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: Professor Tobias Huber, M.D., Chair of the Center of Internal Medicine and Director of the Third 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, Ph.D., CEO, KJC Statistics. He is acting as statistical analysis expert, providing and calculating statistical readouts and advising on clinical study statistical assets.
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 strategy. Should actual results differ from the company's assumptions, ensuing 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 hereof. 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 in QPCTL 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 or 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, reduce 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 QPCTL to unlock inflammatory approach.
We now have the chance to overcome this major hurdle. Vivoryon has identified QPCTL, a key enzyme in inflammatory and fibrotic pathways, through its impact on CCL2 and, more importantly, pE-CCL2, 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 QPCTL inhibitor with demonstrated statistically significant improvement in kidney function in two 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 two years.
With that, I will turn it over to Professor Huber, Director of the Third Department of Medicine at UKE Hamburg-Eppendorf, who will walk you through our exciting new results of Varoglutamstat for kidney disease. Tobias.
Yeah, thank you very much for the introduction and welcome everybody this afternoon. I'm happy to report on the outcome studies. Next slide, please. We can go into the next slide. It's important that you realize my disclosures. I'm rather pragmatically dedicated to improving the outcome of our kidney patients. In my role, I'm advising a series of pharmaceutical companies on their developmental pipelines. Next slide. The reason why I accepted an advisory role for Vivoryon was the data from the VIVIAD studies seen to the left, which has now been complemented by the VIVA-MIND study, a U.S.-based study. As you can see, both of these studies had been designed originally to target Alzheimer patients for patient selection criteria, therefore ranging relatively similar age range. You see the number of patients that had been treated.
There have been slightly different protocols and high-dose protocol in the VIVA- MIND study and two-dose strategy in the VIVIAD European study. The treatment durations were quite similar. As an explorative endpoint in both studies, each eGFR has been sampled and monitored, something that I particularly was quite interested in. You can go to the next slide. Now, the result 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 the GFR. While we usually aim for a slowing of the progression of kidney disease, we very rarely see conditions where the GFR decline is being halted or even being reversed. This was a reason which at least I found quite interesting at the time for seeing the data to the left, the VIVIAD data.
Now these data are complemented, as just mentioned in the beginning, by a U.S.-based study. 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 ahead of one year, you can also see head-to-head of both studies, very similar and comparable results in an increase of eGFR, now even more pronounced than having seen in the first slide, because this is now after the titration period, and it's quite similar results across both study cohorts. Next slide, please.
Now, this was something which in advisory role, we were very much interested in among this Alzheimer cohort, is there a patient subcohort 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 effects of GFR increase are even more pronounced in the diabetes subgroup, and same holds now true also in the second U.S.-based study with a significant increase of the GFR in the diabetic subgroup, but these realized both subgroups are rather limited number of patients. Next slide, please. Now, again here, same idea, looking in this subcohort for the period after the titration phase, and we see the most clear effect after 24 weeks to 48, and after from week 60 to 72 and 96.
We see again very comparable results in terms of the increase of GFR in both studies. Next slide, please. Now, the next basic idea that we questioned ourselves in looking at this data was, are these effects being driven by a few outliers? How can we get a more comprehensive responder analysis in these, again, the subcohort of small subcohorts, I should say, of diabetes patients? What you can see is that in placebos, 71% does not show a response, while in the higher dosage group, 72%, right in green, show a response. This shows that the overarching or the overwhelming majority of patients respond to the treatment, and the effects seem not to be driven by a few outliers. You can go to the next slide.
