Good afternoon, and welcome to the BioVie virtual KOL event. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the BioVie website following the conclusion of the event. Please refer to this slide about forward-looking statements, which describe the disclaimers and risk factors related to such statements, and consult BioVie's public filings made with the Securities and Exchange Commission that can be found at www.sec.gov. I'd like to now turn the call over to Cuong Do, Chief Executive Officer of BioVie. Please go ahead, Cuong. Thank you, Tara. Thank you everyone for joining today. My name is Cuong Do. I'm the President and CEO of BioVie. I'd just like to take a few minutes to give everyone an update on where we stand with our two clinical trials. Our first trial, of course, is in Parkinson's. That trial is nearly complete. The last patient has come in for his last visit. Our team is working through the study closeout process right now to basically go through all the data, to clean up the data, and so forth. Most importantly, we need to wait for the biomarker data to come back in. We are hoping to have everything in and analyzed by the end of this quarter, but it may slip into next quarter, depending on how long it takes for us to get the biomarker back in. In addition, we are enrolling a long COVID trial, and that trial should complete its last patient visit next week. If everything goes according to plan, we should be in a position to have top-line data read out before the end of the summer. Right. Today's KOL event is really aimed at helping lay the groundwork to understand our Parkinson's data readout. Everyone thinks of Parkinson's as a motor disease that's essentially driven by lack of dopamine in the brain, causing motor dysfunction. That's part of the answer, but that's not the only part, total answer. As you will hear today from Dr. de la Monte and our team, there is a big insulin resistance and metabolic component to what really underlies Parkinson's. With that, I'd like to turn it over to Joe Palumbo, our Executive Vice President of Research and Development and Chief Medical Officer, to get us started. All right, Joe, over to you. Well, thank you very much, Cuong. I think we're going to be able to show you quite a bit of science today that really supports the theories we have about our molecule. In looking at neuroinflammation, metabolic, and inflammatory effects, I think there's no one better to comment than Dr. Suzanne de la Monte, who is a Professor, a long-standing at Brown University. She is Professor in Pathology, Laboratory Medicine, Neurology, and Neurosurgery. She is Chief of the Pathology and Laboratory Medicine department at the Providence VA Medical Center. She is exceptionally well-informed, and we are delighted to make her available to present on these topics. Dr. de la Monte, if you'd like to begin, please. Good afternoon. Today I'm going to present the evidence behind insulin resistance and metabolic dysregulation, not only as a feature of brain aging, which is the necessary component of neurodegeneration, but also as a feature of the neurodegenerative processes that take place in most circumstances. I hope to be able to show you that there is an important consideration for benign versus malignant aging. Malignant aging is the thing that sets off the booby trap for us to undergo neurodegeneration, whereas benign aging is something that we have to do because we just get older. Alzheimer's disease has been dubbed Type 3 Diabetes because of the roles of insulin deficiency and insulin resistance. Parkinson's is not far behind in terms of having those abnormalities. We do have challenges, however, that relate to the accurate detection and monitoring of disease. This is a big problem. Co-factor and lifestyle contributions, which are muddying up the features of the disease, but also increasing the rates, and then the potential for therapeutic interventions. First of all, as I mentioned, aging is the most important risk factor for neurodegeneration. Alzheimer's, which we claim accounts for 70% of, or 80% of dementias, is a chronic progressive disease. It keeps going downhill. It's not something that stays steady. There are challenges because these diseases, Alzheimer's in particular, is often mixed. It's not so clean. It often has vascular disease, overlaps with Parkinson's. The second major challenge is the co-factors: obesity, diabetes, hypertension, stroke, environmental factors. These are all adding to the rates and also the picture of what's going on with AD. It's looking different today than it did when Alois Alzheimer saw the first patient. The market for this is huge. We are probably going to have at least 115 million people worldwide with Alzheimer's, or close to it, by 2050. The process begins with mild cognitive impairment, which is an added to this, and a prequel, basically, to AD. The biggest problem are the people who have the asymptomatic, I like to call them sneaky period disease, 'cause we don't know who they are. The patients are often, you know, in denial or not willing to admit anything. The disappointing therapeutic outcomes largely relate to the challenges faced with respect to diagnostics and understanding the disease pathogenesis. As mentioned, Parkinson's we often regard as a motor system disease, and that old idea is very old. Instead, we know now that at least 80% of them go on to develop dementia within 10 years. They may present with motor symptoms or, but they often progress to varying forms of neurodegeneration that impair cognition and behavior. This is an important thing because the treatments are not available for that part of the disease. When we're thinking about Alzheimer's, we still have this old idea about the plaques, which is the AB, the plaques at the center here, versus the neurofibrillary tangles. The last 40, 50 years have been spent on finding these abnormalities in the brain, and as a result, PET imaging has evolved to very accurately detect its, their presence and accumulation in the brain. The problem is that these aren't the only things that are abnormal, and by targeting this alone, we haven't had any success in treatment. There are no treatments that actually cure or actually stall the disease based upon those two molecules alone. The other group, Parkinson's, is we always think of as a motor system disease. This is the substantia nigra shown at the upper left. It should be black and pigmented, whereas on the right in Parkinson's, those neurons die. Those are pigmented neurons. They have, you know, they're important for dopamine, and they get so-called Lewy bodies. Well, the Lewy bodies are just like neurofibrillary tangles in the sense that they're accumulations of stuff that should be in the trash barrel, and they cause stress and dysfunction. They start out with motor symptoms, but actually these eventually hit the cerebrum and the behavioral centers of the brain. Alzheimer's from, I don't know how many years ago, several decades ago, it was known that there's a metabolic