Welcome to the Guard Therapeutics presentation of top-line results of Phase II AKITA study. For the first part of the conference call, the participants will be in listen-only mode. During the questions and answer session, participants are able to ask questions by dialing star five on their telephone keypad. Now, I will hand the conference over to the speakers, CEO Tobias Agervald and CMO Michael Reusch. Please go ahead.
Yes, thank you, everybody, and good afternoon. Welcome to this webcast hosted by Guard Therapeutics. The main objective of this conference is to present the key findings of the recent top-line results of the Phase II AKITA study that was published earlier this morning. So my name is Tobias Agervald, I'm the CEO of Guard Therapeutics, and from Guard, as we heard, we also have Dr. Michael Reusch, our Chief Medical Officer, who will present the actual data from the AKITA. Before handing over to Dr. Reusch, I would like to set the scene by just a few introductory words and put the AKITA study in a larger perspective. So first about the company. So we're a clinical-stage biotech company located here in Stockholm, Sweden. We have a particular interest in kidney diseases, both acute and chronic.
On the chronic end, we have a preclinical platform in development, but today's focus is more on the acute side, which is also relevant for the lead investigational drug, RMC-035, that was used in the AKITA study. So RMC-035 is being developed as a short-term kidney protective treatment, and we chose that indication based on a number of different reasons, and the initial target patient population is an open-heart surgery.
This drug also received a so-called Fast Track Designation by the U.S. FDA. And as you can see, that is for the prevention either of death, dialysis, or an irreversible loss of kidney function. And that's really important because that's one of the main study objectives in the AKITA to demonstrate that sort of chronic protection of kidney function.
We are in Phase 2 development, and we will discuss the AKITA results today. I should also say that the Phase 1b study, we completed that also in a second indication in kidney transplantation with the same objective, essentially protecting the kidney graft in patients undergoing kidney transplantation. At the design stage, just winding the clock back a little bit.
The main objectives in the AKITA study and several considerations that have to be taken into account at the design stage was, obviously, we should be able to robustly evaluate the efficacy as well as the safety profile of RMC-035 in open-heart surgery. Secondly, we also needed to establish the relevant efficacy signals to guide the further development. Of course, this is important for decision making before going into late phase development program, which is going to be larger and more expensive.
The study was not and never intended for regulatory approval, so that's important. Secondly, multiple endpoints in the study are critical for decision making on its continued development. We essentially split this in two different sort of parts. One, or the first one, is the acute endpoints, which are merely used as short-term prognostic markers for what we refer to as the hard clinical outcomes and the clinical relevant outcomes.
The purpose of the acute endpoints were not really to register the drug, but to essentially predict success in Phase 3 , but with a limited sample size. Because otherwise, if you use hard endpoint in Phase 2 , the study typically becomes very large.
However, the chronic endpoints, which were secondary, and they need to be confirmed if in the Phase 3 study to support marketing approval, and obviously, these have the highest clinical relevance. So in other words, we should treat the disease, not the biomarker. And specifically for this indication, it's also important to know that there's not a single Phase 2 endpoint that captures all the relevant treatment effects. So I think this was the framework, one, at the design stage of the study, and as you will see, this is also now reflected in the results. And, I will hand over now to Dr. Michael Reusch, who will go through the actual data from AKITA.
Yeah, thanks, Tobias. Hello, and welcome, everyone. Here, this slide details the study flow, which is visualized over the 90-day course of follow-up. Of note, treatment took place in the period around surgery and during hospitalization. Patients were followed up until day 90, and we focus on the endpoints being studied. First of all, the primary acute endpoint, acute kidney injury or AKI, which was studied within 72 hours of the first dose. But as pointed out by Tobias already, we were equally interested in secondary endpoints, estimated glomerular filtration rate, eGFR, and Major Adverse Kidney Events , MAKE. Overall, in this study, we had randomized and treated 177 subjects in both North America and the European Union.
Out of those patients, there was a slight imbalance of those patients who discontinued study in the active arm compared to the placebo arm. In terms of the baseline characteristics, we can say that the patient populations were well balanced. They were also representative of the target population with regard to age and gender distribution, more males than females, and of particular interest in this study, we had pre-specified two subgroups in the study protocol, which were also used for stratified randomization. The categorization of the subgroups was by eGFR. One subgroup with eGFR of 60 and above, which received a start dose of 1.3 milligram per kilogram for the first two doses.
