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

Okay. So let's get started. On behalf of Vivoryon, I warmly welcome you all to today's breakfast and networking event around the AAIC 2022. Thanks for joining us this morning. It's great to have so many of you here in the room with us in San Diego and I know that there are many of you who are joining virtually, so a warm welcome to you as well. For those of you who don't know me, my name is Ulrich Dauer, I'm Vivoryon's CEO. Together with my team, I'm thrilled to have this opportunity to discuss the future of Alzheimer's disease treatments with you and renowned experts in the field who will provide an overview of our carefully crafted clinical development strategy and updates on our active Phase 2 VIVA-MIND and VIVIAD studies for varoglutamstat, as well as our exciting therapeutic target and our preclinical antibody PBD-C06. Now between May 2016 and May '21, so within 5 years, the FDA approved 207 cancer drugs. In Alzheimer's disease, the last 19 years have only seen a single approval. And we are talking about a disease with a prevalence, which is nearly similar to that of cancer and still to change of being treated with an approved drug that has been proven to hold or at least slow down disease progression. We at Vivoryon want to change the situation with our differentiated approach to the treatment of Alzheimer's disease, which is based on a number of success factors. Firstly, Vivoryon excellent and deep scientific routes in understanding and blocking the misguided activity of QPCT and QPCT/L, our target enzymes, which are known to drive key pathological hallmarks in Alzheimer's disease. Secondly, clinical evidence of the disease-modifying potential of Varoglutamstat, our small molecule inhibitor of these target enzymes. Thirdly, and you're going to hear in detail on this today, varoglutamstat's safety profile supported by an interim analysis based on data of our ongoing VIVIAD trial, which we have presented here at AAIC on Sunday. I don't need to tell all those of you working in Alzheimer's disease in the hospitals and labs, how much passion, persistence and hard work it takes in our field, which has been subjected to disappointments time and time again. This is why we know that one of the most important success factors lies from the group of people involved in all we do. Beyond the unrelenting commitment and passion of our team, this includes our strong network of external partners, 2 of which, Cindy and Howard Feldman, both renown representatives of our field joining us as speakers and many more I see here in the audience. It also includes all those advancing clinical studies in Europe and here in the U.S., including the incredible team at ADCS and NIH and all those of you who are joining us today from our clinical study sites. And of course, it includes all individuals, patients and families who make the decision to enroll in clinical studies. And with this, I'd like to hand over to Michael Schaeffer, our Chief Business Officer, who will introduce our esteemed speakers and moderate the session. Mick, the stage is yours.

Thanks, Ulrich. Yes, very warm welcome also from my side. Yes, at Vivoryon, we are focused on finding a disease-modifying treatment for Alzheimer's disease by 2 different approaches, both are targeting pGlu-Abeta also called N3pE Abeta, especially neurotoxic variant of Abeta that correlates with disease progression. Firstly, we are looking to selectively block the formation of N3pE with varoglutamstat, our clinical Phase 2 oral small molecule inhibitor. And secondly, in an effort to overcome the limitations of existing Abeta antibodies, we are developing the monoclonal antibody PBD-C06. PBD-C06 is specifically designed to bind to and remove neurotoxic N3pE Abeta from the brain. So I think actually, there's no one Abeta suited to explain you why N3pE Abeta is an exciting target than our first speaker this morning and I'm incredibly excited to introduce Dr. [ Finsia Lumer ] to you. In addition to working, as I have learned with [ NASA ], Cindy is adding very much to our understanding of N3pE and pGlu-Abeta. She and her team provide excellent contributions in translational medicine in Alzheimer's disease since many years and I'm actually really delighted that circumstances finally allow us to meet in person for the first time. Cindy is an in associate professor of neurology at Brigham and Women's Hospital at Harvard Medical School in Boston and she's collaborating with us especially in the development and characterization of PBD-C06. Cindy certainly will give us a brief update on this work, as well as telling us much more about the very special and exciting a better variant we are targeting. Cindy, pls come.