Now, again showing the comparing the placebo arm in both studies and at the baseline, similar results, and then to the high-dosage treatment in both studies now. Before that, we show the studies combined, but looking now at both studies separately, we can see that, again, both studies show very similar results. You can go to the next slide. Now, as a translational and basic scientist, 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 kidneys, organoids in the intramural structures, namely podocytes. We also see it in the tubular aquaporin positive compartment. Now, we are being set up 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. 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 mentioned in the introduction, our current clinical standard of care, that we made a lot of progress over the last years, still aims at slowing progression with SGLT2 inhibitors, with RAS blockade, with nonsteroidal mineralocorticoid receptor antagonists now coming on the market. While we do not have a treatment yet holding or reversing progressive kidney disease, we are still, of course, figuring out the synergistic effects of the new drugs on the market. As of now, there remains a significant risk of disease progression associated with premature morbidity and mortality in a still growing disease population of CKD-affected patients and a broader range of cardiovascular kidney metabolic syndrome, which is still rising in our society, causing a significant burden for our patients as well as for the healthcare providers.
We are still looking out for new treatments that reverse progression, eventually lead 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 the chat. Thank you.
Welcome, everyone, and thank you, Tobias, for your analysis of varoglutamstat clinical results related to kidney function and your insights into how they would fit in the worldwide efforts to address the substantial remaining medical need in this space. Now, let me start off with this overview of how exactly varoglutamstat's profile makes it 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 in two independent double-blind placebo-controlled clinical phase II studies.
Kevin will be speaking about how unique and statistically robust these results actually are. We observed that the effect size was substantially larger in people with diabetes compared to the non-diabetes 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 two years of study duration. In summary, we can confidently say that its 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. How does this all work on the molecular level? For that, as a reminder here, varoglutamstat's 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 isoglutaminyl cyclase or QPCTL reduces kidney inflammation and fibrosis and can improve cardiophysiology and kidney function. In detail, the process we are targeting is called post-translational modification, which is a process that helps to functionalize proteins, for example, introducing on-off switches 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. In disease conditions, post-translational modifications can cause additional or accelerated pathological changes. Varoglutamstat targets such a pathological form of post-translational modification called pyroglutaminylation or maybe a bit simpler, pyroglutamate formation.
In the human body, pyroglutamate formation is catalyzed by only two enzymes called glutaminyl cyclases QPCT and QPCTL, and the activity of both is blocked by varoglutamstat. Let us first focus on the left slide here. On the left side here, in pathological conditions, glutaminyl cyclases are upregulated and increasingly catalyze the pyroglutamate formation on pro-inflammatory and pro-fibrotic molecules like CCL2, chemokines, and collagens. This leads to an increased activity and stability of these elements, followed by an increase of known inflammation and fibrosis actors like TNF-alpha, interferon-gamma, alpha-SMA, collagens, and so on. On the kidney function level, we encounter increases in urea and cystatin C, and eventually a drop in the glomerular filtration rate and a loss in kidney function. Now, turning to the right side, you see here in the actual crystal structure how nicely varoglutamstat fits into its binding pocket on QPCTL.
Blocking of QPCTL 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 collagens, 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 onto the clinical findings we have with varoglutamstat. In human cells, the presence of the chemokine pE-CCL2, so the pyroglutaminylated CCL2, here the open boxes, is decreasing dose-dependent when varoglutamstat is applied.
In a CKD mouse model, varo leads to a clear reduction of fibrotic markers like collagen III and alpha-SMA. Finally, in humans, we see a clear dose-dependent decrease of pE-CCL2 levels of study participants. 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. This brings me directly to our positioning within the competitive landscape. On the left here, a summary of the most important differentiating factors of varoglutamstat, and these are oral availability, an entirely novel MOA, single-agent activity with potential for use in combinations, a demonstrated long-term effect on kidney function as measured by eGFR, and a favorable safety profile.
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 prehistoria of drug candidates that still so continue, albeit in some cases slower decline of eGFR. 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. Above the horizontal line, you can clearly see that the only two drugs that have shown to stabilize or even improve eGFR to date are our own varoglutamstat and ProKidney cell therapy. What I want to emphasize here is that not a single compound in development has the characteristics of varoglutamstat.