The complementary subgroup of 60, of 60 milliliter per minute or less, which had received half of the starting dose, 0.65 milligram per kilogram, and which accounted for approximately one-third of the overall study population. We think this is important to keep in mind because it's, you know, to be regarded part particularly when interpreting efficacy outcomes. Now, let me come to these efficacy outcomes, and the first focus is on the primary acute endpoint, acute kidney injury, AKI, where this table shows the numbers and the proportion of patients with an AKI event. This definition of AKI includes serum creatinine increase of at least 50%, or an absolute increase by 0.33 milligram per deciliter.
What we see, if we look on the first data row, is that there is a strong trend favoring placebo, with 51% of patients in the active arm experiencing an AKI event, versus 40% in the placebo arm. If we focus now on the second row, with the subgroup of eGFR more than 60, with a double starting dose, we clearly see that the overall outcomes are driven by the findings where 56% of patients versus 35% of patients had experienced an AKI event. In strong contrast to these findings, there are the findings in the subgroup less than 60 milliliter per minute with a lower starting dose.
Here, we see a favorable trend for the active treatment group, also visualized by the forest plot on the right side of, of, this presentation slide, showing lower AKI event rate compared to the placebo findings. So what is the background of these, of, of these observations? And here, it's worthwhile to look at the course of serum creatinine and its change from baseline, during the acute postoperative period. This is a very busy slide, so let me walk you through it from left to right. The figures overall here show the change from baseline in serum creatinine during the postoperative period until discharge from hospital by subgroups.
In the left subgroup, we see a change from baseline of serum creatinine with the higher starting dose, with which is very pronounced if you compare it to placebo, and that is the one triggering the definition of AKI, which is a biochemical parameter showing an increase, triggering definition of AKI and not representative of a true organ injury. In contrast to this, if we focus on the right plot, where we see the findings for the subgroup starting with a lower starting dose, we see a different pattern. The course of creatinine changes over time are much closer to each other. There is no real difference between placebo and RMC-035 over the whole course of the observation period.
These findings now raise the question: apparently, there is an acute serum creatinine rise driven by the higher starting dose. What is the impact of these findings on the more clinically relevant outcomes, such as MAKE or renal function measured by eGFR? On the following slide, I will familiarize you with the outcomes on these hard clinical endpoints.
These are of particular interest because renal function and eGFR are a measure for improvement of kidney function or stabilization of kidney function. Major Adverse Kidney Events is a composite endpoint of particular interest for regulators like the FDA, and it consists of both mortality, dialysis initiation, and change in eGFR. Let's start with the eGFR course in terms of eGFR change over time. This slide shows the eGFR changes up to day 90.
Of note, if you focus on day 7, a steep decrease in eGFR at day 7, which is reflective of the previously shown serum creatinine increase on the previous slides. Thereafter, we see an upward trend with balanced or even slight improvement even at day 30, and this improvement continues day to day 90, with a difference between placebo and active treatment of more than 4 milliliters per minute. This is a relevant, clinically relevant difference, and if you look at it in a in a model which accounts for missing data, the so-called MMRM model, this effect size is confirmed, and it is associated with statistical significance.
What we can say here as one of the first of the long-term kidney function outcomes, we see here a significant improvement already in the overall subgroup, the overall treatment group. Of interest, of course, what will be the finding or how does the picture look like if we go to the individual treatment subgroups?
This is shown in this slide, which shows again the course of eGFR change from baseline by study visit until day 90, this time divided by study subgroups. We see here on the left side, again, the subgroup with a higher starting dose, with a marked decrease. If you look at the range, more than approximately 10 milliliter per minute in the immediate post-operative period.
But again, at the next subsequent well follow-up visit, improvements with similarity between both treatment arms, and further on until day 90, a further numerical improvement, which ranges between 2.9 and 2.3 mL/min, depending on the analysis we are looking at.
If we look at the right side, again, the subgroup with a lower starting dose, we see no dip as we see on the left side in the eGFR function, and we see a similar picture in the operative period comparing placebo and active treatment. Following onwards at the next follow-up visit at day 30, we see already a numerical benefit for the active treatment group, RMC-035, which becomes even more pronounced when we look at day 90.
The endpoint, which is also relevant in terms of regulatory decision-making, where the effect size ranges between 6.5-7.9 milliliter per minute, and is both clinically relevant as well as statistically significant. So what we take home from this slide is that we see an improvement of long-term kidney function, which is even stronger in the subgroup with a lower start dose.
