Vivoryon Therapeutics N.V. (VVY) Earnings Call Transcript & Summary

Good afternoon. This is Anne Doering, Chief Financial Officer of Vivoryon. Thank you for joining us today for our R&D update webcast with key opinion leader speakers. Today's focus is on changing outcomes in kidney disease. On the call with me today is the Vivoryon management team, including Chief Executive Officer, Frank Weber; and Chief Business Officer, Michael Schaeffer. Importantly, we also have key opinion leaders joining us for the presentation. Prof. Tobias Huber, MD, Chair of the Center of Internal Medicine and Director of the III. Department of Medicine University Medical Center Hamburg-Eppendorf, Germany. He is acting as medical advisor for clinical study design and certain R&D activities. Kevin Carroll, PhD, CEO, KJC Statistics. He is acting as a statistical analysis expert, providing and calculating statistical readouts and advising on clinical study statistical aspects. I would like to remind you that during this conference call, we will present and discuss certain forward-looking statements concerning the development of Vivoryon's core platform the progress of its current research and development programs and the initiation of additional programs as well as results of operations, cash needs, financial conditions, liquidity, prospects, future transactions and strategies. Should actual results differ from the company's assumptions and assuming actions may differ from those anticipated. You are, therefore, cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date here of. Looking at the agenda today, I will say a few opening remarks. Tobias will then present the new scientific data we have for varoglutamstat in kidney disease. Then we will have Michael Schaeffer presenting information on the mechanism of action, the competitive landscape, market opportunity and our new compound, VY2149. Kevin will then walk you through the meta-analysis of VIVIAD and VIVA-MIND as well as statistical considerations for the Phase II DKD study we are planning. Frank will then provide an update on safety data, the Phase II DKD study design and have concluding remarks. We will conclude the webcast with a Q&A session. For a long time, the kidney disease space has suffered from insufficient treatment options, but we believe we have finally reached a turning point in how kidney disease is treated and we are truly excited that Vivoryon with its key findings and QPCT/L inhibition is set up to play a significant role in halting the progression of kidney disease. Firstly, huge unmet medical need. Despite recent advances and even drugs on the market, there is a tremendous unmet medical need for effective treatments to stabilize or improve kidney function. Chronic kidney disease causes progressive loss of kidney function and may lead to kidney failure or end-stage renal disease for a cardiovascular event. It is estimated that around 5.4 million people worldwide will receive kidney replacement therapy in 2030. Second, inflammation, a key underlying driver. It is well established that inflammation and fibrosis play a significant role in the progression of various kidney diseases. By targeting inflammation and fibrotic pathways, drugs aim to slow disease progression, reduced fibrosis and improve kidney function. Attempts to address these pathways and in particular, pro-inflammatory factors such as CCL2, have unfortunately been disappointing to date. More recently, developed therapies have somewhat improved standard of care, but they still, at best, only slow the progression of the disease and are not able to prevent progression of the disease or improve kidney function. Third, targeting QPCT/L to unlock inflammatory approach. We now have the chance to overcome this major hurdle. Vivoryon has identified QPCT/L, a key enzyme and inflammatory and fibrotic pathways through its impact on CCL2 and more importantly, pE-CCL2,an as well as other key inflammatory and fibrotic proteins as promising targets with the potential to stabilize kidney disease. Today, the speakers will present to you a compelling summary of why we believe that varoglutamstat Vivoryon's lead candidate is poised to effectively change outcomes in kidney disease. Varoglutamstat is an oral selective QPCT/L inhibitor with demonstrated statistically significant improvement in kidney function in 2 Phase II studies. This effect, in particular in patients with diabetes, is unprecedentedly large and was shown to be sustainable over a longer period of 2 years. So with that, I will turn it over to Prof. Huber Director of the III. Department of Medicine at UKE Hamburg-Eppendorf, who will walk you through our exciting new results of varoglutamstat for kidney disease. Tobias?

