BioVie Inc. ($BIVI)

Good afternoon, and welcome to the BioVie Virtual KOL event. [Operator Instructions] 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 Bovie's public filings made with the Securities and Exchange Commission that can be found at www.sec.gov. With that, 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 on our 2 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. So 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. But most importantly, we need to wait for the biomarker data to come back in. We are hoping to have everything in and analyze 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. And if everything goes according to plan, we should be in a position to have top line data readout before the end of the summer. And so today's cable of that 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 lease total answer. And as you will hear today from Dr. Dela Monti and our team, there is a big insulin resistance and metabolic component to what really underlies Parkinson's. So 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.

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. And looking at neuro inflammation, metabolic and inflammatory effects, I think there's no one better to comment than Dr. Suzanne de la Monte, who is a professor long-standing at Brown University, Professor in Pathology, laboratory medicine, neurology and neurosurgery. She is Chief of the Pathology and Laboratory Medicine Department at the Providence and VA Medical Center. And 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 regulation. -- not only is 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 boat 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 Type 3 diabetes because of the roles of insulin deficiency and insulin resistance, but 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 the disease. This is a big problem. Cofactor and lifestyle contributions, which are muddying up the the features of the disease, but also increasing the rates and then the potential for therapeutic interventions. So 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 dementia is a chronic progressive disease. It keeps going downhill. It's not something that stays steady, but there are challenges because these diseases, Alzheimer's in particular, is often mixed. It's not so clean it often is vascular disease, overlaps with Parkinson's. And the second major challenge is the cofactors, obesity, diabetes, hypertension, stroke, environmental factors, these are all adding to the rates and also the picture of what's going on with AD. So it's looking different today than it did when always Alzheimer's 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. And the process begins with mild-cognitive impairment, which is added to this and the prequal basically to AD, the biggest problem are the people who have the asymptomatic, I like to call them sneaky period disease because we don't know who they are. And the patients are offering us in denial or not willing to admit anything. The disappointing therapeutic outcomes largely relate to the challenges of face 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. And instead, we know now that at least 80% of them go on to developed debenture within 10 years. So they're being present with motor symptoms, 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. So when we're thinking about Alzheimer's, we still have this old idea about the plaques, which is the AB, the plaques of the center here versus the neurofibulators angle and 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 their presence in 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 2 molecules alone. The other group, the Parkinson's is we always think of it as a motor system disease. This is a substation again at the upper left should be block and pigmented where it's on the right in Parkinson's, those neurons die. Those are pigmented neurons. They have -- they're parting for dopamine and they get called Lewy bodies. Well, the Lewy body are just like neuro fiber tangles and as if their accumulation of stuff that should be in the trash barrel and they cause stress and dysfunction. So they start out with motor symptoms, but actually, these eventually hit the cerebrum and the behavioral centers of the brain. But Alzheimer's from -- I don't know how many years ago, several decades ago, it was known that there's a metabolic disregulation. 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 servation compared with the top, which is a control. But if you study these are you really so happy about it, you study Parkinson's and frontal temporal event, they also have a problem with brain metabolism and glucose utilization. So now we have a mirror thing, and this usually happens particularly after the patient undergoes cognitive impairment. So 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 1 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. And without these pathways, we basically have cells dying and not talking to 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 not wind epidermal growth factor and importantly, recently are the incretin pathways, which we'll touch on in a bit. but the signaling pathways are basically the same. So what's wrong with our concept of Alzheimer's and Parkinson's is that we're only considering neurons only considering neurons in certain parts of the brain. In fact, when you look at the brain, every single cell type, whether all of the dendrocytes which make the Mylan, the astrocytes, which are important for the blood brain barrier, the structure, the vasculature and the microglia, which