dysregulation. Glucose utilization. Glucose is the main fuel in the brain. Glucose utilization, as shown here in the PET imaging, the lower part, the less red and green you have is corresponds with impaired glucose utilization and effectively a brain starvation compared with the top, which is age control. If you study these, everybody's so happy about it, if you study Parkinson's and frontotemporal dementia, they also have a problem with brain metabolism and glucose utilization. Now we have a mirrored thing, and this usually happens particularly after the patient undergoes cognitive impairment. We're dealing with a problem that has to do with metabolic dysregulation in the brain. Just to remind you, the whole process of glucose utilization is dependent upon the function of insulin. Insulin is the master hormone. It does have cousins that are out there that function, but insulin is the big one that helps with glucose uptake utilization and eventually metabolism. The outcome of having good insulin function is we have plasticity, we have learning, we have memory, we have cell survival, and we have mitochondrial function. Without these pathways, we basically have cells dying and not talking to one another. When disconnection happens, that's when we have cognitive dysfunction. It's important to realize that insulin doesn't work by itself. There are other pathways and not enough time to go into it, but they're known as Notch, Wnt, epidermal growth factor, and importantly, recently are the incretin pathways, which we'll touch on in a bit. The signaling pathways are basically the same. What's wrong with our concept of Alzheimer's and Parkinson's is that we're only considering neurons, and we're only considering neurons in certain parts of the brain. In fact, when you look at the brain, every single cell type, whether oligodendrocytes, which make the myelin, the astrocytes, which are important for the blood-brain barrier structure, the vasculature, and the microglia, which regulate inflammatory responses, all of these are impacted by neurodegeneration, and it makes no difference if you're looking at Alzheimer's or Parkinson's. They all are affected. We don't address these points at all. I mean, we deal with the neurons and specific neurons, we need a bigger picture for what, how to address the problems that are going on. In essence, with aging, because the cells aging and neurodegeneration, I say the accelerated aging, we end up with increased sensitivity of the neurons to oxidative stress, meaning that if you have anesthesia, you have hypoxia, anything like that, those neurons are vulnerable, they get hit easily. That's one of the reasons why people who are 60 years old or older and they have anesthesia, they can wake up delirious. They can actually end up with early cognitive impairment. The more trials you have, the worse it is, that's a big deal, we need to know who those people are. Cell survival is impaired in oxidative stress. Neuroinflammation, which will be covered by Clarence later, that's a big deal as well. Every degenerative disease has it. The microglia and the astrocytes are going on, and inflammation could be coming from the periphery into the brain. In essence, it's causing trouble because of the damage that takes place. The vascular dysfunction. The blood-brain barrier is very important for regulating what gets into the brain, but there's also a vascular part that gets trash out of the brain. This backward and forward flow system is impaired because of the vascular dysfunction. If you think about these diseases, the way I like to think about it is we need to remove our narrow focus on the few signature abnormalities in these diseases, and look at the bigger picture, which is basically a metabolic dysregulation that is championed by impaired glucose utilization and oxygen utilization, and having effectively a brain starvation. It seems more complicated, like how did we get this? Look at all these things that are wrong. If you look at metabolism as the driver for all of these, it makes it a lot easier actually, because now you're dealing with every cell type and all of the things that are wrong with them as you undergo neurodegeneration. We could do a comparison for metabolic diseases that take place in other parts of the body, and believe it or not, they're virtually identical. I work in a lab where we study liver. I've always have. I worked in a cancer lab. When we start looking at the metabolic deficiencies that involve carbohydrates and lipid metabolism, those are dittoed. Mitochondrial dysfunction's always a problem. Basically, you run out of good mitochondria, so they can't have full oxidative metabolism. The vasculature is messed up. The stress response is also activated. You have increased cell death and inflammation. These things are make us think about how do we borrow the abnormal the treatments and the approaches across disease processes. How do we know it's insulin? I mean, how do we know that's the problem? Well, when you look at brains with Alzheimer's disease, and you look at severity of Alzheimer's, you can find that there is a decline in the amount of insulin trophic factor, insulin-like growth factor, so IGF-1. There's an impairment in the binding and the receptor function. This is basically graphs showing Braak stage. Braak stage is like a golf score. The higher the number, the worse you are. Basically, with the severity of Alzheimer's going from zero to six, we find that the insulin, the insulin-like growth factor, the receptors, and the ability of the trophic factors to bind all decline with increasing severity of disease, not necessarily age per se. In fact, when you go to earlier stages of disease, we looked at cerebrospinal fluid. We find that the abnormalities begin much earlier than patients would report in terms of their symptoms. That's automatically a kind of biomarker for dysregulated metabolism. When you look at what's going on, what are the roles of insulin and IGF, they basically take care of the neuroinflammatory responses, synaptic plasticity, the learning, the memory, all the things we talked about that were important in the pathogenesis of disease. The other thing to be aware of, and I've taken a keen interest in it, is the role of the incretins. In short, these are the very popular GLP-1 receptor agonists that everybody talks about. It's important to know there are a bunch of them. It's not just GLP-1. There's GIP, there's amylin, there are who knows how many are coming out. These all hit. You can see that white diagram around the medial. This area here is really pretty cool because this is the major region of brain damage in most of the neurodegenerative disease. You know, it hits into the brainstem, which is Parkinson's, cerebellum, it hits into the frontal lobes and the temporal lobes. These are the structures that are impacted by impaired insulin signaling. Incretins also participate in this thing. We have to be aware that these the incretins are signaling, which regulates a lot of the