By that, I mean that they either are not orally available, have limitations of long-known MOAs, lack single-agent activity and 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. Taken together with its characteristics and with the proven clinical evidence of statistically significantly improving eGFR, varoglutamstat clearly stands out. I'm sure you can appreciate why we feel it is extremely well positioned in an indication space that urgently needs new, effective, and safe treatment options. How does our target market look like? What I want to point out when looking at numbers is that there are a plethora of sources in epidemiological data out there, and the numbers can vary greatly.
We, as a management team, are basing our assumptions on an internal analysis of a number of different reliable and credible sources and also factoring in what we believe is important when thinking about our initial target population of stage IIIb-IV diabetic kidney disease. Let me start here 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 one in 10 people with diabetes possibly ending up with end-stage kidney disease. We are currently facing over 70 million patients with diabetes in the U.S. and Europe alone. Roughly 40% of these patients, meaning around 25-30 million, are estimated to be affected by diabetic kidney disease.
We are currently planning a phase II-B study in stage IIIb and IV DKD patients. Our initial target population within a growing market in the U.S. and Europe is estimated to be around 3-6 million. To be clear, this range does not yet include, for example, patients that are categorized as stage IIIa, but whose 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. These numbers could become significantly higher, especially since we believe varoglutamstat would also be investigated in overall CKD, including non-diabetes population, as well as in certain orphan diseases. Speaking of future opportunities, I'd like to show you how we are also looking ahead and beyond varoglutamstat.
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 charts top right. The blue bars are VY2149, and the purple bars are varoglutamstat. Also, VY2149 shows a two to five times 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, and cystatin C levels, as well as on alpha-SMA levels and collagens.
All this is very important because higher intracellular QPCTL 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 our QPCTL inhibitors. Obviously, VY2149 is an important project in the development pipeline update with which I'd like to conclude. For varoglutamstat, we are in preparations for a focused phase II-B 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 methyl inhibitors, which are an early research program with potential for single use or in combination with glutamine cyclase inhibitors in fibrotic indications. All future studies are, of course, subject to further funding and/or 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 into the 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, I'd like to spend a few minutes just reflecting on the data that we obtained in VIVIAD and VIVA-MIND trials. I think I've got control of the slides, so let me double-check.
I'm not sure I have control of the slides, so maybe if you could just paste the next one. Thank you. 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 drugs in terms of its effects on eGFR by bringing your data together, thereby providing a more overall and more precise effect estimation. The second is to ascertain whether there's any evidence of heterogeneity between the trials. Are the trials giving consistent results or not? 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. There are two things the meta-analysis is meant to do.
Now, I'm not going to give a lot of comments on a lot of mathematics here, but when we have the two trials, the VIVIAD and VIVA-MIND, and we want to bring those together to make an overall meta-analysis, there's two 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. Sometimes that may not be correct, that assumption. We have a second type of meta-analysis, which is random effects, and that directly checks and accounts for any difference in result from one trial to the next, any truly statistically significant difference between the trials. We check if that exists, and if it does, then we can execute the meta-analysis using something called random effects. There's two approaches.
As we go to the next slide, I'll show you some of the data that we have. Okay, this is quite a busy slide, so I'll try and just orientate. On the left-hand side, we have the time period. You can see 4 to 16, 24, 48, 60 to 96 weeks. This is the 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 meta—that's the result from a fixed meta-analysis and a random meta-analysis. You can see the sample sizes, and then we have the treatment effects and p-value and 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? I'll 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. 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 two 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 results very nicely duplicated. That gives confidence in the truth of those results. There's no heterogeneity, and now we can actually look at the results themselves or read 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. Thereby, you can see we have a small effect that appears in 0-16 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 shown 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, 60-96. Those kinds of treatment effects in CKD are completely unprecedented. Remember, this is based on two trials that gave consistent results. If we go to the next slide, this is the reverse population.
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. You can see they're smaller. They're still positive, but they're clearly smaller. You can see that in the red. That applies. 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. There were other kinds of risk groups we looked at, and the risk group of focus, I think, is the one in red, which is on this slide, no diabetes, and the previous slide was diabetes. All these data, this slide and the previous slide, is all based on 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 SE formula from, I think, 2021. We regenerated the eGFR data and redid the entire analysis as a sensitivity to check the results we were obtaining. As you can see on the left-hand side, in red on the left are diabetic patients, on the right-hand side in red are non-diabetic patients. 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. 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, that was a very quick run-through.
