Hi, and welcome back. My name is Gonzalo Artiach, Pharma Biotech Equity Analyst here at ABG. The next company presenting now, it's Guard Therapeutics. And with us, we have the pleasure to have here, the Chief Executive Officer of the company, Tobias Agervald. Tobias, the stage is yours. Thank you. very nice to be here, and thanks for listening to us, and I will present on behalf of Guard Therapeutics. And as always, I think a short recap for all of you who haven't heard about this company before, just a quick status and executive summary where we are. So we're a clinical-stage biotech company based here in Stockholm, Sweden. We have a specific focus on kidney diseases, and I will go into more detail about that in a minute. We have multiple development programs. The one asset we have now in phase II clinical development is termed RMC-035, which is a small therapeutic protein mimicking an endogenous native protein termed alpha-1-microglobulin or A1M. So we are specifically focused on protecting the kidneys in patients undergoing open-chest cardiac surgery, and we actually received FDA Fast Track designation for this particular indication. And we're quite excited because a few months ago, we released top-line data from the phase II study called the AKITA study, where we actually demonstrate robust efficacy on the hard clinical outcomes and the kidney-related endpoints. So that really provides the basis for going into late phase clinical development program. I should also mention that we have preclinical platform, also new molecules coming out, which are more intended for chronic indications, for example, various types of chronic kidney disease. We're also a listed company on the Nasdaq First North Growth Market. The brief sort of medical background to this is that I think everybody knows somebody who's done an open cardiac surgery. That's typically something we call bypass surgery or heart valve surgery, or a combination of those two. There's still around 500,000 surgeries being performed each year in Europe and the U.S. What is less known that this procedure often leads to significant kidney injuries, which is being considered sort of as a collateral damage to the surgical procedure. But the problem is that the kidney injuries are not only acute, but they also often become permanent, leading to an irreversible loss of kidney function, patients developing chronic kidney disease, or there's a fair proportion of patients with already existing chronic kidney disease who have an accelerated progression towards end-stage kidney disease, which then obviously requires dialysis treatment or a kidney transplantation. Importantly, there are no approved drugs in this particular indication, either to prevent nor to reduce these types of kidney injuries. This is the first focus of our phase II assets. We really believe that this is a novel paradigm for the treatment of acute kidney diseases because we have a molecule that is really fit for purpose. It's an evolutionarily conserved mode of action. In principle, we're giving insulin to patients with diabetes. We're giving a different endogenous protein that we really think is attractive for protecting the kidneys, but in the acute setting. This molecule or the drug has shown really good solid efficacy in a wide range of different preclinical disease models, so we really have a translational confidence that it also should work in humans. We also give this as an IV delivery, and importantly, for those of us, for you, not are medics, the drug is immediately distributed to the kidney, which obviously is a benefit because you get the drug exactly to the organ and to the cells that you want to protect. So therefore, I'm very happy now to also announce that we have the Phase II results that came out from a relatively robust Phase II study with nearly 200 patients, 177 patients, dosed and randomized. And this is also the first therapy ever in open chest cardiac surgery patient that has a proven efficacy in terms of kidney protection. So that really provides the basis for going forward. So I will spend a little bit of time to going through the high-level data from the Phase II study. This is an overview from the study design itself. Maybe looks a little bit complex, but actually it's, it's pretty simplistic. Patients, if we just follow the patient journey, they are usually screened very close to the surgical procedure, and they are randomized on the day or day before the actual surgical procedure. In contrast to any sort of chronic treatments where you are on the drug for, for a very long time to evaluate the efficacy, as you can see here, we only give a few doses, with the first dose given during surgery and up to 48 hours after the surgical procedure. Then, patients are typically discharged from the hospital about a week after the surgery, and then we bring them back for follow-up visits on day 30 and on day 90, and most importantly, to assess the kidney function. And again, even if this is a short treatment, only given for a couple of days, the magical time point for assessment of any efficacy, that's done on day 90. So that's really the critical time point for two reasons. One, this is the first time the patients are really stable, so you have a good frame to determine whether your drug actually worked or not in terms of protecting the kidneys. Secondly, which is also a good point, and this is also what regulators believe is because they also want to see efficacy data on day 90 to get a market authorization of the drug. So this is the subject disposition. We had over 200 patients screened. At the end, we ended up with 191 patients randomized. There was a one-to-one randomization to active drug, RMC-035, and placebo. So importantly, this is not open label. It's not something where we need to rely on a historical comparison. This is a direct head-to-head comparison with placebo. And And as you can see, we also recruit, this was a global study. We included about 60% of the patients in Europe and about 40% in the U.S. and Canada. We also had some study discontinuations, mainly attributed to the follow-up period and mostly to logistical reasons. So there were no real discontinuations due to adverse effects of the drug, but more during the