once you're in phase III, there's really no turning back. There's usually only one chance to provide your definitive support for your favorable efficacy and safety profile. So I really love to drive a motorcycle, and maybe just to do an analogy to the most recent Mission Impossible movie, I think in the early phase, you wanna be prepared and accelerate as much as you can to climb up that mountain and really make sure you pass that initial phase II-A hurdle. Once you're in phase II-B, you really want to stop and evaluate all options to make sure you safely get down from that mountain, make sure you're not really driving off the cliff, even before starting phase III or during phase III. And, you know, you might be tempted to sort of cut corners and, you know, skip this intermediate phase.
Of course, if you're Tom Cruise, you know, driving off the cliff with a parachute, you may be lucky and actually hit your target. But at the end, more realistically, you will crash and burn and ultimately end up with a failed phase III study, and unfortunately, that is the biggest failure of all failures in clinical development. So let's double-click a little bit just on the optimization part. So why is that critical before phase III? So first of all, it's about increasing your likelihood for success, because again, in phase III, there's only one shot at goal. If you fail, you fail. It's all about optimizing the benefit-risk profile of your drug, and ultimately, this is also for patients. You wanna make sure they get the right drug in the right dose, in the right way, also when you go into commercial phase.
Moreover, in your phase, your phase III design actually drives your, your commercial strategy, because what you feed into your phase III trial, that is what you're going to end up with pretty much at commercial stage. So that's really something you need to carefully think about well in advance before launch. But ultimately, it's also about cost and time versus risk. Again, this is just a highly generic picture where you look at the cost of failure as a function of your development stage. You can see there's really an exponential increase in the cost of failure with a higher development stage, and that's why you wanna avoid a phase III failure, really at all costs. In terms of clinical development, we see this as sort of a yin-yang kind of relationship, but there's a continuous... You have to balance the cost versus risk.
If you increase the one, the other will decrease, and vice versa. So the question is, what is really acceptable to pay for reducing risk, and what is acceptable to risk for reducing the overall timelines? And feeding this into the current status of, of Guard and some of the important questions we had to address after the AKITA results. So how important is it to optimize dose level and regimen? Well, that's very important. We need to do that. What is the optimal patient population? That is, should we focus on CKD patients, like the Alexion AstraZeneca program, or should we go for a broader patient population? What endpoints do we use to actually achieve those objectives and make that decision? Ultimately, once we've focused more on the phase III side, so what is the preferred and attainable phase III endpoint?...
Is there any opportunity for accelerated approval? And how do we even, you know, assume the drug treatment effect in phase III, and how do we improve precision of those estimates? So again, this is just a you know, a short list of important question that has a big impact on your phase III design, including your costs and timelines. So translating all of this again to, to us, I think this is a nice picture of where we are. So we conducted the AKITA study, which was a phase II-A study, really with the purpose of detect the relevant efficacy signal. We now bridge that huge and clear that significant hurdle, so the brick wall is actually gone.
Now, going into the phase II-B, where it's about optimization and getting ready for everything, that's what we'll do with the POINTER study, before going into phase III. But there's also another aspect of this, not only about optimization, that I highlighted a couple of times. In this particular program, we also think it's critical because we actually have an opportunity to potentially modify the phase III design, and actually do something which would be different if we provide a combined package of AKITA and the POINTER study. So, for example, in a hypothetical scenario, going straight to phase III or doing an adaptive phase II-B/III design, you know, your phase III part would most likely look similar to what we see with the Alexion AstraZeneca phase III trial, around 800 patients in phase III with an endpoint called MAKE.
By using a combined package, I think what we are working on as a company is really to prepare an alternate scenario, when you can potentially reduce your phase III sample size and time, and cost, and risk. Also look for a scenario where you can provide a design which would align for an interim analysis and accelerated approval, and I think this is something we're actively working against. On the basis of this, this is what we discussed and proposed, and we have full support by the FDA with a preferred plan forward. With the FDA, we have really a recognition of the efficacy data on kidney function, which we term eGFR, and the currently assumed phase III endpoint, called Major Adverse Kidney Events or MAKE.
There was a confirmation of our existing Fast Track designation, and also confirmation that the indication itself is actually eligible for a Breakthrough Therapy. And again, this is why we think doing a POINTER study really could support that package. We can again apply for a Breakthrough Therapy following the phase II-B. Without being too technical, we also had agreement on a lot of these important, yet small, but important design elements of the phase IIb. So, for example, selection of dose, dose regimen, the number of dose arms, switch from a weight-based to fixed-dose, the use of a primary endpoint to set your dose, and of course, at this stage of development, always risk mitigation measures are important, and they were confirmed to be appropriate.
We also had a fruitful discussion on a phase III endpoint, as I just alluded to, and those are to be continued after the phase II-B, but overall, they support the strategy we have going forward. So before turning over this to Professor Goldsmith, I will just round off with a couple of words on some business development aspects and partnering. This is obviously always questions that come up for biotech companies. So when do you really intend to... How long do you intend to run the program? Do you wanna have a partner, and how do you ultimately bring drug potentially to patients? So let's just double-click again on this concept of project risk versus value. So you see, on the graphical display below, it's really about the success rate for you transitioning from each phase in development.
What you can see that in clinical development, the highest failure rate is really in phase II. This is mostly attributed to the absent or insufficient efficacy signal that you see. And again, that is a hurdle we now actually cleared with the AKITA findings, so very important. That also means that demonstration of what we call a clinical proof of concept. That is a significant value inflection point for the program because the risk goes dramatically down, and that means that the project value actually goes up. Our in terms of BD strategy moving forward, I think now, one, we have an established proof of concept. We also have mapped out the next part of the clinical development plan and vetted that with the FDA.
I believe these are really the cornerstones that needs to be in place to even think about any sort of reasonable deal-making. We plan to intensify and really having business development activities and work on that now in 2024. I will just make a couple of remarks, also some additional aspects. One is industry trend, and I think it's fair to say that the general trend we see now is, you know, large pharma companies, they usually wanna pay more for less risk. Again, going back to this yin yang, and I think that paradigm fits for Guard Therapeutics. You pay more, but you need to be in late-stage development. I also wanna highlight that deal-making, that is a continuous process. It's not only, you know, achievable once you have your study results.
It's not like you, you get your results one day, and you make the deal the next day. I mean, this is something you really always consider and work on. That could happen once you share your study results. It could happen during a study. It could happen after the next study. I think for GARD specifically, we don't, we haven't articulated a clear strategy in terms of whether we should do a licensing or acquisition, but I think there's a couple of points that argues more for sort of the acquisition of the project or an M&A case rather than licensing. I think that really fits for a lot of reasons into this particular program.
