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

Good day, and thank you for standing by. Welcome to the Vivoryon Therapeutics 2023 Full Year Results Call. [Operator Instructions] Please be advised that today's conference is being recorded. I'd now like to hand the conference over to your speaker today, Anne Doering. Please go ahead.

Thank you, Nadia. Good afternoon, everyone, and thank you for joining us today to discuss the company's Full Year 2023 Results and Strategic Update Conference Call. This morning, Vivoryon issued a press release reporting it's full year 2023 financial results, including a strategic update, which is posted on the company's website at www.vivoryon.com. Before we start, I'd like to remind you that during this conference call, we'll 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 materially from the company's assumptions, ensuing actions may differ from those anticipated. You're, therefore, cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date hereof. On the call with me today are Vivoryon's Chief Executive Officer, Frank Weber; and Michael Schaeffer, our Chief Business Officer, who will be available for questions. I will begin today's call with opening remarks, then Frank will speak about Vivoryon's clinical development with varoglutamstat, our lead asset, where he will speak about Alzheimer's disease, and we also have exciting news in kidney disease that we want to share with you today. After Frank, I'll then review the financial results for the full year 2023 as well as conclude the call with our outlook and strategic priorities. Following the prepared remarks, we'll host the Q&A session. Firstly, I'd like to thank the team for 2023, a year with substantial advances, which included showing meaningful progress across clinical studies as well as the successful capital raise, the expansion of our management team and unveiling a growth strategy beyond Alzheimer's disease. Obviously, the events of the last months have overshadowed these achievements. So let me dive right into the most important post-period developments, which have revealed an exciting new opportunity for varoglutamstat. In 2024 to date, we've encountered both challenges and opportunities following the announcement of the results from our VIVIAD study in March. Unfortunately, in line with the top line results reported at that time, our subsequent analysis confirmed that VIVIAD did not meet its primary and secondary endpoints in early Alzheimer's disease. In light of this outcome and in line with our commitment to prudent resource management and allocation, we've made the difficult decision to discontinue VIVA-MIND early and ceased preparations for the VIVALONG study. These adjustments reflect our focus on prioritizing resources for initiatives with the highest potential for success. While the outcome of VIVIAD is disappointing, our thorough analysis revealed encouraging findings related to varoglutamstat potential and improvement of kidney function. These findings provide strong evidence of the potential therapeutic application of our varoglutamstat and kidney disease and opens a new and exciting avenue of clinical exploration, leveraging our learnings from prior data and utilizing the versatility of our investigational therapy. Additionally, in response to our evolving corporate outlook, we implemented changes to our management team. We believe these adjustments ensure alignment with our revised strategic priorities and better position us for future success. As we move forward in 2024, our primary focus remains on unlocking the true value of varoglutamstat and our broader pipeline. We're committed to exploring the potential of varoglutamstat in kidney disease marking a shift in strategic focus for the inflammatory and fibrotic disorders. At the same time, in early Alzheimer's disease, we intend to assess the potential of a higher dose of varoglutamstat. We'll also continue to explore and develop QPCTL inhibitors in inflammatory and fibrotic diseases, leveraging our expertise in this area. While maintaining a focus on our lead candidate, we'll also selectively access -- assess early pipeline development opportunities. In order to support our growth and advance our pipeline, we'll continue to actively pursue funding and business development opportunities that align with our strategic objectives. Our prudent cash runway management ensures financial sustainability, extending our cash runway into the second quarter of 2025. With that, I'll now turn the call over to Frank.