Yes. Thank you very much for the introduction, and welcome, everybody, this afternoon. I'm happy to report on the outcome studies. Next slide, please. So we can go into the next slide. It's important that you realize my disclosures. I'm rather pragmatically dedicated to improve the outcome of our kidney patients. And in my role, I'm advising a series of pharmaceutical companies on their developmental pipeline. Next slide. And the reason why I accepted an advisory role for Vivoryon was the data from the VIVIAD studies seem to the left, which has now been complemented by the VIVA-MIND study in the U.S.-based study. And as you can see, both of these studies have been designed originally to target Alzheimer patients for patient selection criteria, therefore, ranging relatively similar age range. You see the number of patients that have been treated. There have been slightly different protocols and high dose protocol in the VIVA-MIND study and 2-dose strategy in the VIVIAD European study. The treatment durations were quite similar. And as an explorative endpoint in both studies, eGFR has been sampled and monitored something that I particularly was quite interested in. We can go to the next slide. Now when we saw that I was personally intrigued when I was first approached by Vivoryon based on the VIVIAD study was that the application led to a significant increase of eGFR, while we usually aim for a slowing of progression of kidney disease, we very rarely see conditions where we achieve our decline is being halted or even being reversed. This was the reason which at least I found quite interesting at the time for seeing the data to the left VIVIAD data. So now these data are complemented, as just mentioned in the beginning, by U.S.-based study. And interestingly, also the U.S.-based study shows a comparable result of an increase of eGFR in response to varoglutamstat treatment. Next slide, please. Now looking at the periods when the track shows clear efficacy after the titration period. So between 24 weeks and 48 weeks and then later between ahead of 1 year, you can also see head-to-head of both studies, very similar comparable results in an increase of eGFR now even more pronounced than having seen in the first slide because this is now after a titration period and with quite similar results across both study cohorts. Next slide, please. Now this was something which an advisory role, we're very much interested. Among this Alzheimer cohort, is there a patient sub-cohort being at high risk for kidney disease? And it turned out that there is a subgroup of diabetic patients. Now we realized in the first cohort already that the effect of eGFR increases are even more pronounced in the diabetes subgroup. And same holds now true also in the second U.S.-based study with significant increase of eGFR in the diabetics subgroup, but please realize both subgroups a rather limited number of patients. Next slide, please. Now again here, same idea, looking in the subcohort for the periods after the titration phase when me see the most clear effect between -- after 24 weeks to 48 and after from week 60 to 72 and 96. And we see, again, very comparable results in terms of the increase of eGFR in both studies. Next slide, please. Now the next, basically, idea that we questioned ourselves and looking at this data was, a, are these effects being driven by a few outlayers? How can we get a more comprehensive responder analysis? In these, again, the subcohort of -- small subchort, I should say, of diabetes patients. And what you can see that in placebo, 71% doesn't show a response while in the higher dosage group, 72% were right in green show a response. So showing that it's -- that the overarching or the overwhelming majority of patients respond to the treatment and the effects seem not to be driven by a few outlayers. We can go to the next slide. Now again showing the -- comparing the placebo arm in both studies and the baseline similar results and then to the high dosage treatment in both studies now before the show the studies combined, but looking now at both studies separately, we can see that, again, both studies show very similar results. We can go to the next slide. Now as a translational and basic scientists as well as a clinician, of course, we are very interested to understand more about the mechanisms, kidney intrinsic mechanisms for the reason we are now starting a research project which has to be, as a disclosure, is being supported by Vivoryon, and we started to grow mini-kidneys in a dish, kidney organoids and first of all, look on the expression pattern of QC. Interestingly enough, in our mini kidneys, we see a fairly enriched expression pattern in these human mini-kidney organoids in the human structures, namely podocytes. We also see it in the tubular aquaporin positive compartment. And now we have being set up in, in vitro system for further studies, challenging these mini-kidneys and looking on the potential impact of the compound. Let me go to the next and last slide. So in summary, while previously, we have been looking at one study, we now have complementary results of a second study. The results are extremely similar in both studies as well as the overall results as also in the diabetic subcohorts. The current, as I mentioned in the introduction, our current clinical standard of care where we made a lot of progress over the last years still aims of slowing progression with SGLT2 inhibitors with RAAS blockade with nonsterile mineralocorticoid receptor antagonists now coming on the market. And while we don't have a treatment yet holding or reversing progressive kidney disease, but we are still, of course, figuring out the synergistic effects of the new trucks on the market. So as of now, there remains a significant risk of disease progression associated with premature morbidity, mortality in a still growing disease population of CKD-affected patients in a broader range of cardiovascular kidney metabolic syndrome, which is still rising in our societies, causing a significant burden for our patients as well as for the health care providers. So we are still looking out for new treatments that diverse progression eventually leads to regeneration or improvement of kidney function, particularly in advanced kidney diseases and also with applications in the rare kidney disease field. With this, thank you very much for your attention, and I'm happy to take questions via web chat. Thank you.