I also think it comes with certain benefits because you have usually, you know, a high level of upfront payments, and it's not sort of contingent future success, and you may ultimately even lose control in that scenario. So again, it's all about optimizing the shareholders' value and really considering the risk-reward, and I think, you know, there's a continuous sort of change in that sweet spot, but something the company really works on now moving forward. So with that, I'm now happy to give the word to Professor Goldsmith, who will provide more insights on the kidneys, going back to the basics, the unmet medical need, and maybe a little bit of context of the AKITA results. So David Goldsmith, please go ahead.
Yeah. Thank you very much, Tobias. The only bit of Swedish I will say is, "God eftermiddag. Allihop!" And then we're off. Can I have the first slide, please? So, acute kidney injury is an urgent and unmet medical need. I've been involved in kidney medicine for over 30 years. Acute kidney injury was called something else way back in the past. It's now called acute kidney injury. We're no nearer a solution to having a therapy, except perhaps with the promising results that you'll hear more about a little later. But it's a really important unmet medical need, and I'll take you through why that is. And essentially, what we're trying to do is prevent, pre-prevent kidney function decline. Now, the kidney, the kidneys are very important. They excrete waste products, excess fluids, they help to eliminate drugs, and they produce vitamin D.
We all lose kidney function, I'm afraid, a little bit after the age of 40. But for most people, you can maintain enough kidney function to be in good health into your eighth or ninth decade. But if you have things like high blood pressure or diabetes or other problems of that sort of long-term nature, then unfortunately, the kidney is one of the places where these things manifest themselves, and you then find that you have chronic kidney disease, which is a consequence of much repeated acute injury as well as chronic processes. Once kidney function has dropped to around 20%, you are inevitably going to head towards kidney replacement therapy, known as dialysis or transplantation.
So the other thing about kidney disease is that most of the patients I've looked after don't die of kidney disease because we can give them a dialysis or a transplant, but they do die of accelerated cardiovascular disease. It really is a major problem because it, the many of the processes that drive the kidney injury also have adverse outcomes on the cardiovascular system. And my job, really, to be a holistic doctor, is to prevent acute and chronic kidney stresses. And if you only prevent one and don't prevent the other, you haven't really addressed the long-term consequences of a kidney problem. And I'm very keen that we look at the medium and long term, not just a very short-term thing, 'cause in the end, that's where we'll have the most benefit in terms of therapies. Next slide, please. So some perspectives of acute kidney injury.
It's a spectrum of injury. It can be very mild or extremely severe. But one thing we have learned painfully over the last decade or so is that recurrent acute kidney injury, so recurrent isolated episodes of injury, unfortunately, has a tendency to progress to kidney failure itself. And this link between acute injury and chronic injury has really been made us think very long and hard about how we try to prevent long-term damage in the kidney. So changes in serum creatinine. Creatinine is the thing we measure in the blood that tells us how well the kidneys are working, 'cause either they excrete it or they don't.
Even quite minor changes in serum creatinine are associated with significant increases in patient mortality, as much to do with the fact that the conditions that are causing the elevation in creatinine are themselves dangerous, as much as it is to do with the kidney losing function. Really, this elevation in creatinine and acute kidney injury complicate many interventional and surgical procedures, and these lead to increased hospitalizations, prolonged hospitalizations, and delayed discharge, and are associated with significant morbidity and mortality. Now, I said earlier, there's an unmet medical need. As we speak, there is no known licensed specific therapeutic intervention, and this has been the case all through the decades I've been involved with kidney patients.
And one of the highest priorities I could accord anything in the kidney program would be finding something that would work in acute kidney injury, which is why I'm excited when companies come with really good ideas and products. Next slide, please. And really, one way to think about the kidneys is that they are a canary down the mine. If you remember the early years of mining, and I know Sweden has many mines, you would have a canary in a cage to detect carbon monoxide or other noxious gases, and the canary would react much faster than the human being. And we can detect creatinine changes, but the problem is, we don't know why they're happening.
Could it be something to do with an intervention or an illness? We have to look then beyond the creatinine and ask the question, why is it rising? Next slide, please. There are very many causes of acute kidney injury. These include problems with the heart and circulation. That makes a lot of sense, 'cause, of course, the kidney has an enormous blood supply. There are also conditions to do with toxins or drugs affecting the kidney, and a variety of diseases that are quite rare, but devastating when they happen, to destroy the kidney substance. And then there are other conditions, like an increased prostate size or cancer, that can affect the kidney as well by backflow and stopping the urine escaping.
All of these are manifested by an unwell patient and a rise in creatinine, the thing that we measure to tell us whether the kidney is working. Therefore, we have to then work out why this has happened, and in each case, there may be an intervention that we can do to reduce the risk. But what I'd like to do is have an intervention that would work across the board and prevent kidney injury in the medium and long term, not just acutely. Next slide, please. So the current definitions of acute kidney injury are all around this serum creatinine, and they're all defined as the first one or two days after what they believe to be the injury.
While this is of some value in working out what's going on, it is very limited because it only deals with creatinine, and it only deals with short-term change. One of the things that's very clear from the program that GARD have been doing, and many other programs that I've seen, is that you have to look beyond the first two or three days. Indeed, a creatinine rise is not always associated with acute kidney injury alone. It can be due to other things. This, although it is the paradigm, and although originally, regulators would have used this to frame their permissions for clinical trials, it's already been superseded, and new definitions are being sought, and there are consensus conferences about this very topic right now. Next slide, please.
The risk factors for acute kidney injury happen in sick patients, so patients at heightened kidney or medical risk. So they're acutely unwell or have had major surgery, which interrupts the blood supply or poisons the kidney in some way. Recognition of those at risk of acute kidney injury, you can do that with algorithms. AI certainly helps in putting together an algorithm that might help determine which patients are at the greatest risk. But at the moment, all I've got to offer is making sure there's enough fluid in the body and stopping any drugs that might damage the kidney. Now, those are good things to do, don't get me wrong. They are useful, but they're not specific to the problem of acute kidney injury itself.
How much better it would be if we could predict those patients who are very likely to get kidney injury and give them a therapy to prevent it happening? 'Cause that would not only have short-term benefit, but as we know, because kidney injury generates long-term kidney problems, we would also be helping the patient downstream, and those outcomes are really, really important. Next slide, please. So there are... I've only shown you a list like this to tell you that there are a lot of clinical and epidemiological risk factors for a kidney injury. There are so many, it's almost unhelpful to have nine boxes of that sort.
One of the key ones is, if you have a little bit of existing kidney injury from any source at all, you're much more prone to acute kidney injury taking place because you have less ability to restore function in a diseased kidney than you do in a perfectly healthy one. So if you have coincident heart failure, if you are very old or older, if you have diabetes, if you are short of fluid, if you're on drugs that are potentially toxic, if you have an infection, or if you're on a particular cocktail of drugs for high blood pressure, all of these promote the risk of acute kidney injury. But we can use that information the better to predict the people at the greatest risk when they're undergoing procedures that are associated with kidney injury thereafter. Next slide, please.