The results we obtained, if we do a meta-analysis, very strong results in diabetic patients, and the two trials are homogenous. They're giving the same result. When we bring them together, no heterogeneity, clear treatment effects are very large in diabetic patients. 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? 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. Remember, that 4.5 ml is about half of the effect that we actually saw in VIVIAD and VIVA-MIND. That's a conservative effect size, but we'd have 85% power for that.
In fact, the smallest observed difference in a 40 patient per arm trial that would reach a p-value of less than 0.5 is about 3 ml. 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-MIND. That very briefly captures what a phase II trial would look like based upon those meta-analysis results. Finally, on the next slide, I do a similar exercise, but in consideration of a phase III confirmatory type trial. Here, the standard endpoint, the standard time period, I should say, is eGFR measured over two years.
There are many CKD trials ongoing, many drugs, well, about three now have been approved in the last 18 months or so in nephropathy, two-year endpoint for eGFR using SLOPE, rate of decline of eGFR over two years. If we use that paradigm, that is, we're going to look at the rate of change of eGFR over two 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. The smallest improvement to reach a positive outcome would be about 1.6 ml.
The size of this trial and its duration of two 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 and EMEA. We have 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. I have said everything from me, unless there are any questions or maybe you will leave questions to the end. If there are any, I am happy to take them. Otherwise, we will just move on.
Thank you, Kevin. Thank you to Tobia, Anne, and Nick. Thi is Frank, we will finalize the summary and focus on the other side of 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 pooled the placebo data and the 600 mg 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 potentially the drug. The colors are the pink is the active and the 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 looked at study drug discontinuation. You see that overall, there are only really minor percentages more for the drug than for placebo. There is a really, really good safety profile if you compare the incidence of related and potentially drug-induced adverse events, which is very minor percentages difference to placebo.
We can break it down and say, if there is a difference, where does it come from? 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. Those studies were done in the COVID period, and COVID-19 infections were 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 the drug. In nervous system disorders and psychotic disorders, you see the reverse. The drug actually has much less side effects. Musculoskeletal and connective tissue disorders, there is some signature of the drug. It's largely arthralgia and back pain.
These are minor pain symptoms which may come from an anti-fibrotic effect of the drug, and it's probably related to the pharmacology, but these are temporary and not really bothersome where the patient does not stop the treatment. You see there are definitely fewer injuries and falls with the drug, which is a good sign because the population is an elderly one. The drug has a slight signature of skin and subcutaneous tissue disorders that we know usually is kind of a temporary rash, which is mild and restricted to small parts of the skin. At the end, you see there is generally no further difference between the drug and placebo.
Overall, there are a few more incidents of minor potentially related side effects in the musculoskeletal, skin and subcutaneous, 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. 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.
We looked into what influence do we see in VIVA-MIND on this parameter, and we published previously and showed similar data from VIVIAD. Again, we see a consistency. You see in the overall VIVA-MIND population about a kilo weight decrease, so a minor weight decrease. We see a change in the blood pressure. You see about 3.5 ml 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. When there is some inflammation and fibrosis in the musculature or there's some inflammation and fibrosis in the liver, the drug also takes care of that.
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 where inflammation and fibrosis happens in the organs. Moving forward to also what Kevin has shown, we are planning and looking at a novel study, a clinical study where the primary objective is to investigate the efficacy and safety of our lithium study kidney function in patients with IIIb and worse, so more advanced patients, the earlier patients we have. We have also very few patients which are already advanced, but not enough to substantiate the effect robustly. There is a secondary objective. We explore the efficacy of a once-daily dosing also of the lithium study. That potential is given, and I show you in the study design how we do this.