You might be now interested, how does this translate into the outcomes on the other hard clinical endpoint, the major adverse kidney events, which are shown on this table. For MAKE, we have chosen the definition, which includes serum creatinine in the calculation of estimated glomerular filtration rate, and the numbers and proportion of patients with MAKE at day 90 are shown here.
The take-home message clearly here is that there is a absolute risk reduction by approximately 9% and a relative risk reduction of around 60%, which is both clinically relevant and if you, as you see from the bottom line, also statistically significant. And the second important message to be taken from this slide, this difference in risk reduction is driven by the decreased proportion of patients showing an eGFR reduction of 25% or more in the active arm, 3 versus 10.
So basically, these findings confirm the findings from the previous endpoint, eGFR course over time. This is particularly of interest in MAKE, as I stated before, the expected primary Phase 3 endpoint for a registration of study. Now, we also looked at MAKE 90 using a slightly different definition of MAKE.
At this time, the eGFR calculation was done based upon serum creatinine and another renal marker, Cystatin C. You see slightly different numbers, but the pattern is the same as before. We see an absolute risk reduction of 9% and a relative risk reduction by 50%. Again, statistically significant, as shown in the bottom line. And also here, it is the eGFR reduction proportions which drive this outcome, 7 versus 15 patients. A short look at safety. Overall, we saw a safety profile in this population, which was consistent with the expected adverse event profile in the cardiac surgery patients with cardiopulmonary bypass.
If you look at the treatment-emergent adverse events, defined as adverse events with an onset within 72 hours after the first dose, we see, yes, that in the active treatment group, both treatment-emergent adverse events as well as serious adverse events were slightly higher reported in the active treatment group. However, we also saw a balanced for those adverse events, which led to discontinuation of study drug, both in the range of 6% and also with the adverse events leading to death in the postoperative period, with 1 and 2 cases, 1 in the active arm and 2 in the placebo arm.
The findings also showed a more pronounced proportion of patients having experienced an adverse event suggestive of so-called infusion-related reactions, which is a constellation of signs and symptoms often seen with a therapeutic protein, and Guard is further following up on these events. This brings me now to my summary slide, where we can say, yes, the primary short-term endpoint, AKI, was not met. However, we clearly understand why this is the case. These findings were driven by the high dose group, the too high dose in the eGFR subgroup of more than 60, which were triggering the so-called AKI definition without really causing harm to the organ, which were reversible and limited, and didn't have any effect on long-term outcomes.
This means also that against our initial expectations, AKI is not, in the context of the AKITA study, to be used as a predictive marker for Phase 3 reduction—for MAKE reduction in Phase 3. On the other side, these findings are contrasted with very strong and consistent findings for the pre-specified secondary endpoints, both on renal function as well as MAKE, where we saw a significant and clinically relevant improvement for eGFR by day 90, as well as a significant and clinically relevant risk reduction for MAKE by the same time. And as said before, this is of particular relevance, and we are very optimistic about it, since this is a primary endpoint in a future Phase 3 study, as required by regulatory agencies.
Overall, taken the efficacy and the safety profile, we are looking forward to further development of this compound in the target population. And, with this, I'd like to lead over to Tobias Agervald for making his final conclusions.
Yeah, sorry, Michael. I was apparently on mute there, but just concluding the path forward. As we just heard by Michael, we have a robust evidence that RMC prevents irreversible loss of kidney function, which is fully in line with the U.S. Fast Track Designation. We have shown that we have an effect on the clinically relevant outcomes, including eGFR and MAKE. And obviously, the decision to proceed to late phase development on the AKITA results are really a combination of these different outcomes.
So first, we actually meet the primary Phase 3 endpoint. We have a strong and significant effect on eGFR on day 90, but even more importantly, we have a consistency between the continuous eGFR and the binary MAKE endpoint. There are just two different aspects and ways to visualize the overall kidney protective effect.
I think also importantly, the way we assess the eGFR difference, and when we try to translate it, what it means for MAKE, we also have the consistency that it predicts success in Phase 3 with the MAKE90 endpoint. So based on that, we decided to continue the development, and obviously, we will communicate more details shortly about the next sort of steps in development and steps taken in terms of interactions with regulatory authorities. So with that, I will conclude the company presentation, and we can now open up for questions.