So welcome, everyone, and thank you Tobias for your analysis of varoglutamstat clinical results relating to kidney function, your insights into how they would fit in their worldwide efforts to address the substantial remaining medical need in this space. So now let me start off with this overview of how exactly varoglutamstat's profile makes the ideal candidate to overcome the existing gap in kidney disease medical need. We are talking about a single agent compound, which has the advantage of convenient oral administration. We have, and I'll go into this in a bit more detail in a moment, a first-in-class agent with a truly unique mode of action designed to effectively address key pathways in inflammation and fibrosis. As Tobias so beautifully explained just now, we have successfully shown statistically significant and clinically meaningful improvement of eGFR into independent double-blind, placebo-controlled clinical Phase II studies. And Kevin will be speaking about how unique and statistically robust these results actually are. We observed the effect size was substantially larger in people with diabetes compared to the nondiabetes population and can present here a differentiated profile with over 70% of patients showing improvement or stabilization of eGFR in the diabetes subgroup. Importantly, we have consistently shown an excellent safety profile across 2 years of study duration. So in summary, we can confidently say that it's truly unique MOA and benign safety profile make varoglutamstat suitable for not only treatment on top of the standard of care which is what we are focusing on at the moment, but also for potential combinations with other therapeutics. So how does this all work on the molecular level? For that, as a reminder here, varoglutamstat mode of action. Many of you have been following us for a long time now. And you know that we've been proposing and substantiating evidence for this unique MOA for quite some time now. It is centered around Vivoryon's groundbreaking discovery that inhibition of the enzyme iso-glutaminyl cyclase or QPCT/L reduces kidney inflammation and fibrosis, and can improve pathophysiology and kidney function. In detail, the most -- the process we are targeting is called post-inflation modification, which is a process that helps to functionalize proteins. For example, introducing on-off switch to the activity or enabling proteins to bind to each other. This process per se is a physiological event that we all need for our bodies to function normally. But in disease conditions, post-translation modifications can cause additional or accelerated pathological changes. Varoglutamstat take such a pathological form post-inflation modification called pyroglutaminylation or maybe a bit simpler pyroglutamate formation. In the human body, pyroglutamate formation is catalyzed by only 2 enzymes called glutaminyl cyclase QPCT and QPCT/L and the activity of both is blocked by varoglutamstat. So let us first focus on the left slide here. In -- on the left side here. In pathological conditions, glutaminyl cyclase are upregulated and increasingly catalyzed the pyroglutamate formation on pro-inflammatory and profibrotic molecules like CCL chemokines and collagens. This leads to an increased activity and stability of these elements followed by an increase of known inflammation fibrosis actors like TNF alpha, interferon-gamma, alpha- SMA collagens and so on. On the kidney function level, we encounter decreases in urea and Cystatin C and eventually a drop in the glomerular filtration rate and the loss in kidney function. Now turning to the right side. And you see here in the actual crystal structure, how nicely varo fits into its binding pocket on QPCT/L. Blocking of QPCT/L leads to a strong reduction of pyroglutamate formation on the pro-inflammatory and pro-fibrotic effectors, making them less active followed by a beneficial down modulation of factors like TNF-alpha, interferon-gamma and collagen, leading to an improved glomerular filtration rate and hence, improved kidney function. To provide the link between this MOA and the Phase II clinical evidence, I'd like to point out just a few examples of the many scientific findings that support our approach. On this slide, we are moving from left to right, from human cell in vitro models to in vivo mouse data and further on to the clinical findings we have with varoglutamstat. In human cells the present of the chemokine pE-CCL2, so the pyroglutamated CCL2 here in open boxes, is decreasing dose dependent when varoglutamstat is applied. In a CDK mouse model -- CKD mouse model, the varo leads to a clear reduction of fibrotic markers like Collagen 3 and alpha-SMA. And finally, in humans, we see a clear dose-dependent decrease of pE-CCL2 levels of study participants. And to be clear, with all these highly consistent scientific findings in mind, what I'm talking about here is a chemokine that many others in the field have tried to target in the past, but so far, in contrast to our efforts, unsuccessfully. And this brings me directly to our positioning within the competitive landscape. On the left here is a summary of the most important differentiating factors of varoglutamstat and these are oral availability an entirely novel MOA, single-agent activity as potential for using combinations, a demonstrated long-term effect on kidney function as measured by eGFR and a favorable safety profile. And