insulin pathways or cooperates with them, is important in these factors. In fact, when you measure the level of incretin immunoreactivity in the brains, and look at all kinds of biomarkers of it, you know that those are bad. We're dealing with a bunch of things, all of which regulate metabolism in the brain. The last group are the neurosteroids, and I won't go into too much depth, but notice where those signals are. They seem to overlap exactly with the figure I just showed you. We're dealing with the same structures that are abnormal in the brain for the neurosteroids. That gives us hope about the direction. In terms of where can we go with this, the oldest treatment has been to try insulin sensitizers, which have had limited permeability to the brain and effectiveness. Incretins are coming along as being trialed. I know one by one it's not going to work. There is some promise in it. The other group, the third group is, are the neurosteroids, which seem to be really strong for providing both anti-inflammatory, antioxidant, and insulin sensitizer functions. I think the promising view is to include this additional component into the cocktail, if you will, to enhance brain metabolic function that's deteriorating both in Alzheimer's and Parkinson's. I'll stop there. Okay. Okay. Thank you very much, Dr. de la Monte. Clarence Ahlem, who is our SVP in our group looking right now at Parkinson's disease, and he'll give us our introduction to bezisterim. Hello, everyone. I'm Clarence Ahlem. I'm the Senior Vice President of Operations at BioVie, I've been working on the development of bezisterim for about 20 years now. We can get the next slide. Here we go. Introduction to bezisterim. No, you can go back. That's good. I'll start with a quick review of bezisterim characteristics. Here's the molecular structure. Bezisterim is a novel anti-inflammatory agent. It's a sterol, it's not bound by and does not target the steroid-binding nuclear hormone receptors. Bezisterim is not active in the synapse. It does not interact with neurotransmitter receptors. Next slide, please. Bezisterim is orally bioavailable and freely permeates the blood-brain barrier. It targets extracellular signal-regulating kinase in pathology-specific signaling pathways, it doesn't inhibit ERK in signal pathways that are involved with homeostasis. Next. Bezisterim is promotoric and neuroprotective in MPTP Parkinson's disease models. It improved motor and non-motor symptoms in our previous phase II study in Parkinson's. Bezisterim improved cognition and decreased DNA methylation-based biological age acceleration in Alzheimer's patients. Next. Bezisterim's mechanism of action is unique. It binds to ERK in this large protein complex that also contains a signaling protein called MAP3K8, along with the NF-κB complex and mitogen and ERK kinase, that's MEK, M-E-K. This pathway is stimulated by inflammatory mediators interacting with their cognate receptors, which activate ERK and NF-κB in the scaffold to stimulate inflammatory cytokine production and phosphorylation of a tumor necrosis factor receptor one, which is responsible for chronic inflammation. It's important to note that ERK is also an essential component of a different scaffold that promotes insulin signaling than shown here in the lower left. bezisterim does not interfere with ERK in this scaffold, and in fact, the drug was originally developed to improve insulin signaling in Type 2 Diabetes. We believe that the selectivity of bezisterim for inflammatory signaling is essential to its attractive safety profile. Next slide, please. As we heard from Dr. de la Monte, neuroinflammation, insulin resistance, mitochondrial dysfunction, and oxidative stress are causally related in forward feeding. Chronic inflammation drives epigenetic changes that are important to biological age acceleration and Parkinson's disease progression. Next slide, please. Epigenetic age acceleration and unfavorable epigenetic changes in genes associated with Parkinson's pathophysiology promote disease progression. The information theory of aging is based on the notion that epigenetic changes and loss of epigenetic information drive aging. However, this is very important to development of bezisterim, these epigenetic markers that have been lost can be restored under appropriate conditions. Changes in DNA methylation can change the expression of genes to promote Parkinson's disease symptoms and progression. The expression of harmful genes can be increased, and the expression of protective genes can be decreased. The processes controlling methylation of a specific gene or its regulatory elements, like the promoters and enhancers, are complex, and they're not necessarily intuitive. The effect on expression is frequently subtle, but ultimately, inflammation has a deleterious effect, and the cumulative effect of these small changes in cascades can be physiologically significant. Obviously age is the risk factor for disease of aging with biological age, however, and not chronological age being the most important factor. Until recently, the concept of lowering biological age has been more theoretical than practical. We have found that bezisterim alters DNA methylation to lower a person's biological age. When we talk about clinical study results, we usually refer to age acceleration, which is the difference between an individual's chronological age and biological age, with a positive number indicating that the biological age is greater than chronological age, which is not good for that person. A negative number indicating biological age is less than chronological age is of course what we would all like to have. bezisterim, by interrupting the self-reinforcing loop of inflammation, insulin resistance, oxidative stress, and epigenetic drift, lowers age acceleration as measured by an assortment of epigenetic clocks. The results of three DNA clocks computed from the published results from our Alzheimer's are shown here on the lower left. You can see the negative changes in bezisterim-treated subjects in the green column and the positive change in subjects in orange, with the placebo. For age acceleration, negative is good. The PhenoAge clock on the far left is the subject of our next slide. Next slide, please. No, back one. There we go. There was a UK Biobank study analyzed the time for 569 subjects with Parkinson's to progress to death from the time of enrollment. The findings of the study showed that epigenetic age acceleration predicted mortality. On the left, you see that PhenoAge acceleration greater than zero, that is faster aging, progressed to death faster than acceleration less than zero, that is slower aging. On the right, you see that the greater the aging, that is the greater the PhenoAge acceleration, the faster the progression to death. These results and the results of other studies showing a correlation between DNA acceleration and disease progression create a new and exciting possibility of using DNA methylation as a biomarker to predict Parkinson's disease