If you wish to ask a question, please dial star five on your telephone keypad to enter the queue. If you wish to withdraw your question, please dial star five again on your telephone keypad. The next question comes from Ludvig Svensson, from Erik Penser Bank. Please go ahead.
Yeah, thank you for taking my question, and congratulations on the data. So if I understand you correctly, the lower dose performed better in patients with worse renal function. What would be the rationale behind this?
Yeah. Thanks for this question. This is Michael answering the question. When designing the AKITA study, we set two doses for the different eGFR categories, knowing that the availability of the drug was driven by renal function. The reason now for the lower dose being more successful is that this dose is closer to the dose expected to be effective in a Phase 3 study, and that in the higher dose group there was an overdosing, which led to the serum creatinine increase.
All right. Yeah. Thank you for that. Secondly, can you explain why you chose the 10% as the threshold value for statistical significance? And also maybe elaborate a bit on how you believe the lower number of patients included might have affected the P values in the study. Thank you.
Thank you. Yeah, we have chosen the level of 10% because we, it, we thought it was an adequate level of power of statistical power to be achieved with for the purpose of an early Phase 2a proof of concept study. For a pivotal study, certainly, we would choose a different a lower level of significance. The key point here is that apart from interpreting p-values and the threshold for 10%, it's important to keep in mind that we have here consistency of results in line with the logic behind the overdoses. We see consistency of results between MAKE and long-term eGFR improvement, which make us confident that we have a real effect size and a real efficacy signal here.
Okay, great. Thank you for that. That was everything for me.
As a reminder, if you wish to ask a question, please dial star five on your telephone keypad. There are no more questions at this time, so I hand the conference back to the speakers for any closing comments.
Okay, so we have a couple of questions have been published here. So I will just read those, and I think these are medical questions for you, Michael. So one of the question is, since we largely the MAKE endpoint or the outcome of the MAKE endpoint in this trial is driven by the eGFR component, is there a need in a Phase 3 study to demonstrate efficacy on all the components of the MAKE, or would be one component like eGFR, what we see in the AKITA, would that be sufficient?
The MAKE endpoint is a hard clinical endpoint, and I have presented the three components. As we saw from our presentation, it was particularly the eGFR change from baseline, which drove the efficacy, the positive efficacy signal seen here. The other two components, particularly mortality, we think are less subject to, more subject to, variability from post-operative complications rather than a true treatment effect. However, we are confident that if we show a positive signal on the eGFR, in the presence of balanced pattern for either dialysis or mortality, that this will be the basis for a successful Phase 3 study. I hope I could answer the question as expected.
A second question, maybe for clarification. The question is, how did the MAKE endpoint perform in the eGFR subgroups? I believe there was a data slide, but maybe you can provide a clarification on that.
Yes, there was a data slide, and in both subgroups, the trend of the overall population was confirmed without reaching statistical significance. But in both subgroups, eGFR risk reduction was shown consistent with the overall pattern.
Okay, and there's another question about the possibility now on these results to get the fast track to market in terms of accelerated approval. Also, there's a separate question in terms of potential breakthrough designation. Again, I think I can turn this over to you, Michael.
Yes. Well, as we have shown on the MAKE endpoint, the criteria for Fast Track Designation as requested by the FDA have been met in this study. So the designation itself and then the procedures will be, of course, subject to regulatory interaction. And then the same applies to the question of whether breakthrough designations, a Breakthrough Therapy Designation criteria have been met or not. And so this will be one of our next steps to get into interactions with regulators on the meaning and relevance of our findings.
Yep. Another medical question that came up here during the call. So what, what is the more, sort of the medical or the, the reason behind this acute creatinine rise seen with a higher dose level?
The reason behind, yeah, the reason behind the higher dose level, between the, behind the higher creatinine increase with a higher dose is that we know that the drug, when overdosed, and we know that from previous studies, is being secreted in the renal tubuli, which means it triggers the same signs, like signs like AKI, a serum creatinine increase, without being a true or without being reflective of a true organ damage. It's a question of the right dosing to optimize the efficacy, and that is what we will be looking at in, in future, for the future development.
Okay, thank you, Michael. And I think with that, we have some questions about timelines and funding. I think these are items that will be addressed separately. I don't think that's the scope of the call today. We will communicate more information as we have shortly, but understandably, we just looked at the top-line results, and this is one we wanted to present today. So with that, I will close this call, and thank you so much for attending, and good afternoon.