Thank you. Well, thank you, Michael, for that very nice introduction and welcome, everyone. Good morning. I know it's really early and I'm really impressed that so many people are here. Okay. I'm just trying to make sure I hit the right button here. Perfect. So today, I'll be talking about targeting pyroglutamate 3 Abeta amyloid. I'm going to move this because I can't really see that, I'm going to go like this. Okay. So I'm going to be talking about targeting pyroglutamate 3 Abeta amyloid for the treatment of Alzheimer's disease and these are my disclosures. And importantly, I do consult for a number of different companies, but I receive antibodies for this study and you'll see lots of data using the antibodies that we receive from Vivoryon Therapeutics as a gift in kind for our research. The research is actually funded by NIH. So what is pyroglutamate 3 Abeta? I'm guessing that most people in this audience know, but in case you don't know, there were discovered these ragged and termini of Abeta peptides in Alzheimer's disease and down syndrome amyloid plaque cores. This was first discovered by Colin Masters and his group in 1985. Then Hiroshi Mori and Dennis Selkoe and others use mass spec and identified these purified Abeta fibrils, that contained about 15% to 20% pyroglutamate 3 Abeta. Later, others, [indiscernible] and all found them to be up to 45% in the fibrils that were extracted from human AD brain. [indiscernible] has done a lot of work in this area and in the mid-90s, he showed that there were multiple Abeta and terminal modifications in the AD brain. And as you can see here, the most abundant by far is this pyroglutamate 3 Abeta. And then these modified and terminal species have been detected in Alzheimer's plaques and this is worked from our lab showing that if you take very briefly fixed tissue, so we go to the autopsy take tissue, fix it for 2 hours from human brain and then process it in paraffin and stain it or you can use unfixed human brain tissue. And you will see a guarantee, you will see this one-to-one co-localization. We've seen this very consistently when we use briefly fixed tissue or frozen tissue fresh frozen tissue. If we look at and part of my PhD thesis was to look at down syndrome brain, the tissue had been fixed from anywhere from 2 or 3 years to 15 years. And the only staining we saw with pyroglutamate made antibodies were plaque cores, that was it. And so for a long time, people were misled in this field and believe that pyroglutamate 3 wasn't present or it was an artifact, I heard this for at least a decade. So it's been really rewarding to know that using different fixation methods and fresh frozen tissue, it's much easier to see now. So how has this formed? Well, pyroglutamate 3 first occurs by the removal of the first 2 amino acids either by enzymes or endoproteolysis of some sort, which results in a free amino acid at -- the free glutamic acid at the end terminus of Abeta. Along comes glutaminyl cyclase, the enzyme, which causes cyclization of biochemical reaction at the N-terminus and then forms pyroglutamate 3 Abeta and it can have different end sorry C-termini. So pyroglutamate 3 Abeta increases hydrophobicity. It causes faster aggregation and beta-pleated sheet stabilization. It causes rapid oligomer formation, which can then lead to synaptic and neuronal deficits and neurological decline and it has very high toxicity. This has been shown especially by as well several different groups in Germany and George Blooms lab in Virginia. And then lastly, once this is formed, it does not like to be degraded. So it sits around and it stays in the brain, it's very long-lasting. So why target beta and like target pyroglutamate 3 for AV? Well, pyroglutamate 3 is a modified pathogenic form of Abeta found in AD plaques and in vascular amyloid. And that's important because there may be good functions for beta amyloid. I mean, it's there throughout life. So we are trying to avoid removing the normal regular beta amyloid. Unlike general Abeta, pyroglutamate 3 Abeta is undetectable in healthy brain and blood. Brain levels of glutaminyl cyclase enzyme that causes the cyclization correlates with pyroglutamate 3 levels in AD progression. And pyroglutamate 3 Abeta can act as a seed for toxic Abeta oligomers and fibrils that drive inflammation and toxicity and I'll show you little data on that later. So our therapeutic hypothesis is that Abeta oligomers and removal of the plaques will slow cognitive decline. These are possible mechanisms of action. So if you look on the left there, you'll see Abeta monomer along comes glutaminyl cyclase, informs pyroglutamate Abeta monomers. However, those do not last very long because they're very, very prone to aggregation. So they can aggregate and become oligomers and they can actually start seeding oligomers that are nonmodified, so that you get this seeding process with oligomers, they can also see fibrils and plaques and so you get plaque deposition. And all of these both oligomers and the plaques are thought to cause inflammation and neurotoxicity. And by the way, this is my colleague and good friend, Stefan Schilling, who works in Germany and he made much of this slide. I'm just borrowing it and I added my own little special things here to show pyroglutamate 3 Abeta. So how can we attack this? How can we get target this as a therapy? So one way is to use antibodies. So there are 2 antibodies, donanemab and PBD-C06, which you heard about from Uli earlier. And both of these antibodies are meant to remove plaques and block seeding of toxic aggregates and I'll talk a little bit more about them later. The other way is to actually attack the enzyme, so to inhibit that enzyme and in that sense, the idea is to block the formation of pyroglutamate 3 Abeta at the end terminus. So pyroglutamate 3 Abeta has been tested this idea of immunotherapy targeting pyroglutamate 3 Abeta, it's been tested in mouse models of Alzheimer's disease. We were the first to show that passive immunization with a pyroglu antibody reduced plaques in an Alzheimer transgenic mouse model that was in 2012. Later that year, [ Ron DeSantis ] Eli Lilly showed that the precursor antibody, the murine antibody of donanemab was also able to clear not only new plaques, but existing plaques. And then [ my lab ] and in collaboration with Vivoryon, which was Probiodrug previously showed that not only could we clear plaques, we could actually improve cognition in mice. And then lastly, we showed that using isotype switching, we could change the effector function and we found that this IgG2a antibody which in a mouse is similar to IgG1 in humans and that this particular form of the antibody was very effective at both clearing plaques and improving cognition. So what about in