progression. We're hopeful that the DNA methylation results from SUNRISE-PD will be similar to what we observed in Alzheimer's, of course, the data will have to speak for itself. Additionally, I have to say, we have not met with the FDA to discuss DNA methylation as a biomarker, nevertheless, this line of thinking appears to have great potential. Next slide please. The important message here is that there are many interacting inflammatory pathways, NF-κB is the master regulator of inflammatory cytokine production. As a reminder, NF-κB has many important homeostatic activities, which makes bezisterim's apparent selectivity for inflammation signaling critical to its potential usefulness in chronic diseases. Next slide please. Inflammation disrupts homeostatic mechanisms in the brain. Glial cells, that's these microglia and astrocytes, have critical functions in support of neuronal activity. Inflammatory cytokines controlled by NF-κB influence the function of cells and the molecular messages that are released. bezisterim acting in the MAP3K8/NF-κB/ERK signaling pathway can reduce the production of inflammatory cytokines that disrupt homeostatic cell functions. Peripheral inflammation and CNS-infiltrating inflammatory cells disrupt the blood-brain barrier and contribute to the inflammatory milieu in Parkinson's disease. bezisterim, by acting systemically as well as in the CNS, can reduce inflammation globally. Next slide please. Neuroinflammation is a major factor driving motor and non-motor symptoms in Parkinson's. Neuroinflammatory viral infections such as influenza and COVID-19 can induce transient Parkinsonian behavior, including non-motor-like symptoms without apparent extensive neurodegeneration. The inflammatory cytokine storm associated with these viral infections is believed to be responsible to symptoms. In Parkinson's patients, intranasal insulin and GLP-1 receptor agonists can improve movement even though these medicines do not impact dopamine bio availability. In animal models of PD, many of which are created with inflammatory challenges, various anti-inflammatory treatments improve all aspects of disease. We believe that symptomatic treatment with bezisterim will have much less potential for motor complications and neuropsychiatric side effects. Last slide please. To summarize then, bezisterim appears to act in an inflammation-specific pathway. Bezisterim adverse effects have been similar to placebo in clinical studies. Neuroinflammation in Parkinson's disease drives motor symptoms and disease progression. Bezisterim has had positive effects on DNA methylation in Alzheimer's subjects, and we're hopeful that we observe similar effects in our SUNRISE-PD study. Neuroinflammation drives Parkinson's pathology through dysregulation of energy homeostasis, alpha-synuclein folding, and cellular interactions. Bezisterim may reduce inflammation in Parkinson's to improve both motor and non-motor symptoms and slow disease progression. Dr. Palumbo, the floor is yours. Well, thank you very much, Clarence. We're just gonna change slide sets right now, but what I'm gonna be talking to you about is why we hypothesize that bezisterim is going to be a good match for the progression of Parkinson's across the lifespan of Parkinson's. As we bring the slides up, the journey in Parkinson's is quite difficult and it begins well before motor symptoms typically emerge. I'm going to talk to you about the sequence of symptoms, how bezisterim will likely interact with that if our hypotheses are correct, the medical need for a drug that works on multiple stages of the disorder and the path to future therapies and our embracing of precision medicine. I'm going to go to the next slide here and see if I have control, and I do. Okay. I said we would talk about disease evolution and really well before the onset of classical Parkinson's motor symptoms, the tremor, et cetera, there is a progressive non-motor disease that emerges. When I say non-motor, I mean it doesn't necessarily relate to movement, but you can see these in various body systems and brain and behavior. Up to 10 years before the diagnosis, patients may present with constipation and anosmia, which is not being able to smell. REM sleep disorder, and that means acting out your dreams and potentially hurting someone. three to five years before, there is depression, anxiety, fatigue. one to two years before, perhaps cognitive slowing and some apathy. By the time someone reaches a motor diagnosis, there's already tremendous inflammation going on. There is neuronal loss, and these non-motor symptoms have already presented in 90% or greater patients. You've got this path of progressive disability that begins before rigidity, tremor, and slow movements begin. I'm gonna present two of the kinds of patients I might have seen. Now, these are composites. These are not real people. I present them in this way to kind of show what happens. The first person is make-believe. This is James, who's 52, an engineering director. I mentioned this REM sleep disorder. Seven years of REM sleep disorder and inability to smell before slowing of his body starts to be noticed at work. Someone said, "You know, I'm gonna start you on a dopamine agonist." We know that these dopamine agonists, for some people, result in impulsive behaviors like gambling, et cetera. Here he is seven years later, he's now on disability leave, managing his depression and really looking at cognitive impairment and side effects from medications. It's not the motor symptoms that impaired him. It is really the non-motor that contributed to his disruption of career. Here's another make-believe person, Maria, 48, an attorney. Again, a typical progression. five years of fatigue, constipation, restless sleep. After those five years, she develops a right hand tremor that leads to diagnosis. She's started on levodopa, and for some people, that drug begins to wear off. If you look at the drugs that have recently been developed and approved, they tend to be various versions of levodopa that act a little bit longer, are continuously infused, but it's kind of the same thing. For this individual, she's less able to work. She's removed herself from the work that she does, and, you know, she's perhaps a little depressed and more socially isolated. What this the take home from this is while levodopa can control tremor, it doesn't do much or anything really for fatigue, cognition, mood, or the other non-motor symptoms that really impaired her ability to do her work. Let me take you to the next slide. Again, really, what actually drives the quality of life? This is based on a study that was funded by the Michael J. Fox Foundation to look at what impairs you. Listed from top to bottom are depression and anxiety, fatigue, sleep disruption, cognitive impairment, and autonomic dysfunction, none of which typically gets identified as a symptom of Parkinson's, but are part of Parkinson's. These things in order, depression, fatigue, sleep, cognition, autonomic dysfunction, which is like