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

Yes. My name is Uli Dauer. I'm CEO of Vivoryon. A warm welcome from my side and also on behalf of the entire Vivoryon team to our virtual event with the title Addressing the Alzheimer's Disease Puzzle in the Clinic: An Expert Overview. We are extremely proud that from the expert side, we will have distinguished speakers who will address this topic from a general perspective, with recent developments in the Alzheimer's disease landscape and its success factors for clinical development. But also, in particular, on puzzle pieces Vivoryon Therapeutics puts into the landscape of Alzheimer's disease. We believe it's a perfect timing for such an event given the progress we made at Vivoryon but also in the light of other exciting and promising development in the field after a long period of disappointments. The first part will be made by Professor Philip Scheltens, Director of the Alzheimer Center, VU University Medical Center Amsterdam; followed by Dr. Howard Feldman, Director of the Alzheimer's Disease Cooperative Study initiative. Our third speaker today will be Frank Weber, our Chief Medical Officer. He will present an update and important aspects of our European VIVIAD trial, which is enrolling patients as we speak. I'm going to introduce the speakers to you in more detail ahead of their respective talks. Now we take particular pride in the fact that the speakers have been and will continue to be close partners and masterminds in the preparations as well as conduct of our clinical trials for the European VIVIAD trial, where Philip Scheltens serves as study coordinator and the planned VIVA-MIND trial in the U.S. with Howard Feldman as principal investigator. And of course, Frank Weber as our Chief Medical Officer. Now some housekeeping. [Operator Instructions] We will answer the questions after the 3 presentations or blocks, so to speak. And I also want you to be aware that this event will be recorded and made available as a replay on Vivoryon's web page after the event. I can't let you go away without a short introduction to Vivoryon and especially for those of you who are new to our story. Now Vivoryon's innovation potential and key strength is based in science and results from its understanding of post-translational modifications as important factors in the onset and progression of diseases. By leveraging this knowledge, Vivoryon is able to efficiently and precisely modulate crucial aberrant molecular signals in diseases such as cancer, Alzheimer's disease and others. Next slide, which is a boring one, but of course, I have to ask you to be appropriately careful with our forward-looking statements in the context of today's event. Our mission at Vivoryon is clearly to apply and progress our science into clinical development strategies to the benefit of patients. Now what is this target class of post-translational modifying enzymes about? After translation of genetic information residing in our DNA, those enzymes introduce modifications to proteins. If you will, this is one of the nature's tools to increase functional diversity beyond information that is stored in our DNA. We have approximately 20,000 genes, over millions of protein functions. Vivoryon does have a successful track record in targeting such enzymes with small molecules. The first program targeted DPP-4 and led to the development of a new class of diabetes type 2 treatments, the gliptins. With this, it's fair to say that Vivoryon, with our scientific team and founders, has already pioneered the development of a drug that made a true difference in the treatment of a disease of high medical need. Today, we are focusing on glutaminyl cyclase, QPCT and its isoform, QPCTL, as targets in Alzheimer's disease and immuno-oncology as well as meprin in fibrotic diseases. Some corporate facts. Vivoryon Therapeutics is a company which listed in the Netherlands since November last year, and as a result of a cross-border transformation of its legal structure. And with its operational sites in Germany with 2 locations in Halle and Munich, respectively. The shares are being traded at the Euronext in Amsterdam under the ticker symbol VVY. The shareholder base includes strong, strategic shareholders, for example, from Denmark as well as international public generalist and specialist funds. Our pipeline representation and obviously, the most advanced program and in the focus of today's event, is the Phase IIb stage development with our small molecule inhibitor of QPCT and its isoform, QPCTL, varoglutamstat, which actively recruits patients since July last year in our European VIVIAD trial in Alzheimer's disease. Same indication and same molecule, VIVA-MIND, the U.S. Phase IIa trial, supposed to start in the weeks to come and of which Howard Feldman will elaborate on in his talk. We have prepared and will conduct this trial with ADCS under the leadership of Dr. Feldman. And this trial with a funding commitment from the NIH of USD 50 million, of which we are particularly proud. We are addressing additional indications with our proprietary pool of QPCTL inhibitors. Among those, a unique approach in immuno-oncology by modulating the important CD47/SIRP-alpha checkpoint with a small molecule. A newer and early stage program is based on meprin as target, which opens up opportunities to enter into particular fibrotic diseases of unmet need like acute kidney injury. We acquired this exciting program, including a comprehensive IP estate from our long-term collaboration partner, the Fraunhofer IZI in Germany, which is continuing to support our research and development efforts for potent small molecule inhibitors of meprin. Now back to the landscape of Alzheimer's disease and all these figures here, obviously, underline the fact that Alzheimer's disease is the disease with the strongest imbalance between market potential, medical need. Currently, there's only -- that there's no drug approved that would be able to slow down disease progression and development risk. Now this is the view on the historic and new approaches or waves to the treatment of Alzheimer's disease, whereas the first 2 are focusing on pathological hallmarks. In the Abeta space, we've seen probably the highest density but also failures of programs with small molecule inhibitors of, for example, beta- and gamma-secretases and Abeta antibodies with different binding motives, some of which however created recent excitement with at least partially positive clinical data like Biogen's aducanumab and the specific pyroGlu-Abeta antibody donanemab from Lilly. The second hallmark is the tau pathology. And since -- due to the stronger correlation with disease progression, this approach seemed to be more promising. However, the first late-stage programs did fail to show effects on cognition here. In the recent past, newer strategies have [ ended up at the arena ] with a stronger focus on regaining or preserving the integrity of synaptic function instead of pathological hallmarks to improve cognition. We at Vivoryon are targeting glutaminyl cyclase or QPCT at the post-translational modifying enzyme, which is predominantly expressed in brain regions responsible for learning and memory functions. In Alzheimer's disease patients, QPCT is overexpressed and interferes with the degradation process of the amyloid precursor protein to Abeta. QPCT is catalyzing information of pyroGlu-Abeta molecules, which are much more resistant to degradation as compared to physiological Abeta molecules. And they are kind of sticky and inducing the aggregation of oligomers, which induce synaptotoxicity. The second feature of glutaminyl cyclase, and in particular, its isoform QPCTL, is the promotion of inflammatory signaling through stabilization of the chemokine CCL2, which mediates microglia activation. And moreover, CCL2 is promoting the tau pathology. So by inhibiting glutaminyl cyclase with our small molecule varoglutamstat. We modulate all 3 hallmarks of the disease pathology and most importantly, by reducing aggregation to toxic oligomers preserved synaptic function. We will learn in the following talks about elements of clinical evidence that is supporting this [ post mode of action ]. Now interestingly, in January, Lilly published positive data with its antibody, donanemab, which is specifically binding to the very same pyroGlu-Abeta spaces, which we are preventing from being formed with our small molecule inhibitor of glutaminyl cyclase. This data also adds clinical evidence to the relevance of pyroGlu-Abeta in the disease progression and is certainly another element of clinical validation to our approach. Now why it's worth to continue to follow the developments at Vivoryon also from a near-term perspective, as Frank will point out later, there will be an important interim safety and tolerability analysis of our European VIVIAD trial, based on which the Data, Safety Monitoring Board will select the final dosing after dose-escalation phase. We look forward to the kickoff of VIVA-MIND, the U.S. Phase IIa/IIb Alzheimer's disease trial, together with ADCS with Howard and his team. Advancement of meprin program towards clinical development and finally, partnerships based on our glutaminyl cyclase platform technology and in particular, in oncology. With that, I'm now introducing our first speaker, Philip Scheltens. Philip Scheltens is Professor of Cognitive Neurology and Director of the Alzheimer's Center at the VU University Medical Center in Amsterdam, and Managing Partner at LSP Dementia Fund as well as since this year, Honorary Professor at the Kings College London. Philip is a global -- a leading global opinion leader in the Alzheimer's field. His work has changed the way Alzheimer's disease is diagnosed. While diagnosis used to be based on specific signs and symptoms and exclusion of treatable causes, he was the first to MRI criteria for hippocampal atrophy associated with Alzheimer's disease in the 1990s, which improved the diagnostic classification of this type of dementia and fueled development of new diagnostics. Philip Scheltens was one of the first in the Netherlands to start a dementia clinic and started the Amsterdam Dementia Cohort, currently the largest collection of clinical and biomarker data. This enables him to initiate, together with his colleagues, new diagnostic research criteria for Alzheimer's disease based on the presence of a clinical phenotype and the presence of amyloid as reflected in the cerebrospinal fluid. This changed from a phenomenological purely symptom-driven diagnosis to diagnosis based on biomarkers, greatly enhanced sensitivity and specificity. Higher diagnostic precision is the crucial step to develop effective therapies as patients with homogeneous underlying pathology can be included for therapeutic trials, targeting the causative mechanism. The new protein-based diagnostic criteria he fathered are now implemented for trials worldwide. Since the early '90s, Philip is a principal investigator in numerous clinical trials, investigating new drugs for patients with Alzheimer's disease. Like at Vivoryon, where he was PA during SAPHIR, our Phase IIa study, and now at VIVIAD, our European Phase IIb study with varoglutamstat. What should also be mentioned, Philip has been bestowed a royal declaration of Knight in the Order of the Lion of the Netherlands as an ambassador for Alzheimer's diseases. Philip, we are looking forward to your talk.