humans? Well, Lilly's donanemab antibody has completed a Phase II clinical trial. And interestingly, they selected -- they were very careful about this trial design. They selected patients who are amyloid positive, that's critical for all anti-amyloid antibody clinical trials now, but they also selected them based on low to moderate tow by pet. And these people are individuals with MCI due to AD or mild AV, so at the beginning of the not to be, it's actually not the beginning of the pathology, which is something I think we all need to keep in mind. These are people that already have symptoms, which means they're quite a bit further along in the pathology. So these individuals were treated for a period of 76-weeks, there was about plaque lowering to normal levels in about 68% of the patients those that reached normal levels stop treatment. Global tau was unchanged, however, in exploratory analyses of different brain regions, they did see tau lowering, especially in temporal cortex. There was a 32% slowing of cognitive decline in the integrated AD rating scale and that reached significance, 39 had area E or H, area E which is vasogenic edema was seen in 27% of the cases and 6% were symptomatic. Right now, there's a Phase III clinical trial currently enrolling. It's trailed, it's actually well underway. It's called TRAILBLAZER 2 and the readout for that should be, I think in the first half of 2023. And then there's also secondary prevention trial that is underway, TRAILBLAZER-ALZ 3 in which they're enrolling people that have amyloid deposition, but do not yet show signs of dementia. So this is Vivoryon's PBD-C06 monoclonal antibody. This is what we refer to in my lab as 0728(k. This is the miring precursor of PBD-C06, so that's clone, I should just say. This is clone 7, IgG2a antibody. And then the K is a CDC mutation in the Fc region of the antibody that is important for C1q binding. So this is the part that activates complement. So the idea here was that we wanted to block complement binding in hopes of still getting phagocytic function from the Fc-gamma receptor, but avoiding vasogenic edema or inflammation around the blood vessels. And so this antibody is very good at binding both fibrils and oligomers, it does barely binds monomers. It can bind to mixes of Abeta oligomers even as low as 5% pyro Glu-Abeta, you still get some decent binding to that mix with this antibody. In a mouse that -- a mouse model that makes a lot of pyroglutamate 3 Abeta, we saw very robust plaque lowering. And importantly, it was plaque-lowering of both pyroglutamate 3 Abeta and general Abeta. So more recently, my lab has been working on looking at the very tail end, the late-stage part of Alzheimer's disease to see if we could actually see a difference when you immunize old mice, they have lots of amyloid deposition, including vascular amyloid. So we were trying to see if this antibody could prevent area. And so to this end, Dr. [ Koki Makielka ], who was a postdoc in my lab he is back now practicing neurology in Gunma, Japan. He did a study in which he found that there was a trend in these old mice. These are 13 to 17 months old APP/PS1 mice. There was a trend for improved spatial memory and there was very robust lowering of plaque deposition at that time in that model. More recently, people in my lab, including [ Pravin Batini and Martin Grenon and Maria Jose Papaveri ] have been working on looking at even older mice. So these mice were 16 to 20 months of age and they're on the human ApoE4 background. And so Pravin and Martin are here right now joining us. And what they found was that this antibody 3 0728(k was able to improve memory, so the mice that were treated spent more time in the novel arm in the novel object recognition. However, bapineuzumab precursor analog 3D6L also showed some improvement of trend. The IgG2a isotype control showed no difference whatsoever and these are just the PBS controls that are e4 mice without APP. However, we did not see any robust lowering of Abeta with this antibody in these old mice and we're trying to figure out and this is the biochemical, but as Pravin's poster shows, we didn't see it immunohistochemically either. And one reason for that might be that the pyroglutamate 3, if it's a seed is in the middle of a plaque and that it's really difficult to get to it in these older brains where there's so much amyloid, that's one possible explanation. The other one is this is a different lot of antibody than the one used in the previous study. So we're still working on trying to sort that out. But what's really important here is that this is a wonderful this 3D6L antibody causes very robust microhemorrhages. And it's a little bit difficult to see here, but if you look at Pravin's poster over there, you'll see, it's very, very robust. We can now see this even with MRI. The 0728k) does not do this. So it looks like this antibody is good at, at least, avoiding microhemorrhages. And so then this is the humanized PBD-C06 engineered for better safety and efficacy. This is a humanized IgG1 antibody, it's deimmunized to avoid antidrug antibodies. That's an effect that was seen with Eli Lilly antibody and there are a number of mutations that have been added to increase both antibody stability and binding. And importantly, this antibody does include that CDC mutation to avoid complement C1Q binding. And you can see here that it completely avoids C1Q binding. These antibodies still -- the antibody is still able to induce phagocytosis in this in vitro assay and then we showed that it actually still bind quite well to briefly fix human AD brain sections. So in conclusion, anti-amyloid monoclonal antibodies, including those targeting pyroglutamate 3 look promising for Alzheimer's disease. PBD-C06 is a humanized, deimmunized, anti-pyroglutamate 3 Abeta antibody engineered to avoid ARIA and antidrug antibodies and it's licensed to Simcere in China. Varoglutamstat, PQ912 is a QC CCL2 small molecule inhibitor that's now in Phase II clinical trials in Europe and then U.S.A. and we'll hear more about that shortly. And in the future, it might be possible to think about combination therapies where we might try to first clear plaques with PBD-C06 and then block the formation of pyroglutamate 3 in the future using the QC inhibitor. And this might -- if we use them at the same time because of the CCL2 blockage, we might actually also be able to tamper down the inflammation associated with ARIA, if that's an issue. And lastly, I'd just like to thank my lab and in particular, Pravin and Martin have done an amazing job. They're here and they have been working very, very hard on this. And I'd like to also thank our collaborators, long-term collaborators and newer collaborators at Vivoryon Therapeutics. So thanks very much.