In open heart surgery, I mean, I remember open heart surgery 30 years ago, and there was a really high incidence of problems after the heart, after the cardiac surgery itself. Sadly, even with patients dying from open heart surgery. The technology that lies in a heart-lung machine, 'cause basically taking the function of the heart to pump the blood and the lungs to oxygenate the blood, is actually identical or very similar to the, what's inside a dialysis machine. The two sets of machinery were put together with very clever engineers in the early and mid-1960s. So what happens with a cardiac surgery, when you place a patient on cardiopulmonary bypass, is that the effect of pushing the blood from out from the patient through the machine and then back in again, actually causes stimulation of a variety of different things in the bloodstream.
White blood cells are activated, red blood cells are destroyed. You know, it's the same with the dialysis machines, as I was saying. And when the blood that's damaged gets back into the patient, it sets up a cycle of injury, toxic accumulation of reactive oxygen, oxygen species, leading to inflammation within the kidney and damage. So you start with a machine that takes the blood out and oxygenates it, but you end up with something that looks like ischemia-reperfusion injury in the kidney, all of which essentially gives you acute kidney injury from the bypass machine. Now, today, in 2024, the incidence of this is reduced because the machines have got more sophisticated, and also we're better at predicting what might go wrong. But there's still plenty of acute kidney injury caused by this otherwise therapeutically really important process.
Let's not forget, we're doing the bypass because somebody's heart arteries are clogged, and without the bypass, they may die of heart disease. But you don't want them to have a successful cardiac operation, but end up needing dialysis treatment because their kidneys have been ruined, and I have seen that too many times over the years. So it's inevitable, even if it's minimized with, with the current approaches to excellent machinery. Next slide, please. So are we really just looking at short-term changes in kidney function after open heart surgery? Well, because of better case selection and better technology, the majority of post bypass, you don't see any kidney changes in. But you start to see them as you start to have older patients and those with comorbid conditions like diabetes, high blood pressure, poor heart function.
In that sort of selected population, and if you look carefully for the signs of acute kidney injury, you can see quite a bit of it, 10% or even 20%. But most of that will recover, and I say recover, what do I mean? I mean, the creatinine will go back towards normal or even become normal. However, what we now think is that although the creatinine may improve in the short term, in the longer term, that kidney is damaged, more susceptible to future injury, for example, and there may be, over the course of months and years, a faster decline in kidney function because of the acute kidney injury that somebody experienced some years ago. So modern thinking is that kidney injury is much more common.
It could be repetitive and cumulative, and I liken it rather to if those of you play rugby or are very fond of heading a football or boxing, not just in the gym, but actually boxing for fighting, if you have recurrent cerebral injury, then that, unfortunately, in susceptible individuals, is associated with premature Alzheimer's and neurodegenerative disease. Not in everybody, but there's a very clear association now, so much so that people are trying to ban footballs from being headed, and obviously, you need to have better head protection in boxing. And this is the same concept, really, about predetermining and pre-detecting those who are susceptible and trying to minimize injury and the long-term cumulative consequences. And having a treatment that will prevent the injury in the first place would be really beneficial. Next slide, please.
So repetitive acute kidney injury can lead to chronic kidney disease, and this slightly complicated, I apologize for that, pathway. If you start in the top left with the word normal, you then, if you move to the left of that or the right of that, sorry, you get acute kidney injury, and then that can lead you to chronic kidney disease. Underneath that top panel, there's a lower panel of diagrams showing you normal kidney tubule cells, which is the bit that gets damaged. Then there's a, a problem because you have acute kidney injury damaging the tubule cells, and rather than just all recovering and everything going back to normal, we now know that because of oxidative stress in the main and other factors, DNA damage, that you get inflammation and loss of the space between the tubules.
That's known as fibrosis, and that eventually causes blood supply failure and loss of kidney function. We now understand this process, but do you know what? It's really hard to interrupt it, and that's why it's so important that we have something that will potentially prevent this nasty cycle of decline. Next slide, please. Essentially, what we find now is that incomplete recovery of acute kidney injury does increase the risk of chronic kidney disease and the risk of end-stage kidney disease as well. This even happens in children, and it's really important not to have this happen in children, because if you have a child of 15 who could expect to live another 70 or 75 years, that's a long time to live if you have damaged kidneys, and you would definitely need a transplant.
So in this study, which has recently been published, if you go into a process where you have a kidney injury with pre-existing kidney disease, then you do not do nearly as well. You can see a more rapid drop in survival, kidney survival, not patient survival, kidney survival, in children who've had acute kidney injury when they start with abnormal kidneys. So wherever you look and however you define this, it's important. Please look, though, at the timescale. We were talking a moment ago about the definition of acute kidney injury being defined as 48 hours. Look at the X-axis of this diagram here on the graph on the right. It's measured in months, 10, 20, 30 months.
This is where you begin to see the failure of not avoiding the kidney injury in the first place, because you then are on an irreversible slide with loss of kidney function and then needing dialysis or transplantation. And those aren't things you'll wish on anybody, I can assure you. Next slide, please. So we need to also remember that some drugs that are very useful to the kidney can also change the blood creatinine levels, so this is quite a complicated problem. Some drugs that protect the kidney cause a short-term reversible change in kidney function that makes it look worse, but isn't worse. It doesn't sound very easy to explain... but drugs like empagliflozin, which is basically, a, a diabetes drug, is very, very valuable for the kidney and produces very significant long-term protection against loss of kidney function.
Even if, as you first introduce it, the creatinine may go up, it doesn't go up any further over a long period of time. And very quickly, those patients who don't have this special treatment, empagliflozin, and similar drugs like it, very quickly, their kidney function gets worse and overtakes the protected group, and you can see that there in terms of weeks in about 2-2.5 years. So just measuring creatinine on its own can be quite confusing 'cause some drugs can cause a short-term increase in creatinine, but at the same time be incredibly valuable to the kidney, as we will show you later. Next slide, please. So really, what I'm saying to you is when you're looking at how drugs work in this context, it isn't enough just to look at the acute injury and then the day after.
You've really got to look at the whole process, and at the very least, you need to look at about a 3-month period. And that's why, as Tobias and Michael will tell us, the regulators have been very clear that they want endpoints that incorporate a 90-day horizon, not just, you know, like a 90-hour horizon. Because to understand the longer-term implications, we have to look beyond the immediate period of the kidney insult. And actually, as a clinician, I'm interested in the next few years and decades that these patients experience, if they live that long. So the whole process needs to be incorporated, and that can be done by a liaison and negotiation with the regulators to get an endpoint that makes sense in terms of the acute and the chronic impacts. Next slide, please.