Thank you, Anne, and good morning, good afternoon for all who joined in and visit. First, we'll come up with a summary of the results, which we've observed in the VIVIAD study, and then go in quite a technical detail in Alzheimer's disease and kidney disease and then summarize the findings. So as an initial summary, the detailed analysis of VIVIAD, which we did very diligently and turned a lot of tables, listings and figures around do not suggest any consistent effect of the drug in doses up to 600-milligram BID, which we used as the top dose in VIVIAD in early Alzheimer's disease. But at that dose, we found highly significant effects on improvement of kidney function. And these nonsignificant observations in early AD were across all primary and key secondary end points as well as across the majority of the exploratory endpoints with 2 only exceptions and that is a DSST or WAIS-IV test, which is a coding test and the letter fluency test, which showed a significance in favor of the drug at week 48. From a safety perspective, the drug was very well tolerated. We had very low discontinuation rates due to adverse events, and we had no evidence of any symptomatic ARIA in the clinical setting. And in -- the conclusion is jumping a little bit ahead is that we're looking at it that 600-milligram BID lost the efficacy signal, which we saw in the SAPHIR study at 800-milligram BID and maybe we've been too low with a top dose in the VIVIAD study. And therefore, we continue our assessment of potentially higher doses of varoglutamstat higher than 600 probably going back to 800 or 900 in early AD. But these are currently only assessments. That doesn't mean we've started a study or we intend directly to start a study to analyze the data in that respect first. Looking at the kidney function, we saw a statistically significant improvement of the kidney as measured by the estimated glomerular filtration rate, which is the key primary endpoint of all kidney outcome studies and we could measure it across 2 years. So that is a very long period because VIVIAD went up to 2 years and that treatment effect was also sustained up to 2 years. And the effect size was stronger in patients with risk factors for kidney disease, so those who had diabetes type 2 at baseline or hypertension than in patients which had no risk factor for kidney disease. And that clearly supports the mechanism of action of QPCT inhibition in kidney disorders, and that shows that varoglutamstat is a viable molecule for inhibiting the glutaminyl cyclase. So the mechanism has proven to be beneficial and the molecule has proven to be viable at least in the kidney disease. So going now to the detailed results of the VIVIAD study and I'll first start in the section with Alzheimer's disease. And there is a lot of numbers and p values, which I will guide you through in the next chart. I'm sorry, being very technical, but I thought it is important that we're very clear and open and transparent what we observed, and everybody can look at the figures and make his own interpretation. So the next chart shows the key primary and secondary endpoints of cognition as bar charts. So what we did in the study is we developed a slope analysis across all measurement time points for all patients and all visits. And these slopes, of course, show a decline in cognitive function. And each of the boxes shows a different variance of the CogState neuropsychological test battery. The primary endpoint was the 3 items construct, which is on the left side, on the left bar. In the middle, you saw the 4 items construct, which is also called CogState Brief Battery and is an approved scale for measuring cognition, and then you see the full cognitive test battery with 8 items on the right side. And all these slopes show a decline of cognition, as you see, and this is a unit 0.285. And nobody, of course, can say what it is and how important it is because the unit doesn't tell you this. But it is a clinically significant decline from baseline across 96 weeks. But there is no difference between the pink and the yellow bar. The pink is the compound and the yellow bar is the placebo. You see that the p values for the comparison between the 2 treatment arms is for the primary endpoint 0.81, for the key secondary 4 items scale 0.96 and for the 8 items scale 0.77. And you see there is when you look at the effect size, no difference. But what you can see and what we want to mention here is that the overall decline from baseline to end of study was always highly significant for all 3 end points. So there was progression in the patients from baseline to end points. So the scale itself is sensitive and meaningful and measures the progression of the disease. There was just no difference between varoglutamstat 600 milligrams twice daily and placebo. Going to the next chart. We see the 2 further key secondary end points, which were prespecified in the statistical analysis plan. The first box on the left side shows you the Amsterdam scale of activities of daily living at week 48. And you see a very similar picture, both arms declined throughout the study in a very similar way with no statistical significance between the arms. And on the right side, you see the EEG relatively Theta Power, the one which was highly significant in SAPHIR. But here, we see, again, no difference between the 2 treatment groups. And here, a good result would be going down. The bad result is going up. So the Theta Power increased in both arms in a very comparable way. And that concludes that the prespecified primary and key secondary end points did not show at a dose of 600 milligrams, the difference to placebo. Moving to the next chart. And this is a summary of all the prespecified subgroup analysis we did in the statistical analysis plan, and we, of course, conducted these analysis. And here, I summarize what the findings are. We saw no clinically meaningful and no statistical significant differences between varoglutamstat 300-milligram or 600-milligram or both together against placebo for stratifying patients by baseline severity according to the mini-mental scale. According to the stratification by the ApoE4 status, according to a certification of phospho tau in the CSF at baseline, so high versus low phospho tau. No difference between patients who had already been treated for Alzheimer's disease with available -- commercially available and approved medications for this treatment naive and also by stratification of the functional impairment at baseline. And then we conducted an additional series of analysis for exploratory endpoints. That means other endpoints like different EEG endpoints, cognitive domains and biomarker in the CSF, like phospho tau, YKL-40 or neurogranin. And there was in none of those meaningful or statistical difference between active and placebo. The only, as I mentioned, significant difference was for the DSST and LFT at week 48, but the effect sizes were relatively small, and the effect was not sustained at the end of the treatment and not observed at week 24. So that was the summary of the Alzheimer results in the VIVIAD study. Now I come to some -- sorry, quite complicated consideration of pharmacokinetics and