Thank you very much, Uli, and for just making me blush. And also, this only can -- this -- the talk that I will give can only disappoint you after this glorious introduction. And let me just share the screen, if it's possible. We are -- can I just -- I'm looking at another screen, so maybe you should stop sharing.

Stopped then.

Yes.

Okay.

Michael, if you stop sharing, I can start sharing.

He stopped sharing.

Oh, you stopped. Okay. Well, let me try again. Not yet. No.

Maybe this is another way. I mean can we put the -- okay.

Wait a minute. I'll be checking -- yes, yes. I know we're there. Yes. Do you see this?

We see your attempt to share the screen, but we only see...

And now?

Not really.

I'm looking at it, but -- I'm -- he says you're screen sharing. So...

Manuela, do you see the presentation?

No. Unfortunately, no.

Does anybody see it? No? I'm...

No.

Okay. I'll stop share again and try again. Interesting. Okay. And now?

Still the same.

That's funny. He says you're screen sharing. So I am screen sharing.

Yes -- no, it does not show the slides. Any idea what -- we can do it?

No.

Yes. I mean to -- I say a way you can just mail the slide deck to us?

Of course. Yes, of course. It's quite -- yes, yes. Yes, I can do that.

Maybe you can select specific windows to -- you want to share, and not sharing the whole screen.

No. Yes. That's true. So I am sharing the Microsoft PowerPoints, basically.

Sometimes there is a blocking procedure on behind, so maybe it makes sense to share the whole screen instead.

Right. Funny. It always works, I must say, but...

Yes. And does it give different options to you what to share? Can you share a screen? Or do you have to share specific application?

No, I can do both. I can do the desktop. I can do the PowerPoint. So you still don't see anything?

No. So probably, I make a proposal. Maybe we change the order of the presentations, and we start with Howard. Hoping that this works, and this gives us time to fix it. And so let me continue with introducing Howard and -- as the next speaker. Dr. Howard Feldman, a medical doctor, is the neurologist and Professor in the Department of Neuroscience at the University -- oh, now we see it. Okay. Okay.

Yes. But that's his. That's his.

Yes. In the Department of Neurosciences at the University of California, San Diego School of Medicine. Dr. Feldman has served as Dean of Alzheimer's disease and neurodegenerative research and as Director of the Alzheimer's Disease Cooperative Study at UC San Diego since 2016. The ADCS includes a coordinating center and clinical trials network across the U.S. and is currently conducting 9 randomized clinical trials of new therapies for Alzheimer's disease. In his research, Dr. Feldman has made seminal contributions in the areas of mild cognitive impairment, frontal-temporal dementia and diagnostic therapeutic trials. He has contributed to the development and evolution of the clinical diagnostic framework of Alzheimer's disease that includes its preclinical and prodromal phases. Dr. Feldman has led a number of cutting-edge clinical trials across these disease phases, transforming the nature of trials today. Dr. Feldman has been profiled in Lancet Neurology as master of dementia. Thomson Reuters named him one of the most highly cited researchers in neuroscience and behavior and one of the world's most influential scientific minds. In 2019, Dr. Feldman was named the top-ranking principal investigator in neuroscience, funding from the National Institutes of Health by the Blue Ridge Institute for Medical Research. Dr. Feldman is currently directing a portfolio of 12 clinical trials from Phases I to III while also working on interventions directed at prevention of Alzheimer's disease and its risk factors. He's now serving as principal investigator for VIVA-MIND, our U.S. Phase IIa/b study with varoglutamstat. Howard, the floor is yours.

Thank you. Can we confirm that I'm well heard and that the screen is visible, looks good?

I can confirm that part.