We want to generate further evidence of mechanism of action. We do a lot of biomarker assessment in that study. Of course, we want to look into what I showed you in the last chart, and that is to look at concomitantly affected organs in type 2 diabetes patients, so the liver, the musculature, and the body weight, and see whether we can confirm the other beneficial effects we have seen independently in those studies. The timelines here are that we need for recruiting about 80-90 patients, which Kevin laid out. We need about nine months, times of US and Europe. Patients will be treated for a minimum of 30 weeks and a maximum of 48 weeks.
The last patient probably reaches his eight, nine months period at month 15 of 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 these advanced kidney disease patients. Later, we will additionally see in additional analysis and once-daily dosing results. How that puts together everything is in the next chart, where we see that it's a double-blind placebo-controlled study of our lithium study against placebo. We look at eGFR as a primary endpoint. The patient gets double-blind treated up to one year and then switches over to once-daily lithium study, both the placebo group and the active group.
We can see whether the placebo group shows an improvement similar to the twice-daily, and we can show that whether once-daily maintains the efficacy we've seen before in the twice-daily in the active arm. As everybody switches to 600 mg, the study doesn't get unblinded, and you don't know where which patient comes from. There is a certain independence in the trial, even though 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. We will stratify the population, of course, according to CKD severity, standard of care use, SGLT2. The majority of patients will be on standards of care of 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. NGFD1 was as well. Now, let me summarize the perspectives of the pipeline in the next chart and of the company. We're owning the clinical space of QPCTL inhibitors, and they have a large market potential, as shown by Nick, with development opportunities not only in diabetic kidney disease, but also other diseases with underlying inflammation and 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 progress largely through inflammation and 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 our lead compound. I think there is enough space for two or three QPCTL inhibitors in the clinic, in the market, addressing with their various characteristics, various types of kidney inflammatory and fibrotic disorders. 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 as an asset today. Clearly, QPCTL inhibitors are unique in their mechanism of action, targeting inflammation and downstream fibrosis, which sets it apart from any other mechanism which is currently under development. We have undoubtedly compelling and replicated eGFR data in two independent long-term studies with a corresponding good long-term safety database.
We have a study plan which is actionable, feasible, and a development path forward which is doable. With the sample size lined out by Kevin, I think it is a feasible and investable area. We also work, as you know, on the intellectual property, which we have laid out in the last meeting. I think we have a complete program for moving ahead. I want to thank not only the speakers again of today, Tobias, and Nick 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 supports us heavily. With that, we can go through the Q&As. Thank you. Maybe we have some questions online, and maybe we select the first two Tobias because Tobias has a hard stop at 4:00.
The question is whether you think that the wider adoption of GLP-1 and SGLT2s in 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?
Yeah, thank you very much for the question. Right now, as we can see, all of these drugs are just slowing the progression by approximately one-third. They're not holding it, and they're not reversing it, while we don't know how all the combinations of the existing drugs will do.
From 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, particularly in the global north. The problem is not likely going to be solved by the existing drugs. Basically, yes, progression will be slower, but probably this will be outweighed by the increase of age and still increase of risk factors.
There's another question in the same area, Tobias, and that is, where would you use such a drug like our varoglutamstat? Would you use it early? Would you use it in progressions 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?
Yeah, thank you very much. I mean, in my role as an advisor, I suggested advanced stages of CKD in a space where it's not just about holding the progression because old people with advanced CKD might eventually end up on dialysis. Here, we would really need game changers that hold or even reverse progression. This would be the field where I see an indication number one. Number two, don't forget about rare kidney diseases. In the U.K. radar study, we recently learned that just 5%-8% of all kidney diseases account for over 30% of end-stage renal disease. Some of rare kidney diseases does have a significant impact on end-stage renal disease.
Most of these rare kidney diseases have a tendency of strong progression while there are no drugs available yet. 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. All the best for your next meeting.
Thank you so much. And Frank, thank you very much, everybody else, for attending. I'm going to leave then now. Thank you so much. Bye-bye.