regulates inflammatory responses. So all of these are impacted by neurodegeneration. And it makes no difference if you're looking at Alzheimer's and Parkinson's, they all are effective. We don't address these points at all. I mean, we deal with the neurons and specific neurons, but we need a bigger picture for what -- how they'll address the problems that are going on. In essence, with aging, because the cells aging and neurodegeneration, accelerated aging, we end up with increased sensitivity of the neurons to oxidative stress, meaning that if you have anesthesia, you have hypoxia or anything like that, those neurons are vulnerable so they get hit easily. And that's one of the reasons why people were 60 years old or older, and they have anesthesia, they can wake up to various, they can actually end up with early cognitive impairment and the more trials you have, the worse it is. And that's a big deal. So we need to know who those people are. Cell survivals impaired and oxygenates. Neuroinflammation, which will be covered by a Clarence leader, that's a big deal as well. Every degenerative disease has the microentheastrocite it 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 and then the vascular dysfunction, the blurb barrier is very important for regulating what gets into the brain, but there's also a vascular part that gets trashed out of the brain. So it's backward and forward flow system is impaired because of the vascular dysfunction. So if you think about these diseases, the way I'd like to think about it, 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 metabolise -- oxygen utilization and having effectively a brain starvation. And it seems more complicated like how do we get this to get all these things that are wrong. But if you look at metabolism as a 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 when you go neurodegeneration, we could do a comparison for metabolic diseases that take place in other parts of the body. And believe it or not, they are virtually identical. I work in the lab where we study liver I always have with the cancer lab. And when we start looking at the metabolic deficiencies and involve carbohydrate and lipid metabolism, those that did on by the kind dysfunction is always a problem basically right out of good mitochondria, so they can't have full oxidative metabolism. The vasculature is messed up, the stress response is also activated and you have increased cell death of inflammation. So these things are make us think about how do we borrow the treatments and the approaches across disease processes. So 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, Ig1, there's an impairment in the binding and the receptor function. So this is basically graph showing brock stage, brock stages like a golf score, the higher the number the worse you are. And basically, the -- with the severity of Alzheimer's going from 0 to 6 we find that the insulin, the insulin-like growth factor, the receptors and the ability of the truck effects, all declined with increasing severity of disease, not necessarily age per se. In fact, when you go to earlier stages of disease, we looked at cerebral fluid, and we find that the abnormalities began much earlier than patients would report in terms of their symptoms. So that's automatically a kind of biomarker for dysregulated metabolism. And when you look at what's going on, what are the roles of insulin IgF, they basically take care of the neuroinflammatory response, synaptic plasticity, in learning the memory, all the things we talked about that were important in the pathogenesis of disease. Now the other thing to be aware of, and I take a keen interest in it is the role of the incretins and ensure these are very popular GLP-1 receptor agonist, I think talks about. But it's important to know there are a bunch of them. It's not just GLP-1, GIP is AMOLED, who knows how many are coming out. These all hit. You can see that white diagram around the media that this area here is really pretty cool because this is the major region of brain damage in most of neurodegenerative diseases, other hits into the brain stem, which is Parkinson's. Cerebellum in is into the frontal lobes and the temporal lobes. And so these are the structures that are impacted by impaired insulin signaling, but incretins also participate in this thing. So we have to be aware that these incretins signaling, which regulates a lot of the insulin pathways or cooperates with them is important in these factors. And in fact, when you measure the level of incretin and reactivity in the brains and look at all kinds of biomarkers that those are bad. So we're dealing with a bunch of things, all of which regulate metabolism in the brain. And then the last group of the neurosteroids and won't go into to HF, but notice where those signals are, they seem to overlap exactly what the figure I just showed you. So we're dealing with the same structures that are abnormal in the brain for the new steroids. And so that gives us hope about the direction. So 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 and curtains are coming along as being trial, but I know one by one is not going to work, but there is some promise. And then the other group, the third group are the neurosteroids, which have added, which seem to be really strong for providing both anti-inflammatory, antioxidant and insulin sensitizer function. So I think the promising view is to include at this additional component into the cocktail, if you will, to enhance brain metabolic function that's deteriorating, both in Alzheimer's and Parkinson's. And I'll stop there.