Thanks very much, Cindy, for this very nice overview. I think for the sake of time, we probably will skip questions in the meantime, but we will have a Q&A session after the last talk. So the next speaker is Dr. Howard Feldman, a distinguished key opinion leader in Alzheimer's disease. Howard is Professor of Neuroscience and Director of the Alzheimer's Disease corporate study, ADCS at the University of California, San Diego Medical School. And Howard is also the principal investigator of Vivoryon's U.S. Phase IIb study, VIVA-MIND. So in this function, I experienced him as an extraordinary canny leader who always provides like a 360-degree view on everything. And I'm sure Howard is going to tell us more about Vivoryon now and also in the context of current AD drug development landscape in general. Howard?

Thank you, Michael and good morning, everyone. Thank you for joining us this morning. I'm going to talk about the clinical program of Varoglutamstat this morning and I'm going to follow and on the building blocks that Dr. Lamar has provided around why this is a target of interest. Here are my disclosures. The most important disclosure of this morning is that we're going to talk about the VIVA- MIND study, a Phase 2 AB randomized clinical trial that we also have a contribution from Vivoryon to the conduct of the trial. So it was about if I was reflecting this morning, it was about 5 years ago that I met Dr. Louis and Weber for breakfast to talk about this program here in San Diego and here we are returning 5 years later to see some of the extraordinary progress that's been made in the clinical program. Dr. Lamar has done some of the stage setting for really why are we excited about this program and what has tweaked our interest about it. So one of the things at the Alzheimer's disease cooperative study is that we do many clinical trials, we support their development, being able to test hypotheses as fundamental to the work that we do and the choices that we make in our programs. This program is particularly attractive. You've heard about the enzyme QC or glutaminyl cyclase. There's a sister enzyme called ISO QC, which is also inhibited by varoglutamstat. And together, we have the ability to measure the inhibition of these enzymes to correlate and correspond to clinical effects. So here you see in this little cartoon, a dose panel of ranges that can be tested, you see a cross-hatched line of 50%, which is the translation level of enzyme inhibition that one wants to see in order to see clinical benefit. And you can see the area under the curve between 150 and 600 milligrams painted green of where we are desiring to see the enzyme inhibition. So we get a nice degree of relationship to go after with which to test the hypothesis. Our testable hypothesis is that there is a safe and well-tolerated dose of varoglutamstat that will give us at least 50% target occupancy of the enzyme, therefore, inhibit the enzyme by at least 50%. And if we achieve that degree of inhibition, we will have sufficient drug available to translate into clinical efficacy with which to really test whether this works or not. Some of the reasons to believe about this program are and things that have been learned are that there's a dose-dependent degree of enzyme inhibition. So as people get older, they get more -- it's possible with this medicine to get greater degrees of inhibition. In this program, as I'll show you in a moment, the initial starting dose of 800 milligrams in Phase IIa was tested. It proved to be the maximally tolerated dose, enabling us to dial back our doses, as you'll see in the trial that we designed. So we [indiscernible] at a dose of 150 to 600 milligrams twice a day, which we predict will give us a target occupancy of 50% to 87%, which should be ample to test our hypothesis. What did the early program of varoglutamstat look like? And when we evaluate it, there were a few things that stood out. One that a large experience had been acquired. As you see, there were over 150 persons in Phase 1. You see the terms SAD and MAD, single and multiple ascending doses in the SAD where persons take a single dose, 10 milligrams to 1,800 milligrams were tested, so well above the target range that we're testing in the clinical trial. In multiple ascending doses, 200 to 800 milligrams taken for up to 11 days. Within the MAX -- the MAD, a maximally tolerated dose was not achieved. And the effect, as I've noted in older persons was well characterized, which is fundamental because older people and younger people do not have the same PK relationships. Clinically relevant target inhibition was achieved, so the stage is set to now proceed to our clinical trials in Phase 2. The SAPHIR trial was the first clinical trial led by Philip Scheltens in the Netherlands. It was a 12-week test, double-blind placebo of 800 milligrams twice a day versus placebo. And as you can see from this table, there were some quite interesting results. The degree of enzyme inhibition was upwards of 90%. By coMD, it was a large effect size over 1 standard deviation effect. So there was little doubt that this dose hit its target well. There were some encouraging biomarker findings that came out of this study. They looked at spectral EEG and looked at the degree of feta frequency, noting that with varoglutamstat, there was a lowering in the increment of feta. So as this disease goes along, the evo frequencies on EEG increased and the goal of trying to keep healthier frequencies becomes a meritorious goal. And there was a small to moderate coMD effect size between 0.3 and 0.37 in maintaining EEG waves and not seeing increase in feta. Looking at some neuropsychological tests, the one back test had a small effect size within a computerized test battery and looking at CSF biomarkers, looking at neurogranin and YKL-40, again small effect sizes, coMD between 0.1 and 0.2. Again, not entirely convincing, but certainly taken together, there's a package of information that looks like there may be some converging evidence and sufficient to advance beyond phase early Phase 2 into the trial that I'm going to tell you about called VIVA-MIND or [ Vivamentin ]. So we were challenged to come up with an innovative design and one that would as Uli said, there's a huge unmet need, what could we do that would be innovative and might allow us to move more quickly in its development. And we came up with this idea that in Phase IIa, we might do an adaptive dosing evaluation of 3 dose levels. I showed you the range of 150 to 600 milligrams twice a day. We thought that we could optimize our dose selection during Phase IIa. And then interestingly came up with a design, whereby we would have a stage gate at the end of Phase IIa, a futility analysis and without stopping the trial would continue on into a longer-term efficacy and safety within 72 weeks of treatment. When we imagine