So just relying on a few days of plasma creatinine is, as some people try to do when they look at these programs for kidney protection, has proved, I think, to be a rather facile approach, and it really doesn't reflect the complexity of the process that we now know that we're looking at. So this is why the FDA and other regulators now prefer to look at kidney function later on. So we, of course, we measure the impact on kidney function of the injury and of the administration of the protecting drug, but we have to look downstream of that to see what's actually going to persist and how well the kidney is going to be working some weeks later. 90 days is the traditional amount.
This is why the FDA have come up with the concept of Major Adverse Kidney Events, which mirror their previous, and the cardiovascular community's previous, definition of Major Adverse Cardiovascular Events, MACEs. But these are MAKEs, Major Adverse Kidney Events, and these are the things that you have to be fully understanding of, to really appreciate whether a therapy is helping a patient in the longer term. Next slide, please. So this is really the context of the phase II, AKITA results. You have an immediate short-term effect on the kidney, and is something that causes a transient rise in creatinine and is likely to be eliminated by dose optimization.
Tobias was telling us that a lot of the phase II-B programme is going to be dose optimization, to be sure you've got an excellent therapeutic signal that you can confidently take forward into phase III. The medium-term objectives, that's looking at GFR improvements over that period of time and reduced risk of Major Adverse Kidney Events. And a change as small as 3 or 4 mL per minute, which would be about 3%-4% of kidney function, believe me, is significant. That's the sort of thing that the regulator would agree is a potential strong, positive benefit for the therapy itself.
Long-term outcomes, the things that really also interest me, 'cause I have to look after the patients years later, there are fewer data available at the moment, but I'm sure that we will need to collect such data, whether that's as part of a development program or just good clinical care, I can't say, but the major adverse kidney endpoint is regulatorily accepted, and it reflects clinically significant and irreversible loss of kidney function. And essentially, patients of this sort will need to be looked after by kidney specialists in the long term, and that's, I think, in my opinion, the right way of doing things. If they are completely recovered and there are no problems after 90 days, that's another story.
But really, we have to look after these patients holistically, and in as a clinician, I would definitely want to see these sorts of patients with acute kidney injury in my clinic to establish whether or not they have made a full recovery. Next slide, please. Just very quickly on the National Health Service estimates, we have a bit Sweden also, of course, has a health economics approach to the regulation and approval of drugs. Not all countries do, but we do, and you do. And it's been estimated that acute kidney injury costs a significant sum of money. Now, it's a lot of money that's worth trying to save, and particularly when it's more than we spend on breast, lung, and skin cancer combined. And this is potentially something that's at least in part reversible.
According to our National Institute of Clinical Excellence, which is our pharmacoeconomic advisor, 42,000 deaths a year. Now, that's not been proved with a trial, but that's an estimate of the clinical impact of acute kidney injury. Acute kidney injury occurs in 70% of critically ill patients, and it excluded this analysis, so the four hundred million or so excludes long-term additional costs because of progressive loss of kidney function. So the true cost is likely to be significantly higher than that cost there. So there's a lot of money isn't the only driver, but, I mean, it's patient harm that really concerns me. But all healthcare systems are constrained at the moment, and therefore, saving money by not having these injuries and problems, it just makes very sound clinical and financial sense. Next slide, please.
So in summary, acute kidney injury, acute kidney stress is common. You see it after medical and surgical procedures, and especially if you are older and have comorbid conditions such as diabetes or hypertension. It extends hospital stays, increases costs, and leads to long-term disability and premature death. We have no therapy in 2024, other than trying to look after the patients as best we can, and any drug or therapy that can reduce the risk of acute kidney injury and progression, I really want to use. It's really important. I think this would be a true breakthrough, a little bit like getting a therapeutic that will work for Alzheimer's disease. There's very little out there, as you know, in Alzheimer's. It's not nothing, but very close to nothing, and in acute kidney injury, it is pretty much nothing.
So as Tobias showed you, there are other things that have been tried that haven't yet shown much positive impact, and I'm hoping that we will find compounds that will translate themselves into clinically available therapies that I could use to save kidneys, save lives, and cut healthcare costs as well. Thank you very much for your attention.
Thank you so much, David, and I think we will continue immediately to the phase II-B POINTER study, and nice to introduce Michael Reusch, who will speak to this topic.
Yes. Thanks, Tobias, and thanks particularly, Professor Goldsmith, for this nice and excellent talk, highlighting the relevance of AKI kidney injury, particularly in terms of long-term progression, and also about the relevance of long-term or short-term and long-term endpoints for regulatory approval. With the following slides, I will make you familiar with the clinical development plan for RMC-035, and particularly introduce you to the next step we are planning in terms of clinical development, which is the dose-finding study called POINTER. Next slide, please. This slide basically puts, or visualizes the context, Tobias had brought in the beginning. It is the reflection of the textbook textbook approach to clinical development, here transferred to RMC-035 in open heart surgery. Where we are today is phase II, with the start of the POINTER study.
The way up to today was marked by conduct of several phase I studies, both in healthy subjects as well as in patients, where we have established learnings such as the pharmacokinetics, meaning how the drug is being distributed and also eliminated from the body. We also have learned about what is the maximum tolerable dose in healthy subjects, particularly, and we have also become aware of the safest administration pathway to apply this product to a patient. Based on the learnings from phase I, we have moved into phase II with the already provided and earlier discussed AKITA study, which was the proof of concept study, meaning the first tool to establish whether this drug works or not in the setting in this case, cardiac surgery patients.
As you know, it had been successful and provided the way for the POINTER study where we are today. We have confirmed long-term efficacy, which you just heard by Professor Goldsmith, is also highly clinically relevant for treating physicians. We have learned about the maximum safe exposure where this drug can be used with, and we also have expanded our knowledge about the safety of the product, be it in terms of adverse events or other safety parameters. So this allows us now to move into the POINTER study, where the aim is to optimize the dose, and also other aspects from the feasibility of study and treatment.
Together with the AKITA study, results from the POINTER study will allow us to build a data package, supporting the phase III study design, allowing us to interact with regulators for getting the phase III study, which you see on the right part of this slide, which will be a single pivotal trial with the objectives of confirmatory efficacy and safety. Following this study, the usual path forward is to put together the data package, from all studies with large weight, of course, on the phase III study, submit this for, review, by regulatory agencies for approvability of the product. Guard will continue the dialogue with the FDA, of course, once we have completed the POINTER study.