in this graph on the right side, you can see where our peers stand with the drugs in various stages of clinical development. Below the horizontal line, you see the plethora of drug candidates are still so continued, albeit, in some cases, slower decline of eGFR. And we are also including here development candidates for which no eGFR data are available at this time because they have not yet been tested in studies using the state-of-the-art FDA-approved endpoint. And above the horizontal line, we can clearly see that the only 2 drugs that have shown to stabilize or even improve eGFR to date are our own varoglutamstat and ProKidney's cell therapy. What I want to emphasize here is that not a single compound in development as the characteristics of varoglutamstat. And by that, I mean that they either are not orally available have limitations of long-known MOAs like single-agent activity can only be used as combination therapy or cannot provide evidence of improved kidney function as measured by eGFR analysis or even a combination thereof. So taken together with its characteristics and with a proven clinical evidence of statistically significantly improving eGFR, varoglutamstat clearly stands out. And I'm sure you can appreciate why we feel it is extremely well positioned in indication space that urgently needs new, effective and safe treatment options. And how does our target market look like? What I want to point out when looking at numbers is that there are plethora of sources in epidemiology data out there, and the numbers can vary greatly. So we, as a management team, are basing our assumptions on an internal analysis of a number of different reliable incredible sources and also factoring in what we believe is important when thinking about our initial target population of Stage 3b/4 diabetic kidney disease. So let me start it from the top. Diabetes is a significant and growing global challenge estimated to affect nearly 800 million people worldwide in the next 20 years. Diabetes is also the major risk factor of chronic kidney disease with 1 in 10 people that will just possibly ending up with end-stage kidney disease. And we are currently facing over 70 million patients with diabetes in the U.S. and Europe alone and roughly 40% of these patients, meaning around 25 million to 30 million, are estimated to be affected by a diabetic kidney disease. We are currently planning a Phase IIb study in Stage IIIb and IV DKD patients. So our initial target population within a growing market in the U.S. and Europe is estimated to be around 3 million to 6 million. And to be clear, this range does not yet include, for example, patients that are categorized as Stage IIIa, but those disease is not adequately managed by standard of care or that are fast progressors in Stage IIIa, both of which actually are at higher risk for severe outcomes. So these numbers could become significantly higher, especially since we believe varoglutamstat would also be investigated in overall CKD, including nondiabetes population, as well as in certain orphan diseases. And speaking of future opportunities, I'd like to show you how we are also looking ahead and beyond varoglutamstat. So our continuous activities to fully exploit our compound portfolio led to the identification of our next-generation development compound, VY2149. This compound is now in preclinical development and has shown improved molecular properties, including an improved peak concentration of VY2149 compared to varoglutamstat as well as a markedly increased overall drug exposure, both shown here in the bar chart top right, the blue bars are VY2149 and purple bars are varoglutamstat. Also VY2149 shows a 2 to 5x higher passive uptake into cells here on the bottom right. Moreover, assessment of once daily dosing of VY2149 in an animal model has shown strong effects on eGFR creatinine cystatin C levels as well as on alpha-SMA levels and collagens. And all this is very important because higher intracellular QPCT/L inhibition translates to better activity and lower doses and, as we believe, is a major step in the context of exploring once daily dosing for QPCT/L inhibitors. So obviously, VY2149 is an important project and development pipeline update with which I'd like to conclude. For varoglutamstat, we are in preparation for focused Phase IIb study in DKD patients, and Frank will share a lot more details on this in a bit. In addition, we have the potential to investigate varoglutamstat in orphan kidney indications. Our earlier-stage projects now comprise VY2149 as well as investigation of meprin inhibitors, which are an early research program with potential for single use or in combination with glutaminyl cyclase inhibitors in fibrotic indications. All future studies are, of course, subject to further funding in our partnerships. Based on the confirmatory findings that we have generated recently with our meta analysis of kidney results, from the VIVIAD and VIVA-MIND studies and in line with focusing our resources on the exciting and promising advances in the kidney disease space, we have decided to discontinue investigation of varoglutamstat in Alzheimer's disease. Similarly, the pyroglutamate specific antibody is also not being advanced at this time. To give you additional insights, it will be important meta-analysis for VIVIAD and VIVA-MIND, I'd now like to hand over to our next speaker, Dr. Kevin Carroll. Kevin?