what this trial would look like, it includes and as [ Albin ] brought to life, it includes early Alzheimer's disease persons age 50 to 89, meeting diagnostic criteria for having Alzheimer's disease as a stage of severity of mild cognitive impairment or mild AD, what might otherwise be considered to be early Alzheimer's disease. We settled on a signature of molecular diagnosis of Alzheimer's by CSF Abeta and phosphor tau or phosphorylated Abeta ratio, so all persons entering into the study would be confirmed as having Alzheimer's disease molecularly. Randomization, drug to placebo 1:1 for the IIa portion, we thought that 180 participants would be sufficient to make our adaptive dose decision and that we would add 282 participants to a final sample size of 462 across Phase IIa and B. This is a complicated schema and I'm not going to go into too much detail only to show you that we took a very interesting paradigm shift here to try and understand a dose strategy that might be most efficient. And where we landed on this one was in the first cohort, cohort A, we would titrate up to the highest possible dose. If tolerated, that would tell us that this was the dose to take forward with the highest degree of enzyme inhibition into Phase IIb. So the strategy is to dose cohort A, 30 persons, 30 persons, active versus placebo. If it's tolerated at a dose of 600 BID, then we continue that dose as a selected dose throughout the rest of the trial. If for some reason, it does not achieve a safety and tolerability bound and we have the safety monitoring bound, we step down to in cohort B to the next lower dose, 300 twice a day and we stopped the 600-milligram and so on down to cohort C, which is the lowest dose of 150 BID. If at 150 BID, we don't have tolerability and safety, we declare the trial as being futile and the trial was stopped. At the end of our dose finding, all persons will have a minimum of 24 weeks of treatment at the optimal dose and we will make a dose decision and I'll show you what the stage gate looks like into IIb. We do this as a way of ensuring that the treatment is not futile to try and lessen the opportunity cost of this trial. Okay. So where have we come to on this trial at the moment? We have 13 sites that are approved to enroll. You see those sites and the PIs are with us in the room. You see that we have enrolled 47 participants, 14 participants in screening, 19 screen fails, 14 participants randomized, by quick calculation it looks like we have about a 58% screen fail, which is very close to what we predicted and very -- in fact, a bit lower than what is often seen in clinical trials of this nature where a molecular signature is needed. We have our recruitment team here this morning that is doing some very innovative approaches to how we can optimally recruit for the study. Moving to the stage gate, so you see that there are 3 different scenarios that will play out at the end of Phase IIa. If we have a positive cognitive signal and by positive cognitive signal, the futility element of this is that placebo is not better than active treatment. So if placebo is better, that would be the stopping rule met. If no effect, if cognition is no, which is placebo is better than active than the trial stops. And if cognition succeeds, but our biological measure, which is our EEG measure, shift in global feta power is not, then we pass to our study steering committee to do further analyses to inform the decision to proceed and you see what we've currently set aside as the information that would go to the study steering committee to help make an unbiased decision of the future of the study, so that would include a raft of measures. Moving on to the Phase IIb. We extend over 72 weeks, primary outcomes are a global staging measure, clinical dementia rating some of the boxes, continued safety and tolerability, secondary outcomes, including quantitative EEG, cognitive and functional composite, what we refer to as CFC2, neuropsychological test battery composite, the elements of PK and PD and blood, functional assessment questionnaire, the ADAS-COG 13 and the neuropsychiatric inventory. In terms of measuring the biological impact of this therapy, we'll be looking in an exploratory way at volumetric MRI, including cortical thickness, global cognitive measure for translation factors of the Mini-mental and MoCA, an extensive battery of CSF biomarkers, quantitative EEG connectivity network and a variety of subgroup analyses based on the metabolic pathway of this medicine. In December of 2021, Vivoryon put forward this program for fast track designation of the FDA, it is potentially makes it eligible for accelerated approval and I'm sure Vivoryon will be prepared to answer questions about that decision. Spending the last moment or 2 in considering where the field has come to, we owe a debt of gratitude to Jeffrey Cummings for this biblical proportion work that he does every year, summarizing the entire field. We drew a square around Phase 3. In Phase 3 green, you see the variety of monoclonal antibodies of which we will have readouts Dr. Lamar mentioned donanemab. I will also mention lecanemab, gantenerumab and you've heard the story of aducanumab. These will all be reading out within the next year from now. There's a variety of -- in the purple of other Phase 3 programs, I'm not sure that any will be as impactful as the amyloid lowering antibodies. There is an important consideration to the landscape and for those that are recruiting for the study. We wrote this paper following the decision of Medicare on coverage or lack of coverage of anti-amyloid monoclonal antibodies. This was in nature reviews neurology just a short time ago. And largely CMS has indicated that it will require if all you show is amyloid lowering, there will be a need for further randomized clinical trials before they're willing to pay. If clinical efficacy can be shown, there will be a need for comparative effectiveness within the context of registry and for those attending AAIC, you may have heard that the Alzheimer's Association is beginning to set up such a registry of users of monoclonal antibodies. So in conclusion, monoclonal antibodies are in late-stage development. Lecanemab will be reading out in the fall of 2022, CTAD will be the tone that it presents. It will have a regulatory deadline of January 6, 2023. Donanemab will read out in mid-2023, gantenerumab will read out in mid to late this year and will be read out at CTAD. I've told you about varoglutamstat small molecule inhibits QC and ISO QC reducing the production of Pyroglutamate Abeta and modulating CCL2, an important cytokine in Alzheimer's disease. And we like this program very much as it gives us a testable hypothesis for clinical proof of concept through VIVA-MIND and the study that Frank Weber will tell you about now the VIVIAD study. Thank you very much.