follow-up period. The baseline characteristics, it's also important, but this really reflects what we would expect. As you can see, they are relatively high median age, about 70 years. We have a large number of males, about 80%, which is also reflective of the population undergoing open chest cardiac surgery. But I just want to draw the attention to also the kidney function before they went into the cardiac surgery procedure. So we really had a cutoff in this study of something called eGFR, which is a measurement of kidney function. So if patient had an eGFR above 60 mL/min, which means a better kidney function, they were allocated to higher start dose. By contrast, patients with a lower kidney function, with an eGFR less than 60, which essentially is the definition of chronic kidney disease, they had a lower start dose. The reason for that is that we knew that there is a risk to overload the kidneys. As I mentioned before, the drug immediately goes into the kidney, and if we give too much in a too short time frame, that will have some consequences in terms of changes of biomarkers that we don't want to see. And this is essentially the outcome. Looking at the baseline values, the discharge at the hospital, day 30, and the 90 visits. And you can see the active arm in orange and the placebo arm in gray. And very counterintuitively, you see at the hospital discharge, there's actually a decline in kidney function or the assessment of the kidney function at this time point, which is a little bit surprising. This has been seen with a lot of different drugs that actually have shown to be kidney protective. We understand why this is, and this is we think this, well, we know this is a dose-dependent effect, and I will show you that in a minute. But despite that, we see that at day 30, that's being fully reversed, and at day 90, again, the critical time point when the patients are sort of in a steady state, we have a significant improvement of the kidney function as compared to placebo, numerically, somewhere between 4-5 mL/min when we triangulate this in different ways. And that is also to be considered a highly clinically significant effect. That said, as I mentioned, we had two different start doses, and again, drawing the attention to the left, which is the patient group, with a higher start dose and the better kidney function. This is really where you see this huge initial decline in eGFR, something we actually want to stay away from. So that indicates that this particular dose, it's actually too high. Despite that, there's a full reversal of that at day 30, and you start to see some kind of treatment effect emerging on day 90, but this is not statistically significant. However, with the lower start group, which is essentially our patients with chronic kidney disease, having the highest unmet medical need, they're already on drugs to protect the kidney. This behaves exactly the way we want because you avoid this initial dip, and you have a complete stabilization of the kidney functions all the way through follow-up, whereas the placebo arm continues to decline. If you look at the numerical improvement of that, it's somewhere in between 6-8 milliliters per minute, which is a huge effect. So many of these CKD patients are on drugs that protect sort of 0.5-1 milliliters per minute per year of chronic treatment. So this would equate to many, many years of chronic treatment. So this really provides a good basis for the drug and the proof of concept. Another way to assess whether there's a kidney benefit is using an endpoint called Major Adverse Kidney Events, or MAKE-90. This is actually what the U.S. agency, FDA, has indicated they want to see as a primary endpoint in a registration trial. So the MAKE endpoint is a composite of three different components. It's either death, any dialysis treatment up to day 90, or at minimum, a 25% eGFR decline or more on day 90. And as you can see here, we have no differences in death, which is expected. We don't want a drug to kill people, but we don't also expect to save life in the immediate sort of postoperative period. There's no really difference in terms of the number of events of dialysis, but there are small numbers. But we again see a strong difference in the proportion of patients receiving this threshold of at least 25% eGFR decline, a relative risk of 0.4, and that seems to be consistent, actually independent of the start dose. Even if you look with various sensitivity analysis around this important phase III endpoint, we still see that the numbers still hold true, and we have a relative risk of 0.4-0.5, which is far above actually what we would need to get the drug on the market in a phase III study. I think this really provides a solid basis for moving forward now into late phase development program. We all know that we already met the anticipated phase III endpoint. We also have a clinically significant and important improvement of the kidney function as a continuous scale. Even more importantly, there's a consistency between these two different outcome variables. And also, when we do some more sophisticated modeling work, we also predict that based on this effect size, we should also be able to be successful in Phase III. So that really provides an excellent base for moving forward. So obviously, the big question now is what does Guard Therapeutics do now in the coming months and six months? So the really important triggers, as always, when you're through a phase II study, is that you have to go back to regulators, first of all, inform them about the data, and you have to discuss the premises of a late phase program. So I think for us, specifically, this means three different things here. So first of all, we envision we need to do some kind of dose optimization, which is also according to the school book. This was a proof of concept study, but FDA and, and other regulators, for good reasons, are critical about selecting the lowest possible dose that are still efficacious. And we've proven now what is the highest possible dose that is efficacious, but we might go far below that, actually, and that's something we need to tease out. Also discussing that with the authorities. Also, we want to discuss the registrational endpoint. As