Okay. Thank you very much, Dr. De La Monte. Clarence, 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 and 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 a bezisterim. Now you 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 sterile, but it's not bound by and does not target 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 briefly permeates the blood-brain barrier. It targets extracellular-signal-regulated kinase in pathology specific signaling pathways, but it doesn't inhibit ERC in signal pathways are involved with homeostasis. Bezisterim is promotor and neuroprotective and MPTP Parkinson's disease models, it improved motor and nonmotor symptoms in our previous Phase II study Parkinson's, and Bezisterim improved cognition and decreased DNA methylation-based biological age acceleration in Alzheimer's patients. Next, Bezisterim's mechanism of action is unique in BunstoRCand this large protein complex that also contains a signaling protein called MAP3K8, along with the NF-Kappa-B complex, and mitogen and ERK kinase, that's MEK. This pathway is stimulated by inflammatory mediators interacting with their cognate receptors, which activate ERC and incapabin the scaffold to stimulate inflammatory cytokine production and phosphorylation of a tumor necrosis factor receptor 1, which is responsible for chronic inflammation. It's important to note that ERC is also essential as an essential component of a different scaffold that promotes insulin signaling that's shown here on the lower left. Bezisterim does not interfere with ERC 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 oxinative stress are causally related in forward feeding. Chronic inflammation drives epigenetic changes that are important to biological age acceleration in Parkinson's disease progression. Next slide, please. So epigenetic age acceleration and unfavorable epigenetic changes in genes associated with Parkinson's pathophysiology of promote disease progression. The information theory of Beijing is based on the notion that epigenetic changes and loss of epigenetic information drive aging. However, and this is very important to development of Bezisterim, these epigenetic markers that have been lost can be restored under appropriate conditions. So 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 process is controlling methylation to specific gene or its regulatory elements like the promoters and enhancers are complex, and they're not necessarily intuitive. And the effect on expression is free when we sell, but ultimately, inflammation has a deleterious effect. And the cumulative effect of these small changes in cascades can be busy logically 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. However, we have found that Bezisterim alters DNA methylation to lower 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. And 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, resistance, oxidative stress and epigenetic drift lowers age accelerations measured by assortment of epigenetic clocks. The results of 3 DNA clocks imputed from the published results from our Alzheimer's study 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 placebo. Again, for age acceleration, negative is good. The Pheno a clock on the far left is the subject of our next slide. Next slide, please. Okay. So there was a U.K. 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 Pheno age acceleration greater than 0, that is faster aging, progressed to death faster than acceleration less than 0 and it is slower aging. And on the right, you see that the greater the aging, that is the greater age acceleration, the faster the progression to debt. 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, but of course, the data will have to speak for itself. And additionally, I have to say we have not met with the FDA to discuss DNA methylation as a biomarker, but 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 that NF-kappa-B, is the master regulator of inflammatory cytokine production. And as a reminder, NF-kappaB has many important homeostatic activities, which makes Bezisterim apparent selectivity for inflammation signaling critical to its potential usefulness in chronic diseases. Next slide, please. So inflammation disrupts homeostatic mechanisms in the brain. Glial cells that is microglia and astrocytes have critical functions in support of neuronal activity. Inflammatory cytokines controlled by the Napa influence the function of cells and the molecular messages that are released. Bezisterim acting in the MAP3K8 in FCoRC signaling pathway can reduce the production of inflammatory cytokines that disrupt the homeostatic cell functions. Peripheral inflammation and CNS infiltrating inflammatory cells disrupt the blood-brain barrier and contribute to the inflammatory mailman Parkinson's disease. Bezisterim by acting systemically as well as in the CNS can reduce inflammation quote. Next slide, please. So neuroinflammation is a major factor, IV motor and nonmotor 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. And in Parkinson's patients, intranasal insulin and GLP-1 receptor agonist can improve movement even though these medicines do not impact dopamine bioavailability. 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 applications and neuropsychiatric side effects. Last slide, please. So to summarize, the 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 nonmotor symptoms and slow disease progression. Dr. Palumbo, the floor is yours.