Now, let's talk a little bit more about the POINTER study, moving on to the following slide, which is this second study in the phase II, as already mentioned, based upon the learnings from the prior study. In terms of the patients to be studied, we will look at patients undergoing open-heart surgery with cardiopulmonary bypass. Professor Goldsmith has nicely talked about that, and the harm which is introduced by this life-saving method, and these patients are to be at increased risk for kidney injury. So we have defined a certain list of predefined risk factors, also mentioned already in Professor Goldsmith's presentation. We stay broad with regards to the kidney functional status of those patients before surgery, meaning we will allow for patients with, but also without existing chronic kidney disease.
Since this is an important risk factor, as we heard, we plan a stratified randomization for that. That means we assure that patients with and without chronic kidney disease will have a similar chance to receive the placebo or the active drug, and therefore have a balanced randomization when later analyzing for the impact of CKD on outcomes. Learnings from the AKITA study also show us that based upon the effect size, meaning the eGFR difference we have observed, we will have a sample size of around 160 patients distributed across the three arms, three treatment arms, which is either a high-dose arm with 60 milligram, the low-dose arm with 30 milligram of RMC-035, and both comparing them against placebo.
Based upon the AKITA results and compared to the AKITA setting, we have now introduced simplifications. The data from AKITA allow us to do so with regard to the dosing. Number one, we will have a fixed dose instead of a dose based upon body weight. This is more straightforward to be used for physician investigators, but also later on for treating physicians in the clinical setting. And this dose is also independent, will be set independent of kidney function, and will be applied in 3 infusions. If you compare to AKITA study, this was 5 infusions, and these 3 infusions will be given within 24 hours upon surgery. The first dose and infusion just at surgery, the second one, 6 hours after the first dose, and the third one, 24 hours later.
In terms of endpoints, Professor Goldsmith nicely paved the way there, so the focus on regulatory, regulatory acceptable, relevant endpoints includes an assessment of, I call it long-term renal function at day 90. Of course, we understand Professor Goldsmith is, for his patients, interested in really long-term outcomes across years. But the good thing here is that the regulators are agreeable to assess, the effect size at day 90, because it would allow, or experience tells that it allows, basically forecasting, long-term efficacy results. Of course, a relevant effect size has to be seen there, but we are on the right path there with the AKITA study. Now, a couple of words on the endpoint we are going to study. This is being shown on the following slide, please. Oh, sorry. First of all, the study scheme itself.
Let's stay with the study scheme. Sorry for that. This is basically the list of visits, study visits the patient will undergo during the study. Usually, the patients is coming, for a screening visit the day before surgery or even sometimes on the day of surgery, which is day 1, where surgery, a green arrow, will start. Usually, it takes 3-10, but also up to 5 hours. And, prior to surgery, the first dose will be given, the second arrow, red arrow, 6 hours after the first dose, and the third and last one, 24 hours. This is usually when the patient is in the operating room or in the post-operative ward and intensive care unit.
Following discharge of the patient from hospital, usually at 4-7 days after the surgery, patients remain on follow-up, and that's very important because I said before, we are looking for data on the long term. We have instituted 2 endpoints, one at 2 visits, one at day 60, the other one at day 90, day 90 marking the relevant endpoint, a relevant date for assessment of the primary endpoint. And this is what we see visualized by the green target here. So the scheme in itself is very similar to the AKITA, so we can build on our scientific but also practical experiences during the AKITA contact. But again, the emphasis is on assessment of outcomes at day 90, which is in contrast to AKITA, which was more focusing on short-term outcomes.
Now coming to the endpoints, which are a reflection of the long-term direction. If we look at the primary endpoint, where we want to evaluate the efficacy of the pooled active arms, 30- and 60-milligram put together versus placebo, we look at change from baseline in a marker, which is called estimated glomerular filtration rate, which is a good marker for kidney function, acknowledged by clinicians as well as by regulatory authorities at day 90. We will use the same endpoint if you focus on the bottom row of the table by also discriminating the efficacy of each single dose versus placebo, so we will not look in a pool, but also by dose manner, and the change from baseline in eGFR at day 90.
And this will be complemented by the assessment of the already mentioned Major Adverse Kidney Event, so the composite of either, death and/or dialysis or a significant change of eGFR at day 90. Again, a regulatory accepted endpoint, and this will be another key secondary endpoint. There's a list of other endpoints which address also efficacy, but also safety and pharmacokinetics. They are not in here, but they are state-of-the-art and will be part of the study protocol, which we are working on right now, and that brings me to the following slide, please, where I want to make you familiar with where we are right now. Study preparations are ongoing, and we progress well according to schedule. We have selected those key vendors which support us with the conduct of the study.
Guard will keep the supervision, but we have key vendors organized with the site monitoring, statistical analysis, and other aspects relevant for the conduct of clinical trials. Following industry benchmarks, we plan for enrollment of the first patient in the third quarter of 2024, after we have gone through the relevant process of setting up the sites, making contracts with them, but also including submission of the whole dossier to ethical committees and regulatory agencies for review and approval of the conduct of the study. This study will be run mainly in Europe and Canada. Selected European countries will contribute, and Canadian sites already... most of them are already known from the previous AKITA study, so they are familiar with the product and the way we run the studies.
And this will be run under a so-called US IND, meaning, also the US FDA will have an eye on the study, on the safety of patients, and, will then later be also part of the package submitted to the FDA. I think we will be in a good position to share more detailed information once we are closer, closer to the study start, but as stated above, all is progressing well and according to schedule at this stage. This brings me to the end of the tour around the clinical development program for RMC-035, but we have more news for you, too, also on other developments, at this stage, more in the preclinical stage. And I'll hand back to Dr. Agervald for, making his points on the GTX program. Thank you very much.
Thank you much, Michael, for summarizing that. Yeah, so in the final part of this R&D update, and maybe it's time just to sit back for a while because now we're really leaving all the clinical parts of the program. And this is now to provide a summary going back to, you know, some of the early sort of discovery and preclinical efforts that's been ongoing in the past couple of years. And I will explain a little bit about the, I think, significant progress and advancements we've done, which is also important and supportive for the lead program with RMC-035.
So just to set the basics for everybody to understand what we're trying to accomplish here. So as you heard today from me and by Dr. Goldsmith, and also by Dr. Reusch we believe we're actually a leader in acute kidney therapies, and we do that by targeting the biology of a native protein called alpha-1 microglobulin, A1M. So this particular protein, that's actually what we're trying to mimic with RMC-035 that's now in clinical development.
Based on a lot of public published data, and also the knowledge of this endogenous protein called A1M, that actually support a therapeutic potential far beyond acute kidney injury, actually beyond the kidneys, in multiple different types of chronic diseases, both kidney and non-kidney. However, we also been transparent with RMC-035 on the basis of its characteristics, the way it's being built, and the way it's being developed. This is really confined to a short-term intravenous treatment. So that essentially means we cannot use RMC-035 long-term in patients in chronic conditions.