I alluded to, MAKE, or major adverse kidney events, has been the traditional endpoint that FDA has pushed for in this space, but, we want to explore, actually, if we can use eGFR. And why is that? Well, that would essentially reduce the sample size with about 50% in the phase III studies. We think that has an important ramification for the conduct of a registration trial. Also importantly, because this is the first time, as I said, ever, that a drug has shown this level of efficacy on hard clinical outcomes. So that really provides the basis, we think, for exploring something called a Breakthrough Therapy Designation by the FDA, and that would be sort of the third element. So based on these, these three different components, we will make an integrated assessment and make a decision about the next development steps, and that's something we will communicate then, of course, as soon as we can in the coming months. We also, just to put a flavor on this, we in beyond cardiac surgery, which is, of course, it's a niche patient population. We also see opportunities in other indications, kidney transplantation being one of them, and we already completed a pharmacokinetic and safety study, phase I-B study, in, in this particular indication. And we really believe there are synergistic effects because the reason why you have a kidney injury is very similar between kidney transplant patients and patients undergoing cardiac surgery. So what we want to do is, again, do the dose optimization in cardiac surgery, but that really provides a leverage to move more aggressively also in kidney transplantation. So that is also yet to come. So I think to sum it up, I mean, we are really now in one of the few companies with a novel asset, a new molecule, going through into late phase clinical development. We have robust, placebo-controlled phase II data to support us moving forward. As I mentioned, we have a kidney transplant program that is now not in hibernation mode, but we want to work out the right dose in cardiac surgery first before we move forward. We have, as I said, in a couple of months, we have probably the full feedback from the FDA, and also regarding potential breakthrough designation. The company also, which is good these days, we have a strong financial position with more than SEK 100 million in cash, so we can methodically, we can continue to work and actually provide the best possible development plan for the company. And finally, not in scope for today's presentation, but, more is also to come in terms of our preclinical platform, where we have new molecules with a very similar mechanism as RMC-035, with very promising data in multiple different disease models, for example, of chronic kidney disease. So that really provides a nice sort of, again, synergistic view, because we can use RMC-035 for acute protection, and we have new sets of molecules that can be important for chronic treatment in much, much broader patient segments. Again, with the clinical validation of the mode of action of RMC-035. So that's really, really important to us. So I think with that, I will, I will close and open up and make sure we have some time for questions. Thank you very much. Great, Tobias. Thank you very much for such a nice presentation, and we have some minutes for questions now. And I will start asking you, I mean, with the AKITA study, the one that you just have reported not long ago. And, I mean, I guess that you have learned a lot with the study for the future steps. And I was wondering in terms of the dose that you will select for the future studies, a little bit, if you could give us some words on how wide or tight is the dose range? that now you will have to, and where you have to play now. Yep. How, how low could you go now? Or are we seeing any scenario where every patient will have to get their own personalized dose? So a little bit on that. Yeah. No, as always, I mean, again, if you go back to the sort of school book of drug development, normally, you establish, or in this particular indication, you would establish proof of efficacy and proof of concept with a single dose. And the principle we choose when we designed the AKITA study was really to push the dose to the maximum, essentially to the highest possible, what we assessed as a safe dose. And the reason for that, if you're gonna assess, you know, a number of different doses in your proof of concept, then obviously, you get very front-loaded in your investment. It becomes a very large study, so that's something you want to do in the second step. So there are... In several drug programs, you may have a hundredfold difference, potentially, of a dose that you could explore. That is not the case for us. We think it's more like a five to tenfold dose range that we may need to explore. And that is exactly part of the conversation we will have with the FDA. So we will essentially, we have now the AKITA results, which provide sort of a reference for the maximum safe dose, but we propose to use a lower dose. But I think one additional lower dose would suffice to meet that objective and really determine the optimal dose. So I think that's where we stand right now, and that's also what we're proposing. Okay, very interesting. And, and going back to the design of the study, a follow-up on this, is how about the number of doses that you gave? Do you think that you could reduce the number of doses and still play with, with, dose level that you have? Yes, it's, as always, it's a good question. At some point, you have to define your sort of your posology, exactly how the drug is going to be administered. Again, in this particular study, we really pushed the boundaries. All the non-clinical data that we have actually support we can use only two doses instead of five. That, as we applied in the AKITA. So it really seems that the operative dose that is given during surgery, that's critical, and then the immediate sort of post-operative dose, that also seems to be important. So essentially, that may suffice. So that's something also we're looking at now and trying to do some modeling simulation work. And most likely, we will end up with at least a somewhat reduced number of doses, but still maintaining exposure, because now we have