Well, thank you very much, Clarence. So we're just going to change slide sets right now. But what I'm going to be talking to you about is why we hypothesize that bezcterin is going to be a good match for the progression of Parkinson's across the lifespan of Parkinson's. So as we bring those slides up, the journey in Parkinson's is quite difficult. And it begins well before motor symptoms typically emerge. So 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. So I'm going to go to the next slide here and see if I've got control, and I do. So 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's a progressive nonmotor disease that emerges. And 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. So up to 10 years before the diagnosis, patients may present with constipation and anosmia, which is not being able to smell, REM sleep disorder, that means acting out your dreams and potentially hurting someone. Three to five years before there's a depression, anxiety, fatigue, and 1 to 2 years before perhaps cognitive flowing and some apathy. But by the time someone reaches a motor diagnosis there's already tremendous inflammation going on. There is a neuronal loss, and these non-motor symptoms have already presented in 90% or greater patients. So you've got this path of progressive disability that begins before agility, tremor and slow movements begin. So I'm going to present 2 of the kinds of patients I might have seen. Now these are composites. These are not real people, but I present them in this way to kind of show what happens. So the first person is, make believe. This is James, who's 52 and engineering director. And I mentioned this REM sleep disorder. So 7 years of REM sleep disorder, an inability to smell before slowing of his body starts to be noticed at work. And someone said, I'm going to start you want a dopamine agonist. And we know that these dopamine agonists for some people result in impulsive behaviors like gambling, et cetera. So here he is 7 years later, he's now on disability leave, managing his depression and really looking at cognitive impairment and side effects for medications. It's not the motor symptoms that impaired him, it is really the nonmotor that contributed to his disruption of career. This is another, make believe, person Maria, 48 an attorney. And again, a typical progression 5 years of fatigue, constipation, restless sleep. And then after those 5 years, he developed a right hand tremor that leads to diagnosis. So she started on levodopa and for some people, that drug begins to wear off. And 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. So for this individual, she's less able to work. She's removed herself from the work that she does. And it's just perhaps a little depressed more socially isolated. So 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. So let me take you to the next slide. So we can really what actually drives the quality of life. And this is based on a study that was funded by the Michael J. Fox Foundation to look at what impairs you. And 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. So these things in order, depression, fatigue, sleep, cognition, autonomic dysfunction, like orthostasis, constipation. These things compound disability and control for 65% of the impairment and quality of life, we don't have a treatment for them. So why do the current treatments fall short? Because you can look at that slide and say, "Well, no, we've got treatments for depression and anxiety. Well, for nonmotor 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, but there really isn't any therapy that manages the underlying neuro inflammation. It's not a small thing. This is an $82 billion per year burden in the United States. And the majority of that is actually lost function, right? So 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. So this is really a tremendous loss. Now for motor therapies. And next slide, part of the slide, yes, we have to levodopa. It is a gold standard, but it's 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 5 years. We've mentioned dopamine agonist and that other patients in yet. And that happens in -- with some dyscontrol in post and maybe 1 in 6 patients. MAO-B inhibitors provides some symptomatic benefit, but no disease modifying efficacy. And 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. So let me take you to the next slide. So what's our testable hypothesis why are we developing Bezisterim? Because 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? And try to slow down -- slow that down. So testable hypothesis. Number one, remember that Parkinson's is a multisystem disorder. You heard that earlier for Dr. De La Monte, inflammation-driven cellular dysfunction for see a company's neuronal loss. And we think an anti-inflammatory strategy makes sense there. Number two, and again, why is evident space? Do are inflammation clearly contributes to nonmotor symptoms. And as I've mentioned before, this is the strongest in determined -- independent determinant of quality of life. And now three, it can be measured, right? The standard measure, the MDS UPDRS part 2, which looks at activities of daily living reflects combined nonmotor domains, including mood, cognition and fatigue, autonomic function, we talked about, as well as motor functional impact. This is a functional scale. This is not looking and seeing how much you're shaking or how little you're shaking, this is really looking at the part 1, along with function to see if a person can benefit. And this is really where we're invested. And again, just to review Part 1 is a nonmotor experience as a daily living, Part 2 or the motor experiences of daily living and Part 3 is motor examination. With Part 2 really being about function. And this is what FDA likes. So 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 lesion marmoset, gave them this strong and they did well. So if you go to that Northeast primate key findings. We improved mobility statistically, lower immobility, reduction in dyskinesia and neurons for viable. And so you'll recall a couple of years ago, we presented data on our first translational study in unit 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 3, which is motor. And in this part of the disease, yes, 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. So why are we looking at early Parkinson's disease because this is a brain-derived molecule. We have made it oral. We have made a blood-brain barrier permeable, the measure -- the mechanism of action is what Clarence had described. And you heard a little bit about increnins, 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. And again, our prior Phase IIa study that I had just talked about was an 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 and they said, "Fine. Let's move on. Let's go early, and that's what we've decided to do. So that's that early study. Now looking at those folks, we decided on a precision Phase IIa study in early Parkinson's, Cuong told you earlier that the last subject had enrolled and had really had moved along very, very nicely. So 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 4-week follow-up period, right? And the idea here is to show target engagement to characterize this drug. This drug is first in class, which you can't expect it to an MALB inhibitor. We can't expect it to look like any of the other medications that improves. We have our hypothesis and we need to, therefore, look at how does the drug interact with the experience of having early Parkinson's and the endpoints are what I imagined 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. So let's take a look at the next slide. And this is not an easy thing. You have to match your drug design to the patient. So we know that when you use the UPDRS, you tend not to look at signals early really, really well because there's a lot going on. On the other hand, we're very much aware that there are targeted measures. The PAR comms is one where there are awaited composites. We're aware of that. We've incorporated some of that. But again, it's to finding the drug's differential profile. And 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 nonmotor domains. And you can do it. It's been done, right? So this is another 1 of the incident. They showed some efficacy using this kind of model, but about 50% of the patients really had adverse events. And for us, with the oral route and what we've seen so far in our previous studies, we think we're going to be very well tolerated. So I've told you we're doing things in a very precise way. You can certainly read that. But 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 going to be working on them. So we're looking at a unique signature and a new class of medication. We're looking at the effects of an anti-inflammatory and nonimmunosuppressive 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 but how this drug works. We will have a coherent data package that will justify additional investment. And with that, I'm going to turn it back to our CEO, Cuong Do to hear his viewpoint 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 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. And a lot of that really affects insulin resistance, expires with insulin resistance. So 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 1 of the strategies. I wanted to clarify that the abnormal to take place in the brain actually reflect neurodegeneration. So the brain neurons, all those cell types are metabolically disregulated. However, their function is also heavily impacted by systemic insulin resistance. And if you add that to an ongoing problem in brain, that's what's driving these increased cases of Alzheimer's, Parkinson's, et cetera, because I didn't show you a graph of it, but there -- if you look at a person who is 70 years old in 1980 versus somebody today, the rates of Parkinson's and Alzheimer's have skyrocket it. And that doesn't make sense if it's only genetic, but what we do know is they parallel with 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, but it will certainly reduce the onset, severity and really probably pretty much delay 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 attract the brain.