But we've been working actually on a solution to that problem, where we can essentially leverage and use the A1M function, and I think the biology of A1M by creating novel molecules, which we term peptides, which are essentially shorter fragments of the native A1M protein. By doing that, we can create new potential candidate drugs that really can be used and are intended for chronic administration. This is really the logic and the rationale for why we've been working now on this particular platform. I think if there's one slide to remember from this short presentation, I think this is the one, because I think this is a nice conceptual overview, how we see this development proceed.
So on the top, we already heard about RMC-035, and we heard a lot about the kidneys, and we focus now on the acute aspect of the kidney, although the translation is much more on the longer term. However, for the GTX peptides, and we just label them X, Y, Z, because this is really a platform of new potential molecules that all can be, you know, designed and, you know, fit for purpose for multiple different types of diseases and actually indications organ systems. And I just list some examples of potential use, which we have in mind and currently scrutinizing based on knowledge of the biology and/or existing data that we generated, and I will share some of that data with you. So one example is, is in chronic kidney disease. This is a very broad concept.
It could be chronic kidney disease due to specific diseases within the kidney, but it could also be due to, for example, diabetes. We also see potential opportunities in diseases of blood vessels, for example, peripheral vascular diseases, atherosclerosis. There might be other diseases of red blood cells, like hemolytic disorders, and this is something we currently are looking at in more detail and trying to figure out where we can position these molecules in the best possible way. Just a quick word on the evolution of the program. So we took the approach of what we call a targeted screen. That means we already knew which component of the native A1M protein, and also RMC-035, which were predicted to be the active site, really leading to the pharmacological, the treatment benefit that we see in patients.
So we sort of triangulated that area, and we created more than 100 different peptides molecules, which were then sequentially optimized. Essentially, that you do optimization step, you test them again in vitro, and then you proceed, and ultimately, you have to, at some point, put them into different animal models to show if they have the treatment effect in animal disease models. And we're now actually close to the ending of that stage, when we have identified multiple different potential candidates and drugs that can be brought forward for further preclinical testing. So far, based on the non-clinical work, we also focused on the kidney, but now not so much on the acute part, but actually also on chronic kidney disease part, because we think there's a nice paradigm where it fits.
We already know they seem to protect the kidney in the, in the short term, so presumably, they should also protect the kidney in the long term also, if there's a chronic treatment element to that. So we tested several of these new candidate drugs in four different disease models. One termed ischemia-reperfusion injury, which essentially means we're shutting off the blood circulation to the kidney, whilst also removing the other functioning kidney. That means you have a lack of oxygen supply, which causes an acute kidney injury. That was used as the screening model, because that's the model we also used for RMC-035 for our program in, in, in open heart surgery. After that, we also sequentially tested multiple different molecules in three other different models. One is called cisplatin-induced kidney injury.
Cisplatin, it's actually chemotherapy, but it's still commonly used in many different types of cancers, and we know that it's really toxic to the kidney, and produces long-term issues. It might even be an issue, and you have to switch your dosing from cisplatin to something different because it's not really tolerated by the kidney. We also looked specifically at two different, what we call chronic kidney disease models. One model reflecting diabetic kidney disease. Second model reflecting a more uncommon type of cause of chronic kidney disease called focal segmental glomerulosclerosis. That's a long name. We usually abbreviate that FSGS. In the next couple of minutes, this is just to provide and give you a flavor of the data that we actually produced, which are very consistent, and I think congruent, across all these different models.
In this first model, where we tested ischemia-reperfusion injury, as I already described, we took one of the lead candidates, called GTX-11, and we just tested whether that has an impact on the injury itself and also on the kidney function. We measured this by two different ways. So one is uACR, or something we call albuminuria or proteinuria, and I think a lot of Swedish people in the Swedish audience have heard about this because we now, now know that a reduction of uACR may even lead to an accelerated regulatory approval in drug development programs in chronic kidney disease. This is a highly clinically significant damage marker. And, creatinine, as we heard, that's a plasma marker that we measure. If you have a reduced function, the creatinine level actually goes up.
As you can see here to the left, we have a clear and significant reduction of injury, as measured by a reduction of uACR, but also an improvement on the kidney function by a reduction of the plasma creatinine level. We also measured another injury marker in this particular model. It's called Kidney Injury Molecule-1 . That is a more specific cell injury marker on a particular cell type from the kidney, and we can actually measure that both as a soluble product in the urine, but we can also measure that directly in the tissue. In principle, to the left, you see that if you now use GTX-11 and treat these animals, you see that also the reduction of KIM-1, indicating a reduced injury, by using measuring the urine marker. To the right, this is what it looks like in a...
If you look in the kidney in the microscope, and you see the dark staining with the vehicle treatment, the darker the area you see, that's indicative of an acute kidney injury. And as you can see with GTX-11, you essentially see that the staining in these dark regions of KIM-1 actually disappears or severely is being reduced. So in principle, we've shown that you can reduce on different types of cells and tissue, you can reduce the injury, and you can improve the kidney function with GTX-11. Going to another molecule called GTX-086, which is also one, actually one of the front runners and lead candidates. We evaluated that in a cisplatin-induced kidney injury, and essentially, that means we're essentially treating the animals with cisplatin, and you can see clearly that the kidney function and damage markers goes up.
This is something we measure now with BUN, or blood urea nitrogen, or creatinine, and again, these are biomarkers that are used clinically, also when you try to assess kidney function in patients. Similar to the previous slide, we can see in a nice and dose-dependent way, which is important, but that with a higher dose, you can actually have an improved efficacy. That's normally what you would like to see. And you can see that you reduce both BUN and creatinine in this particular model, essentially protecting the kidneys from the toxicity that is imposed by cisplatin. We moved on and tested this in some more chronic models. This is a model of diabetic kidney disease, and I think everybody who knows anyone with diabetes know that one of the long-term, severe long-term consequences of diabetes is actually an impairment of kidney function.
And diabetes remain as one of the key reasons why patients at the end up in end-stage kidney disease, requiring a kidney transplant or dialysis. In this particular study, we induced type 1 diabetes chemically by essentially providing a substance which knocks out the insulin-producing cells of the pancreas. So they get a—this is a model of what we call a type 1 diabetes. And again, you now get familiar with the injury markers, uACR and creatinine. And in again this study, we actually evaluated the chronic treatment, so the animals were treated for 28 consecutive days. And when you follow up and measure uACR and creatinine on day 14 and day 28, again, you see a nice dose-dependent response in terms of reducing the injury and improving the kidney function also in this diabetic kidney disease model.
And finally, switching over to this, complicated word or the disease, we term FSGS, which is an orphan disease, but again, leading a very common cause of, of chronic kidney disease and end-stage kidney disease. We use the same molecule, GTX-086, and in this particular model, we induce FSGS, again, chemically by infusion of a substance called Adriamycin. We treat these animals for 14 days, so it's also sort of a chronic treatment, with daily injections for 14 days. And you see the same pattern, that the creatinine level is gradually being decreased with an increasing dose of GTX-086, and so does the uACR.