data to also model and support that. And again, thinking now, this was to establish proof of concept. The next step is really to think about actually the commercial phase and what this product actually gonna look like? How it's going to be used, and I think that thinking also needs to be integrated in the design. Yeah. And one question on the endpoints for the study? If we put ourselves in the situation that you have to discuss with regulators, you're saying that you have to discuss with them if you will use MAKE-90 or eGFR. And how likely is that you would get, let's say, a green light for going with eGFR as primary endpoint? And in terms of long-term effects, would it be a case where the FDA requires longer times than 90 days with MAKE-90, for example, for six months or one year? Yeah. So, so I think this is all part of the conversation that we're gonna have now in a couple of months. Yeah. But in principle, there's no indication as of yet that the FDA would require a longer-term follow-up than three months. In this particular indication, they already stated that three months, and that's something we discussed on beforehand, even, you know, in the preclinical phase, before moving into clinical development. So I think a longer follow-up than three months, that we don't really expect that. If that would be part of the discussion as part of using eGFR instead of MAKE, that is something we have to consider. But I think there are always pros and cons of those two different options, and I think in all the scenarios we have on the table right now, three months is sufficient. Which is, again, also important from a development standpoint, and I think from an investor standpoint, because it, it provides confidence. You need time to recruit, but once you're recruited, you have a definitive projection of how much the study is going to, how long it's gonna last for, how much it's going to cost. Because all the events actually accumulate within 90 days. Yeah. Okay, I understand. In terms of the data, if we go a little bit more in detail in the data you have presented, you report yeah, a favorable effect from your compound compared with yeah, with standard of care, let's say, or... But you reported with using eGFR measured with creatinine- as well as creatinine in the formula of eGFR- As well as creatinine with cystatin C. In both methods, as I said, you have a favorable effect, but you have different numbers of patients that go to this eGFR 25%, benefit. Which one of those two methods is the correct one? And would it be... I mean, do we have any reason to believe that one could report better results than the other one, and which one is the one that you use in the clinic? So we used the analysis that I've shown was the one using in the primary analysis set. This is also what we propose moving forward. I think that there's an ever-ending debate on, you know, marginally, which method would be better, and they might perform a slightly different in different settings. I think the good thing for us is that we see congruencies. It doesn't really matter. Yeah. We actually see the same level of efficacy using both, which is perfect. I think that, again, supports the story of the efficacy. We don't really propose any changes to what we've done right now, but- Right ... if that would be imposed to us, that would also be acceptable, of course. There is no limitation from that side? No. Great. And then we move to the other indication that you are planning to... That you have in your pipeline. And you didn't mention much on it, but it's transplantation. And I was wondering if you could give us some words on the setting of this indication? and how much dosing plays a role here. Are you more flexible or less flexible? I mean, yeah. Yeah. So the difference between cardiac surgery and kidney transplantation is that in cardiac surgery, you have one very specific moment when the kidney injury actually occurs, and that's mainly during surgery. In kidney transplantation, that is also true. So the main bulk of the injury, and now we're actually speaking about the so-called deceased donor transplantation, when the organ is stored outside the body before it's being implanted. So you already have a fair amount of injuries occurring before it's being implanted in the recipient. But then, of course, once the organ is attached and being perfused now with the circulation in the recipient, then that's also time point where a lot of the injury occurs. Yeah. But it seems to be more sort of low-grade, lingering injury that occurs for a longer time period than during cardiac surgery. So actually, the way we dosed the compound in the phase I study was not as aggressively as in the AKITA study, but we gave that compound once daily for five days. So the same number of doses, but extended for five days. Okay, interesting. Yeah. One final question. You have mentioned that you have right now SEK 100 million in cash. With this amount, how much can you cover of your future plans, and yeah, a little bit on your runway? Well, as always, I mean, you know, since first we need to establish what are the future plans, and I think there are multiple different options, as you can see, and I think that's really what we need to anchor first and make an assessment of that. I think if it comes to the dose-finding study, actually, we have a pretty solid cash position to cover majority of direct cost of that particular study. If it's a matter of getting breakthrough or you're going straight into a pivotal study, that becomes a different ball game. But I think the benefit, we're not really stuck, sort of in the sense that you need to raise huge amount of money, on the same time going into huge, full-blown phase III program. We know this is going to be more limited. We know already that one pivotal study is sufficient. And again, it's quite attractive again for drug development because it's more predictable, and I think recruitment projections are more predictable. So I think that's how we see it right now, is it's all a stepwise approach, but first define the plans, and then you define your financial objectives. Sounds very promising. Yeah. Tobias, thank you very much for being with us today and for your nice presentation. Thank you.