Okay. Good. Thank you for that very warm introduction, and I'm humbled by that introduction. It is my pleasure to be speaking to you all today about the varoglutamstat program in early Alzheimer's disease, a.k.a. VIVA-MIND. There are 2 things that I'd like to present to you today, and I'd like you to leave this talk with. The first is that I would like you to understand pyroglutamate-Abeta as a novel treatment target in Alzheimer's disease. In doing so, I'm going to cover the scientific rationale of how we approach this target with specific reference to varoglutamstat and donanemab, which you've mentioned already. I'm going to cover some of the program milestones that have been reached by varoglutamstat and how it is that the ADCS took particular interest in this program and in partnering with Vivoryon. And I'd like to share with you some of the design and methodology of the VIVA-MIND clinical trial in early Alzheimer's disease. As you've heard, this is an NIH-funded Phase IIa trial. And it was designed to be a seamless IIa, IIb. So as you'll see, there is a stage-gate that we meet between Phase IIa and b, but the trial enrolls continuously through the end of Phase IIb. Uli introduced you to the idea of post-translational modification, and this slide goes into this in a little bit more detail. In Alzheimer's disease, there's unambiguously an increased pool of Abeta peptides in the length of 1 to 40 and 1 to 42 amino acids. This increased pool results from either overproduction or decreased clearance. It creates a substrate pool for post-translational modification with aminopeptidases. In this instance, pyroglutamate-Abeta is one of the post-translational modifications that occurs at the N-terminus of Abeta between amino acids 3 and 11. The action of glutaminyl cyclase, as you can see on the left-hand side of this panel, catalyzes a cyclization of glutamate-bearing amino acids. It is these forms that are cyclized that become pyroglutamate-Abeta. So under the influence of this glutaminyl cyclase, which we call QC, there is increased production of this cyclized post-translationally modified pyroglutamate-Abeta. Pyroglutamate-Abeta is a bad actor in the brain. It has increased hydrophobicity. It aggregates faster and forms into beta sheets. It rapidly forms oligomers which are resistant to degradation. And importantly, it has a higher toxicity than Abeta40 or 42 alone. The rapid oligomers of pyroGlu-Abeta cause synaptic and neuronal deficits and eventually the cognitive impairment that we know to be the dementia of Alzheimer's disease. This becomes a modifiable target, QC, it's quite important. What attracted us to this program is the idea that you may inhibit this enzyme to prevent the post-translational modification to pyroGlu-Abeta. There have been 2 major approaches attracting attention for pyroGlu-Abeta. As Uli mentioned, donanemab, being developed by Lilly Pharmaceuticals, has taken a biological, monoclonal antibody approach to this target. They've developed a humanized IgG1 antibody that's directed at the N-terminus of the pyroGlu-Abeta epitope. The idea of this monoclonal antibody is to remove pyroGlu-Abeta and additionally, to reduce neuritic plaques. So those are the targets of the monoclonal antibody. Varoglutamstat provides us a small molecule approach to the same target by inhibiting glutaminyl cyclase. The goal is to reduce pyroglutamate-Abeta. There is a related enzyme called isoQC, which helps mediate the pyroglutamate formation of CCL2, one of the important neuroinflammatory cytokines in Alzheimer's disease. And through a dual mechanism of action by reducing pyroGlu CCL2, one can modulate the neuroinflammatory response that gets induced by some of these amyloid toxic proteins. Donanemab attracted a lot of attention recently in the New England Journal of Medicine in March 2021. There were some very encouraging Phase II trial publications. The trial was done in what is now known as early Alzheimer's disease. That is a trial done in individuals with mild cognitive impairment and mild Alzheimer's disease, whose mini-mental status exam scores were between 20 and 28. It was an interesting study insofar as requiring both a tau PET positive scan and an amyloid positive PET scan. So evidence of Alzheimer's disease by the novel biologic criteria for this disease. The primary outcome measure, which you can see in this panel on the left, was the iADRS score. This is a composite measure of a cognitive test, the ADAS-Cog 13, which has a range of 0 to 85 points. Points are scored by errors made in the test and instrumental activities of daily living scale developed by the ADCS, with a range of 59 points, giving a total score of 144. As you can see, the placebo decline over the course of 1.5 years was 10 points in the negative direction, contrasted with the beneficial treatment effects of donanemab. Now as you can see, this did not stop the disease. However, it did attenuate the slope and the rate of decline over 72 weeks. A very encouraging Phase II result. The biological evidence was similarly quite important. You see on the left -- on this right-hand panel, the Centiloid scale, which is a way of commonly using PET scan data, you see placebo of amyloid PET being relatively stable throughout the 76 weeks. You see the donanemab significantly reducing the degree of amyloid deposition over the first 24 weeks. And in fact, as you can see in the small table below at 24 weeks, 40% of individuals that had been amyloid positive turn -- had been amyloid positive now were amyloid negative; by 55 weeks, 60%; by 76 weeks, 67%. So 2/3 of persons clearing amyloid to a point of becoming amyloid negative, so much so that in the protocol, it was possible to stop the monoclonal antibody after persons became amyloid negative. So turning to varoglutamstat. To summarize some of the development stages that this molecule has been through. We've mentioned its mechanism of action, which is the inhibition of QC. This has had an extensive preclinical package of tissue models, cell models, transgenic models across multiple species and establishing nice dose response curves. As Uli mentioned, the mRNA expression of QC has increased in relevant areas of the brain, including the entorhinal cortex and cortical regions involved by this disease. It co-localizes with pyroGlu-Abeta. If you take an HEK293-APP cell line, in order to express increased levels of pyroGlu-Abeta, you need QC. And if you use a QC inhibition -- inhibitor in this cell line, you can attenuate pGlu production. In transgenic mouse models, particularly crossing, knocking in, knocking out QC, you can increase pGlu-Abeta and phenotypic impairment within the model. If you knock out QC, you will rescue the wild-type phenotype. So compelling evidence that this is a relevant target behaviorally and pathologically. The pathological evidence is that when you reduce QC, you reduce pyroGlu-Abeta and in the Tg2576 mouse model, you decrease cortical plaque and its immunoreactivity in parallel to behavioral benefits. So we view this as being a strong preclinical package. Phase I was well sized and informative. In the single ascending dose program, 10 milligrams through 1,800 milligrams were tested. In the -- and 83 individuals. So a nice-sized SAD program. The MAD program involved 80 individuals treated with 20 to 800 milligrams, twice daily for 11 days. Older individuals were studied and noted to have an increased area under the curve. Clinically relevant target inhibition was achieved within the MAD dose ranges tested. Philip Scheltens was the principal investigator of the SAPHIR study, which tested 800 milligrams bid. It established the upper bound of tolerated dosing. It demonstrated preliminary signals of target engagement, clinical response and biomarker movement. So the attractiveness of this program to the Alzheimer's Disease Cooperative Study, and eventually to the successful grant that we wrote was the testability of this hypothesis. So the hypothesis here is that there will be a safe and tolerable dose of varoglutamstat that will achieve a target occupancy of the anti-QC of greater than 50%. So we've done this mapping, in this panel on the right, of doses between 150 and 600 milligrams bid, which are the doses that we'll be testing in the Phase IIa trial, and we cross-referenced this to the degree of QC inhibition. If you read out across 50%, you can see that we get into the green area under the curve, and this would be the testable level of enzyme inhibition that we're seeking. Why 50%? This degree of inhibition in the preclinical models was sufficient to translate into preclinical efficacy. So Uli mentioned some of the challenges in developing successful treatments for Alzheimer's disease. One has been the difficulty in defining levels of target engagement and being able to measure them. In this instance, we're able to measure the target occupancy in blood and in CSF of the QC inhibition. So this is a very important pharmacodynamic biomarker. With 800 milligrams in the SAPHIR study, there was greater than a 90% QC inhibition. So the bracketing of dose of between 150 and 600 milligrams should give us a sufficient 50% to 80% target occupancy. Taking a look at the safety data at the 800-milligram bid dose, as mentioned, it defines the maximum tolerated dose. I think it was apparent that this would not be a well-enough tolerated dose to take into further development, but it was informative of the pattern of treatment-emergent adverse events. Gastrointestinal disorders, GI intolerance stood out. There was a low incidence, but a noted incidence of increased liver enzymes. And skin rashes occurred, as you can see, 15 compared to 5. Having said this, these drug effects -- side effects occurred early and tolerated beyond the first period of weeks. By about 12 weeks, did not recur or develop de novo. Overall, while the dose was maximum -- was the bracket of the upper end of tolerability, the drug was overall considered to be safe for use and further development. The dose that we will use again is 150 to 600 milligrams twice a day. Some of the encouraging signals that came out of the SAPHIR study [ were a large effect sized ] on the inhibition of QC activity as expected. There were some benefits on spectral EEG in reducing the extent of the growth of theta frequency on EEG. There was some neuropsychological benefit on the one back test within the neuropsychological test battery, a test that reflects on working memory. And there were some small effect sizes that were seen on neurogranin and YKL, measures of axonal and neuroinflammation in CSF. So overall, as exploratory readouts, there were encouraging signs across some of the clinical measures, some of the electrographic measures and some of the CSF measures. Supporting the hypothesis that pyroGlu-Abeta is, in fact, a synaptotoxic variant and worthy of attempts to inhibit. This program development occurred in parallel to donanemab. We did not have the benefit of knowing what the Phase II donanemab would be. And we felt that there were grounds to advance this development program. This leads us to the trial -- the Phase IIa trial that I'd like to tell you about for a few moments in early AD, given the acronym VIVA-MIND. You see the clinicaltrials.gov identifier and the funding sources. In this Phase IIa/b proof-of-concept study, Phase IIa is highlighted by adaptive dosing evaluation of the 3 dose levels that I've mentioned through the first 24 weeks of treatment. Phase IIa serves as a stage gate Phase IIb, which will evaluate the longer-term efficacy and safety over 72 weeks. Individuals who will have early Alzheimer's disease by the NIA-AA diagnostic criteria, my clinical criteria, supported by a CSF AD biomarker signature that draws on an Abeta and p-tau181 criterion or alternatively the p-tau181 to Abeta42 ratio. Randomization will be 1:1 varoglutamstat to placebo. We've calculated a sample size of 180 for Phase II for the safety phase and tolerability, and Phase IIb will add 282 participants to a final sample size of 462. This is a complicated schematic but I would just deal with it at a high level for today, indicating that there are 3 dose panels that will be tested: 600 milligrams bid, 300 milligrams bid, 150 bid. We are inverting the usual dose escalation under the premise that if 600 milligrams bid can be titrated up to successfully, and if this dose works, this would be the selected dose for Phase IIb. If for some reason, cohort a, 600 milligrams bid, were to meet discontinuation criteria by virtue of a Pocock safety boundary, we would then down titrate in the next cohort to 300 milligrams bid. The same paradigm would apply in determining whether we continue cohort b at 300 milligrams bid or if intolerant, down to 150 milligrams bid. If at 150 milligrams bid safety and tolerability are not achieved, then the program discontinues. And here, you see some of the intervening stage gate criteria between Phase IIa and IIb. They're at center around a cognitive signal and an EEG signal. I'll elaborate this a little bit further. Here's what the stage gate looks like. We have a cognitive criteria that is determined by a composite, some of standardized scores from 9 items of the ADNI test battery. And we try and replicate the global relative theta wave power on spectral EEG. There is a yes criteria and a no criteria. If cognition is no, the trial gets stopped. If cognition is yes, the trial will continue, if supported by EEG. If cognition is yes and EEG is no, further -- more detailed analysis will be undertaken prior to a IIb decision. The primary outcome measures are the clinical dementia rating scale and safety and tolerability. Secondary outcomes include a derived cognitive functional composite, QC inhibition, the PK of varoglutamstat, neuropsychological test battery composite, spectral EEG, functional activities of daily living, ADAS-Cog 13 and neuropsychiatric inventory. I'd like to just close this presentation by telling you just a bit more about the Alzheimer's Disease Cooperative Study. As mentioned in the introduction, we have a coordinating center and a national network in the U.S. Its mission as described here as trying to improve the lives of those at risk, were affected by Alzheimer's disease. It has been in existence since the early 1990s. It has a well-established and very valuable infrastructure. It serves as an academic partner and an academic research organization, particularly to small companies such as Vivoryon. We have strong institutional support for Alzheimer's disease research at UCSD, and we focus particularly on early-phase clinical trials and how to accelerate proof-of-concept with disease treatments that include symptomatic and disease-modifying approaches in addition to preventive strategies. So I'd like to acknowledge colleagues at the ADCS that have brought this to life, our colleagues at Vivoryon that have served as collaborators and close partners on this, our protocol committee and the funding sources from the NIH. So thank you for your attention.

Thank you very much, Howard. Fantastic. [Operator Instructions] Yes. Philip, let's try another shot. That looks better. And yes, we look forward to your overview on the Alzheimer's landscape, and the floor is yours.