Thank you. I hope you can hear me okay. If not, please do say. Yes, so I'd like to spend a few minutes just reflecting on the data that we obtained in VIVIAD and VIVA-MIND trials. And I think I've got control of the slides, let me double check. I'm not sure I have control of the slides, so maybe if you could page the next one. Thank you. And to reflect on those data. And -- so we decided to execute a meta analysis. The reason for that, the objectives are twofold when we do this. The first is to provide the best overall assessment of the efficacy of drug in terms of its effects on eGFR by bringing your data together, thereby providing a more overall and more precise effect estimation. And the second is to ascertain whether there's any evidence of heterogeneity between the trials. So -- are the trials giving consistent results or not? So we try and formalize that assessment. It's self-evident, I think that they look very similar, but we can actually assess statistically whether there's any evidence of heterogeneity. So there are 2 things that meta analysis is meant to do. Now I'm not going to give a lot of comments on and a lot of mathematics here. But when we have the 2 trials the VIVIAD and VIVA-MIND, and we want to bring those together to make an overall meta analysis, there's 2 ways that, that can be done. One of them is so-called fixed effects. And that assumes that both trials are estimating the same effect of eGFR as an assumption in that analysis. So sometimes that may not be correct, that assumption. So we have a second type of meta-analysis, which is random effects. And that directly checks and accounts for any difference in results from one trial in the next, any truly statistically significant difference between the trials. So we check if that exists. And if it does, then we can execute the meta-analysis using something called random effect. So there's 2 approaches. And if we go to the next slide, I'll show you some of the data that we have. Okay, so this is quite a busy slide, so I'll try and just orientate. On the left-hand side, we have the time period. So you can see 4 to 16, 24-48, 60 to 96 weeks. So this is a time period of assessment of eGFR in both trials. Next along, you can see the trial column which is VIVA-MIND, VIVIAD and then fixed and random. That relates to the previous slide. That's the kind of -- that's the result from a fixed meta-analysis and a random meta-analysis. And then you can see the sample sizes and then we have the treatment effect and p-value in the interaction p-value at the end. The interaction p-value is important. That tells you is there any difference between the results obtained in VIVA-MIND and VIVIAD or are they consistent? And I actually make a comment about that now, which is you can look down the interaction column, you see all those p-values are not significant. And that means that the results from VIVA-MIND and VIVIAD are statistically consistent. They are estimating the same thing, which reinforces comments made by my colleagues earlier that we have replication of the results on eGFR in 2 independent trials, which is quite a novelty, I think, not just in CKD, but generally anywhere where you have small trials, and you get the result very nicely duplicated. So that gives confidence in the truth of those results. So there's no heterogeneity, and then now we can actually look at the results themselves very briefly. We can focus on the fixed in blue, the reason we can do that is there's no heterogeneity, so the fixed and the random results are the same. They will be identical because there's no difference between the trials. And thereby, you can see we have a small effect that appears in 0 to 16 weeks of about 2 ml per minute and then that strengthens considerably as we go through to 24, 48, 60 and 96. These are the same data just show graphically. You can see on the right-hand side the diabetes group, where the treatment effects are very large, 8 to -- over 8 ml per minute in the period, 24, 48, 60 to 96. Those kinds of treatment effects in CKD are completely unprecedented. And remember, those -- this is based on 2 trials that gave consistent results. And if we go to the next slide. This is the reverse population. So on the very right-hand side in red is the no diabetes. Population, you can see that the treatment effects are smaller than the previous slide, which is the diabetic population, so they're smaller, they're still positive, but they're clearly smaller. And you can see that in the red. And that applies -- and the other columns we're looking at here are just different populations that were looked at, for example, no hypertension or diabetes in green and no hypertension or diabetes or cardiac risk factors in blue. And they were the other kind of risk groups you looked at -- the risk group of focus, I think, is the one in red, which is -- on this slide, no diabetes, on the previous slide it was diabetes. Now that's all -- these data -- this slide and the previous slide is all based on the data that was reported as part of the trial. If you go to the next slide. In VIVIAD, we have the opportunity to recompute eGFR based on remeasured creatinine using the CKD-EPI formulated from I think it's 2021. So we regenerated the eGFR data and redid the entire analysis as a sensitivity to check the results we were obtaining. And as you can see on the left-hand side in red on the left, a diabetic patients; in right -- on the right-hand side, in red are nondiabetic patients. And you can see that the results are virtually identical to those that we obtained using the trial data that was generated, the eGFR and the trial databases and when we remeasured creatinine and regenerated eGFR, we got exactly the same answer, which is very reassuring, I think. Now maybe we can switch to the next slide, please. Okay, so that was a very quick run through. The results were obtained if we do a meta-analysis and very strong results in diabetic patients and the true trials are homogeneous. They're giving the same result. So when we bring them together, no heterogeneity, clear treatment effects are very large in diabetic patients. So if we take these data into account and then start asking ourselves what would a kind of a Phase II trial look like in diabetic subjects. Then I won't go through every step on the slide, but you end up with about 40 per arm would be sufficient to test for a true difference of 4.5 ml. And remember that 4.5 ml is about half of the effect that we actually saw in VIVIAD and VIVA-MIND. So that's a conservative effect size, but we'd have 85% power for that. And in fact, the smallest observed difference in a 40-patient per trial that would reach a p-value of less than 0.5 is about 3 ml. So that would be the smallest observed to have a positive outcome and you would have power of 80% if the true difference was 4.5 ml, which is around about half of what we saw in VIVIAD and VIVA. So that very briefly captures what a Phase II trial would look like based upon those meta-analysis results. And finally, on the next slide, I do a similar exercise, but in consideration of a Phase III confirmatory type trial, here, the standard end point -- the standard time period, I should say, is eGFR measured over 2 years. And there are many CKD trials ongoing. Many drugs -- well, how about 3 now have been approved in the last 18 months-or-so in IgA nephropathy, 2-year endpoint for eGFR using slope, rate, the decline of eGFR at 2 years. So if we use that paradigm that is we're going to look at the rate of change eGFR over 2 years, then we can arrive at a requirement of about 150 per arm would give 90% power to test the hypothesis that this rate of decline, the annualized rate of decline, was improved by drug -- by 2.65 ml. And the smallest improvement that reach a positive outcome would be about 1.6 ml. And so that, the size of this trial and its duration of 2 years is very much in line with very many ongoing pivotal trials in CKD that have been -- the design of which and endpoints within which have been agreed with the FDA in EMEA. So we've reflected a design that is consistent with designs that we know have been accepted and are currently ongoing. I think that would be my last slide. It's everything for me unless there are any questions or maybe we'll leave questions to the end. But if there are any, I'm happy to take them. Otherwise, we'll just move on.