Yes, thank you very much, Howard, for explaining to us the rather complicated design of the USS trial, but it's certainly well thought through and it works hand-in-hand with our European study, that's important to mention. And in terms of the European study, I would like to give the word now to my colleague, Frank Weber, who is the CMO of Vivoryon. So, Frank is an MD with over 35 years of experience in the pharmaceutical life science industry. I think he is a brilliant mind actually that comes with a good amount of out-of-the-box thinking, I like that very much. And as our current Phase IIb study in Europe, the VIVIAD study, is kind of his baby or well, I should rather say it's maybe 3-year-old toddler and he will entertain us with this view now on the most recent and highly -- yes, I even would want to say satisfying data points we have in that trial. Frank?

Good morning, everybody. Thank you for the kind words. As programs mature, initially they cry out a lot and make a lot of problems, then they educate the drug, so development and they get better. I want to give you today an overview of the safety findings, I just need to find one more. The safety findings of the VIVIAD European study at the stage of the DSMB decision to which those should continue until the end of the study. And this VIVIAD study is a double-blind, placebo-controlled Phase IIb study in patients with early Alzheimer's disease comparing varoglutamstat with placebo. And short disclosure, I'm an employee of Vivoryon and I hold stock options of the company. Yes, let's go to the design of the VIVIAD study to understand what is the relevance of the DSMB decision? When was it taken? And what does it mean for the product profile. The study is designed to enroll 250 patients and randomize them between varoglutamstat and placebo on top of standard of care, so patients can be treated with approved medicines for Alzheimer's disease. We select patients by biomarkers. They are 50 to 80 years old, so they need to have an amyloid signature, which means a better and tau-positive. And after 90 patients, the study designed foresees that DSMB takes a decision which does to carry forward. So what was the choices? So the first 90 patients are randomized 1:1:1 between placebo 300-milligram and 600 milligram, all the doses are given twice daily. And so we have 30 patients on each of those arms. And these patients need to be on study for at least 24 weeks to have sufficiently robust safety profile available and then the DSMB unblinds the data and decides whether 300 or 600 milligrams should be carried forward. Should be mentioned that this was a safety decision only, so there is no futility analysis done by the DSMB, it's just a decision to carry forward the highest well-tolerated dose. Just for completing the study design, the primary endpoint of the study is a neuropsychological test provided by the company, Cogstate, reading out between one and 2 years after randomization for each patient. We have a quality of life questionnaire. We have an EEG, we have CSS biomarkers and a speed assessment. So what was the maturity of the study when the DSMB took a decision. And as you have seen, 90 patients supply is with the wrong way, 90 patients have passed 24 weeks, that was the condition for the DSMB analysis. But of course, we didn't stop the randomization of patients. And patients, of course, initially randomized earlier could continue while the DSMB was deciding. So we have a total of 181 patient randomized and exposed in the study. 128 were older than 12 weeks, 90 patients were in the study longer than 24 and 25 patients already were longer than 60 weeks in the study. And then we looked at the compliance. The compliance at this stage was very good, 90% of the patients had a compliance more than 85%. So study directly was taken fully, so the analysis was valid. And then we have calculated what the exposure of the patient in the study would be. And the mean duration of these 181 patients at the DSMB decision in the study was 6 months, the medium was 5.5%. The maximum duration 20-month, as the total patient exposure about 1,000 months, so it's about 100 patients a year, a little bit less. The total estimated drug exposure because we have, of course, some placebo in that study 780 months, which is about 65 patient years. And then, of course, because we titrate slowly up the drug, the exposure at pharmacologically active doses of 300 or 600 milligrams, the 2 doses, which were up for decision of 415 months. And then let's look what the safety findings were and I can only show you blinded data here because I don't know the unblinded data. The unlined data is only known to the DSMB and has not been communicated to anybody, the DSMB, of course. So we had 181 patients randomized, of which 96% of patients were ongoing. So we had only 7 discontinuations, which is 4%, which is a very low number. And 2 of those discontinuations were due to adverse events, I show you the type of adverse events in the next chart. We had one protocol deviation actually, where we took the patients out of the study because it has not met the inclusion criteria was not prudent to continue. And we have focused roles, which largely are patient caregiver withdrawals because we asked for a study partner for the patient to come within the clinic and the study partner can't do it anymore, patient drops out. So only 2 were due to adverse events. And then on the right side of the chart, you see the overall safety findings at that point in time. So 110 patients had treatment-emergent adverse events, which is 60%. Nobody died, we had a total of 4 patients with serious adverse events and I'll show you those on the next chart. We had 6 patients with severe adverse events, about 56 patients had related adverse events or potentially related. Of course, investigator assesses this blindly and we didn't see any ARIA. Looking into more specifically, what is the safety profile and what is behind all this treatment emergent adverse events I showed you in the previous charts. So on the left block here, you see in a descending order listed all treatment-emergent adverse events above 5 equal or above 5 we saw in that study so far and the most frequent was actually COVID-19 infection, 23 patients had it. We had headaches, diarrhea, nausea, constipation, depression, fatigue and rush in descending order in about 6% to 3% of patients. On the right side of the chart, you see the serious adverse events and the treatment adverse events leading to study withdrawal or to treatment withdrawal better, the patient can stay in the study, of course, but doesn't get treatment anymore. And you see we had a pulmonary embolism, we have a palpitation, we had a patient with a stoma previously and had a complication of stoma, we needed hospitalization for that and we had somebody with peripheral other disease, which was preexisting. None of those use adverse events were related to the drug, all were related to prior disorders of the patients or the Palpitation actually was Alzheimer patients who had 3 hours tennis match before and needed to go to the hospital because we started exhausted and for a check, but he had nothing else. So I think he has a good quality of life. So then we had 2 patients who discontinued the treatment due to fatigue at rest. And then below, we have -- I give you the number of patients with adverse events of special interest. And as today, in development, you need to define the potential drug-related risks and count them and we have defined both in the VIVA-MIND and the VIVIAD study, disorders of the liver and the subcutaneous issues as potentially related and have interest in the context of our close up treatment. And you see that the total number of adverse event or special interest is low with about 12%, of which is some rashes, some night sweat, some erythema and some bright skin. And as you have seen, only one patient discontinued. How does that compare to SAPHIR? And because we had in SAPHIR, we had reached the maximum tolerated dose at 800 milligram given twice daily. And now we give the 600 milligram and the 300 milligram, how does that compare? And you see that in SAPHIR we had 120 patients and at this decision, we had 181 now. The patients on drugs is 60 SAPHIR and we can only estimate it because we haven't unblinded the study, of course, for us, but it's about 75 estimated are on drug and we had 4 severe event. And if you would allocate them all to the active arm and none to the placebo, our rate would be 5% and then SAPHIR on the active was 22%. And we had 2 patients, as I said, discontinued due to treatment-emergent adverse event in VIVIAD. And we had 20 in SAPHIR and if we put them all to as a worst-case analysis in the treatment arm, we have clearly much less discontinuations than we had in SAPHIR. And when we can correct that in the next line on exposure, because percentage is only relevant if you have a similar exposure when you correct it for the drug exposure, the numbers become even more convincing because we had much more drug exposure in terms of months in the VIVIAD study at the time of the DSMB decision compared to SAPHIR, we had 415 months on active 300 or 600 milligram VIVIAD and we had 180 in SAPHIR, so we're about 2.5x more drug exposure. And if you compare then the incidence corrected by months, you see about a factor of 5 to 10 reduction of SAEs in discontinuation due to adverse events in VIVIAD compared to SAPHIR. So we have clearly significantly improved safety profile in VIVIAD compared to the previous Phase IIa study. So what happened and what did we change from SAPHIR to VIVIAD and what actually did we not change? And here you see 2 things. You see the titration regimen in SAPHIR and in VIVIAD on the upper part of the chart. And you see that in VIVIAD, we started the first one week and 2 weeks only with 50 milligrams, then we go carefully up with 50 milligram twice daily to 150 milligram twice daily, 200 or 300 milligrams twice daily up to week 12. In SAPHIR, we went up much more radically going with 400 and then with 800, so analysis for SAPHIR was we went too fast up to steep and that caused a little bit of trouble at the beginning of the study. And the second thing is we reduced dose by -- from 800 to 600, which seems a 25% reduction of the dose. But as Howard explains, actually a 33% exposure reduction because we have a little bit of overproportionate increase of the exposure compared to the drug in the higher dose range, so we have a 33% exposure reduction, but only reduces the target occupancy by around 5%. Why is this? This is because we are in the asymptotic part of the target occupancy, this means you can increase the dose quite heavily, but the target occupancy doesn't change anymore a lot. You have reached the maximum what you can reach with -- achieve with the drug. And if you lower it a little bit, it drops only a tiny little bit. So it's not a linear relation, it's basically at the end of an asymptotic narrowing to the maximum target occupancy. It's difficult words. So summary, the VIVIAD Phase IIb study is progressing very well. In June 2020, the DSMB has recommended to continue the study with 600 milligram twice daily and all patients randomized will now be shifted blindly to the 600 milligram twice daily. Of course, only those which are in the active arm, the placebo continue on placebo. We conclude so far that 600 milligram twice daily titrated up slowly is very safe and well tolerated and we expect the unblinded top line results of this study by end of 2023. I thank you for your attention.