target occupancy. And it becomes very technical here, and I apologize for this. But for some of you, it may be very important information to make an assessment of what we did. So the first message is we measured varoglutamstat concentration in the cerebral spinal fluid under treatment at week 48 in the VIVIAD study and we measured in the 300 and the 600-milligram dose. That is in the left chart, the pink and the orange colors and you see that the median concentration in the CSF was 21-nanogram per milliliter or microgram per liter, and that's the same thing. And 68-microgram per liter at the median for the 600-milligram dose. And what we plotted in green are the data from SAPHIR we had obtained at 800 milligrams. And you see it was 115. And you see that the difference between 300 and 600 is about the same as between 600 and 800, and that is because the drug has a little bit of accumulation at higher dose. So that is all expected and we knew all this. And when you look at the right side, you see the target occupancy of the drug in the CSF. So in the fluid of the brain, and you see that the blue curve with the red dots is the PK/PD model we developed in Phase I. The little orange dots are the target occupancy values we observed in the VIVIAD study. And the green dot is the target occupancy we observed in SAPHIR. And you see that all these dots fit perfectly that line, they're exactly where they should be. And so we can conclude that the VIVIAD study was perfectly conducted. There is no issues in formulation or drug availability or bioavailability, the drug went in the predicted way where it should go. The only observation you can see is that the target occupancy for the 800-milligram is very similar to the 600-milligram in the CSF, but the kinetic is very different and, of course, that raises question whether the CSF is the right place to look at target occupancy or whether we need to look more into the intracellular compartment in the brain, which is, of course, really impossible to measure in the clinical study because we don't -- cannot puncture brain cells in an Alzheimer patient. Going to the safety data now. And here, we see that what we summarized before that the drug was very, very well tolerated. You see that the number of patients who discontinued treatment is comparable, specifically when you look at adverse events, the reason for adverse events are basically identical because there is, of course, more patients in the active arm than the placebo arm. So when you're pre-centralized due to adverse events, you come to the same number. And you see the majority of patients actually withdraw from the study, usually because they lost their study partner or they were so more severe in advance that they -- basically they didn't want to come to the study site anymore because it was too cumbersome. And that was the majority of the reasons. And then you see the lower part of that table, that for related adverse events, treatment adverse events, you've exactly the same number for active and placebo and serious related treatment adverse events were roughly 2 and severe related were only 4 and we didn't see any ARIAs. So overall, the safety of varoglutamstat at 300 and 600-milligram was very good, and I can add that there were actually -- and that's an analysis we just got here recently that there were no difference between 300 and 600 when you divide the dose. So there is no increase in adverse events when you move from 300 to 600 milligrams. And then on the left side, we summarized also what was most frequently observed and that was COVID-19. Actually, we had a probably 1/4 of the patients at least had a COVID-19 infections. We saw some diarrhea, dementia, headache and arthralgia, but only arthralgia showed the light side trend in favor of the drug. All the others were very equally distributed between the treatment arms. And for your information, because COVID-19 can, of course, impair the cognitive performance at a certain level, we also looked at a non-prespecified postop analysis where the COVID-19 patients with infection had a different outcome than those which had not, but there was no difference if you would exclude the COVID-19 patients from the analysis. So the results on the primary and secondary endpoints stayed what they were, if we look at all patients or only patients, which had not COVID-19. And this is -- now the summary on the next chart, the summary of our key learnings in Alzheimer's disease. So what we saw is no treatment signal at 600-milligram twice daily. So we lost the treatment signal, efficacy signal we saw in SAPHIR in this study. And the PK and QPCT inhibition in plasma and CSF showed that varoglutamstat can inhibit the QTC enzyme and is a potent inhibitor and is also exactly represented on the target occupancy, where it should be. The drug at 600-milligram was very well tolerated. And the key learning is probably that the slow uptitration led to a clear improvement in the tolerability, if you compare it to SAPHIR while maintaining the overall safety -- overall favorable safety profile. So what are we planning now in early Alzheimer's disease. We announced today that we've decided to discontinue the VIVA-MIND study in the second half of 2024. And the reason is that we've, of course, the results of VIVIAD already, and they show a 600-milligram no effect and the patient population is very similar in VIVA-MIND compared to VIVIAD. And we'll, of course, see that whether VIVA-MIND gives similar data or different data and we'll then integrate all the Phase II data from SAPHIR, VIVIAD and VIVA-MIND together to understand the dose response and then understand whether it makes sense to investigate and go to higher doses with varoglutamstat in early AD or not. And then, of course, we also want to investigate a little bit the science behind QPCT pathways looking at biomarkers and understanding what we actually trigger at these doses. That is the summary of varoglutamstat in early AD and then I now switch to the kidney order. Next slide. And probably, I want to start with saying that kidney function was prospectively integrated via the protocol amendment before we unblinded the data based on preclinical findings, we had generated and also published before on 1 of 2 compounds and internal assessments, and we thought that the kidney is a very good organ to look into that study because patients with Alzheimer's disease have comorbidities, which reduce the kidney function and also age is a risk factor for impaired kidney function. So our assumption was this patient have already some kind of impaired kidney function in that study, and we can study the effect of varoglutamstat on that impaired kidney function. But turning now to the scientific rationale. Why could that be that a QC inhibitor can improve kidney function. And that is based on a lot of scientific publications, where it has shown that many diseases are driven by inflammatory and fibrotic processes induced by a variety of stimuli, including metabolic, vascular and autoimmune dysfunctions. In other words, all these disorders upstream and frequently had an inflammatory and fibrotic effect on the kidney, which then impairs the kidney function at