Thank you, Kevin. Thank you Tobias, Anne and Mick. It's Frank, who will finalize the summary and focus on the other side of the efficacy, and that is the safety. First of all, I think the efficacy is undoubtedly given and well portrayed. Let's go to the first slide on the safety. What we have done, we have pulled the placebo data and the 600-milligram data from VIVIAD and VIVA-MIND and looked at what is the incidence of treatment-emergent adverse events and those which are considered related by the investigator to the potentially the drug. The colors are pink is the active and yellow is the placebo. We looked at the serious adverse events and those which are potentially related to the drug according to the investigator, and we look at study drug discontinuation. And you see that overall, there are only very minor percentages more for the drug than for placebo. So there is a very, very good safety profile if you compare the incidence of related and potentially drug-induced adverse events, which is very minor percentages different to placebo. When we can break it down and say if there is a difference, where does it come from? And we go to the next slide, and we look at the system organ classes where -- there may be a difference and there may be a drug signature. And you see infections and infestations. There was -- those studies were done in the COVID period and COVID-19 infections where the majority of the infections. There is no real difference. You see a minor difference in gastrointestinal disorders, and that is occasional and temporary occurrence of nausea, which patients may have when taking in the drug. Then in system -- nervous system disorders you -- in psychiatric disorders, you see the reverse. The drug actually has much less side effects. Musculoskeletal and connected tissue disorders, there is some signature of the drug, it's largely arthralgia and back pain. So these are minor pain symptoms, which may come from an antifibrotic effect of the drug and it's probably related to the pharmacology, but these are temporary and not really bothersome where the patient stops the -- where this patient does not stop the treatment. You see there are definitely less injuries and falls with the drug, which is a good sign because the population is an elderly one. Then the drug has a slight signature on skin and cutaneous tissue disorders that we know that usually is kind of a temporary rash, which is mild and restricted to small parts of the skin. And then at the end, you see there is generally no further difference between the drug and placebo. So overall, there are a few more incidents of minor potentially related side effects in the musculoskeletal, skin and subcutaneous and probably nausea and anything else is pretty much placebo-like or better. With that, a very good safety profile of the drug at the dose we want to carry forward. We want to look at additional pharmacological effects, which we also portrayed for the VIVIAD study, and in line with what Tobias said, it's the cardiovascular renal complex, which we have to look at because the patients not only have kidney disease, but they have, of course, usually are obese or have a weight problem. The patients have high blood pressure usually, and the liver often is affected by these patients because they have a metabolic associated steatohepatitis. So we look into what influence do we see in VIVA-MIND on this parameter and we published previously and showed similar data for VIVIAD. And again, we see a consistency. You see in the overall VIVA-MIND population about a kilo weight decrease, so a minor rate decrease. We see a change in the blood pressure. So you see about 3.5 milliter in reduction in the blood pressure. And you see a reduction in transaminases, which are mild, of course, which are small changes, but you see it in the right direction, and it's different from placebo. So when there is some inflammation in fibrosis in the vasculature or there is some inflammation fibrosis in the liver, the drug also takes care of that. So overall, I think the drug is very well suitable for being used in patients with diabetic and metabolic syndrome as it targets also other areas for inflammation and fibrosis happens in the orals. So moving forward to also what Kevin has shown, we are planning and looking at a normal study, a clinical study where the primary objective is to investigate the efficacy and safety of varoglutamstat in kidney function in patients with 3B and worse, so more advanced patients, so the earlier patients we have. We have also very few patients which are already advanced, but not enough to substitrate the effect robustly. Then there is a secondary objective. We explored the efficacy of once-daily dosing also varoglutamstat. That potential is given. And I show you in the study design how we do this. And we want to generate further evidence of mechanism action. So we do a lot of biomarker assessment in that study. And then, of course, we want to look into what I showed you in the last chart and that is to look at concomitantly effective organs in type 2 diabetes patients so the liver, the vasculature and the body weight and see whether we can confirm the other beneficial effects we have seen independently in [indiscernible]. The time lines here are that we need for recruiting about the 80 to 90 patients, which Kevin laid out, we need about 9 months in U.S. and Europe that patients will be treated for a minimum of 30 weeks and a maximum of 48 weeks and the last patient probably reach his 8, 9 months period at month 15, the study start and latest after 18 months with some safety margin built in, we should have the top line results and see what the drug delivers in this advanced kidney disease patients. And later, we will additionally see additional analysis and once daily dosing results. And how that puts together everything is in the next chart, where we see that it's a double-blind placebo-controlled study of varoglutamstat against placebo. And then we look at eGFR as a primary end point. The patient gets double-blinds treated up to 1 year and then switches over to once daily varoglutamstat, both the placebo group and the active group. And then we can see whether the placebo group shows an improvement similar to the twice study, and we can show that whether once daily maintains the efficacy we see before in the twice daily in the active arm. As everybody switches to 600 milligram, the study doesn't get unblinded, and we don't know where which patient comes from. So there is a certain independence in the trial even everybody gets the same. The key characteristics of this study will be type 2 diabetes patients as said, with eGFR as a primary and albuminuria as a secondary endpoint and some exploratory endpoints as already laid out and we will stratify the population, of course, according to CKD severity, standard of care use, SGLT2. Majority of patients will be on standard of care for SGLT2. We make that sure, but maybe some are not eligible or cannot tolerate or -- for that treatment. So we need to open that as well and GLP-1. Now let me summarize the perspectives of the pipeline on the next chart of the company. we are owning the clinical space of QPCT/L inhibitors, and they have a large market potential as shown by Mick with development opportunities, not only in kidney disease, but also other diseases with underlying inflammation in fibrosis. Going to earlier stages of CKD, CKD then mentioned or also later ones. We have always considered to also look at rare kidney disorders, and disorders which progressed largely through inflammation fibrosis like metabolic associated steatohepatitis in the metabolic syndrome situation of diabetic and obese patients. That also explains why we have a follow-up molecule, which can then address indications which we do not address with varoglutamstat. And I think there is enough space for 2 or 3 QPCT/L inhibitors in the clinic in the market, addressing with their various characteristics, various types of kidney inflammatory and fibrotic disorders. And we are, of course, working towards completing that pipeline and platform in the future. Going finally with the final slide and with my ending slide summarizing everything what we have shown and Vivoryon has an asset today. Clearly, QPCT/L elements are unique in the mechanism of action targeting inflammation and downstream fibrosis, which sets us apart from any other mechanism, which is currently under development. We have undoubtedly compelling and replicated eGFR data in 2 independent long-term studies to the corresponding good long-term safety database. And we have a study plan, which is actionable, feasible and the development path forward, which is doable. And with the sample size lined out by Kevin, I think it's a feasible and investable area. We also work, as you know, on the intellectual property, which we have laid out on the last meeting. So I think we have a complete program, so moving ahead. And with that, I want to thank not only the speakers again of today Tobias and Mick and Kevin, but also the people behind that, our research team, who permanently works on it and our IR team who organizes all these meetings and support us heavily. And with that, we can go to the Q&A. Thank you.