So I think conceptually, we see this in a way that we now have a lead program with RMC-035, with AKITA results passing the hurdle, going into phase II-B, showing an effect on the kidney, but in the acute space. So we really think that that supports now the concepts that you can generate similar molecules, but that you can use for long-term treatment. And I think what I've shown you now that are, you know, experimental results of these novel GTX peptides, they really seem to validate what we see in the clinic with RMC-035. But you can also see that the other way around, that the clinical results we have, they also seem to validate and actually confirm what we see now with the similar sort of molecules in the chronic setting.
Of course, this provides great opportunity to expand far beyond acute kidney injuries and far beyond sort of acute any acute injuries. As a company, you always need to be mindful about securing your intellectual property rights. So we have submitted a series of patents, but most importantly, we have a composition of matter. That means we're protecting all these different peptide fragments that I mentioned and these lead candidates. We've also submitted novel medical use claims based on some data that we cannot share as of yet. But according to the patent laws, we actually anticipate the patent protection all the way up to 2044. And there might also be an option for an additional exclusivity period beyond 2024, based on, for example, orphan indications like FSGS, where we already have animal data to support that.
So this is my final slide and just summarizing up the GTX platform. So hopefully, I've explained that the overall goal of the platform is really to enable chronic treatment, but with the same mechanism that we have with RMC-035. We have identified several new potential drug candidates, and we've demonstrated robust efficacy in numerous different kidney disease models, both acute models, but also chronic models, which should carry a broad sort of translational value. And I think this is really something we need to work on now and make decisions and see, you know, where do we actually fit these different molecules and, and how are we gonna develop those further. And this is a pretty comprehensive work, so I think the overall development options within this platform and also the strategy, that will be further reviewed.
This entails a lot of thinking, a lot of desktop work, a lot of understanding of the biology, and a lot of tactics, and that's something we will work heavily on in the coming year before making any definitive decisions how they're being further developed. So with that, I think we are through and on time. So that means we're open up for any questions and answers we may have, and I'll leave it down now to the moderator to pick up the questions, and hopefully, we should be able to respond to those.
Thank you very much for that, presentation. Like you said, now we'll jump into the Q&A section. We'll start with the first question here for Dr. Goldsmith. [Humanizations] may cause a short-term negative impact on eGFR, even though they demonstrate a positive therapeutic effect in the long term. In your opinion, what is the shortest duration for monitoring eGFR to assess the impact of a medication? Is it one month, three months, or another time frame?
Yeah, it's an interesting question you've posed there. The changes that you can detect could be as swift as a few days. So this sort of change that you observe with certain therapies when you introduce it, very typically, in clinical practice, when we introduce these drugs, we might recheck the blood tests at maybe 2 weeks. But of course, all of these patients, by definition, will be being followed up on a regular basis, and because we're dependent on blood tests to tell us about kidney function, they will have blood tests anything from annually to twice a year, 4 times a year.
Many patients have them monthly. So that it can be detected early, but you would then have to roll that in with the overall monitoring of the process, which is always by blood tests and repeated blood tests, and comparison over time, so you can see the rate of change.
Thank you for that answer, and we'll take the next question, also posed to you, Dr. Goldsmith. You mentioned that the bypass machines have become more sophisticated over time, resulting in a lower incidence of AKI. Is there a risk or possibility that with further improvements in these machines, that the marginal benefit of a drug for AKI could decrease?
I think not. I think most of the improvements have come about. For example, there's a lot of pumps involved in these machines, and the pulsatile nature of the squeezing and backwards and forwards, that's been smoothed out. There are other factors, like filters that prevent coagulated micro fragments going back into the circulation. All of that's quite old now in terms of application to existing technology. I suspect it won't get much better than it is, and as much as the improvements are there, and they're very valuable improvements, don't forget that the coronary bypass procedures are being done on older and older subjects. So for all the improvements you have in the technology, you also have the increased risk of causing injury because you're having a more morbid, comorbid constellation of patients. So I think it will balance out.
The other thing, just quickly to say, is although the Guard have sensibly looked at a particular intervention with the heart, don't forget that the heart is also often intervened with, with cardiac catheterization, with the insertion of artificial valves, both mitral and aortic. And although that isn't quite the same as a bypass, there are definite associations with that sort of more complicated cardiac procedure and acute kidney injury, too. So my own personal view is that whatever works for coronary artery bypass grafting is very likely to work in other situations, too. That would be my hunch.
Thank you for that answer, and we'll take the next question here. How many clinics are you planning to involve in the Phase II-B study?
Yeah, I think I'll take that question, Michael Reusch. We are planning to include 25 sites, set across Canada and Europe.
Okay, thank you. And if you were to do the phase II-B study yourself and had to take in, let's say, SEK 100 million for it, are you also looking at alternatives, such as taking a loan instead of dilution through issue?
Yeah, so maybe that, that's a question for me. Yeah, so that, that's the inevitable question about funding, and ultimately, as a biotech, how, how do you best and optimally fund the next stage of development? I think what I can say now is that we're looking at essentially, we don't exclude any options at this particular stage. I think we're looking at multiple options, how you can ultimately support, not only the next study, but ultimately, how are you gonna bring this product to the market? Without saying anything specific, I could also say that loans, that, that's something that, that could be used.
But typically in biotech, that's something when you're very close to markets and where there's very low sort of residual development risk, because of course, you don't want to be putting yourself where you have, a big loan or actually that, that you have debts. And then ultimately, when you've got to, you know, proceed in development, that becomes prohibitive. But that said, we're not excluding anything at this particular point.
Thank you. Which indication or area of use do you see as the most promising for GTX peptides?
Yeah, so I think as we pointed out, I think one of the... Which we didn't touch upon today, but I think one of the, you know, key reasons why we see such good treatment effects preclinically with RMC-035, but also with the peptides on the kidney, it's actually because the peptides and RMC-035 is being specifically, you know, directed to the kidney because it has a natural sort of distribution to the kidneys. So when we do distribution studies, more than 90% of the compound actually ends up in the kidney, and it ends up exactly in those cell types that we want to protect in acute kidney injury. So I think there's a logic attached to why we, you know, performed initial screening and actually validation on all these chronic kidney disease models. I think-...
Since we already know it works on the acute side, I think there's a high degree of logic to also now look on the chronic side, and I think that's obviously where we generated the initial pharmacology data. That said, we are looking at some other, you know, potential orphan indications and some indication as mentioned, for example, in terms of hemolytic disorders. But we haven't generated any pharmacology data there yet, and I think that's what I alluded to. I think that's some residual work that needs to be done.