the end that can lead to end-stage kidney disease, dialysis and transplantation. And many of those inflammatory and fibrotic pathways in the kidney require the formation of a pyroGlu version of a peptide to be fully inflammatory and to be fully pyroglutamated. And those examples are, for example, CCR2 or fractalkine, which has been shown to contribute to the progression of the kidney disorders. And there has been and published, I think in 2021 a rat model in CKD, where we can show that a 2-compound to use a QC inhibitor in an animal model can improve kidney function, reduce inflammation in a glomerulonephritis model, including the urinary albumin-creatinine ratio. And therefore, when you see on the right side, you can see that if the peptides, inflammatory and profibrotic peptides are pyroglutamated, they've a strong activity, and they're resistant against degradation. So they drive the inflammatory and the fibrotic process and the disease progresses. And if you prevent the pyroglutamization, you still have the inflammatory peptides, but they're weaker, they're faster degradated, they're less potent and you can stabilize disease and recover the disease, at least partially. So we put that rationale in the protocol, and we define the estimated glomerular filtration as a key parameter for measuring kidney function. And on the next chart, let's go to next chart. Just to make you understand what we did here, we followed the FDA guidance of measuring kidney function based on the estimated glomerular filtration rate, sorry, by creatinine. And we measured it through slope analysis across 96 weeks, and that is the recommended methodology on which the FDA usually bases the approval of drugs for kidney function. And also the kidney -- that the FDA usually requires for kidney disorders 2 years duration. And luckily, in VIVIAD, we've exposed patients up to 2 years. So these data are probably a very good proxy of what the drug can do in kidney disorders. And now I leave you to some results. First of all, we looked at the total population, this is 258, one patient didn't have a post baseline creatinine value. So we couldn't measure that. So total was 259 patients, but 258 went in that analysis. And what you see is in the placebo group, the patients lost about 1.55-milliliter per minute per year. And in the active arm, they gained 1.92-milliliter per year. That means it's a change between the 2 arms of 3.5-milliliter per minute per year per square meter, by the way. And that p-value is 0.001 or smaller than 0.001 based on only 250 patients. And then on the right side, we carried out the dose response. And of course, in the dose response, we still have the same placebo value, but you see the differences between 300 and 600 milligrams. 300-milligram basically shows a stabilization of the disease, whereas 600-milligram shows a bigger improvement than 300-milligram and the difference between 600-milligram and placebo was 4.16 milliliter per minute per square meter per year with a p-value again below 0.001. And the representation here is a patient that's randomized into the study. Going to the next chart. We see here that we try to identify patients with risk factors for chronic kidney disease. So those who have more inflammatory and fibrotic process is ongoing. And the way we defined it, we took all the patients who had type 2 diabetes at baseline or hypertension at baseline, which are known risk factors for kidney disease and which drive usually chronic kidney disease and end-stage kidney disease in many patients. So we look here at patients with risk factors on the left side and with no risk factors on the right chart. I want to start with the placebo group in patients with risk factors. And you see that patients in the placebo arm declined by 2.7 milliliters per minute per year, whereas with no risk factors, they've on the right chart, only 0.4-milliliter per year. And this is a very credible value because patients who have risk factors, of course, decline much more than patients have no risk factor. Elderly patients who have no risk factor usually have a relatively stable kidney function and are at no risk of deterioration, but those which have risk factors have, of course, a risk of deterioration, that is well known. And when you look at the left chart, what the dose response is in patients with risk factors, you see a significant difference between 600-milligram and placebo, again of value of 0.001. And you see that the differences increased to 6.6-milliliter per minute per squre meter per year. On the right side, you see that there is a very similar picture, but the effect size when there is no risk factor is, of course, much smaller and the improvement much less with 600 milligrams. And that is also very reassuring because it tells us, if the pathological pathways of inflammation and fibrosis are not activated in patients with no risk factors, they've also a smaller effect size because the drug, of course, has very little effect, if there's no inflammation and fibrosis. The drug has a much better effect in improving kidney function, if there is inflammatory fibrosis. So we believe these data are very credible and reliable and we're very positively encouraged by these data. Going to the next chart. We summarized here the key findings and look ahead what we do. We believe that these data actually are transformational for our organization because we've the first time shown in a robust endpoint, which is accepted as a key primary endpoint for pivotal studies also by the FDA that QC inhibition has a beneficial effect on health outcome. We would have wished, of course, that would have been observed in Alzheimer's disease. But in VIVIAD, it didn't happen. One explanation is that the dose was maybe too low for the brain. And -- but we saw it very robustly in the kidney function. And therefore, we think we've a very good platform to develop our molecules further in kidney and other inflammatory and fibrotic disorders. And that significant improvement is specifically noteworthy in patients with type 2 diabetes and hypertension as they're patients with improved risk or increased risk of end-stage kidney disorders. What will we do looking into the future? We, of course, will further analyze the data, we're only 7 weeks after the key outcome data. So I think we're well advanced for 7 weeks. But of course, there is still some things to do and some way to analyze the data and look at subgroups and do some analysis, which further increase our learning and our opportunities. We also will understand -- try to understand whether we should do one or the other nonclinical study to improve our understanding of the pharmacology of the drug in kidney disorders and other inflammatory disorders and understand the pathways behind the QC inhibition. And then we'll create a clinical development pathway for varoglutamstat in kidneys disorders. Of course, if you'd do further clinical study, we'd require funding or collaborations for this. And that is then our business target in further moving forward kidney disorders and analyzing the potential for early Alzheimer at higher doses. Then I want to switch to Anne to conclude this meeting. Please, Anne.