Thank you very much, Uli. Sorry about this first, but thank you again for the nice introduction. And it's also nice to follow Howard. I follow Howard in many ways. And so we have done a lot of work together. You mentioned the criteria, and this would not have been possible without the intense collaboration I had with Howard at that time, 2007 and onwards. I'm now sort of putting -- try to put the -- what you just heard from Howard into the perspective of what the changing landscape of Alzheimer's disease and dementia, in fact, is from a trial perspective. And I think there is reason to be optimistic, and I will hope to show you. And as you said, Uli, I'm the Director of the Alzheimer Center Amsterdam. I'm also a managing partner at the Dementia Fund, which was recently created at LSP Amsterdam. And to be completely transparent, LSP was an investor at the early days in Vivoryon, as you could see, with a small percentage, and they still hold this. But I'm not involved in that part. So I think I should say next slide probably now. Yes. These are my disclosures. And as you can see, it's mainly -- has to do with drug trials, advice on drug trial developments, of design and execution. So next. This here also covered -- and I think it's always important just not only to mention the amount of patients because we will always be incorrect on estimation of that particular figure. But I think compared to, for instance, oncology and patients with cancer or which the prevalence is almost the same, dementia is characterized by the fact that it is making patients so dependent on others. So around every patient, there are at least 3 to 4 caregivers. And that makes it also a very -- a sort of an economically burdened disease because people have to just stop working sometimes to take care of their father, mother or spouse or children, sometimes even. And it is very expensive in terms of the care part that is always at the end of the disease for a couple of years, which is probably taking up most of the budget in -- actually in every country. And it's also a very global disease. There is no country in the world that is spared from dementia. And every 3 seconds, somewhere in the world, somebody gets the diagnosis. So this is important to realize. So -- and this is also contingent on the fact that if we don't do anything, so we have to -- it's the obligation of us, researchers, as you are hearing today, to do something about these numbers and to stop the disease before it starts basically or to develop therapies that stop the disease developed further after it has started. So the secondary prevention part that we are mainly discussing today. Next. I must say that it's interesting to see that finally, the dementia space is catching up in terms of investment. As you heard the example of NIA and also supporting Howard in this particular trial. And I must say, we have to be proud of the colleagues in the U.S. that they have increased the funding of NIA and NIH funding to dementia. This has been followed by many other countries in the world. And you can see that it has led to an exponential growth of dementia research. But again, compared to oncology or even HIV or cardiovascular disease, it's still very small, and we have to change that. Next. People always ask, well, there is no therapy. And in dementia, nothing happens, and it's a graveyard or all these other remarks have been made, but that's actually untrue. So this slide shows you that indeed, between 1906, when Alois Alzheimer first described the case, and 1984, it was relatively quiet, you can say. But after 1984, also notably the year that the first clinical criteria were formulated and the discovery of amyloid beta and the presence of amyloid in that particular plaque and also the presence of tau in the neurofibrillary tangles was followed on by rapid discoveries in establishing these proteins also in CSF. So using [ CSF ] biomarkers and more recently, being able to visualize the pathology of Alzheimer's disease in vivo using PET imaging, amyloid PET imaging and tau imaging. And most recently, and a very, very exciting and very sort of staggering amount of progress has been made in the plasma biomarker assay. So it's now possible to measure amyloid and tau also in plasma, which makes in the end, probably the use of these expensive and invasive biomarkers like CSF and amyloid, less important. And it will never replace it completely, but it may be used as a prescreener. So don't tell me that there has been no progress, but it is also a recent progress. As you can see, it's only 30 years max of progress. While in oncology, they started many, many years before that. Notably with the war on cancer that was signed by Nixon in 1975. That actually sort of also -- or sort of marked the start of a lot of oncology research. So that's way further down. Next. So look at here, this is the 2021 most recently updated Alzheimer's disease pipeline of drugs in trials. And this is too difficult to look at, of course. But you can see there are the different phases. Phase I, which is the early discovery first in man. Part -- Phase II where you establish the dose and you establish safety as well. And ultimately, you prove that the drug is safe and tolerable and has a good sort of efficacy profile in Phase III. You can see that there are agents in all 3 phases, ranging from small molecule, a disease-modifying biologicals or other disease-modifying agents. I would say, still, the majority is in Phase II in clinical trials, which is a good sign. So they are hopefully expected to also go through to Phase III, as we are discussing today with the Phase II program. Most of them are disease-modifying therapies, the DMTs. And some of them are also -- and not a small percentage, are repurposed drugs, which is an extremely interesting part of the Alzheimer's spectrum, where many old drugs are actually being looked at again, whether they could serve as a drug for Alzheimer's or other dementias. Relatively few cognitive enhances. And I'll go with the next one. That's fine. Next slide. And contrary to what you may expect, I mean, you would see that -- you would think that the majority of the trials is focusing on amyloids and tau. But if you look at this particular graph, you can see that there are even more trials ongoing now in the information part of Alzheimer's disease and also synaptic plasticity and neuroprotection is also quite prevalent. Less so other growth factors, hormones, vascular interventions, proteostasis. And there are -- many others actually are ongoing. But -- so the majority are the 4 -- in 4 bottom lines, which is synaptic plasticity, which is partly what we are doing with the varoglutamstat, and also exactly acting on tau or amyloid or inflammation. Next. So many of the Phase III trials, and this is also something that has been made possible because of what we have done in the past on changing our minds on what Alzheimer's disease actually is. Is it a clinical diagnosis? It is, of course, but then it's a very late stage. And if you want to change something, you have to diagnose this earlier. And this could not have been made possible without the biomarkers. So that's why it's so important that we first made the discoveries in biomarkers, and then we can now treat the populations in a very early phase. As you can see, some of the trials are actually in the preclinical phase, which is a very early phase. And all in all, 46% of the trials involve patients who have not yet reached the state of dementia, which is completely different from the cholinesterase inhibitors that were tested in the face of dementia, where people have profound complaints and also impacting on their daily living. Here, we are talking about early-stage patients that have, of course, complaints and they have cognitive impairments or other impairment, but it's actually not that impacting on their -- in their daily living, so we cannot speak about dementia yet. It's very early on that they have the disease, as is evidenced by the biomarkers. And as you saw that Howard presented, the inclusion criteria for also the VIVIAD, also the MIND, the VIVA-MIND, is to have this signature at baseline. You have to have Alzheimer's disease proven by biomarkers. Next. So this is just an overview, far from complete, of some of the current amyloid beta-targeted drugs in Phase II and III. The red ones have been discontinued. But as you can see, there are still many that are being tested. And they range from monoclonal antibodies, active vaccinations, small molecule as with varoglutamstat or monoclonal antibodies with gantenerumab and the BAN2401, most notably, and of course, solanezumab. Sorry, not -- solanezumab is only tested in the familial AD. So this is just an overview. There's a lot of them. And donanemab is not even on this slide, as you -- oh, yes, it's on the slide, sorry. Is now being done in Phase, yes, IIb/III, as they call it in the TRAILBLAZER 2 study, which is ongoing. Next. Of course, we have to just go back a little bit by the aducanumab story because it will impact also the future of drug development, and it will probably also impact the future of how we treat patients. This was, of course, breaking news. First, having heard about the interim analysis and the futility analysis, stopping the study. And then in October, there was news that there was, yes, of course, an effect on amyloid PET, that was not a surprise. We knew that there was a strong target engagement of this monoclonal antibody. But 1 of the 2 trials also showed a small but important effect on the CDR sum of boxes as you can see here. And these data have been discussed endlessly by a lot of people. Everybody has an opinion on it. And next slide. This was also very evident at the FDA hearing because they, of course, filed for registration. And also the -- a few of the publications that I've shown here, pro and con, the probable sort of possible registration of aducanumab. So the 6 November FDA hearing was quite chaotic and not very -- sort of, I would say, hopeful to listen to. But still, the judge is out there, and we will hear June 7 of the decision by FDA, whether it will be a yes or no or a yes on certain conditions, for instance. Meanwhile, the EMA is also looking at it. What I know is that currently, the process has been stopped because Biogen has to answer a few questions, and they will only -- they will start answering the questions after they have heard from the FDA. But for us in the field, a lot of questions need to be answered, of course, after that, which population to treat, what will be the costs and how will it impact the health care system, and it will impact the health care system for sure because you need a amyloid PET probably to be done, you need MRI to monitor these patients. So it's not an easy thing to do. But I think it will be hopeful also a signal to the field if this gets approved because it will signal the field that, yes, it is possible to have a treatment for Alzheimer's disease. And this will only be the first one of a long list that will follow. I just remembered, the multiple sclerosis field, after 1993, when the first -- that interferon was approved, and now we have more than 20 treatments for MS available and the -- and it's still counting. So this is the state of the art where we are now. Next. But as both previous speakers have already alluded to, the Lilly news was probably even more exciting because it's another monoclonal antibody. And interestingly, it targets exactly the same target as we do with varoglutamstat, but only perhaps more in the [ pluck ] stage. But it doesn't really matter because it worked in that sense that it sort of showed an effect on the combined cognitive functional scale as a primary end point. And it also greatly reduced the amyloid PET uptake, which is, again, an important fact to note that all of these treatments