And you mentioned earlier that what you saw in the brand, 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 that be fair to say that the big that if you could affect -- if you can reverse the metabolic dysregulation you could basically affect multiple diseases at once, not just Parkinson's or Alzheimer's in particular.

No, absolutely. I think that our mistake, whether you're dealing with the brain, the liver, the kidney, whatever his metabolic is disregulated, we're going to have to cross talk and borrow from one another because the mechanism seems to be quite related. The big deal will be, can you get those drugs across the blood-brain barrier? Can you make the more specifics of the brain is targeted more directly than say, skeletal muscle? If we think about -- I'd 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. And so 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 De la Monte said it's all about metabolic dysregulation, insulin resistance and so forth, but you focused a lot on inflammation and neuro inflammation. Can you help really draw the link between inflammation and insulin resistance for metabolic dysfunction.

Certainly, I mean, they are closely interrelated, and they are mutually inducted. And so wherever you have inflammation in the brain, you will have insulin resistance, even if you do not measure it in the periphery. And I think that's where some people frequently think of the insulin resistance problem in terms of a systemic and in insulin or in model treating Type 1 diabetes, most people mostly think of that. The type 2 diabetes where you have the systemic insulin resistance. It's a lot -- there's a lot of inflammation that drive type 2 diabetes. And in fact, as term was made for that. And again, when you have oxidative stress, you will have inflammation when you have inflammation, you have insulin resistance. We think with Bezisterim, we have one drug treating by treating inflammation, we treat both sides of that. [indiscernible] information.