Thank you, Frank. I'll now walk you through a few financial highlights for the year and importantly, our cash modeling. Reflected in our 2023 financial is careful and selected spending through the year as we worked towards the VIVIAD readout in the first quarter of 2024. What you see in the revenue line is a EUR 3.6 million reversal in license revenue. The reversal is related to license revenues recognized in 2021 from our partnership with Simcere, which had concluded -- which has included a variable milestone payment of EUR 3.6 million based on the initiation of the first human clinical trial of varoglutamstat in Mainland China. After reassessment of the anticipated first milestone payment, it is expected that this trial will not start before further clarity from an in-depth analysis of the VIVIAD results as well as from additional analysis of the full data and its implications. As such, we've impaired the milestone with the respective revenues being reversed. This reversal is noncash as was the milestone in 2021 at that time. R&D expenses amounted to EUR 17.6 million this year versus EUR 20.2 million in 2022. This decrease is primarily attributable to lower manufacturing costs of EUR 3.6 million, which is partially offset by higher clinical costs of EUR 1.7 million, mainly due to the progress of the Phase II VIVIAD clinical study. We've also seen a decrease in G&A expenses with a cost of EUR 8.6 million in 2023 compared to EUR 8.9 million in 2022. This decrease is largely due to the release of EUR 2.6 million of previously capitalized capital raising costs in 2022, partially offset by EUR 2.2 million higher expenses for personnel, legal and consulting as well as costs for nonexecutive directors. All of this resulted in a net loss for 2023 of EUR 28.3 million compared to EUR 28.2 million in 2022. On this next slide, I'd like to highlight selected KPIs. Most importantly, the company held EUR 18.6 million in cash and cash equivalents as of December 31, 2023. This cash should be combined with our term deposits of EUR 10 million when considering our total liquid assets of EUR 28.6 million. This is compared to cash and cash equivalents of EUR 26.6 million as of December 31, 2022. Our cash runway now extends into the second quarter of 2025, reflecting an overall reduction in cash utilization. But how do we actually get there? As you can imagine, the majority of our spending has been associated with varoglutamstat in early AD. VIVIAD spending is ramping down in the near term as the study comes to a conclusion. Furthermore, we've decided to discontinue VIVA-MIND in the second half of 2024 as well as stop VIVALONG preparation activities and API manufacturing campaign. As Frank has been outlining today, we believe we've exciting data with varoglutamstat in kidney disease. This cash runway should allow us to put the pathway together to explore this initiative and additional opportunities. However, clinical studies will require further funding for partnerships. And in addition, this would also be needed to extend our cash runway beyond the second quarter of next year. I'd like to conclude by reiterating our continued dedication towards unlocking the potential of our lead asset, varoglutamstat. Based on the very encouraging kidney data from VIVIAD, we're shifting our research and development focus towards inflammatory and fibrotic disorders. We're particularly excited about the opportunity in kidney disease with a strong proof of concept and improving kidney function observed in VIVIAD biomarker analysis. We're moving forward at a quick pace to create a development pathway in kidney disease. In early AD, we'll continue to analyze incoming data as well as looking at the totality of the Phase II data in early AD and are accessing a development path forward for varoglutamstat at a dose higher than 600-milligram BID. At the same time, we continue to explore select early-stage pipeline programs. Moving forward, prudent financial management remains a priority for Vivoryon, and we were able to extend our cash runway into the second quarter of 2025, as I've just detailed. We're also actively pursuing funding and build business development opportunities to support varoglutamstat and our realigned company strategy. We look forward to keeping you informed on our progress. And with that, we'll now open the call to take questions. Thank you.