do have a target engagement. Again, the -- all patients were amyloid and tau positive to start with, which is, again, important to note, that this is really different from a couple of years ago. So we have learned our lessons to do the clinical trials better. The New England Journal publication came out just a few weeks ago. So all the details have now been known, and the next trial is ongoing, and we'll see how that plays out. Next. But here, it's again, to -- for us -- for me, personally, and we wrote a comment also on ALS Forum, it's very interesting to see that a different approach to basically the same target actually yields these results because it actually offered us a little bit and also helped us to believe that we are also on the right track targeting this particular pyroGlu-Abeta. And perhaps QC inhibition has more of a role to play in preventing the pyroGlu-Abeta and the toxic effect on oligomers, but it may also -- so probably also decrease the amount of pyroGlu-Abeta and plaques. Next. Are there any other things on amyloids to target? Yes, of course. There is tau. And tau has various approaches as well here. We have small molecules. We have monoclonal antibody. We have active vaccines, actually a couple of them. And you may have heard that AC Immune also had a press release a couple of weeks ago that they have -- they reported very, very promising and very good immunogenicity of the now vaccine. And the difference between all the targets is that they either form -- they target the N-terminus or the mid-terminus or the aggregated tau or the tau messenger RNA, which is very exciting. The Ionis antisense oligonucleotide approach is very, very sort of elegant as well. And they're all in Phase I to II at the moment. So a little bit sort of yes, falling sort of lagging behind the amyloids, of course, but that's one thing. Next. Outside of amyloids and tau, there are a huge number of therapeutical targets that we now can acknowledge as well. One of the most -- the things that struck me most is that we know for -- since 1993 that ApoE4 is the most important risk factor for Alzheimer's disease, yet targeting ApoE4 as a treatment has only been addressed recently. And there are many ways to look at this. And importantly, ApoE4 has an important role for the intracellular cholesterol metabolism as well. So there are also drugs targeting intracellular cholesterol in AD that now come to the forefront. But also into influencing the ApoE4, so nulling it down to an ApoE2 effect or ApoE3 effect already would help. And this is all being tested at the moment in a very early stage. Microglia is back from the past. I would say, neuroinflammation has always been an issue in Alzheimer's disease, but the developments have gone a little bit up and down, but there are now -- especially to TREM2, there are some drugs that are targeting TREM2 as an important influencer of microglial response to the presence of Abeta in plaques. So this is all -- so there's much more ongoing than just Abeta and tau. This is just to illustrate this. Next. What is also very, very important to realize that if you speak to cardiologists or internal medicine physicians, they look very wary to our field because you can actually recruit patients for yet another statin-lowering therapy within a couple of weeks and months. While we, in the Alzheimer's space, recruitment is a very important part. And that's why we need all the world to participate in trials. And this is just to -- just a snapshot from clinicaltrials.gov that you can see that at least 30% of the Phase III trials are global trials, and 20% of the Phase II trials are global trials. Meaning, on both sides of the oceans in the U.S. and Europe and sometimes also Asia although sometimes there are differences over there, of course. But I think this is absolutely necessary that we have to work together on a global scale to do the trials as many parts of the world as we can do. Next. And that is -- and this is another example of a new development that to accelerate, especially Phase II because the traditional model of drug development, Phase I, Phase II, Phase III is quite a slow process. It takes a lot of time, and we don't have the time, as I alluded to earlier. So we have to accelerate the Phase II. So whether we can do this in having multiple agents test at the same time, multiple designs and with a shared placebo group, for instance and then see whether we can sort of quickly decide whether this will work or this will not work and we'll go on to the next drug in the same amount of patients on a common platform. Another thing that helps in honestly, is to go for more homogeneous groups of patients. And for instance, a good example is the amount of the sort of the familial AD patient population, which is in the [ DRNTU ]. The disadvantage is that it's actually a very small group worldwide still, but it's a very pure form of AD because these patients are bound to develop AD at 100% rate because they carry the gene. Another example is to have trial-ready platforms like EPAD, like GAP, that patients are actually worked up already. And then the first trial comes along and they can immediately join or another -- and that's a hobby of me to look more closely in the earlier onset AD patient population, of which there is also quite an abundance. 10% to 20% of the population of patients with Alzheimer disease is younger than 65 years at onset. And they are also a very pure form, but they don't have a genetic causal gene, but they are very eager to participate in trials, and they have no comorbidity almost. So that's also an interesting part. So this is how the trial field in AD is evolving quite rapidly, I must say, and this is extremely important. Next, here, you can see that we faced the greatest challenge actually still in recruitment, as I made the comparison with cardiology. It is especially so for some of the trials, for instance, if you test a cognitive enhancer, so if you have the only a short treatment period, the long recruitment period is in your disadvantage. It's a little bit less so with disease-modifying therapies because they take such a long time for treatment. Then while you're treating a part of the group, you're still recruiting other parts of the group. But still, you can see it takes an enormous amount of weeks and time to finish the trial. And this is especially for Phase II, where you want to have a quick readout and say, is this a go or no go, it's extremely important to develop other measures, and that's why I brought to your attention the platform, in fact. But this is the one of the main challenges. And I think we all have to work together also in making more awareness of clinical trials in this particular space because still, the feeling is once you have been diagnosed with Alzheimer's disease, nothing can be done about it. So why would you -- why would you be enrolling in a trial? And this has to change really. And the success we have in the Netherlands with that approach is to go directly to the patient and skip the doctor and say, well, patients are aware of this. And if we address them directly and say, "Well, there are trials for you to participate in," that probably works as well. Next. So just to address a little bit the gray chart that some investors and some companies are actually sort of considering Alzheimer's disease to beat. I think in every field, you have failures. If you look percentage-wise, in fact, the drug failures in Alzheimer's disease have not been different from oncology. But we have much -- we have so much fewer shots on goal that every failure is magnified in a sense. And it always reaches the newspaper. While there are percentage-wise, even as many failures in oncology, but you never read about it. And of course, we know now what has gone wrong, incorrect inclusion criteria, incorrect timing, too late in the disease course, incorrect dosing, fear of getting too high; which we, by the way, didn't do in the varoglutamstat development, which we actually started with a higher dose, and it's actually a better approach than just going down because some of the trials that we have seen were just under-dosed, and then you have to do all the homework again. Incorrect, the understanding of the biology of the disease or in the incorrect pharma model. It's just bluntly sort of skipping Phase II because you think you have a very good drug in your hands. It's just not the way to go. And so Jeff Cummings, myself and Howard Feldman, the 3 of us, we got together, and we have defined the rights of precision drug development for Alzheimer's disease. And this may be used as a cookbook, and it may be as simple as it is, but it's actually saying, by everything that you do when you develop a drug, do you have the right target? Is -- does it make sense? Is it druggable? And is it supported by genetics or other factors in the specific disease that you're studying? Is it the right drug? Has it the right properties? Just a simple question, does it enter the brain, for instance. The right biomarker crucial to select the right participants, of course, and demonstrate target engagement and also drug efficacy. And the right participants, also again, selecting them by biomarkers, but also not too late in the process. So preclinical, prodromal and the right trial. And this is, of course, everybody thinks they're doing the right trial, but is it really well conducted and well powered? And do you -- and still, we face trials that have -- are being underpowered ultimately. So this is just to highlight that we have learned from our mistakes and that we are doing a better job now than we did before. And I think this particular space for investors is much more important than it was a couple of years ago because we do -- we can do so much more than we used to do. And if we are doing it carefully and we do a step-by-step discovery and development programs, we can prevent failures and we can make success. So next, just my conclusions. And if you want to read back, we just finished a seminar on Alzheimer's disease that was published early March and launched it, where many of the things I told you have been summarized. And I would say that I'm very happy that many shots on goal are currently tested. We see more targets being tested. And it's increasingly a diversified field, which is good. Also the treatment modalities are diversified. It's not all in the monoclonals, the small molecules, it's also the antisense and also gene therapy and many more. Amyloid target therapy started first and its closest to registration. Sorry, I lost my -- yes. So as I said, and still, we have to wait for the FDA decision and afterwards, the EMA decision as well. But having said that, I mean, it's for sure, not the only amyloid targeted therapy for the rest of our lives. There will be others, and it will never be enough because Alzheimer's disease is such a complex disease. You probably need also an anti-tau therapy. You need also an anti-inflammatory therapy or your sort of cocktail that we like to treat our patients with in the future. What I think what you see, although, is that the innovation really comes from biotech because pipelines of many of the big pharma actually are empty and they need filling, and pharma is looking around for good innovation and good targets from biotech. The 5 rights are implemented widely, and you saw that the Lilly trial actually did their best to implement them completely like we are in both of the varoglutamstat studies. I would say the dementia field is now where oncology was 15 years ago, and you have seen what oncology has done over the last 15 years. We will get there ultimately. And vision of funding has to go hand-in-hand. But I'm for sure, I'm very optimistic that the future looks much, much brighter than the past. Thank you very much for listening, and happy to take any questions.