So maybe we have some questions online and maybe we select the first for Tobias because Tobias has a hard stop at 4. And the question is whether you think that the wider adoption of GLP-1 and SGLT2 in the clinical practice in the future would significantly reduce the incidence of end-stage kidney disease or how do you see the dynamics of that? Will it disappear when everybody uses SGLT2 and GLP-1s? Or how do you estimate and see the clinical evidence today for these drugs?

Yes. Thank you very much for question. So right now, as we can see, all of these drugs are just slowing the progression by approximately 1/3. So they are not holding it and they are not reversing it. While we don't know how other combinations of the existing drugs will do. But from, I guess, our estimates as of today, with the just slowing of progression effect, but not holding on the one hand. On the other hand, there's still increase in risk population of the cardiovascular kidney metabolic syndrome and the increase in CKD populations, also being associated with our aging populations in the global -- particularly in the global North. The problem is not likely going to be solved by the existing drugs. So basically, yes, progression will be slower. But probably this will be outweighed by the increase of age and in still increase of risk factors.

Well, let me -- there is another question in the same area Tobias, and that is where would you use such a drug like varoglutamstat? Would you use it early, would you use it in progress as of standard of care? How would you make a decision or a recommendation to a patient to use such a drug? Where do you see that?

Yes. Thank you very much. I mean in my role as an adviser, I suggested advanced stages of CKD in a space where it's not just about holding the progression because all people with advanced CKD might eventually end up on dialysis. So here, we would really need game changers that hold or even reverse progression. So this will be the field where I see an indication, number one. Number two, don't forget about rare kidney diseases. In the RaDaR U.K. RaDaR study, we recently learned that just 5% to 8% of all kidney diseases account for over 30% of the end stage renal disease. So when some of rare kidney diseases, does have a significant impact on end stage renal disease. And most of these rare kidney diseases have a tendency of strong progression while there are no drugs available yet. So I think in this field, I would love to see new drugs being placed and being explored.

Good. Thank you, Tobias. I think that were all the questions on the medical area. I think if you need to go, then thank you for your contributions and yes, all the best for your next meeting.

Yes. Thank you so much, Frank. Thank you very much, everybody else for attending, and I'm going to leave then now. Thank you so much. Bye-bye.

Yes. Thank you. Then we go to the sample size assessment for the next study because we have initially cautiously said maybe we need 120 patients. And now we have the meta-analysis and the sample size calculation. Kevin, there is still I think some question of how robust that assessment is based on the data. And maybe you can say a couple of words on that sample size, how much you believe that 40 per arm is probably enough or not?