orthostasis, constipation, these things compound disability and control for 65% of the impairment in quality of life, and yet we don't have a treatment for them. Why do the current treatments fall short? You can look at that slide and say, "Well, you know, we've got treatments for depression and anxiety." Well, for non-motor symptoms, there's nothing actually approved specifically in the area, and we use antidepressants and anxiolytics off-label. We may try cholinesterase inhibitors for cognitive decline. We try to symptomatically manage sleep fatigue and pain, there really isn't any therapy that manages the underlying neuroinflammation. It's not a small thing. This is an $82 billion per year burden in the United States, the majority of that is actually lost function, right? You know, less than half of that relates to medical cost, right? The rest of this is, "I can't work." People have to look out for me. This is really tremendous loss. For motor therapies and in this next slide, part of the slide, yes, we have levodopa. It is a gold standard. There is, after a period of time, there's some wearing off, decreased efficacy, dyskinesia, which are unusual motions. And that happens to about half of patients within about five years. We've mentioned dopamine agonists in that other patient vignette, that happens in a, you know, we get some dyscontrol impulsivity in maybe one in six patients. MAO-B inhibitors provide some symptomatic benefit, but no disease-modifying efficacy. Then once you get to deep brain stimulation, which requires a neurosurgical intervention, the implantation of electrodes, they can be effective. That's a procedure that can be effective for advanced disease, but it doesn't slow progression. Let me take you to the next slide. What's our testable hypothesis? Why are we developing bezisterim? Our core hypothesis is that if you can get in early, and you can target neuroinflammation, you can intercept and improve non-motor symptoms. We can affect quality of life in the short term and engage those systems that drive motor progression over time, right? Try to slow down, slow that down. Testable hypothesis number one, remember that Parkinson's is a multi-system disorder. You heard that earlier from Dr. de la Monte. Inflammation-driven cellular dysfunction precedes and accompanies neuronal loss. We think an anti-inflammatory strategy makes sense there. Number two, again, why is this evidence-based? Neuroinflammation clearly contributes to non-motor symptoms. As I've mentioned before, this is the strongest independent determinant of quality of life. Now, three, it can be measured, right? The standard measure, the MDS-UPDRS Part II, which looks at activities of daily living, reflects combined non-motor domains, including mood, cognition, fatigue, autonomic function we talked about, as well as motor functional impact. This is a functional scale. This is not looking, seeing how much you're shaking or how little you're shaking. This is really looking at the Part I along with function to see if a person can benefit. This is really where we're invested. Again, just to review, Part I is a non-motor experiences of daily living, Part II are the motor experiences of daily living, and Part III is motor examination, with Part II really being about function. This is what FDA likes. Let me remind you of where we've been. This has been a 20-year story, but more recently, with funding from the Michael J. Fox Foundation. As Clarence has told you, we did a primate study. We looked at lesioned marmosets, gave them this drug, and they did well. If you go to that northeast primate key findings, we improved mobility, statistically, lower immobility, reduction in dyskinesia, and neurons survival. You'll recall a couple of years ago, we presented data on our first translational study in humans, in which we sought to replicate these primate findings, and we were able to do that. We were able to show an improvement in the UPDRS III, which is motor. In this part of the disease, yeah, motor is really important. We showed greater on time, and our adverse event profile was really quite similar to placebo, in fact, equal to it. Why are we looking at early Parkinson's disease? Because this is a brain-derived molecule. We have made it oral. We have made it blood-brain barrier permeable. The mechanism of action is what Clarence had described. You heard a little bit about incretins, the GLP-1s being an example. We know that those are being looked at. We don't have some of those burdens, and I'll talk a little bit about that. Again, our prior phase II-A study that I had just talked about was in advanced Parkinson's. These are people who are on levodopa, who are having that loss of efficacy that we had talked about earlier. We presented that study to a group of international experts. They said, "Fine." Let's move on. Let's go early. That's what we've decided to do. That's that early study. Now, looking at those folks, we've decided on a precision phase II-A study in early Parkinson's. Cuong told you earlier that the last subject had enrolled and had really moved along very, very nicely. Our study design is very efficient. We're looking at about 50 to 60 early patients who are drug naive, who have been approved by an executive committee to make sure that they meet the diagnosis. They're on 20 milligrams twice a day versus placebo for 12 weeks, followed by a four-week follow-up period. The idea here is to show target engagement, to characterize this drug. This drug is first in class. We can't expect it to look an MAO-B inhibitor. We can't expect it to look like any of the other medications that have been approved. We have our hypotheses, and we need to therefore look at how does a drug interact with the experience of having early Parkinson's. The endpoints are what I had mentioned earlier, along with measures of quality of life, safety, tolerability, and as Cuong mentioned very much earlier, a number of biomarkers that are related to the mechanism of action of the drug, DNA methylation, which is really telling your DNA how to function. Let's take a look at the next slide. You know, this is not an easy thing. You have to match your drug design to the patient. We know that when you use the UPDRS, you tend not to look at signals early really well because there's a lot going on. On the other hand, we're very much aware that there are targeted measures. The PARCOMS is one, where there are weighted composites. We're aware of that. We've incorporated some of that. Again, it's defining the drug's differential profile. Small studies really do that well. You get a lot of biological signal per patient as long as you concentrate on mechanism. You can get a rapid proof of mechanism before committing pivotal scale resources. We think that's a wise use of funds. You're basically fingerprinting across motor and non-motor domains. You know, you can do it. It's been done, right? This is another one of the incretins. They showed some efficacy in using this kind of model, but about 50% of the patients