Thanks very much, Philip. Brilliant. So thanks for encouraging the brave ones among us. We are still committed to develop treatments against Alzheimer's disease. And yes, please stay tuned for the Q&A session. I'm now going to introduce our third speaker, Frank Weber. He joined as the Chief Medical Officer of Vivoryon Therapeutics in 2010. Frank has over 10 years of academic experience as clinical researcher in cancer, immunology and infectious diseases, 30 years in pharma, of which 15 years in C-level positions covering R&D, medical affairs and market access. He contributed to several marketing authorizations in the EU, U.S. and Japan, some of them in first indication, including Potasol, Alfuzosin, Erbitux, Raxone, just to mention some of them. In market access agreements for zolpidem, Esbriet and Raxone. From here, he spearheaded personalized medicine, biomarker and companion diagnostics at Merck for more than 10 years. Next to this, he has broad experience across many medical areas, including cancer, immunology, infectious diseases, internal medicine, urology, pulmonology and neurology, covering later or larger indications as well as the orphan drug space. He has contributed to 3 M&A transactions and several licensing deals. At Vivoryon, he's known as having an innovative minded problem-solving attitude and is highly valued by his colleagues and our team. Frank, the floors is yours.

For this very kind introduction. Let me do the screen sharing. So do you see the screen?

Yes, we do.

Perfect. Yes. It's -- I'm honored not only by the introduction, Uli, but also by being a speaker together with Philip and Howard. And over, I'm honored to collaborate with both for quite some years on the program of varoglutamstat for developing it in Alzheimer's disease and all their and know-how, of course, feeds into our development program and makes it stronger and better. And that is, of course, a big pleasure and honor. I'll try with my presentation to give you an overview of the development program as is and got good effect of mechanism of action. And then as a second step, I want to present you the ongoing Phase II study, VIVIAD, how it's designed and what is special about it and how it's proceeding. These are the disclaimers. We have mentioned them already and going directly to matters, and you heard already Howard extensively talking about the target. And also, Philip mentioned the pyroGlu-Abeta approach we have. And this is the sketch to bring it altogether. This enzyme resides in the brain and basically erratically forms a pyroGlu version of the Abeta. Abeta actually is something physiological, which is in the brain and probably has even beneficial function, but there are over the aging process of the human apparent form shorter versions of it. And then this enzyme comes along and basically forms a pathological species from this Abeta, which we call pyroGlu-Abeta. And these pathological species, which causes neurodegeneration like Alzheimer's disease and inflammation through its production, that is only possible through that enzyme. Without that enzyme, you cannot generate these pathological Abeta species. And the approach of Vivoryon is to inhibit this enzyme, so it cannot produce any more these neurotoxic species and the de novo production basically goes to 0 and then the problem is solved. And that is the same target as the antibodies but a different approach because the antibody can probably be seen more as a vacuum cleaner, sucking up the produced, whereas ours is a stopper of any new production. So it doesn't come up even. And so I think that approach has a certain benefit that de novo neurotoxicity cannot be generated at all by basically eliminating the new production of these neurotoxic Abeta variant. Moreover, as already elucidated by Howard, there is a chemokine in the brain, which when the pyroGlu-Abeta is around gets upregulated and supports and triggers neuro inflammation and down of this neuro inflammation pathways then that comes to tau pathology. And there is a specific version of this chemokine, which again needs this pyroGlu version to become more potent and strong. And we inhibit this pyroGlu as well, the neural inflammation gets down-regulated, and we believe we have also a positive effect on the tau pathology, downstream of reducing the chemokine 2 in the brain. So that is the overall sketch of the mechanism. Moving forward, we've always taken a very diligent approach to Alzheimer's development with not cutting any corners. And as Philip alluded to cutting corners by finding out the right dose, by finding out their own study, by not having the right biomarker, hurts in terms of a late failure quite significantly. At Vivoryon, we had a Phase I and Ib study of 200 healthy volunteers starting the development, but it's not only that we look for safety and tolerance in this study with a dose range from 10 milligram to 3,600. So we had a 364 dose range covered in this study. But we also looked at the food effects of whether food would change any of the kinetics. And we already developed a target engagement model, which Howard presented where we looked what dose had, what effect on the inhibition of the enzyme, and we didn't use blood. We went to the cerebral spinal fluid, so we tapped the volunteers and looked at directly in the target compartments to have a very precise understanding what those of our drug led to what degree of inhibition, so that we do not fall in the trap for having the wrong dose. Having done that extensive preliminary work, we went into a 2 -- Phase IIa study, the results presented by Howard and also commented by Philip. And here, we took the highest possible dose that we could apply to humans and looked at a safety and a pharmacological signal of this highest dose, not to leave an opportunity in turn, but also to educate what type of biomarker we should develop for our Phase IIb studies. And what is probably the right dose range to be tested further on to understand what the safety signals were and how we can circumvent them. That is relatively important in Alzheimer as the treatment duration, as Philip said and explained is quite long in these studies for disease-modifying effects in Alzheimer's disease. You need to treat the patients between 1 and 2 years in order to see a separation from the placebo group. And in that period, if you have the dose long and you have dose-limiting side effects or you're too slow, you'd basically lose these 2 years of treatment plus a year or 2 of recruitment. So you're back 4 years in development. And of course, this is very painful. So this is why we did in the target population of early Alzheimer's disease, a first pharmacological and safety study in order to establish what we actually systematically wants to study in a bigger dose-ranging studies. And these bigger dose-ranging studies here mentioned as IIb and found in pinkish color are the 2 studies, which we are currently running or starting. One is called VIVIAD, and I will talk more about this study, it is the European study. And then there is the VIVA-MIND study, which is the study Howard is conducting and Howard talked very nicely about this. So I will not talk about this. And then depending on how those studies go on, we're going to have an interaction with the regulators. And if both studies are clearly positive on primary and key secondary endpoints, we see an opportunity of a very fast conditional approval. If there is a little bit more mixed signs and the magnitude of effect or one of the study shows a little bit bigger effect and more on a smaller effect like we have seen in other development programs, we probably need to run a bigger Phase III study to confirm in the efficacy, which is the typical path forward for a full approval. That is our development strategy in basically 1 slide. And here is just a summary, which also Howard talked [indiscernible] what we saw and what evident. On top, we have replicated this dose response in a target population of early Alzheimer patients in the Phase IIa study. So we're absolutely sure that the dose range we are testing now of 300 to 600 milligram is a dose range, which is pharmacologically active and quite beneficial. Now we also have basically ring-fenced our exploratory neurocognitive outcome, as you see on the right part of that slide, indication of starting neurological recovery because you see within 12 weeks already, we see some nice changes in terms of effect size for some of the cognitive function we measured. And those we identified in a group of endpoints, which we measure in the VIVIAD study, and I come back to this later. What is completely new and actually was spearheaded by Philip, and it's probably one thing in 5 years. People were safe in it. Also started EEG as an endpoint of -- in this clinic, as an endpoint of clinical studies. EEG is a quite objective and sophisticated measure to look into synaptic activity of these patients as the synaptic activity is, of course, decreasing. And we saw in a post hoc analysis clearly an improvement of the connectivity in the brain, indicating a better synaptic function. We saw also a reversal of the theta power, which is usually increased in Alzheimer's disease. And we saw clearly a reversal of that effect when treated with our drug. So we basically have a lead biomarker, which is 1 of the 5 things to do, as Philip talked before. And of course, at the end, we found the safety and tolerance signals we needed to identify the dose range we test in the Phase IIb studies now in this Phase IIa study. So we go into the next series of study with a quite robust understanding how the drug acts, what types of biomarker and cognitive effects we can basically expect, and we have a very strong hypothesis generated and evidence generated in the previous early development phase. Leading to that strategy that we run 2 separate Phase II studies and they are very complementary. They are not just repeating itself. They have different objectives and look at different parts of Alzheimer's disease and how patient react to our drug. And in the European study, we look at a very sensitive marker of cognitive function and neurocognitive test battery as a primary endpoint, which is a computerized testing. And we look at this through a vendor called Cogstate, which is known for many years to produce a very reliable test. We have secondary endpoints of EEG and biomarker in that study. And we also have in that study a very mild up-titration to the doses of 300 to 600 to see whether up-titration is something which improves tolerance. And on the other hand, on the right side, we have the VIVA-MIND study where we have the CDR Sum of Boxes as a primary endpoint, which is, I would say, a very robust classical endpoint. And we have, of course, also the ADNI test battery as secondary endpoints. And we have as well, 300 and 600, but also in this study, we have 150 milligrams. So we have a lower dose included in the safety range. But here, we do not titrate so slowly up. We titrate a little bit faster up, so we can compare the safety of the titration regimes between the U.S. study and the European study. And we have a complete view on the neurocognitive picture, basically, depending on what scale you look by -- in the U.S. with a cognitive disease rating scale. And in Europe with the neurocognitive test battery of Cogstate. The time lines are also slightly different, but both studies will read out within probably 9 to 12 months in 2023 to 2024. We think that VIVIAD is probably a little bit faster because we started it slightly earlier. And it's recruiting already, and it has also a shorter total minimum treatment duration of 48 weeks versus, finally, if we conduct a U.S. study of 72 weeks in the U.S. So that is the Phase II strategy. And as I said, we run 2 studies. One was presented by Howard already and I'm going to present you a second study, which actually was designed with the support of Philip, who serves as the study chair in the study. And this is a study which is conducted in conjunction with the CRO of Nordic Bioscience, and that CRO is placed in Denmark. This is why we have Danish sites. And we have sites in the Netherlands, and we have sites in Germany. And we, in terms to mitigate the COVID slowing down of recruitment. We're going to open likely sites in Poland and Spain in order to speed a little bit of the recruitment without exposing patients to an undue risk during that period. The study comprises 250 patients, always early AD. They are randomized. This study, double-blind, placebo-controlled. It is biomarker as secondary endpoints. We look at the dose escalation up to 600 milligrams. We have a treatment duration, which is flexible between 48 and 96 weeks. That is quite interesting because it's a slope analysis. The typical studies always look at or what is the cognitive function when the patient starts the treatment and what is it at the end of the treatment. And depending on the scale you use, there's, of course, some variability of assessment. That is not what we do in that study. We take all the measurement point -- time points into account for looking at the cognitive decline of the patients. So also those were measured at week 12, 24, 36 or every 3 months, the patient comes. We look at the cognitive function of the patient. And then we built a slope of decline and we compare the steepness of the slopes over 2 years between the patient groups, and that is probably a much more precise and robust assessment than just looking at 2 different time points in time span of 1.5 to 2 years. And the objective of that study is to find the right dose and to prove the efficacy on working memory and attention, which are cognitive key domains, which are impaired in early Alzheimer's disease. We look at brain activity through the EEG, and we could look also, of course, at quality of life. And we used the Amsterdam scale also something which was created in Philip's environment in the past scientifically. And we have a few additional, I would say, goodies in the study or special things in the study because it's an innovative study design. We look at language and speech assessment of patients. We look at CSF biomarker endpoints, and there is also a special scale, which is education and age adjusting the cognitive function of the patient quite well, which is called DSST. And that allows us to overcome the hurdles that cognitive function is education, age-specific and the decline probably as well, so we can adjust for this using the scale. Going forward, as already indicated, this is a very cautiously designed study where we titrate our drug up over 12 weeks to the first potentially efficacious dose. And then the patients gets treated either with 300 or 600 milligram for up to a year. And patients which were early randomized in the study can continue treatment up to 2 years. And as said, every treatment visit counts. So there -- all these visits contribute to the slope of decline over 2 years, and then we can compare the slopes. And at the end, we have a 4-week follow-up period. So the longest duration a patient can be in the study is 2 years, the minimum is 1 year. And all these periods contribute to measuring the efficacy and safety of the drug. As already mentioned by Howard and quite, I think, similarly, we have, of course, an independent data safety monitoring board who looks at the tolerance of the study. And after 90 patients in this trial, there is a decision whether we go with a 300-milligram dose over the 600-milligram dose for efficacy, and that is purely based on the safety findings. So if the 600-milligram dose is well tolerated, that will be carried forward. And if the 600-milligram dose is not so well tolerated, we're going to go for the 300-milligram dose. This sounds maybe a little bit scary, but I want to highlight here that in Alzheimer's disease, we need chronic treatments which are basically very well tolerated in a geriatric population. Otherwise, patients are not stay very long on it, and then, of course, it's very hard to measure the efficacy. So we need basically a drug, which is well tolerated in a quite sensitive and elderly geriatric population, which will also get other drugs for other concomitant diseases. And therefore, we need to play safety quite carefully. There is a lot of discussion in the community whether that should not be seen a little bit more aggressively because the disease is so bad that it would warrant probably a more aggressive treatment. The problem is just the more aggressive treatment with more side effects wouldn't be tolerated for such a long time. And then you couldn't see the efficacy at the end. And therefore, we take a really careful approach to have a drug, which can be long-term used. And as both 300 and 600-milligram are full in the pharmacological dose range of efficacy, we have, I think, a quite good therapeutic window to take a choice here. Finally, it's a little bit a scientific complex situation, and probably most of you who listen, find it a little bit confusing. But actually, it is a quite solid planning of our endpoints. So as said, the clinical study readout is always defined by the primary endpoint and if it's significant or not and if the significance is clinically meaningful. So we powered that study on an effect size of Cohen's d of 0.35, which is in the middle between a small and medium effect size, and clearly, an effect size which would be clinically meaningful in Alzheimer's disease. And then what we did is we took the Phase II data, the IIa data in the SAPHIR study, which were generated in collaboration with Philip and then which was only 12 weeks, but you see a nice separation between the black and the red line here. And we took that and extrapolated these results for up to 2 years. And this is how we came to the sample size calculation. So we are not blindly fishing in that study for anything we hope for, but base it on what was observed already in a therapeutic benefit in the Phase IIa. And what was always looked in the natural history cohort, the company Cogstate provided to us. So that is why we came to the 250 patients we need in that study to investigate the efficacy of our drug. And here, you see a little bit more how nicely and robust it plays out. So we took 3 items from this cognitive scale of attention and short-term memory. The 3 on the left side of the bars, which are the results of the 12-week studies, we put it in a statistical model. And you see how nicely it separates. You see how patients in placebo group get a worsening in that cognitive function already at 12 weeks. You see the trend and how stable the patients were on the drug. And then we took a linear extrapolation approach statistically and looked how the data would look at about 1 year ahead, which is around the minimum treatment duration or the average treatment duration, and we see the separation here. And from that, we basically developed our statistical model and our sample size. So this is a quite, I would say, robust finding and a stepwise development of a clinical endpoint in that study, building on the Phase I and IIa data we have already and try to eliminate any surprises, which came later in development. So now talking on one of my last slides about the operational progress in this study. We have, as said, about 10 sites. We have about a screen failure ratio as we are recruiting about 70%. We have a little bit north of 30 patients already randomized. That means we have been much more than 100 already screened as permanently screening in that study. So this study is well on track and recruiting. We have saw some COVID-19 restrictions in German sites. And currently, we have the advantage that we are working with clinical research centers, which exclusively look at the study patients and do not have a major clinical traffic. And so patients are quite safe. And in the Netherlands, I think we have implemented in the studies in these Alzheimer's centers -- or the centers have implemented very good measures to avoid COVID infections. And therefore, in Denmark and Netherlands, it goes relatively well. Whereas in Germany, we need to wait a little bit until the wave is over and these clinics can start dedicating resources again to clinical research in Alzheimer's disease. We are activating around 10 additional sites in Spain and Poland. Spain was already part in the previous study, in the Phase IIa study. We know these investigators very well. And we have also initiated the DSMB already. We had a first meeting. We set up a charter. And to summarize, we have weekly talks about the patients, and we have monthly reviews of all the safety data. And in those first around 30 patients, we haven't seen any worry -- some safety signals. So the patients have been already up to 6 to 9 months in the study. So we are quite confident that we can progress the study according to plan, with delivering the full results by the fourth quarter of 2023. So thank you for [indiscernible].