Sure. The meta-analysis provides us with a greater degree of confidence, not only in the likely effect size but also in the actual estimation of the underlying variability. So we have more data, so we have what's called more degrees of freedom for estimating the SD. So they are critical inputs into the sample size of calculation. So now we have a much stronger basis for postulating the treatment effect and for our estimate of the standard deviation. So that's -- so I think that, that means that we have a much clearer and we're confident handling how big that Phase II would have to be. I'd also point out that we currently have suggested a hypothesized effect of 4.5 ml, which would mean that an observed difference of 3 mil would have -- is what you'd have to observe to get a positive result from the proposed Phase II. But that 4.5 in and of itself is somewhat conservative vis-a-vis the meta-analysis results where we saw treatment effects in the region of -- I think it was -- I forgot the time period now, but I think it's 24 to 48 and 60 and later of up to 8 mil, so we've come substantially down and lower than the actual data suggest. If we were to hypothesize 8 mil, we would literally need a handful of subjects. I mean you would -- the trial would be so small, it would lack credibility because it's just too small, yet that is actually what the data do suggest. So rather than go all the way out there, we hypothesize what we thought was a reasonable effect that is rather lower than what the meta-analysis tells us. And consequently, overall that the Phase II design as we have it now and we have a lot of confidence that, that is indeed the right magnitude of -- in terms of size of study in a Phase II setting.

Thank you, Kevin. That's clear messages. I think you answered the question very well. Then we have a couple of questions regarding the mechanism of action, which should probably go to Mick. And probably Mick spend another minute or 2 on why we believe that previous approaches to target CCL2 are -- have not been successful and why we have now find a pathway to target the inflammatory fibrotic access in kidney disorders efficiently and different from previous approaches?

Yes. Thanks, Frank. Yes, I would say, a main difference, obviously, to earlier approaches is that we are working a little bit more upstream, I would say. So we are targeting, obviously, for example, not only CCL2, we are targeting a lot of other relevant factors in the fibrotic inflammatory field. So there are other CCLs and the family of CCL2, which are basically using same receptors at times also like 7, 8 and 13. And by our approach, all of those got targeted, let's say. So that's the main difference as opposed to just targeting very specifically just CCL2, I would say. And we see that actually in our experimental results that we got this effect also on collagens, which in part also require, obviously, this pyroglutamate formation on the N-terminus to get fully active and to form triple releases as they have to do. So that's certainly, I would say the main difference we see here as opposed to other factors and then obviously also looking at this pyroglutamation specifically, let's say, as opposed to just looking at CCL2 per se in its normal or non-pyroglutamated form makes obviously also different. So that's my answer to that.

When you look at the literature for those who are more interested, there's already applications in around 2,000 that the inhibition of non-pyroglutamated pyroglutamated CCL2 doesn't lead to a lot of things because the main effector on inflammation is the pyroglutamated version and not the naked CCL2. There is studies out what the mixture and the relation is actually, it may happen that if you inhibit CCL2, you even upregulated pyroglutamate CCL2 and therefore, increased inflammation. So I think targeting the naked CCL2 was just not considering the biology and physiology of pyroglutamization [indiscernible] which we now have understood and targeted and I think robustly shown scientifically that, that is meaningful. And in that context, I want to point out what we show in the clinical studies. In the clinical studies we show that we don't inhibit pyroglutamate CCL2. There's no effect. If we inhibit pyroglutamate CCL2 and reduce the concentration of there is a clinical effect. There is a direct correlation between that. And I think this is the best group of [indiscernible]. Let me look into other questions. There's actually portfolio questions and the question comes up as you have such a great follow-up compound with the [indiscernible] varoglutamstat? I think I tried to make clear that there are other medical indications and Tobias also made clear that the medical need is across various kidney indications and also other cardiometabolic indications, which we can target. So we not necessarily want to have the second compound directly in the same indication, but target complementary indication for which during the development period, we don't have the time for varoglutamstat. So a second follow-up compound, I think, is highly valuable. So let me see some final questions. What do we have else? Yes, there is a question on the patent protection that we have answered that in the last meetings. In the press release, we have published the composition of matter patents of varoglutamstat, which should run if approved another 20 years because we found the special polymorph which has a very favorable characteristics. So that is a process which has been long triggered and initiated. And so I think that was -- that was all questions. And then there is questions going beyond the R&D focus of the meeting and specifically about partnering and collaborations. And while we cannot be extensive on this point, we can confirm that we are having conversations with interested parties on that. How that will come out is always an unknown. So I cannot make any promises here, but I can confirm we are talking to our of peers about these assets. And with that, I want to thank you for your attention and following the company. And yes, up to the next meeting. Thank you. Goodbye.