So I think the short answer is there are multiple options, but I think, again, chronic kidney disease, but different types of patient segments, because it's not one disease, it's multiple different diseases, multiple different types of patients. But I think that's really when you can find a niche and also have high differentiation points to existing therapies, because this is really something fundamentally different than what was proven to be efficacious so far and being available to patients so far in the clinic. So I think that, that would be my answer at this point.
Do you intend the GTX peptides yourself for the clinic, or do you see the possibility of early collaboration?
Again, I think that is a great question, and I think one of the benefits that we see now is that we see this as a platform. And I think it's quite clear that Guard will not be able to, you know, deliver and execute, you know, preclinical development programs and clinical development programs for all these different peptides and all, you know, possible indications. So I think that's really part of the package. You know, trying to pinpoint what is the best indication or indications, you know, how can you develop these as efficiently as possible? What is the most attractive market?
And, you know, bringing overall that strategy. And I think, of course, the funding also becomes part of that package, and I think that's part of the desktop work. Again, we're definitely not excluding, but I think would even appreciate to have some early collaborations on this point, really to make sure to, you know, release the full potential of this platform.
Can you explain how there is any opportunity to influence the phase III design by doing the POINTER study first instead of going straight to phase III?
Also, very good question. So I think what I was trying to explain in my earlier slide is that we are, it's about two things. It's about optimization. So I think it's a hypothetical scenario because we do want to do the optimization, and we actually looked at the concept of doing an adaptive phase II/III. But it becomes essentially overly complex, and we think that this leads to an unacceptable risk. So I think that that's if you do the adaptive phase II/III. But I think, to the question, I think it's also a matter of we know that if we don't do the optimization work, and you have to fix all the aspects of the current phase III design, we know what that's going to look like.
But as Michael also explained, you know, if you build the AKITA study with a POINTER study, I think that that provides a different package and I think a different opportunity to really both potentially reduce your size by changing your endpoint, but also allowing for an accelerated design. And I think that's what I mean by influencing the phase III design, by coming with a more even more sophisticated, robust package, allowing you essentially to break new grounds. And that's what we're working for. And I think that's where we ended up in terms of tactics and strategy around the further clinical developments.
Thank you. Take the next question here. You mentioned a full acquisition more likely than licensing. Do you think you need to perform a phase II-B study before this, or can it be before?
Yeah. So I think that that's, you know, we don't, we don't have a crystal ball exactly when that's going to happen. As I alluded to, we, we don't see this as a binary process, that it has to happen now, or it has to happen after the next study. I think that is something we will continuously work on, and again, look, what is really the best option and what is really the best for the company and, and for the shareholders? If you're asking me what would be potential sweet spot for a big pharma company, you know, as I said, there are now, I think, the industry trend, you're paying more for less risk.
And I think if you, you know, translate that, that might be you want to run your phase II-B study alone, because that might be an even better value inflection point and ultimately to create more value for the company and for shareholders. But I think this is something, you know, we will continuously monitor and work on. And I think the most important thing now is just to, you know, continue to run the program as planned, with a clear plan in place. And I think that's that put us in the best position to even have a discussion about licensing agreements or acquisitions.
Thank you. Do you have any updates from the ASN Kidney Week?
Yeah. So there are, there are no specific updates. So just for everyone, so the ASN Kidney Week, that's an annual congress, it's American Society of Nephrology, and it's, it's really the largest nephrology congress, that's, that's being conducted. We had a presentation in there, where we essentially presented the top-line results of the AKITA findings. I think that was well received. As in all conference, you tend to... you explain your data, you also interface with peers. It's a highly scientific congress. So I think that's what we can share from that.
And in terms of more, more corporate-associated discussions, I mean, that's not something we can really discuss or comment at this particular point. But I think from a scientific standpoint. It was a useful congress for us, and I think this is really now putting Guard on the map, and also explaining that there's this Swedish biotech company that really has good Phase II results, and I think that mission was accomplished.
Is there a possibility of a future breakthrough therapy for RMC-035?
Short answer, yes. And as explained in my presentation, we already have a Fast Track designation. Now, when we had a conversation with the FDA quite recently, they confirmed that we maintained the Fast Track designation, and also confirmed the unmet medical need, and essentially what we're trying to do with preventing an irreversible, permanent loss of kidney function, that is being considered a serious and potentially life-threatening condition. So by indication, we actually fulfill the definition of breakthrough criteria. And again, that's another sort of tactical element of this, because if you build your package with the AKITA plus the POINTER, then you may actually benefit from a breakthrough after the end of phase II.
You mentioned a kidney transplantation as a second indication for RMC-035. Are there any plans for a next study in this area?
Also good question. Yes, as explained, we've done a small phase I-B study, which is essentially about characterizing the safety and again, the pharmacokinetics of RMC-035, but specifically in the kidney transplant setting. What we said now is that we really are focusing on the lead program in cardiac surgery, and especially when it comes to dose optimization. Because we think that the learning source in terms of dose optimization study, that can be extrapolated and actually leveraged into kidney transplant program.
So I think the current strategy we have is to execute the POINTER study, and then potentially you can accelerate development, and you can apply all those learnings into a kidney transplant program. Potentially, again, with a more aggressive design or a more aggressive clinical development plan, as one would have taken without sort of figuring out the right dose and posology of the molecule in cardiac surgery.
Okay, gentlemen, that was all the questions that we had for today. Do you have any closing remarks before we wrap this webcast up?
No, thank you. So first of all, I want to appreciate... I want to thank both Dr. Michael Reusch and Professor Goldsmith for attending. I think that was highly helpful. I'll just want to provide some concluding remarks and a take-home message. So I think the purpose and the objectives today hopefully have been filled. I think we've shown that we had significant recent progress. We've created clear value in the projects by establishing a clinical proof of concept in a larger phase II study, which we've shown it's really a key value inflection point if you look at this generically from a drug development standpoint.
We have vetted and have a support by the FDA for the preferred development plan forward, and I think not, we shouldn't underestimate, we also now have a track record of a successful global study execution, because there are not so many small companies that execute studies of the size of AKITA. And I think, as Michael alluded to, we can now leverage all those learnings and experiences and translate that also into the POINTER study. And then finally, I really think that the novel GTX platform, that provides a flavor of some of the non-clinical and discovery work, but that really provides new therapeutic opportunities, and that's something we will now start to work further on.
And in terms of Phase II-B POINTER study, that's really the biggest chunk of work, and now everybody is working heavily towards getting the first patient in in Q3 2024. And finally, based on the results, and I think based on the plan forward, as explained, we're also now really intensifying business development efforts from 2024, but of course, onwards all the way. So with that, I want to thank all the speakers again, and I will close the meeting. Thank you.