Thanks very much. Thanks, Frank, and that kind of concludes the presentations. So we got a lot of questions coming in during the talks. I'm a little bit afraid we won't be able to cover all of them. But for those of you who have identified yourself with the questions, we will work on those and try to get the answers to you as soon as possible. So I just start with the question, which we received from Joseph Hedden to Philip as well as to Howard, whoever may want to take the lead here. So what is your view on donanemab and also the importance really seem to place on clearing plaque. The soluble amyloid was not really mentioned by them and that's also kind of a question. They even mentioned that they believe pyroGlu-Abeta's only relevant in established plaque. Any kind of thoughts?

Howard, do you want to first?

Sure. So the way I would respond to this is to recognize that we have established with treatments like aducanumab and other monoclonals that you can decisively lower levels of aggregated Abeta. Disappointingly, the effect -- the clinical effect sizes in the measured period of time don't match the effect sizes of the removal of amyloid. So in other words, you can remove 70% of the amyloid. You do see consistent, small therapeutic effects, but they're not as big as the effects you achieve by the actual amyloid removal. So there's a bit of a discordance between the clinical measures and the actual degree of amyloid removal. The more subtle part of the question is our ability to measure the soluble forms of amyloid. And we're just a bit hampered by assays that don't have that much sensitivity to measure oligomers. Occasionally, we get some reports that someone in a lab has the ability to measure them. But that may, as the questioner is asking, be the key element of determining the mismatch between the effect sizes on removing aggregated amyloid versus removing soluble amyloid.

I would agree completely, and you can only measure what you can measure. So they were not able to measure the effect. It may be that they saw a combined clinical and functional effect. I mind you that the pure clinical effects were not statistically significant. Only the combined was. It may also because of some effect on the soluble Abeta fraction impacting on synaptic function already. In our study, we deliberately choose to look for biomarkers for synaptic function because that was much more logical than where we act and where we impact on. And to answer another question that was also there. I think the ultimate sort of nice combination would be to combine the 2 sort of removing all your plaques with the antibody and working on the front side of the pathology with varoglutamstat. That's something that you could just imagine.

Uli, it's Howard. Could I just show -- I need to show 1 slide, I did not get to show a disclosure slide. Would you allow me 30 seconds?

Yes, sure. Absolutely.

Thank you. So Philip reminded me, I was horrified to not have the disclosures like, can everyone see that?

Yes. No, we don't want to get you into trouble.

Yes. Okay. Thank you. So I'll just leave this here for a moment, assuming everyone can see it. And if there are any questions, I'm happy to answer them. Thank you for that opportunity.