[Operator Instructions] And now we're going to take our first question. And it comes from the line of Luisa Morgado from Van Lanschot Kempen.

I have 2 questions. So first one, on the next steps for the -- for assessing varoglutamstat in kidney disease, do you have any time lines on this? So when are we going to hear a bit more about it? And my second question would be in terms of assessing varoglutamstat in higher doses, higher than 600 milligrams. What would be your approach here since we've already seen some tolerability issues, would you tackle that only by adjusting titration or anything else?

Okay. Let's start with the second question first. We've now, of course, much more safety data. And what we can say is that we -- with the titration protocol, we've implemented in VIVIAD, we've probably eliminated most of the safety issues. So by slowly titrating the drug up, most of the safety issues disappeared. And we looked, of course, at the safety in the titration period versus safety at the full dose period and we didn't see any meaningful difference in the titration period 3 in the drug and placebo, which means titration is totally safe. And we didn't see safety differences between 300 and 600, actually 300 was a little bit worse than 600, which is a little bit counterintuitive, but it's not meaningful differences. So I think we can say that titration contributes a lot to the safety. And we saw that also in the VIVA-MIND study, we've a little bit of a different titration regime, but we also saw good safety. So our conclusion is that the titration is necessary for that mechanism of action. The speed can vary a little bit. We can still play a little bit with the speed of titration, but that is probably taking out a lot of problems we saw in SAPHIR. We're basically more or less immediately went into the full dose. And therefore, we believe, based on this larger safety database, that it's likely room for going higher. I don't think there's any appropriate finding. And I think we'll have further titration with better tolerance. But of course, there is -- that has to be studied and confirmed. The second question, kidney. Of course, we're super excited about the kidney, and we do a lot of additional analysis, and we've a lot of biomarkers still ongoing. And I think good next point will be when we've first quarter earnings. I think that is a milestone we set ourselves to, we haven't announced when it is, but at the first quarter earnings, we've probably some more data. We'll not have all the data probably, but we can enrich our findings at that point in time and show the robustness of our findings. Did I answer your question?

Yes. Yes, that was very helpful.

Now we're going to take our next question, just give us a moment. And the next question comes from the line of Samir Devani from Rx Securities.

So I guess I wanted to just dig in a little bit deeper on the kidney disorder opportunity. And some of the data you presented look quite interesting. So I guess the 6.61-milliliter improvement that you're seeing after 2 years. I just wondered if you could maybe qualitatively, just tell us, is that plateaued earlier? Or is it still improving at 2 years? And maybe you can give us some perspective on the clinical relevance of that improvement.

Okay. So first of all, the way you analyze the data for a regulatory scientific purpose is to make a slope analysis. And these are annual improvements. So it's per year. So you're running at 2 years, we're probably more. But these are trajectories based on all the data points you've. And of course, there's variability between patients and so on. So -- and the way the curves go is that varoglutamstat mean values always stayed above the baseline. So you've always a better result at any observation time point than at baseline across the 2 years. And the placebo curve, of course, declines and it declines at a speed of 2, 3, 4-milliliter per year. And so what you see is that there is across 2 years and longer, we cannot say because longer we've the study, there is a consistent mean improvement above baseline, and there is a meaningful and even statistical significant decline in a placebo group and patients at risk with kidney disease or hypertension, diabetes, which is expected by the way. It's not a new finding that actually we expect. And the difference, of course, is a widening difference if you look at the slope analysis. If you look at the observed case analysis, it is widening and constant, I'd say.