Thank you very much, Frank, for sharing this, yes, as I say, kind of satisfying data because they kind of also confirmed our strategy to go down from the 800 milligram to a study to 600. So we're yet keeping, as Frank mentioned, kind of the same -- almost the same level of target inhibition. So let us conclude with a brief Q&A session. I think we have some more minutes left. Are there any questions within the audience present? We also would have, I think, maybe some questions from online, but there's a question in the back.

Were you surprised by the dropout rate? It was so low in the second VIVIAD?

I didn't hear you very well, but Frank maybe heard you, he has an ear for probably these kind of questions, I guess.

Yes, it's probably one of the -- yes, it's one of the probably lowest dropouts and discontinuation rate we see in long-term Alzheimer's trial so far. First important thing is that we do not have [indiscernible]. And secondly, we avoided through the careful titration, the adverse event we have seen in the Phase IIa. And obviously, there is nothing else in long-term talks which pops up. We have done in animal long-term talks for 6 and 9 months and there was no also new safety findings in animals. So we assume that if the patient likes the drug and gets the drug, it's good. And also the study is designed in a way that it is not too heavy for the patients. We have not overloaded the study with an enormous amount of scale. So our feedback from the sites is that the patient like the study. It's a manageable study set up for the patient and I think that explains the good maintenance on the trial.

Cindy?

I would like to ask either of you about the effects of varoglutamstat on CCL. I was just wondering if you've looked in any of your exploratory analyses of biomarkers at CCL2 levels and what kind of inhibition you're getting for CCL2 both in CSF and plasma?

So probably I have to take this. We measure a series of biomarkers in that study and of course, we haven't analyzed those, but we have done it in Phase 1. And what we can see is that the pyroglu CCL2 drops clearly dose dependently about 30%, 40% over the time depending on when you look at it at trough or a peak level. The total amount of CCL2 actually lowers very little or not, which tells us that the regulation works that basically if the -- I mean, for the audience, physiologically, the human body makes pyroglu out of peptides in order to prolong the half-life of the peptide. So from a glutamine asset endpoint, there's no glutamate asset like an Abeta, it's glutamin and a lot of peptides have glutamine at the end and then the enzyme comes around and makes a pyroglu version of it. And that helps the body not to produce more of the peptide, but to make it just live a little bit longer. And that is, of course, a very efficient way to extend the pharmacodynamic half-life of any physiological peptide through the glutaminyl cyclase. And if we lower the pyroglu CCL2, which is an immunocytokine, which is involved in inflammation also in Alzheimer's disease inflammation, if we inhibit that in a healthy volunteer, then of course, the healthy volunteer produces more CCR2 and CCR2 fragments, which then are fragmented found in the plasma. And then when you take the total out of the CCL2, it's still the same amount, but it's less pyroglu CCL2. So the effective anti-inflammatory load of CCL2 is reduced because the pyroglu version, which is longer there and more effective is, of course, lower. And that, of course, we also test in our Phase 2 studies, but I don't have data.