Another question for you, Clarence, is your presentation was -- I'm not sure how clearly everybody got the point about DNA methylation and how that is actually accelerating or driving disaster rating diseases or particularly age-related diseases. So can you help -- you talked a lot about age deceleration. That's great. We all would like to be younger, healthier, right? But how does that directly affect individual diseases that we tend to think about?

Well, the role of epigenetics in disease is become increasingly well understood and that -- in the past, people thought of genetics itself in the DNA sequence has been a thing people are more prone to a disease or not, but actually, the dominant factor is the way that DNA gets methylated controls gene expression and the identical twins can have different expressions based on different exposures and environmental exposures. It's DNA inflation is for most of us in the -- typically, things go downhill, okay? As you get old, you have all this damage, things which alter the methylation, the epigenetic signature for pattern your DNA, and it just gets worse. Inflammation is what drives that. systemic inflammation. TNF is a big driver of that. And the theory of aging or the mechanisms of aging are complex. I mean people are always proposing theories of how they all relate in what comes first, which is the chicken and which is the egg, and how do we move forward. But 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. And then we have modifications of the expression of these inflammatory factors, which are driven by think of most of the environment. What we experienced either when we find it even stressed like all the people who are in -- grow up in economically disadvantaged environments have more stress and they alter their epigenetic profiles as well. These things are all related to inflammation and the reversibility of it is the key here. And that once at least there are elements of it that are reversible. And those elements appear from our Alzheimer's results appear to be specifically associated with the disease. And that -- or with inflammatory type diseases. And we know that Bezisterim doesn't just increase or decrease methylation nonspecifically, it doesn't in a way that's extraordinarily specific. And we, of course, can't understand how it does so in each instance because of if you want something complicated to -- if you want to be confused, start studying gene regulation, the involvement of epigenetics and things, it's not very intuitive, but it is for people spend their lives trying to understand how a gene or a system of genes are regulated. We happen to have an activity though because the inflammation is at the top of these changes by controlling that, we can control in what seems to be specific ways these changes in a beneficial way only, and that is we have yet defined, things which are moved in the wrong direction.

I assume that you are 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 -- I'm sorry, Parkinson's disease.

There are a couple of ways that we're doing things. One, firstly, this linked to the clocks, like the the age clock, where where others have shown that this site progression is linked to time of debt. 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 2 different types of questions. And 1 is that type where we're looking at specific genes in their function or influence on Parkinson's is more the traditional way of looking at, hey, what could launch progression. However, the studies that have done, for instance, by Horvath as well and the U.K. biobanks study that 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 try to understand how we are influencing these progression pathways. And again, progression is the most important thing for Parkinson's. If we can get the drug available to people and using even itself with its a nontraditional therapy for nonmotor symptoms, anything that will allow people to use it. They will have the potential then of significantly arresting the disease, and that's our objective because 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 going to be.

All right. And now moving on to Joe. Joe, you spoke a lot about the non-motor symptoms of Parkinson's and the fact that it could show up, let's say, early as 10 years before 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. People know the warning signs of heart attack. People know the warning signs potentially of dementia. We've not done a great job of educating the public or even in 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. And 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 these kinds of REM disorders can lead the 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. So it's going to require education. I think we can do it. But there also has been a treatment, right? And physicians like to treat things for which they have 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 nonmotor symptoms. If you think about, say, Prozac, we were very reluctant to use, drugs to treat depression because those drugs you can actually suicide on. When a good solution came out, then primary care physicians started diagnosing and now you can't go to a doctor's office without someone screening you for anxiety and depression. And I would imagine that medicine will evolve in that way once someone is able to engage with the early portion of the disease and make folks understand, yes, there is something you can do about it. So 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. So yes, please hold for a brief moment while we poll for questions from the audience. So our first question, what are your benchmarks for success in the PD trial? And how will you define that success?

Why don't we go back to my very last slide or we don't pull it up, I think 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 genes create things. Once we understand all of that in its complexity, then it tells us where to go next, how we can be different. Now we expect to be differentiated. We do not want to leave value on the table. So we're going to interrogate everything. We have access to really great computing capacity. We can look at every single element of data and related to every other element of data. We're looking at over 350,000 gene products or actually genes. We're going to 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?