Can you tell us what the baseline eGFR for the overall population and then just the subgroup was?

Yes. Sure. We've not now -- I mean, we've not fully analyzed the subgroup baseline eGFR severity. That is something, which we will announce later. But I can tell you we've patients -- the majority of patients were in the 60 to 90-milliliter eGFR group, but we had patients below 60-millimeter also, and we had some patients above 90 millimeters. Above 90-milliliter is fully normal, between 60 and 90 is a minor impairment, and below 60 is already starting a major impairment of the kidney function. And this is what we saw. And about the mean value is about 80 -- between 78, 80. And it's, of course, a little bit lower with patients with diabetes and hypertension than it is in the patients without these risk factors. So there's a difference with Alzheimer's disease.

Okay. Great. And then I guess moving on to -- you mentioned the paper that was published, and I believe there were some Astellas' researchers exploring PQ529 some while ago in glomerulonephritis. So I guess I'm trying to understand what happened. There's obviously some collaboration with Astellas at that point. Perhaps you could just tell us what happened? What's the differences between PQ529 and Varo. And is there any, I guess, prospect for any other compounding Vivoryon's portfolio that might be more suitable than Varo to explore further?

So maybe I'll answer the second part, and I'll give Michael this for the first part. The second part is -- 529 is very similar to 912. So varoglutamstat is basically a 2-compound we use specifically when we go to very exploratory new situations in order to keep also the records clean for our regulatory compounds. But from a pharmacological activity, it is basically a selective important inhibitor of QC and iso-QC and is very comparable between the 2 compounds. So Michael, if you want to add.

Yes. Devani, this is Michael. Nice to talk to you again. Yes. I mean the difference is basically or, let's say, PQ529 was drawn out of the, let's say, development candidate process also because it was not really good possible to come up with initial selective stag for this molecule. So this is basically really just a 2-compound and PQ912 was much more suitable for production.

And to be clear, there's no other company with any rights to the kidney applications of the QC inhibitor portfolio that you've.

Pardon, I didn't get the question.

Just to clarify that Astellas doesn't have any rights of kidney applications.

Not at all. I might want to actually add on that point even. I think we don't disclose that, but we also filed, of course, appropriate medical use claim patents for the application in kidney diseases for our compounds. So that's also an important point. It's an important step, which solidifies our position here.

Okay. That's great. And then just my final question is really just you mentioned that you wanted to do some additional biomarker analysis in the kidney disorder opportunity? What do you mean by that? What additional analysis that you're looking to do?

We wouldn't probably disclose it for kind of -- so if I answer the question, I'd say for -- also for IP reasons, I'd probably not want to go too much into detail with that. But of course, we'll look into kind of the obvious biomarkers in the field, but we'll refrain from that for awhile.

I think that we want to keep that still secret. I mean we've selected, of course, a couple of biomarkers, which are on the pathway in that area. But I think it's too early to disclose it. We also have not results in-house. So we'll do this diligently like we did today with the data, we don't have data. But what we don't have really and what we probably need to use for substantiate our intellectual property, we don't want to disclose now, if you can understand it, please.

[Operator Instructions] And now we're going to take our next question. And the question comes from the line of Markus Scharhag from Hauck.

Can you hear me? Frank.

Yes. Sure.

Yes. Okay. So my question would be on this surprising kidney results that you presented to us. What do you think is the pathway forward? Because you -- my question would be, do you think that this data plus the data that you'll further collect in the next weeks, will this be sufficient to find a partner because it's probably quite difficult to imagine doing kind of capital raise at this current share price? So do you think that this data is strong enough to find a partner for this?