really had adverse events. For us, with the oral route and what we've seen so far in our previous studies, we think we're gonna be very well-tolerated. You know, I've told you we're doing things in a very precise way. You can certainly read that. For us, what does success look like? It means we've got target engagement, we can map a biological effect, and then map that clearly to a clinical effect. That we have a signal, we have a path, and we have prospective endpoints really identified with precision. We've looked at a spectrum of disease elements, and we're gonna be working on them. We're looking at a unique signature and a new class of medication. We're looking at the effects of an anti-inflammatory and non-immunosuppressive drug, and that's really important. This is not a steroid, right? This is not immunosuppressive. This is anti-inflammatory, and that makes us unique. We will understand our time course, the signal of the drug, and we think we'll be able to give investors and regulators clarity about how this drug works. Now, we will have a coherent data package that will justify additional investment. With that, I'm gonna turn it back to our CEO, Cuong Do, to hear his viewpoints on this and whether or not we've got any questions, because we've probably got good answers. Thank you, Joe. Thank you, Dr. de la Monte, and Clarence for walking us through this great presentation. Let me see if I can get us started on the Q&A. My first question is actually for Dr. de la Monte. You had mentioned that metabolic dysregulation is really the key driver for a lot of disease conditions, like a lot of things that start to go wrong in the body, right? A lot of that really affects insulin resistance, right? It starts with insulin resistance. If you had an agent that is able to reverse or modulate the insulin resistance that's going on in the body, would you expect that to be able to address not only the disease symptoms, but also perhaps modify the progression of the disease? I would hope that that would be one of the strategies. I wanted to clarify that the abnormalities that take place in the brain actually reflect neurodegeneration. The brain neurons, all those cell types, are metabolically dysregulated. However, their function is also heavily impacted by systemic insulin resistance. If you add that to an ongoing problem in the brain, that's what's driving these increased cases of Alzheimer's, Parkinson's, et cetera. I didn't show you a graph of it, but if you look at a person who was 70 years old in, you know, 1980 versus somebody today, the rates of Parkinson's and Alzheimer's have skyrocketed. That doesn't make sense if it's only genetic. What we do know is they parallel the changes in obesity, diabetes, et cetera, meaning that the Parkinson's is there, but it's made much worse and much more common because of the systemic disease. Will it take away the Parkinson's if you cure the diabetes? No, it'll certainly reduce the onset, severity, and really probably pretty much delay it, the whole process, by taking care of those systemic problems. Once the brain cascade gets going, we need to address it specifically with medications that affect the brain. You mentioned earlier that what you saw in the brain, kind of the mechanism, the pathway of what affects the brain affects the rest of the body as well, right, in other diseases? Wouldn't it be fair to say that to think that if you can reverse the metabolic dysregulation, you could basically affect multiple diseases at once, and not just Parkinson's or Alzheimer's in particular? No, I Absolutely. I think that our mistake, whether you're dealing with the brain, the liver, the kidneys, or whatever is metabolically dysregulated, we're gonna have to crosstalk and borrow from one another because the mechanisms seem to be quite related. The big deal will be, can you get those drugs across the blood-brain barrier? You know, can you make them more specific so that the brain is targeted more directly than, say, skeletal muscle? You know, if we think about I always like to think about it as atherosclerosis. We don't really think of athero in the heart, the kidneys, the aorta as being different. It's all the same thing. It's just a real estate problem. The consequences are different because of the organs. In the brain, we really do have to address what's going on in the brain, specifically, but we also need to address the systemic problems because they're making the brain worse. Right. Thank you for that. I'd like to next go on to Clarence. You heard from Dr. de la Monte that it's all about metabolic dysregulation, insulin resistance, and so forth. You focused a lot on inflammation and neuroinflammation. Can you help really draw the link between inflammation and insulin resistance? Well- metabolic dysregulation? Certainly. I mean, they are closely interrelated, and they are mutually inductive. Wherever you have inflammation in the brain, you will have insulin resistance, even if you do not measure it in the periphery. I think that's where some people frequently think of the insulin resistance problem, you know, in terms of the systemic and insulin, you know, for in the model of treating like Type 1 Diabetes most, you know, how people mostly think of that. Type 2 Diabetes, where you have the systemic insulin resistance, there's a lot of inflammation that drive Type 2 Diabetes, and in fact, bezisterim was made for that. Again, when you have oxidative stress, you will have inflammation. When you have inflammation, you will have insulin resistance. We think with bezisterim, we, you know, have one drug treating. By treating inflammation, we treat both sides of that, insulin resistance and the inflammation. Thank you for that. Another question for you, Clarence, is your presentation, it was I'm not sure how clearly everybody got the point about DNA methylation and how that is actually accelerating or driving or exacerbating diseases or particularly age-related diseases. Can you help. You talked a lot about age deceleration. That's great. We all would like to be younger, healthier, right? How does that directly affect individual diseases that we tend to think about? Well, the role of epigenetics in disease is becoming increasingly well understood, that in the past, people thought of genetics itself in the DNA sequence as being the thing, you know, people were more prone to a disease or not. Actually, the dominant factor is the way that DNA gets methylated controls the gene expression. The identical twins can have different expressions based on different exposures, environmental exposures. It's, DNA methylation is, for most of us in the, you know, typically things go downhill, okay? As you get older, you have all this damage, things which alter the methylation, the epigenetic signature or pattern in your DNA, it just gets worse. Inflammation is what drives that. Systemic inflammation, TNF is a big driver of that. The theory of aging or the mechanisms of aging are complex. I mean, people are always, you know, proposing