Sure.

I thought you were making a very big announcement suddenly.

Yes, it was a big announcement.

Okay. So I got another question from Chris Redhead of goetzpartners to all of the panelists, actually. So lots of talks about potential of Abeta targeting in combination with other therapies. With its dual action targeting both Abeta and inflammation, this already is the case with varoglutamstat. Is there evidence that Abeta toxicity and inflammation occur independently and/or at different phases of Alzheimer's disease? And a follow-on to that, what inflammatory markets are being monitored in the Phase IIa/b products? So whoever wants to go first on that.

So I can have a go at that. So to start, the relationship between neuroinflammation and amyloid is complex. And I expect that we are learning some of the complexities. For example, there is probably a beneficial phase of inflammation. So the ability to have microglia respond to amyloidopathy, in a sense, may be protective in the brain at some point early in the disease. However, the neuroinflammatory response, once it becomes excessive or doesn't stop and you start getting excessive release of chemokines and cytokines, becomes destructive rather than protective. So it may be that the inflammatory response has multiple functions, and they may be, in some ways, phase locked. I don't know that we're there yet in terms of really understanding it precisely what the target is and how to approach it, which represents a challenge in relationship to knowing how to successfully implement a neuroinflammatory modular event. In this instance with varoglutamstat, we're targeting on pyroglutamated form. So we have a hypothesis that will, to some extent, enable us to have some test stability based on the target, but it's complex. In terms of what we're measuring, we're measuring as TREM2 and YKL-40 as inflammatory biomarkers, neurogranin and SNAP as synaptic biomarkers and NFL and VILIP as neuronal markers, injury markers.

Same for us. Yes. Nothing to add from me, Uli.

Okay. Then I have a question for Frank. And this question, again, comes from Chris Redhead. So should we assume that most patients will be COVID-vaccinated? That's an interesting one.

We have discussed whether COVID vaccination during the trial is an option. And that is seen with a yes. We do not have an immune suppressive effect of the drug or an immune modulatory effect of the drug in the sense that pyroGlu CCL2 will not affect the efficacy of the vaccination as we know so far. We do not have a condition that patients must be vaccinated when entering the study. I think that would be unfeasible and probably even unfair and would introduce a bias in the study, which actually could change the validity of the outcome because it's a selection, which is probably also somehow cognitive for the patient. And therefore, we are open to recruit all-comers in the studies and allowing vaccination in the study and during the study in both trials.

Great. There's another interesting question coming from Aliaksandr Halitsa from Hauck & Aufhäuser, which I'm not going to answer, but it's basically also for the entire panel. So do you think both companies, Vivoryon and Eli Lilly could benefit in any way, any synergies is they -- if they were to join forces and pursue further development of the p-group targeting drugs in a joint corporation?

I still think you should answer this question. But I think -- I mean, they are interesting. So when you look at the target that they both have, I mean, I would be surprised if there were no talks going on or should be going on between the two. Because I think a small molecule as you have versus a monoclonal antibody, that's the sort of an idea that you could think of in the rationale of combining therapies, that's something that really sort of comes to play. So interestingly, so when you have removed all the plugs as they showed in the donanemab, they stopped actually the dosing. And that could be a starting point from -- to start with varoglutamstat in order to stop the formation of pyroGlu-Abeta and forming it into plaque. So that's a scenario that you could say with stopping and starting and doing this. But that's certainly attractive to me to think about.

I'd might just add that the small molecule enables you to inhibit production. The monoclonal enables you to enhance clearance. So it may be that a combination is rational. I think, as Philip mentioned, the question is, will it be tolerated? Will there be adverse events from having the 2 therapeutics together, and that would have to be evaluated. But I think that's a very intriguing possibility.

And from the inside of Vivoryon, I may want to add that we have tool antibodies against pyroGlu-Abeta ourself. And we tested in animal models, the combination of our small molecule with such a tool antibody. And we saw synergies in animal models of cognition. Now there is animal models known to not necessarily be 100% predictive. Actually, there are sometimes not really predictive for the human situation. But the concept, which Howard said simultaneous or Philip said, if the tolerance of parallel dosing is not good, a sequential dosing of both treatment regimes, I think, make a lot of sense in the clinic.

I'm glad, Frank, you touched on that topic because I was getting a question. Fully in view of the positive results from the Lilly antibody, could you talk about opportunities for your similar antibody? So now you made us aware that we do have an antibody, which is protected. And from the preclinical data we have, it gives us reason to believe that there are some advantages, especially with respect to immunogenicity and others over probably the Lilly antibody. And the question is, okay, so what is kind of our commitment. I mean the antibody is there. We are a small company with limited resources. We have now decided to put our efforts in the progression of varoglutamstat. And as you have seen today, I think we have very ambitious plans here. But still, we believe that this antibody is a business development opportunity, and many companies are getting excited. And the approach is kind of validated by the data of donanemab. So our strategy is really to have it as a kind of partnering opportunity here. There's probably time for a final question. And the question is to our panelists, is the relative lack of defective behavioral effects in aducanumab and donanemab, et cetera, as compared to amyloid removal measures, perhaps due to the relative bluntness and insensitivity of the behavioral measures selected?

I could almost guess from whom this question is coming from, and I won't do it. But yes, that's true. The cognitive measures used are quite insensitive. But apart from that, I would also add the question of time. People always think that if you -- in a disease that has already been taking place for 15 to 20 years with amyloid buildup that you remove it from -- for 78 weeks, and then you suddenly see dramatic cognitive responses. I mean it just takes time. And you could see this also in the figures from the EMERGE study. They started to actually diverse only just after 1 year or more. And if the study had run for 2 or 3 years, we would have seen more dramatic, I think, functional and cognitive effects. It's a question of time. But again, it illustrates the fact that you -- plaque removal only doesn't really work for the patient. You need other interventions as well. And that's why, again, I think synaptic-based strategies give much more cognitive enhancement and cognitive improvement than you would expect from a plaque removal.

Uli, I made comment as well that we aim in development to try and have effect sizes that are worth pursuing. And those are a -- you'd like an effect size that's at least moderate to be a game changer. So we sort of drive towards a moderate -- Frank touched on this a little bit, but you'd like to see a moderate effect size. I think it's fair to say that, yes, we can always use more sensitive neurocognitive measures. But if we're going to try and impact someone's life, it's got to be apparent. Like when penicillin was discovered, it didn't take a very sensitive measure to see that something really dramatic had happened. And eventually, we want to get to a point where we're seeing something that large. Now Philip touches on this very critical point in neurodegenerative disease that the payback on aducanumab is clearly not 18 months for a cognitive signal. It's very modest, the difference, a point of 2 on the ADAS-Cog. But the payback might be if the slopes really diverge, and if 5 years later, there was a dramatic difference, we would not know it. And that remains unknown at the moment. And I think part of the reason the debate about this is so passionate is that having achieved the amyloid clearance people say, "Oh, well, the curves will diverge and just wait till you see what at 5 years." But we don't know. That's still an open question.

Maybe I can add finally something to this, and this is that we do not know what the onset of action time for drugs is. We can measure, of course, pharmacologically, we basically, with our drug, immediately stop the new production. It doesn't take more than a week that it goes down and with the antibody, of course, you're relatively fast resolve the plaques, but that doesn't mean that the neurodegeneration is directly stopped and that the synaptic dying is stopped because those synapses are already on the verge of dying, and some are not continuous for a while. And until you are a new equilibrium, it may take a couple of months until you reach a new equilibrium. And then you are in an elderly population where sort of rebuilding and recovery translating into memory functions is, of course, also delayed compared to young person because the new learning and memory -- if those patients ever can gain new learning functions, even the neurodegenerative processes have stopped, isn't unknown because we have no positive control in that situation. We know how do you get, the more difficult it is to learn new things. So we are probably in a situation where slowing down the disease substantially, as Howard and Philip said, is probably a good first step. And if we have a 30% to 50% decline reduction with an effective drug that given over the couple of years will probably result in nearly 5 to 10 years, better life at the end with less care needed, if you follow the slope. And I think that is our first step we need to try to get to and then build with multiple therapies like oncology. You don't have a single drug. You have combinations. You switch lines, you have first line, second line, third line. You're just like in a mess. Once therapy doesn't work anymore, you switch to the next, you switch to the next. And these armamentarium at the end, all together in a couple of years and hopefully, more early than late will then probably come to a much more stable disease situation as we see it now.

Thanks. Frank, I'm afraid the system will kick us out in less than a minute. So before that happens, I think let me thank you again, thank all the speakers for your impressive talks and sharing your wisdom. And I'd also like to thank our team here at Vivoryon involved in the preparation of this event. And of course, thanks to all who have participated. We really look forward to speaking with you again on next location. And again, we try to follow up all the questions that have been sent to us in due course. Again, thanks very much, and see you next location. Thanks a lot. Bye.

Bye, everyone.

Bye-bye, everyone. Bye-bye.

Bye.