Thank you. We go to the sample size assessment for the next study because we have initially cautiously said maybe we need 120 patients. 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. 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. We have more data. We have what's called more degrees of freedom for estimating the FDs. They are critical inputs into the sample size calculation. Now we have a much stronger basis for postulating the treatment effect and for our estimate of the standard deviation. I think that means that we have a much clearer and more confident handle on how big that phase is 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 ml is what you'd have to observe to get a positive result from the proposed phase two. That 4.5 ml in and of itself is somewhat conservative vis-à-vis the meta-analysis results where we saw treatment effects in the region of, I think it was, I've got the time period now, but I think it's 24-48 and 40-60, and later of up to 8 ml. We have come substantially down and lower than the actual data suggest. If we were to hypothesize 8 ml, we would literally need a handful of subjects. I mean, 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.
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. Consequently, overall, the phase two design as we have it now, we have a lot of confidence that that is indeed the right magnitude in terms of size of study in a phase two setting.
Thank you, Kevin. That's clear messages. I think you answered the question really well. We have a couple of questions regarding the mechanism of action, which will probably go to Nick. Probably, Nick, you can spend another minute or two on why we believe that previous approaches to target CCL2 have not been successful and why we have now found a pathway to target the inflammatory fibrotic axis in kidney disorders efficiently and different from previous approaches.
Yeah, thanks, Frank.
Yeah, I would say a main difference, obviously, to earlier approaches is that we are working a little bit more upstream, I would say. We are targeting, obviously, for example, not only CCL2. We are targeting a lot of other relevant factors in the fibrotic inflammatory field. There are other CCLs in the family of CCL2, which are basically using the same receptors at times also, like 7, 8, and 13. By our approach, all of those got targeted, let's say. That is the main difference as opposed to just targeting very specifically just CCL2, as I would say. We see that actually in our experimental results that we got these effects also on collagens, which in part also require, obviously, this pyroglutaminylation on the end-terminus to get fully active and to form triple helices as they have to do.
That is certainly, I would say, the main difference we see here as opposed to other factors. Obviously, also looking at this pyroglutaminylation specifically, let's say, as opposed to just looking at CCL2 per se in its normal or non-pyroglutaminylated form makes obviously also a difference. That is my answer to that. Franky, what do you have to say?
When you look at the literature for those who are more interested, there are already publications around 2000 that the inhibition of non-pyroglutaminylated, pyroglycinated CCL2 does not lead to a lot of things because the main effector on inflammation is the pyroglycinated version and not the naked CCL2. There are studies out what the mixture and the relation is. Actually, it may happen that if you inhibit CCL2, you even upregulate pyroglycinated CCL2 and therefore increase inflammation.
I think targeting the naked CCL2 was just not considering the biology and physiology of pyroglutaminylation and post-translational modifications, which we now have understood and targeted. I think robustly shown scientifically that that is meaningful. In that context, I want to point out what we show in the clinical studies. In the clinical studies, we showed that we do not inhibit pyroglutaminylated CCL2. There is no effect. If we inhibit pyroglutaminylated CCL2 and reduce the concentration of serum, there is a clinical effect. There is a direct correlation between that. I think it is the best proof of this hypothesis in the unit. Let me look into other questions. There are actually portfolio questions. The question comes up as you have such a great phenomenon compound with the cannabis water lutein study. I think I tried to make clear that there are other medical indications.
Tobias also made clear that the medical need is across various kidney indications and also other cardiometabolic indications, which we can target. 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 do not have the time for varoglutamstat. The second follow-up compound, I think, is highly valuable. Let me see some final questions. Yeah. What do we have else? Yeah, there is a question on the patent protection, but 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 a special polymorph, which has very favorable characteristics. That is a process which has been long triggered and initiated. I think that was all questions.
There are questions going beyond the R&D focus of the meeting and specifically about partnering and collaborations. 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. I cannot make any promises here, but I can confirm we are talking to our peers about these assets. With that, I want to thank you for your attention, for the company. Yeah, up to the next meeting. Thank you. Goodbye.