theories of how they all relate and what's comes first, which is the chicken and which is the egg, and how do we move forward. We know it's a lot of different factors. They contribute to both. There are both mutations, real point mutations, which can impact, for instance, TNF expression. Then we have modifications of the expression of these inflammatory factors, which are driven by, you can think of mostly environment. You know, how what we experience either When we find that, even stresses, like all the people who are in a economically disadvantaged environments have more stress, and it alters their epigenetic profile as well. These things are all related to inflammation, the reversibility of it is the key here. That once, at least there are elements of it that are reversible, those elements, from our Alzheimer's results, appear to be specifically associated with the disease or with inflammatory-type diseases. We know that bezisterim doesn't just, you know, increase or decrease methylation non-specifically. It does it in a way that's extraordinarily specific, and we of course, can't understand how it does so in each instance because if you want something complicated to, if you wanna be confused, start studying gene regulation and the involvement of epigenetics and things. It's not very intuitive, people spend their lives trying to understand how a gene or system of genes are regulated. We happen to have an activity though, because the inflammation's the top of these changes. By controlling that, we can control with what seems to be specific ways, these changes in a beneficial way only, and that is we have yet to find things which are moved in the wrong direction. I assume then you're capturing or collecting a lot of DNA methylation data in your trial and, with that, how are you trying to link DNA methylation to the physical progression of Alzheimer's, sorry, Parkinson's disease? There are a couple of ways that we're doing things. One, first, this link to the clocks, like the PhenoAge clock, where others have shown that this links progression, the progression is linked to time of death. We also are looking at specific genes which are associated with Parkinson's pathophysiology and looking are we going to increase or decrease the expression of those. Those are two different types of questions. One is that type where we're looking at specific genes and their function or influence on Parkinson's. This is a more traditional way of looking at, Hey, what could influence progression? The studies that have done, for instance, by Horvath as well, and the UK Biobank study, where they're looking at here population studies looking at the influence of DNA methylation on time to death progression of disease is a new topic, a new way. We'll be looking at both of those together to understand how we are influencing these progression pathways. Progression is the most important thing for Parkinson's. If we can get the drug available to people and using, even if it's a, with its a non-traditional therapy for non-motor symptoms. Anything that will allow people to use it, they will have the potential then of significantly arresting the disease. That's our objective. That's the thing that everyone with Parkinson's needs, and the sooner they get it in after diagnosis or even before official diagnosis, the better off they're gonna be. Right. Now moving on to Joe. Joe, you spoke a lot about the non-motor symptoms. Right of Parkinson's, and the fact that it could show up as early as 10 years before. Right the official diagnosis with the motor symptoms. Why is it not discussed more often, and why does everybody still believe that Parkinson's is fundamentally a motor disease? In part because we're not educating people particularly well. Now people know the warning signs of a heart attack. People know the warning signs potentially of dementia. We've not done a great job of educating the public or even the medical community, frankly, on what to look for. Now, I'll give the example of Alan Alda, who had done some research for a television program he was doing. In that program they discussed REM disorder, REM sleep disorder. He noticed that he had it. He was able to engage in treatment much earlier because he was educated as to, well, you know, these kinds of REM disorders can lead to Parkinson's, and you should be evaluated. Had he not participated in that particular educational work, he would not have been able to be diagnosed that early. We don't do a good job looking at these kinds of symptoms. It's gonna require education. I think we can do it, but there's also has to been a treatment, right? Physicians like to treat the things for which they have a, you know, a therapy. If we're incredibly fortunate, right, if this all goes well, things will change. Medicine will change. We'll have an agent in which we can treat non-motor symptoms. You think about, say, Prozac. You know, we were very reluctant to use drugs to treat depression because those drugs you could actually suicide on. When a good solution came out, you know, primary care physicians started diagnosing and now you can't go to a doctor's office without someone screening you for anxiety and depression. I would imagine that medicine will evolve in that way once someone is able to engage with that early portion of disease and make folks understand, yeah, there is something you can do about it's worth asking the questions. All right. Thank you, Joe. Tara tells me that there are a number of questions that have been submitted online, so let me turn it over to her for those questions. Great. Thank you, Cuong. Yes, please hold for a brief moment while we pull for questions from the audience. Our first question, what are your benchmarks for success in the PD trial, and how will you define that success? Well, why don't we go back to my very last slide. I Don't pull it up. It'll take too long. Success is identifying a mechanism of action that gives us target engagement, that shows us a clear relationship to clinical symptoms that we are able to change and modulate, that gives us a clear path to design of our next study. It's really about taking this very efficient study with the biomarkers, understanding what's happening to genes and gene function, which is really what methylation is about, right? Genes create things. Once we understand all of that in its complexity, it tells us where to go next, how we can be different. Now, we expect to be differentiated. We do not wanna leave value on the table, we're gonna interrogate everything. We have access to really great computing capacity. We can look at every single element of data and relate it to every other element of data. We're looking at over 350,000 gene products, or actually genes. We're gonna crunch through it all and be able to tell you what the personality of this molecule is in early Parkinson's, and it may be different from what we saw in late Parkinson's, and put together a program that takes advantage of what we've learned. That would be a win. Great. Thanks, Joe. Our