I'll start, then to Clarence and perhaps Dr. De la Monte. 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 of white cells. We're certainly going to be looking at those -- systems biology that underlies at all. We'll be able to look at what happens to nerves and genes out of that with epigenetic work, and we may have a few other secrets.

Thing I'd like to add, Dr. Palumbo, that the Demaethylation results are really for the program overall. And 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 obviously, the nonmotor symptoms or something which have not been adequately addressed because the tools -- the pharmaceutical tools are not there. They haven't been there and because they're very difficult to develop without adverse side effects or undesirable side of it. But 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 and a big step to developing a drug to that every Parkinson's patient needs. We use that in conjunction with anything that emerges for a symptom, whether it's motor or nonmotor that is developable by the -- in cooperation with the FDA, we have then a treatment that everyone will need or want.

And Dr. De la Monte, what would you look for a few you are giving me advice. So what advice would you give relative to this particular question. What should we be looking at?

So one of the things we always want to do is to lay back to what we know already and what people are looking at. So we would probably make sure that we obtain the standard biomarkers of the people looking for cynically neuropathies and the like for Parkinson's disease because you always want to take your new findings and relate them to the old findings 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 oxide is stressing, but there's a lot of lipid peroxidation and oxygen indices that are out there. These are either biochemical or they can be immunomarkers of it. Their panels, I think the goal would be to instead of working one by one model because you have small panels that would kind of collectively tell you that you have an inflammatory, an oxidative stress index that's abnormal, and that with your treatment, they've actually gotten better. You don't want a delta 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. So a few more questions here before we wrap up. What can be done with patients that are 5 to 8 years down the line?

I mean are ideal for the treatment because basically, that's the window where their cognitive impairment is starting to show up. So I would think it would be ideal candidates for intervention because thus far, we don't have anything.

Yes. And we can reflect on our earlier study and folks who are maybe a little further along in 5 to 8 years, but who were sort of wearing out of their medicine, we were able to show some interesting effects there and motor as well as nonmotor. Obviously, we want to replicate that. But I think those are good signals.

At any point, no matter how far down the road the patient is, slowing progression that Parkinson's is good. It's better than having the disease move forward because Parkinson's symptoms into late stage are especially horrific. And improving cognition to the degree we can and all the non-motor symptoms that will -- that are apparent all good, there is no downside in making a patient better or slowing the progression of the disease, no matter how far along they go.

Tara. Do you have another couple of questions.

Yes. So that's actually all the time that we have. So I'll turn it back to Cuong for quick closing remarks.

Thank you, Tara. First of all, 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 put something away from this conversation. I certainly did. Let me just share with you my take away from the last hour, I took away following points. First, from Dr. De la Monte, is that disease is really has its roots in metabolic disregulation. Many diseases start there and we displayed through insulin resistance and so forth that metabolic dysregulation is the underpinning of many human diseases has been one. The second, we heard from Dr. De la Monte and in clearance is that inflammation is that often at the root of this, and information often goes hand-in-hand with insulin resistance, right? It's practically impossible to have inflammation without having insulin resistance and vice versa. And that's why it inflammation and its own resistance becomes a treatment target for many diseases. And if you have insulin resistance, net of by disregulation, you're not going to have just one disease, you're going to 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 nonmotor symptoms and the needs to treat the nonmotor symptoms of Parkinson's, Joe told us about how those symptoms could show up as early as 10 years before the motor symptoms. But 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 nonmotor symptoms, right? And the last point I took away from Joe's slides is that in Bezisterim, there is the potential for the first time to go and address both the motor and the nonmotor components of it, right? And the trial, the last patient has come in for his last visit. The team now is going through the data cleanup process. And 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. And as such, we will -- we hope to have top line data readout. We hope to have the results from the trial and now it's by the end of second quarter, although that may slip into third quarter a bit. Time will tell, all depends on what we -- how long it takes to get things back in the lab and how long it takes to analyze the mountain of data that we have. So with that, I thank you, everybody, for joining, and you have a great day.