How can I know about other ones? This is a question I cannot really answer, but what I can give you is I mean everybody can look at market capitalization of companies who are in the kidney field, either in Phase Ib or IIa or in the later stage, what the M&A activities were in the past. I think kidney disorders in general are commercially even more attractive than Alzheimer's. There are many more people with kidney problems than there are with Alzheimer's problems in the world. The disease is extremely expensive when you go into dialysis and in kidney transplantation. It is extremely battlesome also. So I don't think it is a step backwards. When we go from -- if we'd go away from us or what we haven't announced because we still need to analyze data, we've still a study coming. But if we'd shift to fully to kidney, that's not the step backward from a commercial perspective. Our other companies are interested in playing with us, I cannot comment on this because it's, first of all, much too early, second of all I'm not other companies. I think we need to build from our own strengths, from our own sites and our own data. And then we can see what is the development pathway. We also didn't announce today where we'd go in kidney disease and how we'd do it, that is dependent on further analysis and another public statement later this year. But of course, we're working on this, what is in our mind. And then you -- there is still a little bit of time, just 7 weeks after we saw the top line data. It's probably 4 weeks after we -- or 3 weeks after we saw the first kidney data, not even those which are presented to you. So this is incoming use everyday. And I don't want to jump the gun now to say, we go there and there and there. Let us have a little bit of time to consolidate the data to make an attractive package to understand where we best go and where the drug fits best to the patient needs and then we're going to see what happens.

Okay. Well understood. Then just maybe as an add-on to give us a little bit more flavor because many people are not that experts who are invested in the stock. Can you give us a little bit more flavor of how significant and how strong this data is?

Well, what can I say? If you look at the current standard of care in kidney disease and look at the current molecules, which are used, including SGLT2 inhibitors or the GLP-1 of Novo Nordisk, who had a kidney study, which will be announced now in Stockholm at the European Kidney Congress. They only show a reduction in progression. There is no approved drug and no drug probably in major development, which shows an improvement of eGFR in a placebo-controlled study across with probably the exception of 2, at least to my memory, there can be more, don't kill me, but 1 is a cell therapy, which is an autologous transportation from the kidney. They had some Phase IIa data. And they showed some improvement in eGFR, but it is a population of probably 50 patients and it goes over 1 year and the second year was not placebo controlled. And the second study, so the drug from Reata, which actually is called bardoxolone. It showed the continuous improvement of eGFR over nearly 2 years. But the drug had some safety issues. And additionally, it didn't improve the urinary albumin-creatinine ratio. So it actually didn't improve on the protein loss for the kidney and didn't change the number of end-stage kidney disease. We've at least in the preclinical setting shown in the publication that also show an improvement of the urinary albumin-creatinine ratio. So that is quite a good finding, and we're reassured that we can differentiate from these other 2 compounds, which have shown some improvement. So I think we're quite unique in the current situation in the kidney field. We're showing an improvement above baseline over 2 years, and I think that gives us a reasonable strong position to look forward. That's probably what I can say at that point.

Okay. And then sorry, last question from my side. Just to understand correctly, would you want to decide to go into a clinical phase, given the fact that you've already done the Phase I and IIa and VIVA-MIND studies? At which point, could you enter starting a study for the kidney?

We consider as a clinical stage, mid-stage Phase II company with now having a proof of concept in an endpoint, which is accepted by the FDA in kidney disorders. What is the next study? It is depending on the development pathway. And just to give you a little bit more flavor to this because you want that to concrete. So if you'd go in chronic kidney disease, Stage IIIb and IV, of course, these are huge studies with probably a couple of hundred patients, maybe even thousands. If you go to more of an orphan drug setting, of course, you'll start differently with lower patient numbers and probably start a little bit more advanced. But these decisions depend, of course, on further analysis of data, consultation of experts and understanding of the financial needs and so on. So this is analysis, which we still have to do, and this is why I said we're looking for a development pathway. But in kidney disorders, there is a lot of options. This is not only the big indications of CKD IIIb or IV or even V, we could go, but then we probably need a few less patients, or you could go in an orphan. And there is also other fibrotic aspects we can touch in kidney disease and others. So there are decisions, which are still ahead of us and that requires a very diligent review for which we had actually not the time until the results came in after today to be very specific on this. And then I'm sorry, apologies to be a little bit evasive on this, but it's just a fact.

Dear speakers, there are no further questions for today. I'd now like to hand the conference over to Frank Weber for any closing remarks.

So yes, I see that there are a lot of other people who want to ask questions, but the time is over, the hour. I'm sorry that we couldn't take all the questions today. I understand the transformation of the company raises a lot of curiosity and we're very happy about your interest. Those who couldn't ask a question, I'd -- please send it in writing an e-mail to our Investor Relations team. We'll immediately come back to you either in writing or scheduling a telephone conference with you because, of course, you may have very specific question remarks or recommendations for us, and we're very happy to hear all of that. With that, I want to wish you a very happy day and thank you for your interest in the company, and goodbye.

This concludes today's conference call. Thank you for participating. You may now all disconnect. Speaker, please stand by.