next question here, what are the key biomarker results that we should be focusing on? Again, I'll start, and I'll hand it over to Clarence and perhaps Dr. de la Monte. You know, we're looking at metabolic outcomes, and those are standardly evaluated. We're looking at inflammatory outcomes, which can be as simple as looking at your composition and of white cells. We're certainly gonna be looking at those, at the systems biology that underlies it all. We'll be able to look at what happens to nerves and genes, a lot of that with epigenetic work. We may have a few other secrets. I think I'd like to add then, Dr. Palumbo, that the DNA methylation results are really for the program overall. For Parkinson's patients. is key because the data, I believe, are compelling that progression is linked to biological age, DNA methylation age, and that is the unmet medical need. I mean, the obviously the non-motor symptoms are something which have not been adequately addressed because the tools, the pharmaceutical tools are not there. Right. They haven't been there, and because they're very difficult to develop without adverse side effects or undesirable side effects. For us, DNA methylation, if we have this lowering of biological age, as we've seen in Alzheimer's before, we have the first step then, and big step, to developing a drug that every Parkinson's patient needs. We use that in conjunction with anything that emerges for a symptom, whether it's motor or non-motor, that is developable by the, you know, in cooperation with the FDA. We have then a treatment that everyone will need or want. Yeah. Dr. de la Monte, what would you look for if you know, you are giving me advice, what advice would you give relative to this particular question? What should we be looking at? One of the things we always want to do is to relate back to what we know already and what people are looking at. We would probably make sure that we obtain the standard biomarkers of, that people are looking for the synucleinopathies and the like for Parkinson's disease, because you always want to take your new findings and relate them to the old findings so that people can connect them. I think that's an important component. The second thing would be in terms of biomarkers of it wasn't clear what the oxidative stress thing, but there's a lot of lipid peroxidation and oxidative indices that are out there. Now, these are either biochemical or they can be immunomarkers of it. There are panels. I think the goal would be to, instead of working one by one molecules, you'd have small panels that would kind of collectively tell you that you have an inflammatory, an oxidative stress index that's going on that's abnormal, and that with your treatment, they've actually gotten better. You'd want a delta. You'd wanna look at the change over time and how fast it changes and whether people continue to clinically improve. A subjective report of how you're doing as well as objective findings in terms of cognition. The motor is easier to look at because those are standardized, but the cognitive piece, behavior, sleep, all the things that are disturbing patients with Parkinson's should be assessed. Thank you. Great. Thank you. A few more questions here before we wrap up. What can be done with patients that are five to eight years down the line? Dr. de la Monte? I think they're ideal for the treatment because basically that's the window where their cognitive impairment is starting to show up. I would think they would be ideal candidates for intervention because thus far we don't have anything. Yeah. We can reflect on our earlier study in folks who are maybe a little further along than five to eight years, but who were sort of wearing out of their medicine. We were able to show some interesting effects there in motor as well as non-motor. Obviously, we'd wanna replicate that. I think those are good signals. At any point, no matter how far down the road a patient is, slowing progression of Parkinson's is good. It's better than having the disease move forward because Parkinson's symptoms in late, the late stage are especially, you know, horrific. Improving cognition to the degree we can and all the non-motor symptoms that are apparent, all good. There's no downside to making a patient better or slowing the progression of disease, no matter how far along they are. Tara, do you have another couple of questions? Yeah. That's actually all the time that we have. I'll turn it back to Cuong for quick closing remarks. Thank you, Tara. Thank you, Dr. de la Monte, Clarence, Joe, for walking us through our discussion today. It's been very, very helpful. Thank you everyone who joined us. I hope you took something away from this conversation. I certainly did. Let me just share with you my takeaway from the last hour. I took away the following points. First, from Dr. de la Monte, is that disease has its roots in metabolic dysregulation. Many diseases start there and work its way through insulin resistance and so forth. Metabolic dysregulation is the underpinning of many human diseases, as we know it. The second we heard from Dr. de la Monte and Clarence, is that inflammation is often at the root of this. Inflammation often goes hand in hand with insulin resistance, right? It's practically impossible to have inflammation without having insulin resistance and vice versa, that's why inflammation and insulin resistance becomes a treatment target for many diseases. If you have insulin resistance, metabolic dysregulation, you're not gonna have just one disease, you're gonna have multiple manifestations of diseases out there, right? The third thing I took away, unfortunately, is that we are under-informed. We are not sufficiently well-informed about the non-motor symptoms and the needs to treat the non-motor symptoms of Parkinson's. Joe told us about how those symptoms could show up as early as 10 years before the motor symptoms, unfortunately, the community just has not been very well-informed to look for them, partly because there hasn't been a drug available to treat those non-motor symptoms. Right. The last point I took away from Joe's slides is that in bezisterim, there's the potential to, for the first time, to go and address both the motor and the non-motor components of it, right? The trial, the last patient has come in for his last visit. The team now is going through the data cleanup process, as Joe mentioned, there are hundreds of thousands of genes and so forth that the team needs to kind of compute the study. We need to wait for the biomarker information to come back from the various vendors and labs and so forth. As such, we hope to have top-line data readout. We hope to have the results from the trial be announced by the end of second quarter, although that may slip into third quarter a bit. Time will tell. All depends on how long it takes to get things back from the lab and how long it takes to analyze the mountain of data that we have. Right. With that, I thank you everyone for joining, and you have a great day.