Maybe I'll just make one comment about that, which is, we'll be looking downstream at markers of inflammation and that was some of the significance of the YKL in the SAPHIR study, looking like there was some reduction, albeit we're still not sure how much reduction will be clinically relevant.

More questions in the audience? If not, we can maybe also take a question from online. Uli, if you might read it maybe.

Yes, sure. There were a couple of them and starting with the antibody. There was a question, is this antibody proprietary to Vivoryon? I guess it's referring to PBD-C06? And is it in any way related to Lilly's molecule currently in clinical trials? I can easily answer the first part. Yes, it is certainly proprietary to Vivoryon and it's heavily protected by our patents. And yes, maybe, Cindy, you want to answer the second part of it?

So right. So it's similar to donanemab in the sense that it does -- sorry, I feel like I get back to everyone. It is related in the sense that it recognizes the same target, pyroglutamate 3 Abeta. But there are some differences and soon we will be comparing PBD-C06, the murine version with an analog of ME, which is the precursor to donanemab murine version. So we'll have a better handle on it after that. But my understanding and I might be wrong with this, but I thought that it also maybe have a slightly higher binding affinity to pyroGlu-Abeta than donanemab. One of the big differences is that we know that donanemab actually induces a lot of neutralizing antibodies, that was one of the issues with it in the -- at least in the Phase 2 clinical trials. PBD-C06 has a mutation that's been introduced into the antibody to avoid this neutralizing antibody effect. So hopefully, that will leave more antibodies around buying Pyroglutamate 3.

Thank you. One more, Michael, yes, there was a question as to the mode of action. And the question is, is there evidence that Abeta oligomers have this modification? I assume it's referring to N3pE and whether modified oligomers are more toxic than non-modified and what fraction of oligomers are plaques that have this modification? I'm not sure would you?

Sure. So George Bloom has done a lot of work on this with pyroglutamate 3 oligomers. And he's shown that even with just 5% pyroglu Abeta oligomers, he gets rapid oligomerization of nonmodified Abeta. He also has shown that this mixture can induce tau pathology in vitro and in vivo. So it looks like as we used to say, at least for the Americans, they might recognize this term, a little dabble do you -- this is for a hair product in the 70s. But a little dabble do you. So you just need a small amount of pyroglutamate 3 to start this conversion and it can convert the nonmodified pyroglu -- sorry, nonmodified Abeta oligomers. And George has also shown that these pyroglutamated oligomers are extremely toxic to synapses and neurons at least in vitro. So I think there is good evidence that these can -- I think in the mechanism slide I showed, you could see that these -- once the monomers, nonmodified monomer becomes pyroglutamated, it can form these oligomers, which then convert almost a prion-like mechanism, convert the nearby nonmodified oligomers into these complexes, which then probably drives the fibrillization and the toxicity.

Thank you very much. So if there's still any more question in the present audience, we would take, this as a final question maybe, if not...

I have a question -- do you have a question that I'm interested in. I'm a bit intrigued by the ARIA, if one looks at the emerging data from the amyloid antibodies, it looks like they tie to CAA and ARIA kind of has that relationship. You mentioned that some of this ties some of this mode of action ties to CAA. Why do you think you're spared, why do you think the antibody is sparing area?

Well, I mean, this is something that we're still looking at. We know that for sure, we don't see any increase in microhemorrhages in APP/PS1 E4 mice. So that was good news, whereas we do have a positive control now the 3D6L antibody induces a lot of microhemorrhage. But I think from my hypothesis is that complement is involved in this inflammation around the blood vessel. So complement is expressed, C3 in particular is expressed by endothelial cells. So I'm hypothesizing that maybe that's actually playing a role in this perivascular inflammation. And I don't think that it's necessarily only if somebody has CAA. Reisa Sperling and I have been talking a lot about this lately. And we think that it's actually the movement of the beta amyloid toward the blood vessels for clearance that may be inducing this inflammation around the blood vessels. It might be that the CAA is more related to the microhemorrhages, but the vasogenic edema I think is just this inflammatory effect near the blood vessels. And that's why I think having combination therapy with something that's an anti-inflammatory like varoglutamstat might actually be protective.

Thank you very much. So I think I would hand back to Uli for some closing remarks, but certainly, you are invited to stay, do some networking and have maybe something more to eat. So thank you for your attendance from my side definitely.

Thanks, Michael, and thank you so much, Cindy, Howard and Frank for your presentations, providing deep insight into the current state of development and for answering incoming questions here from the audience and from the web. Let me conclude today's breakfast event by emphasizing that we are laser focused on progressing Varoglutamstat through clinical development in Alzheimer's disease. The encouraging key clinical results along with the preclinic data and supporting its broad potential in combination Alzheimer's disease treatment regimens is a testament to the advancements made with Varoglutamstat to date. And this makes us believe that we are on the right track to deliver a treatment to patients that can make real difference. Once again, thank you all very much for joining us today live here in San Diego and virtually. We highly appreciate your attention and questions and have a nice day, everyone and bye-bye.